Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study

Rabdomiosarcoma metastásico; Sarcoma de tejido blandoRabdomiosarcoma metastàtic; Sarcoma de teixit touMetastatic rhabdomyosarcoma; Soft tissue sarcomaPURPOSE Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study. PATIENTS AND METHODS In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible. RESULTS MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% (P < .0001) and 3-year OS 60.0% versus 26.0% (P < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance. CONCLUSION Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors

Prognostic value of cutaneous reinnervation with GAP-43 in oxaliplatin-induced neuropathy.

Background and purpose: Oxaliplatin-induced neuropathy (OIN) implies axonal damage of both small and large sensory nerve fibers. We aimed at comparing the neurophysiological changes occurred after treatment and the capability to recovery based on histological marker of re-innervation GAP-43. Methods: 48 patients with cancer were assessed before and after chemotherapy (at 3 months and 12 months if available). We recorded ulnar and sural sensory nerve action potentials (SNAP), determined quantitative sensory thresholds for warm and cold (WDT, CDT), pain thresholds and collected a distal biopsy of skin to assess the intra-epidermal nerve fiber density (IENFD) with PGP9.5 and GAP-43 markers (in a subgroup of 19 patients). Results: Increased WDT and CDT as well as diminished IENFD at distal leg were already found in 30% of oncologic patients before treatment. After oxaliplatin, there was a significant increase in thermal thresholds in 52% of patients, and a decrease of SNAP amplitude in the sural nerve in 67% patients. IENFD was reduced in 47% and remained unchanged in 37% after oxiplatin. The density of GAP-43 + fibers and GAP-43/PGP 9.5 ratio was similar before and after treatment showing that cutaneous re-innervation is preserved despite no clinical recovery was observed after one year. Conclusion: Non-selective axonal loss affects sensory fibers in OIN. However, the presence of intra-epidermal regenerative sprouts detected by GAP-43 may reduce the impact of neurotoxicity in the small fibers with long-term sequelae mostly on myelinated nerve endings. Pre-oxaliplatin GAP-43 failed to identify patients with higher risk of damage or worse recovery after treatment

A perspective on polo-like kinase-1 inhibition for the treatment of rhabdomyosarcoma

Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers

A perspective on polo-like kinase-1 inhibition for the treatment of rhabdomyosarcoma

Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers

Violence against healthcare workers during the phases of the COVID‑19 Pandemic: a descriptive observational study from 2018 to 2023 in the metropolitan city of Genoa (North-Western Italy)

Background: Violence against healthcare workers is an escalating public health concern, affecting the quality of care and leading to significant psychological and physical impacts on healthcare professionals. This study aims to analyse the trend of aggressions in healthcare settings, particularly focusing on the pre-pandemic, pandemic, and post-pandemic phases. Methods: An observational descriptive study was conducted to analyse reports of violence against healthcare workers from January 2018 to June 2023 at a Local Health Authority “ASL3” in the Liguria region of Italy. The study considered variables such as severity of aggression, professional category involved, and location of incident. Multinomial logistic regression was used to examine associations between the pandemic phase and various factors, while controlling for relevant variables. Results: The study noted an increase in reported aggressions from 48 in 2018 to 35 in the first half of 2023. The pandemic phase saw a rise in incidents classified as Green codes, accounting for 58.3%, and significant involvement of District Services. The post-pandemic phase showed a reversion to pre-pandemic conditions but with an increase in Yellow codes (5.6%). Nurses were predominantly affected, ranging from 50.8% to 95.6% across the years. The Emergency Department and Psychiatric Services emerged as the most critical contexts for aggressions, with recorded incidents in these areas constituting over half of the total cases. However, an increase in violence has been recorded in district healthcare settings during the post-pandemic phase. Conclusion: The findings reveal an urgent need for comprehensive violence prevention strategies in healthcare settings. The trend of increasing violence, especially during the pandemic, necessitates integrated approaches encompassing training, psychological support, security policies, and a strong organizational culture promoting safety and respect. Protecting healthcare workers is crucial for their wellbeing and the quality of healthcare delivery, highlighting the necessity for effective policies and targeted interventions to ensure a safe working environment

Interaction between Fish Skin Gelatin and Pea Protein at Air-Water Interface after Ultrasound Treatment

The interaction between fish skin gelatin (FG) and pea protein isolate (PPI) was investigated at the air-water interface (A-W) before and after a high intensity (275 W, 5 min) ultrasound treatment (US). We analyzed the properties of the single protein suspensions as well as an equal ratio of FG:PPI (MIX), in terms of ζ-potential, particle size, molecular weight, bulk viscosity and interfacial tension. The foaming properties were then evaluated by visual analysis and by Turbiscan Tower. Confocal laser scanning microscopy (CLSM) was employed to explore the role of the proteins on the microstructure of foams. The results showed that the ultrasound treatment slightly influenced physicochemical properties of the proteins, while in general, did not significantly affect their behavior both in bulk and at the air-water interface. In particular, PPI aggregate size was reduced (−48 nm) while their negative charges were increased (−1 mV) after the treatment. However, when the proteins were combined, higher molecular weight of aggregates, higher foam stability values (+14%) and lower interfacial tension (IFT) values (47.2 \ub1 0.2 mN/m) were obtained, leading us to assume that a weak interaction was developed between them

Desmoplastic small round cell tumor:from state of the art to future clinical prospects

Introduction: Desmoplastic small round cell tumor (DSRCT) is an extremely rare and highly aggressive soft tissue sarcoma, presenting mainly in male adolescents and young adults with multiple nodules disseminated within the abdominopelvic cavity. Despite a multimodal approach including aggressive cytoreductive surgery, intensive multi-agent chemotherapy, and postoperative whole abdominopelvic radiotherapy, the prognosis for DSRCT remains dismal. Median progression-free survival ranges between 4 and 21 months, and overall survival between 17 and 60 months, with the 5-year overall survival rate in the range of 10–20%. Area covered: This review discusses the treatment strategies used for DSRCT over the years, the state of the art of current treatments, and future clinical prospects. Expert opinion: The unsatisfactory outcomes for patients with DSRCT warrant investigations into innovative treatment combinations. An international multidisciplinary and multi-stakeholder collaboration, involving both pediatric and adult sarcoma communities, is needed to propel preclinical model generation and drug development, and innovative clinical trial designs to enable the timely testing of treatments involving novel agents guided by biology to boost the chances of survival for patients with this devastating disease.</p

Treatment at Relapse for Synovial Sarcoma of Children, Adolescents and Young Adults:From the State of Art to Future Clinical Perspectives

While the overall prognosis is generally quite satisfactory in children, adolescents and young adults with localised synovial sarcoma at first diagnosis, the outcome remains poor for patients after relapse. Conversely to the front-line standardised treatment options, patients with relapse generally have an individualised approach and to date, there is still a lack of consensus regarding standard treatment approaches. Studies on relapsed synovial sarcoma were able to identify some prognostic variables that influence post-relapse survival, in order to plan risk-adapted salvage protocols. Treatment proposals must consider previous first-line treatments, potential toxicities, and the possibility of achieving an adequate local treatment by new surgery and/or re-irradiation. Effective second-line drug therapies are urgently needed. Notably, experimental treatments such as adoptive engineered TCR-T cell immunotherapy seem promising in adults and are currently under validation also in paediatric patients.</p

Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas:Standard of Care and Treatment Recommendations from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG)

This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma.</p