Local treatment in initially unresected non-rhabdomyosarcoma soft-tissue sarcomas of children and adolescents: A retrospective single-center experience.

BACKGROUND: Pediatric non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) are a heterogeneous group of aggressive tumors. Patients with locally advanced/initially unresected disease represent a subset of patients with unsatisfactory outcome: limited data are available on the best treatment approach, in particular regarding local therapy. METHODS: This retrospective analysis concerned 71 patients < 21 years old with nonmetastatic, initially unresected adult-type NRSTS, treated at a referral center for pediatric sarcomas from 1990 to 2021. Patients were treated using a multimodal approach, based on the protocols adopted at the time of their diagnosis. RESULTS: The series included a selected group of patients with unfavorable clinical characteristics, i.e., most cases had high-grade and large tumors, arising from axial sites in 61% of cases. All patients received neoadjuvant chemotherapy, 58 (82%) had delayed surgery (R0 in 45 cases), and 50 (70%) had radiotherapy. Partial response to chemotherapy was observed in 46% of cases. With a median follow-up of 152 months (range, 18-233), 5-year event-free survival (EFS) and overall survival (OS) were 39.9% and 56.5%, respectively. Survival was significantly better for patients who responded to chemotherapy, and those who had a delayed R0 resection. Local relapse at 5 years was 7.7% for patients who did not undergo delayed surgery. CONCLUSIONS: Our series underscores the unsatisfactory outcome of initially unresected NRSTS patients. Improving the outcome of this patient category requires therapeutic strategies able to combine novel effective systemic therapies with a better-defined local treatment approach to offer patients the best chances to have R0 surgery.

Caring for children with cancer evacuated from Ukraine: The patients' perception.

BACKGROUND AND AIMS: Since the beginning of the war in Ukraine on February 24, 2022, many pediatric oncology centers welcomed evacuated patients. To better understanding the needs of patients and families arriving at two Lombardy hospitals in the period March to November 2022, an anonymous questionnaire investigated the families' backgrounds, feelings, and impressions about hospitality and care. METHODS: Twenty questions investigated how patients had reached Italy, from whom they had received help (logistically/financially); the emotions regarding their status as war refugees; the knowledge, expectations, and opinions about Italy and Italians; the quality of medical care received and the relationships with the healthcare staff; lastly, suggestions to improve assistance. RESULTS: The questionnaires were completed by 19/32 patients/parents in November 2022 in two different pediatric-oncology centers. Most families had reached Italy (58%) and received medical care (95%) with the help of charities and the Italian Public Health Care System. A significant majority (69%) expressed satisfaction with the assistance provided. The Italian population demonstrated remarkable warmth, for 95% exhibiting friendliness and for 58% generosity. An improvement in their stay could be linked with the positive outcome of their children's cancer (15%), achieving complete family reunification (15%), the cessation of the conflict (10%), and the overcoming of language barriers (10%). CONCLUSIONS: Providing care for children from another country, not only grappling with the trauma of fleeing their homeland but also battling cancer, is an immense undertaking. It demands a diverse range of efforts and resources to ensure a positive and fulfilling outcome for this experience.

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.

Relapse after nonmetastatic rhabdomyosarcoma: Salvage rates and prognostic variables.

BACKGROUND: Patients with relapsing rhabdomyosarcoma (RMS) pose a therapeutic challenge, and the survival rate is reportedly poor. We describe a retrospective series of relapsing RMS patients treated at a referral center for pediatric sarcoma, investigating the pattern of relapse, salvage rates, and factors correlating with final outcomes. METHODS: The analysis concerned 105 patients <21 years old treated from 1985 to 2020 with initially localized RMS at first relapse. For risk-adapted stratification purposes, patient outcomes were examined using univariable and multivariable analyses based on patients' clinical features at first diagnosis, first-line treatments, clinical findings at first relapse, and second-line treatments. RESULTS: First relapses occurred 0.08-4.8 years (median 1 year) following initial diagnosis and were local/locoregional in 59% of cases. Treatment at first relapse included chemotherapy in all but two cases, radiotherapy in 38, and surgery in 21. Median event-free survival (EFS) after first relapse was 4 months, while 5-year EFS was 16.3%; median overall survival (OS) was 9 months, while 5-year OS was 16.7%. Several variables influenced survival rates. Considering only clinical findings and treatment at relapse, Cox's multivariable analysis showed that OS correlated significantly with time to relapse, radiotherapy administered at relapse, response to chemotherapy, and whether a second remission was achieved. CONCLUSION: Survival following first relapse of patients with localized RMS at initial diagnosis is poor. The variables found to influence survival can be utilized in a risk-adapted model to estimate the chances of salvage to guide decisions for second-line treatments.

Relapse after non-metastatic rhabdomyosarcoma: The impact of routine surveillance imaging on early detection and post-relapse survival.

BACKGROUND: Patients with rhabdomyosarcoma (RMS) whose disease relapses have little chance of being cured, so front-line treatments are usually followed up with surveillance imaging in an effort to detect any recurrences as early as possible, and thereby improve post-relapse outcomes. The real benefit of such routine surveillance imaging in RMS remains to be demonstrated, however. This retrospective, single-center study examines how well surveillance imaging identifies recurrent tumors and its impact on post-relapse survival. METHODS: The analysis concerned 79 patients <21 years old treated between 1985 and 2020 whose initially localized RMS relapsed. Clinical findings, treatment modalities, and survival were analyzed, comparing patients whose relapse was first suspected from symptoms they developed (clinical symptoms group) with those whose relapse was identified by radiological surveillance (routine imaging group). RESULTS: Tumor relapses came to light because of clinical symptoms in 42 cases, and on routine imaging in 37. The time to relapse was much the same in the two groups. The median overall survival (OS) and 5-year OS rate were, respectively, 10 months and 12.6% in the clinical symptoms group, and 11 months and 27.5% in the routine imaging group (p-value .327). Among patients with favorable prognostic scores, survival was better for those in the routine imaging group (5-year OS 75.0% vs. 33.0%, p-value .047). CONCLUSION: It remains doubtful whether surveillance imaging has any real impact on RMS relapse detection and patients' post-relapse survival. Further studies are needed to establish the most appropriate follow-up recommendations, taking the potentially negative effects of regular radiological exams into account.

Secondary osteosarcoma: a challenge indeed.

BACKGROUND: The risk of survivors developing a secondary bone sarcoma after being treated for pediatric cancers is well established. The aim of this study was to examine the clinical characteristics and outcomes of patients with secondary osteosarcoma (SOS). METHODS: The study concerns survivors of childhood and adolescence primary neoplasms (PN) treated with chemotherapy, with or without radiotherapy and surgery, subsequently diagnosed with SOS. RESULTS: We identified 26 patients (13 females, 13 males) who developed SOS a median 7.3 years after being diagnosed with a PN (5/7 of these patients tested for Li-Fraumeni and found positive for the syndrome). The sample's median age was 8.0 and 15.0 years when their PN and SOS were diagnosed, respectively. To treat their PN, 24 out of 26 patients had been given radiotherapy, and 19 had received chemotherapy including doxorubicin. A considerable number of SOS occurred at unfavorable sites (nine hip bone, six skull). All but one patient received chemotherapy with tailored schedules, omitting doxorubicin in 19 cases. Eighteen of the 26 patients underwent surgery. The 5- and 10-year overall survival and probabilities after the diagnosis of SOS (95% confidence interval) were 50% (32.7-76.5%) and 38.9% (22.4-67.4%); 5- and 10-year progression-free survival was 47% (29.9-73.7%) and 35.2% (19.3-64.4%), respectively. CONCLUSIONS: The survival rates after SOS are lower than in patients with primary osteosarcoma, but not negligible. It is therefore mandatory to discuss the best choice of treatment for such patients at a referral center, in terms of their chances of cure and quality of life.

Langerhans cell histiocytosis in adults: a retrospective, single-center case series.

Langerhans cell histiocytosis is rare in adults, and most of what we know about its diagnosis and treatment comes from pediatric studies. We report clinical findings and results of treatment in a retrospective series of 63 consecutive adult patients (18-76 years old), treated at our pediatric unit from 1990 to 2020 using the same approach as for children. Patients were classified as having single-system disease (SS-LCH) in 41 cases, which was unifocal in 34 of them and multifocal in 7, or multisystem disease (MS-LCH) in 17 and primary pulmonary (pLCH) in 5. Twenty patients also had diabetes insipidus. A "wait and see" strategy was recommended after biopsy/surgery for patients with unifocal SS-LCH. Systemic treatment was proposed for cases of SS-LCH involving "special sites" or with multifocal disease, and in cases of MS-LCH. EFS and OS for the cohort as a whole were 62.2% and 100%, respectively, at 5 years and 52.5% and 97.6% at 10 years. Three patients died due to the damage caused by the multiple therapies administered. The rate of disease reactivation was high (affecting 40% of cases), with several reactivations over the years despite multiple lines of treatment. Though clinical history of LCH may differ between adults and children, in the absence of specific, tailored protocols, clinical approach to adult cases may draw on pediatric experience. Patients with limited disease have a good prognosis without any need for systemic therapy. Potentially greater toxicity in adults of systemic treatments generally used in pediatric setting should be borne in mind.

How ten-years of reirradiation for paediatric high-grade glioma may shed light on first line treatment.

PURPOSE: Recurrence incidence for paediatric/adolescent high-grade glioma (HGG) exceeds 80%. Reirradiation (reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches. METHODS: We re-evaluated MRI + RT plans of 21 relapsed HGG-patients, accrued 2010-2021, aged under 18 years. All underwent surgery and RT + chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed. RESULTS: Relapse after 1st RT was local in 12 (7 marginal), 4 disseminated, 5 local + disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local (2 marginal) and 4 local + disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation (CSI), 1 spine reRT and further relapsed with dissemination and local + dissemination in 3/four assessed. Five local + disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally (2), disseminated (1), n.a. (1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6-16.2 months)/6.9 months (0.6-17.9 months), improved for longer interval between 1st RT and re-RT (P = 0.017) and for non-PD after reRT (P < 0.001). First marginal relapse showed potential association with dissemination after re-RT (P = 0.081). CONCLUSIONS: This is the biggest series of re-RT in paediatric HGG. Considering the dissemination observed at relapse, our results could prompt the investigation of different first RT fields in a randomized trial.

Metastatic rhabdomyosarcoma: Evidence of the impact of radiotherapy on survival. A retrospective single-center experience.

BACKGROUND: The prognosis for patients with metastatic rhabdomyosarcoma (RMS) remains largely unsatisfactory despite the adoption of intensive multimodal therapy. To assess the role of different treatments adopted over the years, we retrospectively analyzed a cohort of patients <21 years old with metastatic RMS, treated from 1990 to 2020 at a referral center for pediatric sarcomas. METHODS: Patients were treated using a multimodal approach that included surgery, radiotherapy, and chemotherapy (both high-dose chemotherapy and maintenance therapy in some cases). The type of radiotherapy administered was categorized as radical (to all sites of disease); partial (to at least one, but not all sites of disease); or none. A landmark analysis was used to examine the impact of radiotherapy on survival, that is, patients who had an event before day 221 were excluded from the analysis. RESULTS: The series included 80 patients. Event-free survival (EFS) and overall survival (OS) rates at 5 years were 17.3% and 21.3%, respectively. Survival was significantly associated with radiotherapy to metastatic sites, and with the radiotherapy category. In particular, 5-year EFS and OS rates were 70.6% and 76.0% for patients given radical radiotherapy, and 4.8% and 10.7%, respectively, for those given partial radiotherapy or none. Using the Cox multivariable analysis, OS correlated significantly with radiotherapy category. CONCLUSIONS: While confirming the poor overall outcome of patients with metastatic RMS, this study identified radiotherapy-when given to all sites of disease (including metastases)-as the main variable influencing survival.

Extraosseous Ewing sarcoma in children and adolescents: A retrospective series from a referral pediatric oncology center.

BACKGROUND: Extraosseous Ewing sarcoma is a rare entity and less is known about its clinical behavior and optimal treatment than for its counterpart in bone. This study is a retrospective analysis on a cohort of patients <21 years treated according to a "soft tissue sarcoma approach." METHODS: The "extraosseous" origin of the tumor was established on radiological findings, based on the lack of any bone involvement. Patients were treated using a multimodality approach including surgery, radiotherapy, and chemotherapy. All patients received chemotherapy with alkylating agents and anthracyclines for 25 weeks (nine courses). Radiotherapy (45-54.8 Gy) was required for all cases except those who had an initial R0 resection of tumors smaller than 5 cm. RESULTS: Fifty-seven patients (age 2-20 years, median 14) were treated from 1990 to 2020. Ten-year event-free survival (EFS) and overall survival (OS) were 77.5% and 85.5% in patients with localized disease, and 11.1% and 29.6% in those with metastatic disease (p < .001) (follow-up 5-349 months, median 107 months). In patients with localized disease, the most recent IVADo-IVE regimen achieved excellent survivals, that is, 10-year EFS 95.5%. CONCLUSIONS: Our study showed that satisfactory results were achieved in patients with localized extraosseous Ewing sarcoma treated with a tailored approach derived from soft tissue sarcoma protocols, which was less intensive and shorter as compared to the standards utilized for the management of bone Ewing sarcoma. Our study suggests that the extraskeletal site might be considered as a variable to stratify patients and modulate treatment intensity accordingly in Ewing sarcoma protocol.

MiR-223 Exclusively Impairs In Vitro Tumor Growth through IGF1R Modulation in Rhabdomyosarcoma of Adolescents and Young Adults.

Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) form a subgroup of patients whose optimal clinical management and best possible access to care remain a challenge and whose survival rates lag behind that of children diagnosed with histologically similar tumors. A better understanding of tumor biology that differentiates children (PEDS-) from AYA-RMS could provide critical information and drive new initiatives to improve their final outcome. We investigated the functional role of miRNAs implicated in AYA-RMS development, as they have the potential to lead to discovery of new targets pathways for a more tailored treatment in these age groups of young RMS patients. MiR-223 and miR-486 were observed de-regulated in nine RMS tissues compared to their normal counterparts, yet only miR-223 replacement impaired proliferation and aggressiveness of AYA-RMS cell lines, while inducing apoptosis and determining cell cycle arrest. Interestingly, IGF1R resulted in the direct target of miR-223 in AYA-RMS cells, as demonstrated by IGF1R silencing. Our results highlight an exclusive functional role of miR-223 in AYA-RMS development and aggressiveness.

SARS-CoV-2 vaccination for adolescents and young adult patients treated at a specialist pediatric oncology unit.

This brief report describes the SARS-CoV-2 vaccination program at our pediatric oncology unit. Adopting Italian regulations, patients treated for cancer within the previous 6 months were offered vaccination with the Pfizer-BioNtech vaccine if aged ≥16 years, and with the Pfizer-BioNtech or Moderna vaccine if aged ≥18 years. From March 24 to April 28, 2021, 80/89 adolescent and young adult patients enrolled were vaccinated, while nine refused the vaccine due to fear of side effects, disbelief regarding the pandemic, or lack of trust in the scientific community. The refusal rate in our cohort was lower than in the Italian general population.

Integrating irinotecan in standard chemotherapy: A novel dose-density combination for high-risk pediatric sarcomas.

BACKGROUND: Irinotecan is a drug active against pediatric sarcomas with a toxicity profile that theoretically allows for its association with more myelotoxic drugs. We examined the feasibility of a dose-density strategy integrating irinotecan in standard chemotherapy regimens for patients with high-risk sarcomas. METHODS: Between November 2013 and January 2020, 23 patients ≤25 years old were included in the study. Eleven patients newly diagnosed with metastatic disease received nine cycles of IrIVA (irinotecan-ifosfamide-vincristine-actinomycin D; ifosfamide 3 g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on day 1, actinomycin D 1.5 mg/m2 on day 1, irinotecan 20 mg/m2 for 5 consecutive days starting on day 8) as first-line therapy. Two relapsed patients received IrIVA and 10 IrVAC (irinotecan-vincristine-actinomycin D-cyclophosphamide; cyclophosphamide 1.5 g/m2 on day 1 instead of ifosfamide). Feasibility was assessed in terms of toxicity and time to complete the treatment. RESULTS: Seventeen rhabdomyosarcomas, four Ewing sarcomas, two desmoplastic small round cell tumors received a total of 181 cycles (range 2-10). Grade 4 neutropenia occurred in 62.4% of the cycles. Thirteen patients had febrile neutropenia. Diarrhea occurred in 14 cycles. The median time to complete the treatment was 195 days (range 170-231), 83.4% of cycles were administered on time or with a delay <1 week. With a median follow-up of 2.6 years (range 0.2-5.0), 12 patients are alive, nine complete remissions, three with the disease. CONCLUSIONS: A dose-density strategy combining irinotecan with standard chemotherapy is feasible. This approach will be investigated in the next trial coordinated by the European pediatric Soft tissue sarcoma Study Group.

Complexity index in sarcoma and genomic grade index gene signatures in rhabdomyosarcoma of pediatric and adult ages.

BACKGROUND: Rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma in childhood, shows extensive heterogeneity in histology, site and age of onset, clinical course, and prognosis. Adolescents and young adults (AYA) with RMS form a subgroup of patients whose survival lacks behind that of children while diagnosed with histologically similar tumors. PROCEDURES: A 67-gene prognostic signature related to chromosome integrity, mitotic control, and genome complexity in sarcomas (CINSARC) is considered a powerful tool for identifying tumors with a highly metastatic potential. With this study, we investigated the prognostic value of CINSARC signature on a cohort of 48 pediatric (PEDs) and AYAs-RMS. RESULTS: CINSARC resulted not significantly correlated with age, suggesting other determinants to be responsible for that difference in survival. It remained a significant prognostic variable in both the groups of PEDs and AYAs. Also, genomic grade index signature was tested on the same cohort and showed very similar results with CINSARC. CONCLUSIONS: Our study showed that CINSARC correlated with outcome in RMS patients and may be potentially considered a tool to predict outcome, and so stratify RMS patients.

Extra-appendicular neuroendocrine tumors: A report from the TREP project (2000-2020).

BACKGROUND: Extra-appendicular neuroendocrine tumors (NETs) are very rare tumors. While diagnostic and therapeutic guidelines are well established for adults, data on children and adolescents are lacking. PATIENTS AND METHODS: Patients with a diagnosis of extra-appendicular NET registered on the Tumori Rari in Età Pediatrica - Rare Tumors in Pediatric Age (TREP) from 2000 to 2020 were analyzed. Clinical characteristics including patients' presentation, tumor features, treatment, and outcome were reviewed. RESULTS: Twenty-seven patients with extra-appendicular NET registered on TREP with a median age of 173 months. The primary site was the pancreas (12) or bronchi (10) in the majority of cases. Other primary sites included the thymus, Meckel's diverticulum, and liver. Thirteen (48%) of tumors extended beyond the organ of origin: four invaded neighboring organs and/or regional nodes and nine involved distant metastases. The 3-year event-free survival (EFS) for those with localized disease was superior to those with metastatic disease (66.6% 95% CI 5-95% vs 33% 95% CI 5-68%, respectively; P = .005). A complete resection was feasible in 17 patients. The 3-year EFS in these patients was superior to those with no or incomplete resection (R0 vs R1/R2, respectively; P = .007). Overall, 16 children had no evidence of disease at follow-up, and one is alive with disease; five died, and five were lost to follow-up. CONCLUSIONS: Data from our experience demonstrated a wide heterogeneity of presentation and outcome of these tumors. Localized disease and complete surgical resection were the main prognostic factors of good outcome. Other therapies may have a role in prolonging survival in metastatic disease.

Medulloblastoma and familial adenomatous polyposis: Good prognosis and good quality of life in the long-term?

INTRODUCTION: Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) wingless-related integration site (WNT) subtype, the course of which has only recently been described. METHODS: We retrieved all patients with documented germline APC mutations and a diagnosis of MBL to examine their outcome, late effects of treatment, and further oncological events. RESULTS: Between 2007 and 2016, we treated six patients, all with a pathogenic APC variant mutation and all with MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine, and vincristine for a maximum of eight courses. Five of six diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Methylation profile score (in two cases) and copy number variation analysis (chromosome 6 deletion in two cases) performed on four of six retrieved samples confirmed WNT molecular subgroup. Four out of six patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other two cases. Four patients developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. DISCUSSION: Our data confirm a good prognosis for patients with MBL associated with FAP. Patients' secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

Cutaneous melanoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Cutaneous melanoma is rare in children and, like other very rare pediatric tumors, it suffers from a shortage of knowledge and clinical expertise. The clinical management of pediatric melanoma is often challenging. Its clinical and pathological diagnosis may be difficult, and there is no standard treatment. In the absence of specific treatment guidelines, young patients are generally treated following the same principle as for adults, but concern remains about their access to clinical trials and new drugs, which have been shown to dramatically change the natural history of advanced melanoma. This paper presents the internationally recognized recommendations for the diagnosis and treatment of children and adolescents with cutaneous melanoma, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded project called PARTNER (Paediatric Rare Tumours Network - European Registry). Main recommendations for melanoma are to discuss pediatric patients in multidisciplinary teams that include both pediatric oncologists and specialists in adult melanoma; to enroll patients in prospective trials, if available; to collect data in national-international databases; and to develop an effective international collaboration between pediatric and adult melanoma groups in order to facilitate the transfer of potentially effective new agents from the adult to the pediatric setting.

Correlation between oncological family history and clinical outcome in a large monocentric cohort of pediatric patients with rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS), an aggressive soft tissue sarcoma of the skeletal muscle generally affecting children and adolescents, shows extensive heterogeneity in histology, site and age of onset, clinical course, and prognosis. Tumorigenesis of RMS is multifactorial and genetic predisposition together with the family history of cancer may provide critical information to enhance the current knowledge and foster genetic counseling and testing. METHODS: In our study, we evaluated the possible correlation of oncological family history with clinical outcomes in a cohort of RMS 512 patients and treated at the Pediatric Oncology Unit of our Institute. Family history was retrospectively collected from the specific ad hoc form available in medical records and filled in through an interview with the patients' parents at the time of RMS diagnosis. RESULTS: While our series did not show a specific association between oncological family history and clinical variables, we observed an association with survival probabilities: among patients with a history of cancer-affected first-degree relatives at the time of the diagnosis, all children with alveolar RMS (ARMS) died of disease. CONCLUSION: Our study not only reports an interesting and not previously described association between a poor clinical outcome and ARMS in patients with young cancer-affected relatives, but also stimulates the discussion on oncological family history in RMS, to improve the clinical management of these young patients and their families.

Wilms tumor, medulloblastoma, and rhabdomyosarcoma in adult patients: lessons learned from the pediatric experience.

Wilms tumor (or nephroblastoma), rhabdomyosarcoma, and medulloblastoma, common embryonal tumors in children, can occasionally occur in adults, for whom survival is significantly inferior than pediatric patients. Available data on adults with Wilms tumor consist of case or case series reports. Among other factors, the unfamiliarity of adult oncologists and pathologists with nephroblastoma and consequent delays in initiating the appropriate risk-adapted chemotherapy may negatively influence outcomes. The survival decrement in adults with rhabdomyosarcoma has been attributed to the lack of centralized care, the inconsistent use of standard protocol-driven multimodal therapy, and lower chemotherapy tolerance in adult patients. In children with medulloblastoma, evidence from randomized clinical trials has led to risk-tailored therapies tuned on histology, extent of initial disease, and biological features. Such refinements are still missing for adults due to the lack of similar trials and studies that might provide the same or a different understanding regarding patients' individual prognosis, treatment morbidity, and quality of life. Recent experiences have suggested that applying or adjusting pediatric protocols to adult patients with these tumors is feasible and can improve survival. Here, we provide an evaluation of the current evidence for the management of Wilms tumor, rhabdomyosarcoma, and medulloblastoma arising in adults. This review aims to promote the referral of adolescents and adults with pediatric tumors to pediatric centers for inclusion into pediatric protocols, or into protocols and studies specifically designed for that age group with the cooperation between pediatric and adult oncologists.

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.