Treatment at relapse for synovial sarcoma of children and adolescents: A multi-institutional European retrospective analysis.

PURPOSE: Though the prognosis for pediatric patients with localised synovial sarcoma (SS) is generally good, the chances of being cured after relapse are limited. This study describes a retrospective multi-institutional series of relapsing SS patients treated at six selected European referral centers for pediatric sarcoma. PATIENTS AND METHODS: The study included 41 patients <21 years with relapsing SS, treated between 2002 and 2022. The analysis included patient's characteristics at first diagnosis, first-line treatments, clinical findings at relapse, and second-line treatment modalities. RESULTS: The first relapse occurred within 3-132 months (median 18 months) after first diagnosis and was local in 34%, metastatic in 54%, and both in 12%. Treatment at first relapse included surgery in 56% of cases, radiotherapy in 34%, and systemic therapy in 88%. In all, 36 patients received second-line medical treatment, that was chemotherapy in 32 cases (with 10 different regimens) and targeted therapy in four. No patient was included in an early-phase clinical trial as second-line therapy-line therapy. Overall response rate was 42%. Median event-free survival (EFS) was 12 months, postrelapse 5-year EFS was 15.8%. Median overall survival (OS) was 30 months, postrelapse 5-year OS was 22.2%. At the Cox's multivariable regression analysis, OS was significantly associated with time and type of relapse. CONCLUSION: Pediatric patients with relapsed SS have a poor prognosis and generally receive an individualized approach, due to the lack of a uniform standardized approach. New comprehensive strategies are needed to improve the knowledge on the biologic landscape of SS and develop tailored prospective clinical trials.

Multimodal Analgesia for Rotator Cuff Repair Should Be Individualized Based on Surgical Location and Complexity and Patient Comorbidity.

Multimodal analgesia in arthroscopic rotator cuff surgery is commonly used for pain control and to reduce opioid consumption in the early postoperative time and the days following. Indeed, the combination of local anesthetic peripheral nerve blocks and systemic or oral analgesics ensures a better outcome than the isolated use of non-steroidal anti-inflammatory drugs. In particular, intrascalene block (ISB) has significant advantages in more complex procedures involving the anterior aspect of the shoulder. However, ISB should be discouraged under conditions of respiratory comorbidity such as severe chronic obstructive pulmonary disease, obstructive sleep apnea, and morbid obesity. In such cases, a multimodal approach based on peri-articular infiltration (PAI) analgesia combined with pharmacological therapies can ensure excellent pain control with limited use of opioids in the immediate postoperative period. When selecting the best therapeutic combination, it is essential to consider factors that can determine the best balance between safety and effectiveness, such as the complexity of the surgical procedure, preoperative pain, and any comorbidities that could contraindicate the use of certain medications or that could be negatively affected by potential complications or side effects of the analgesic therapy.

Association of European Paediatric and Congenital Cardiology practical recommendations for surveillance and prevention of cardiac disease in childhood cancer survivors: the importance of physical activity and lifestyle changes From the Association of European Paediatric and Congenital Cardiology Working Group Sports Cardiology, Physical Activity and Prevention, Working Group Adult Congenital Heart Disease, Working Group Imaging and Working Group Heart Failure.

BACKGROUND: Childhood cancer survivors are at increased risk of developing cardiovascular diseases, presenting as the main causes of morbidity and mortality within this group. Besides the usual primary and secondary prevention in combination with screening during follow-up, the modifiable lifestyle factors of physical activity, nutrition, and body weight have not yet gained enough attention regarding potential cardiovascular risk reduction. OBJECTIVE: These practical recommendations aim to provide summarised information and practical implications to paediatricians and health professionals treating childhood cancer survivors to reduce the risk of cardiovascular late effects. METHODS: The content derives from either published guidelines or expert opinions from Association of European Paediatric and Congenital Cardiology working groups and is in accordance with current state-of-the-art. RESULTS: All usual methods of prevention and screening regarding the risk, monitoring, and treatment of occurring cardiovascular diseases are summarised. Additionally, modifiable lifestyle factors are explained, and clear practical implications are named. CONCLUSION: Modifiable lifestyle factors should definitely be considered as a cost-effective and complementary approach to already implemented follow-up care programs in cardio-oncology, which can be actively addressed by the survivors themselves. However, treating physicians are strongly encouraged to support survivors to develop and maintain a healthy lifestyle, including physical activity as one of the major influencing factors. This article summarises relevant background information and provides specific practical recommendations on how to advise survivors to increase their level of physical activity.

A high level of scientific evidence is available to guide treatment of primary shoulder stiffness: The SIAGASCOT consensus.

PURPOSE: Shoulder stiffness (SS) is a condition characterised by active and passive restricted glenohumeral range of motion, which can occur spontaneously in an idiopathic manner or be associated with a known underlying aetiology. Several treatment options are available and currently no consensus has been obtained on which treatment algorithm represents the best choice for the patient. Herein we present the results of a national consensus on the treatment of primary SS. METHODS: The project followed the modified Delphi consensus process, involving a steering, a rating and a peer-review group. Sixteen questions were generated and subsequently answered by the steering group after a thorough literature search. A rating group composed by professionals specialised in the diagnosis and treatment of shoulder pathologies rated the question-answer sets according to the scientific evidence and their clinical experience. RESULTS: Recommendations were rated with an average of 8.4 points out of maximum 9 points. None of the 16 answers received a rating of less than 8 and all the answers were considered as appropriate. The majority of responses were assessed as Grade A, signifying a substantial availability of scientific evidence to guide treatment and support recommendations encompassing diagnostics, physiotherapy, electrophysical agents, oral and injective medical therapies, as well as surgical interventions for primary SS. CONCLUSIONS: A consensus regarding the conservative and surgical treatment of primary SS could be achieved at a national level. This consensus sets basis for evidence-based clinical practice in the management of primary SS and can serve as a model for similar initiatives and adaptable guidelines in other European countries and potentially on a global scale. LEVEL OF EVIDENCE: Level I.

Healthcare Professional Communication on Sexual Health: A Report from the Italian Working Group on Adolescents and Young Adults with Cancer.

BACKGROUND: Sexual function is an important concern for adolescent and young adult (AYA) with cancer. The aim of this study was to explore the attitude of Italian health care professionals who deal with AYA patients with cancer toward sexual health communication. MATERIALS AND METHODS: A 11-question survey was developed by the AIOM (Associazione Italiana di Oncologia Medica) and AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) AYA workgroup and sent to AIOM and AIEOP members. RESULTS: The sample comprised 360 respondents, 54.2% AIEOP and 45.8% AIOM members. Eighty percent were physicians, 14.5% nurses, 4.7% psychologists, and 0.8% other professionals. Medical oncologists are more used to investigate about AYA sexual health than pediatric oncologists (58.2% vs. 46.2%), even if pediatrics more frequently refer patients to specific and shared protocol (40% vs. 26.1%). Both AIOM and AIEOP participants mostly talk about sexual health only on request or occasionally (78.8% and 79%, respectively). Clinician-reported barriers to communication identified in this study are lack of preparation and embarrassment for both the categories, plus the presence/interference of parents for pediatrics and lack of time for medical oncologists. Overall, less than 5% of clinicians in our survey received specific training on potential sexual health issues in AYA patients with cancer and only 2% felt adequately prepared to speak about it. CONCLUSION: Sexual health is a key component of comprehensive care for AYA with cancer during treatments. This study highlighted the need of Italian providers for specific training and guidelines on sex-related health issues encountered by AYA patients.

Pediatric BCOR-Altered Tumors From Soft Tissue/Kidney Display Specific DNA Methylation Profiles.

In the pediatric population, BCL6-correpresor gene (BCOR)-upregulated tumors include primitive myxoid mesenchymal tumors/undifferentiated sarcomas (PMMTI/UND), clear cell sarcomas of the kidney (CCSK), and high-grade neuroepithelial tumors (HG-NET). We investigated DNA methylation (DNAm) and copy number variation (CNV) profiling in these tumors (N = 34) using an Illumina EPIC BeadChip to better define the potential use of these tools to confirm diagnosis and predict outcomes. Twenty-seven tumors from 25 patients (age range, 0-10 years), showed molecular confirmation of genetic abnormalities as follows: BCOR internal tandem duplication in 14 PMMTI/UND, 8 CCSK, and 3 HG-NET and YWHAE fusions in 2 PMMTI/UND. The remaining 7 cases lacking informative molecular data were analyzed by immunophenotyping and were included in the study as a training cohort, clearly separated from the main study group. These were 4 PMMTI, 1 HG-NET, and 1 CCSK in which poor RNA preservation precluded the confirmation of BCOR rearrangements and 1 CCSK in which no rearrangements were found. DNAm data were compared with those of brain tumor and/or sarcoma classifier. Differentially methylated regions (DMRs) were analyzed in the 3 groups. Twenty-two cases of the 24 molecularly confirmed PMMTI/UND and CCSK and 3 of 6 of those with only immunophenotyping were classified within the methylation class "BCOR-altered sarcoma family" with optimal calibrated scores. PMMTI/UND and CCSK showed similar methylation profiles, whereas thousands of DMRs and significantly enriched pathways were evident between soft tissue/kidney tumors and HG-NET. The CNV analysis showed an overall flat profile in 19 of the 31 evaluable tumors (8/10 CCSK; 9/18 PMMTI/UND; 2/4 HG-NET). The most frequent CNVs were 1q gain and 9p and 10q loss. Follow-up time data were available for 20 patients: ≥2 CNV significantly correlated with a worse overall survival rate. In conclusion, soft tissue and kidney BCOR sarcomas matched with BCOR-altered sarcoma methylation class, whereas those from the brain matched with the central nervous system tumor classifier HG-NET BCOR, supporting the notion that DNAm profiling is an informative diagnostic tool. CNV alterations were associated with a more aggressive clinical behavior.

Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study.

INTRODUCTION: Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. METHODS: We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. RESULTS: Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. CONCLUSIONS: In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Malignant ectomesenchymoma in children: The European pediatric Soft tissue sarcoma Study Group experience.

Malignant ectomesenchymoma (MEM) is an extremely rare soft tissue tumor typical of young children, currently included in the category of skeletal muscle malignancies and characterized by a neuroblastic component. This study describes a series of 10 patients prospectively registered in the European paediatric Soft tissue sarcoma Study Group (EpSSG) database Of the 10 cases, seven had an initial local diagnosis of rhabdomyosarcoma. All patients received chemotherapy according to rhabdomyosarcoma strategy, four had radiotherapy. Overall, six patients were alive in first remission, two in second remission and one after second tumor. Only the patient with initially metastatic tumor died of disease.

A Pediatric Case of High-Grade Secretory Carcinoma of the Maxillary Sinus With ETV6::NTRK3 Gene Fusion, Therapeutic Implications, and Review of the Literature.

Secretory carcinoma (SC) is a salivary gland tumor with a generally low grade microscopic appearance, a characteristic immunophenotype, and a recurrent translocation leading to ETV6::NTRK3 fusion gene. Rare cases are reported in children. The maxillary sinus is an unusual localization. SC have an overall favorable prognosis, but cases with high grade morphology have been described in adult population and are related to a more aggressive clinical course. We present a pediatric case of secretory carcinoma involving the maxillary sinus with high grade morphology, with a review of the literature of secretory carcinomas with high grade component.

Sulcus Angle, Trochlear Depth, and Dejour's Classification Can Be Reliably Applied To Evaluate Trochlear Dysplasia: A Systematic Review of Radiological Measurements.

PURPOSE: To summarize data on the reliability of available imaging criteria for the assessment of trochlear dysplasia and to assess the methodological quality of the included studies. METHODS: This systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Search was performed using major electronic databases from their inception to September 2021. All studies enrolling patients of any age who underwent a radiological exam to rule out features related to trochlear dysplasia were included. After the identification of available imaging criteria, reliability studies were analyzed. Descriptive statistics were used to summarize findings. Methodological quality was assessed using the Quality Appraisal of Reliability studies checklist. RESULTS: A total of 2391 articles were identified, and 33 articles comprising 3036 patients with a mean age of 28.6 years were included. Thirty different measurements were extracted. Magnetic resonance imaging (MRI) was the most used imaging modalities (21 studies), followed by computed tomography (10 studies), conventional radiology (8 studies) and ultrasonography (US) (1 study). Sulcus angle, trochlear depth, and Dejour's classification were the most explored measurements. Overall, sulcus angle can be reliably assessed on radiography, CT and MRI, whereas trochlear depth can be reliably measured only with CT and MRI. Reliability of Dejour's classification ranged from poor or fair to very good for all imaging modalities. Methodological quality of included studies varied from 2 to 9 positive items out of 11 possible. Twenty-four studies (72.7%) were considered at high risk of bias. CONCLUSION: Trochlear dysplasia can be reliably evaluated at least with 3 measurements: sulcus angle, trochlear depth and Dejour's classification. Methodological quality assessment showed high risk of bias in most included studies. LEVEL OF EVIDENCE: Level III, systematic review of Level II-III studies.

High variation among clinical studies in the assessment of physical function after knee replacement: a systematic review.

PURPOSE: The purpose of this study was to summarise the current use of outcome measures for the assessment of physical function after knee joint replacement. METHODS: A systematic approach following the PRISMA guidelines was used. Literature search was performed on MEDLINE database via PubMed and on Epistemonikos. Clinical trials (level of evidence I-II) on knee joint replacement reporting data on the 'physical function' domain published between January 2017 and June 2022 were included. Descriptive statistics were used to summarise the evidence. RESULTS: In the 181 articles that met the inclusion criteria, 49 different outcome measurements were used to evaluate clinical outcomes after knee joint replacement. The most frequently adopted patient-reported outcome measures (PROMs) were the Knee Society Score (KSS) (78 studies; 43.1%), the Western Ontario and McMaster Universities (WOMAC) Arthritis Index (62 studies; 34.3%), the Oxford Knee Score (OKS) (51 studies; 28.2%) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) (36 studies; 20%). The most frequently used performance-based outcome measures (PBOMs) were the Timed-Up-and-Go (TUG) test (30 studies; 16.6%) and the 6-min-walk test (6MWT) (21 studies; 11.6%). Among impairment-based outcome measures (IBOMs), range of motion (ROM) was the most used (74 studies; 40.9%). CONCLUSION: There is considerable variation among clinical studies regarding the assessment of the physical function of patients after knee joint replacement. PROMs were found to be the most commonly adopted outcome measures; however, no single PROM was used in more than half of the papers analysed. LEVEL OF EVIDENCE: Level II, systematic review of level I-II studies.

BLU-DAT: a new reliable and accurate arthrometer for measuring anterior knee laxity.

PURPOSE: Although many arthrometers have been developed to assess anterior knee laxity, reliability and diagnostic accuracy of these devices are still debated. The aim of the present study was to evaluate the validity of a new arthrometer in the outpatient setting, with the hypothesis that it had good validity in terms of reliability and diagnostic accuracy. METHODS: Seventy-eight subjects (39 with ACL injury and 39 with normal ACL) were tested. ATT was assessed by means of the Lachman test at 30° of flexion with a new testing device (BLU-DAT) under three different loading conditions: 7 kg (69 N), 9 kg (88 N) and maximum (MMT). The tests were performed on both knees to obtain SSD. In the ACL injury group, the tests were performed by two examiners and one of them repeated a second test series. Inter- and intra-observer reliability were assessed with the intraclass correlation coefficients (ICCs) for the average SSD measures. In the normal-ACL group, the analysis was performed with the same testing setup. Side-to-side difference measures of the two groups at every loading condition were compared by Student's t test. Data of test series were dichotomized based on the threshold value of 3-mm SSD as pathological ATT and 2 × 2 contingency tables were used to assess diagnostic accuracy. RESULTS: The ICCs for intra-observer reliability at 7-kg (69 N), 9-kg (88 N) and MMT measurements were 0.781, 0.855 and 0.913, respectively. The ICC for inter-observer reliability at 7-kg (69 N), 9-kg (88 N) and MMT measurements were 0.701, 0.845 and 0.834, respectively. Comparison between the two groups showed a significant mean difference ranging from 3.4 mm for 7-kg (69 N) load to 4.6 mm for MMT. Overall accuracy ranged from 84.6% for 7-kg load to 98.7% for MMT. CONCLUSION: The BLU-DAT has proven to be an instrument with good intra- and inter-observer reliability and very good accuracy in the diagnosis of ACL injuries in the outpatient setting. So, the BLU-DAT can be a new useful tool in everyday clinical practice to assist in the diagnosis of ACL injury. LEVEL OF EVIDENCE: II.

A new knee arthrometer demonstrated to be reliable and accurate to assess anterior tibial translation in comparison with stress radiographs.

INTRODUCTION: For several years, many arthrometers have been developed to assess anterior knee laxity. The aim of our study was to evaluate the validity of a new practical and handy testing device with the hypothesis that the new arthrometer had good validity in terms of reliability and accuracy. METHODS: Lachman test was performed on five fresh frozen cadaveric knees by five examiners. Anterior tibial translation (ATT) was measured with a new arthrometer (BLU-DAT) and on lateral stress radiographs. Data on ATT were obtained under 7 kg (69 N), 9 kg (88 N), and maximum manual traction (MMT). Tests were performed on the same specimens before and after arthroscopic ACL excision. Inter-rater reliability of the BLU-DAT measures was assessed with the intraclass correlation coefficient (ICC) for single and average measurements. The Bland-Altman method was used to estimate agreement between the BLU-DAT and stress radiographs. RESULTS: ICC values for single measurements were 0.62, 0.54 and 0.58 for 7-kg, 9-kg and MMT assessment, respectively. Overall reliability was good (ICC = 0.63). ICC values for average measurements were 0.89, 0.85 and 0.88 for 7-kg, 9-kg and MMT assessment, respectively. Overall reliability was very good (ICC = 0.90) SEM ranged from 1.4 mm to 1.6 mm for single measurements and was below 1 mm at each testing condition for average measurements. Analysis of agreement between BLU-DAT and radiographic measurements showed a mean difference equal to 0.83 mm ± 2.1 mm (95% CI: 0.55-1.11). Upper LOA was equal to 4.9 mm (95% CI: 5.39-4.41). Lower LOA was equal to - 3.2 mm (95% CI: - 2.71 to - 3.69). CONCLUSION: Measurement of anterior knee laxity with the BLU-DAT testing device has a good to very good inter-rater reliability and good agreement with a gold standard such as stress radiographs. Cadaveric Diagnostic Study, Level of Evidence IV.

Use of the iliac-outlet and iliac-inlet combined views in percutaneous posterior column retrograde screw fixation.

Posterior column fractures are common acetabular injuries. Although displaced fractures require open reduction and fixation, undisplaced patterns may benefit from percutaneous screw fixation. The combination of iliac oblique with inlet and outlet views offers an intuitive and panoramic rendering of the bony corridor into the posterior column; lateral cross table view completes the sequence of fluoroscopic projections. Herein we describe the use of outlet/inlet iliac views and a detailed procedure for percutaneous retrograde posterior column screw fixation.

Endosteal plating for the treatment of malunions and nonunions of distal femur fractures.

PURPOSE: To describe the surgical technique and the outcome of a case series of nonunion and malunion of distal femur fractures treated with an endosteal medial plate combined with a lateral locking plate and with autogenous bone grafting. METHODS: We retrospectively analyzed a series of patients with malunion or nonunion of the distal femur treated with a medial endosteal plate in combination with a lateral locking plate, in a period between January 2011 and December 2019, Database from chart review was obtained including all the clinical relevant available baseline data (demographics, type of fracture, mechanism of injury, time from injury to surgery, number of previous surgical procedures, type of bone graft, and type of lateral plate). Time to bone healing, limb alignment at follow-up and complications were documented. RESULTS: Ten patients were included into the study: 7 male and 3 female with mean age of 48.3 years (range 21-67). The mechanism of trauma was in 8 cases a road traffic accident and in 2 cases a fall from height. According to AO/OTA classification 5 fractures were 33 A3, 3 were 33 C1, 1 was 33 C2 and 1 was 33 C3. The average follow up was 13.5 months. In all cases but one bony union was achieved. Bone healing was observed in average 3.3 months after surgery. No intraoperative or postoperative complications were reported. CONCLUSION: A medial endosteal plate is a useful augmentation for lateral plate fixation in nonunion or malunion following distal femur fractures, particularly in cases of medial bone loss, severe comminution, or poor bone quality. LEVEL OF EVIDENCE: Level IV (retrospective case series).

New bone formation using antibiotic-loaded calcium sulfate beads in bone transports for the treatment of long-bone osteomyelitis.

PURPOSE: Bone transport is one of the most frequently used techniques for critical-sized bone defects due to trauma or infection. To fill the defect area and avoid the collapse of soft tissues during transport, some authors have described the use of polymethylmethacrylate or absorbable antibiotic carriers in the form of cylindrical blocks. METHODS: In this article, we present our experience in the treatment of post-traumatic osteomyelitis of the lower and upper limbs, using a bone transport technique with antibiotic-loaded calcium sulfate in the form of beads. Results With the progressive absorption of calcium sulfate, we observed the formation of a bone-like tissue envelope at the periphery of the defect area. Histological analysis and direct visualization during open revision surgery of the docking site in all patients confirmed the presence of newly formed bone tissue with a high presence of osteoblasts and few osteoclasts; no areas of necrosis or signs of infection were observed. This bone envelope maintained the mechanical protective function of the transport path and docking site, and also provided a biological stimulus to avoid the development of necrotic areas and optimize the consolidation phase. Conclusion Bone transport with calcium sulfate beads improves biological and mechanical support and reduces the number of surgeries required.

Management of distal femoral fractures with metaphyseal and articular comminution (AO/OTA 33C) using nail and plate fixation: a technical note and case series of 14 patients.

PURPOSE: To describe the surgical technique and the outcome of a case series of comminuted intra-articular distal femur fractures (AO/OTA 33C) treated with a nail-plate combination (NPC) implant. METHODS: We retrospectively analyzed a case series of 14 patients with comminuted intra-articular distal femur fractures (DFF) treated with an intramedullary retrograde nail in combination with a lateral low-contact condylar locking plate, in a period between June 2020 and January 2023 at a Level 1 trauma center. Baseline demographic and clinical data were recorded. Time to bone healing, function using Schatzker Lambert Score, and complications were documented. RESULTS: Fourteen patients, 8 males and 6 females, with a total of 15 NPC implants, were included in this study. Eight out of 14 patients had open fractures, all with a Gustilo Anderson type IIIA exposure. The mean age was 48.5 ± 18.05 years. The median follow-up was 392 days, with only one patient lost to follow-up. 11 out of 15 implants achieved complete radiographic consolidation during follow-up, at a mean of 5.40 ± 1.07 months. At the 12-month follow-up, all patients could fully bear weight painlessly or with mild pain. Schatzker Lambert Score was excellent for 4 patients, good for 2 patients, fair for 5 patients, and failure for 2 patients. The main postoperative complications were rigidity (3 cases), limb shortening (2 cases), and septic non-union (1 case). CONCLUSION: This study suggests that the nail-plate combination (NPC) may provide a more effective surgical technique for addressing the challenges associated with comminuted intra-articular distal femur fractures (AO/OTA 33C).

Phase 2 study for nonmetastatic extremity high-grade osteosarcoma in pediatric and adolescent and young adult patients with a risk-adapted strategy based on ABCB1/P-glycoprotein expression: An Italian Sarcoma Group trial (ISG/OS-2).

BACKGROUND: According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed. METHODS: This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis ≥ 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m2 /d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp- patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m2 (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed. RESULTS: In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp-, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp- patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%). CONCLUSIONS: This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults.

BACKGROUND: CWS/RMS-96 was an international multicenter trial with randomization between two therapy arms of the standard four-drug therapy (vincristine, ifosfamide, adriamycin, dactinomycin [VAIA]) versus an intensified six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide [CEVAIE]) for high-risk rhabdomyosarcoma (RMS), extraskeletal Ewing sarcoma (EES), and undifferentiated sarcoma (UDS) in children, adolescents, and young adults aiming to improve their survival. Intensified chemotherapy with CEVAIE did not improve outcome. METHODS: Patients younger than 21 years with a previously untreated localized HR-RMS, EES, and UDS were enrolled from Cooperative Weichteilsarkom Studiengruppe (CWS) centers in Germany, Austria, Poland, Switzerland, and from Italian Soft Tissue Sarcoma Committee (STSC) centers. Randomization (1:1) to receive either 9 × 21 days cycles of VAIA or CEVAIE was performed separately in CWS and STSC. Hyperfractionated accelerated radiotherapy (32-44.8 Gy) was added at week 9-12 according to histology and response to chemotherapy. A secondary microscopically complete nonmutilating resection was performed if possible. Primary endpoints were response to chemotherapy, event-free (EFS) and overall survival (OS). RESULTS: Five hundred fifty-seven patients (HR-RMS: n = 416, EES and UDS: n = 141) underwent randomization: VAIA (n = 273) or CEVAIE (n = 284). Radiotherapy was given to 70% of patients in both groups. A secondary resection was performed in 47% and 48% patients, respectively. The 5-year EFS and OS for the VAIA and CEVAIE treatment arms were 59.8% and 60.8% (p = .89), and 74.2% and 68.3% (p = .16), respectively. No differences in response, toxicity, or second malignancies emerged in the two groups. CONCLUSION: The use of an intensified regimen failed to show a significant improvement in tumor response and outcome of patients with localized HR-RMS, EES, and UDS.

Collective dynamics of molecular rotors in periodic mesoporous organosilica: a combined solid-state 2H-NMR and molecular dynamics simulation study.

Molecular rotors offer a platform to realize controlled dynamics and modulate the functions of solids. The motional mechanisms in arrays of rotors have not been explored in depth. Crystal-like porous organosilicas, comprising p-phenylene rotators pivoted onto a siloxane scaffold, were modelled using molecular dynamics (MD) simulations. Long simulations, on a microsecond scale, allowed to follow the reorientation statistics of rotor collections and single out group configurations and frequency distributions as a function of temperature. The motions observed in the MD simulations support a multiple-site model for rotor reorientations. Computed motional frequencies revealed a complex rotatory phenomenon combining an ultra-fast libration motion (oscillation up to 30°) with a slow and fast 180° flip reorientation. Adopting a multiple-site model provides a more accurate simulation of the 2H-NMR spectra and a rationalization of their temperature dependence. In particular, rotators endowed with distinct rates could be explained by the presence of slower rings locked in a T-shaped conformation.