Successful use of perampanel in GABRA1-related myoclonic epilepsy with photosensitivity.

Pathogenic variants in gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) is a protein coding gene that has been associated with a broad phenotypic spectrum of epilepsies. These have ranged from mild generalized forms to early-onset severe epileptic encephalopathies. Both in mild and in severe forms, tonic-clonic and myoclonic seizures with generalized spike and wave discharges and photoparoxysmal responses are common clinical manifestations. We present the case of a 14-year-old girl referred to our clinic with uncontrolled epilepsy. She was found to carry a heterozygous variant (c.335G > A) in GABRA1, already described in the literature and classified as "pathogenic" according to ACMG guidelines. The patient showed severe drug resistance with seizures often triggered by photic stimulation. The introduction of perampanel therapy led to overall reduction of the focal and generalized myoclonic seizures and complete clinical control of the light-triggered seizures. To our knowledge this is the first report of perampanel efficacy in photosensitive epilepsy, and in particular in the presence of a GABRA1 variant. New evidence is needed to confirm our findings in this case.

Acute encephalitis in pediatric multisystem inflammatory syndrome associated with COVID-19.

OBJECTIVE: To characterize neurological involvement in multisystem inflammatory syndrome in children (MIS-C) related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Retrospective analysis of the clinical, electroencephalographic, CSF and neuroradiological parameters recorded in seven children (3 males, aged 3-10 years) affected by MIS-C with acute neurological involvement. RESULTS: All cases presented acute encephalopathy with drowsiness, irritability, mood deflection and diffuse EEG slowing with periodic posterior complexes. Focal neurological signs, normal brain MRI and CSF, were present in four patients; these patients received intravenous methylprednisolone at 30 mg/kg/day for 3 days. In all cases, the clinical picture rapidly improved in the first three days, and all neurological symptoms and EEG abnormalities disappeared within 10 and 30 days respectively. The severity and duration of the EEG abnormalities was proportional to the extent of the neurological involvement. CONCLUSIONS: Patients with MIS-C may present acute encephalitis characterized by rapid-onset encephalopathy and EEG abnormalities (slow wave activity and/or epileptic abnormalities), in some cases associated with focal neurological signs that disappear with immunomodulatory therapy. The detection through neurological evaluation of sentinel neurological signs and distinctive EEG patterns documentable at disease onset will allow timely diagnosis and treatment of these cases.

Role of centers with different patient volumes in the management of rhabdomyosarcoma. An analysis by the Italian Pediatric Soft Tissue Sarcoma Committee.

PROCEDURE: The survival of children with rhabdomyosarcoma (RMS) has gradually improved as a result of the adoption of multidisciplinary treatments. Dedicated skills and facilities are indispensable and more readily available at reference centers. In this study, we examined the role of centers' experience (based on the number of patients treated) in their management of patients with RMS. METHODS: We analyzed 342 patients with localized RMS enrolled in the European RMS 2005 protocol from October 2005 to December 2016 at 31 Italian centers that are part of the Soft Tissue Sarcoma Committee (STSC). We grouped the centers by the number of patients each one enrolled (Group 1: >40; Group 2: <40 and >10; and Group 3: <10), and compared a number of indicators to assess the appropriateness of patients' diagnostic workup and treatment and their survival. RESULTS: Overall, 74.6% of patients were treated at 10 centers, and only three of them classifiable as high-volume centers. Only minor differences emerged between the three patient groups in terms of diagnostic investigations and treatment modalities. Survival was similar in the three groups. Approximately, one in four children treated at the centers in Groups 2 and 3 traveled to another center for surgery or radiotherapy. CONCLUSION: Patients treated at STSC centers with different amounts of experience had similar results in terms of survival. This is attributable to all centers in the network adhering to protocol recommendations and receiving the STSC's support on diagnostics and multidisciplinary treatments for RMS.

Infantile Abdominal and Pelvic Lipoblastomas: A Case Series.

Lipoblastomas are rare benign mesenchymal tumors that arise from embryonal fat cells. They are usually discovered in infants and children under 3 years of age, and mostly occur in the trunk (from 10 to 60%, depending on the study) and extremities (from 40 to 45%), while head and neck localizations are rare, with only five cases described to date. We report on three cases of lipoblastomas in infants younger than 4 years, with unusual localizations: one intra-abdominal, discovered during a laparotomy for an intussusception; one pelvic, misdiagnosed as an ovarian mass; and one gluteal with a pelvic extension. All children underwent magnetic resonance imaging as preoperative workup. All tumors were completely resected with free surgical margins and ultrasonographic follow-up was uneventful for all patients.

Biliary tract rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica.

INTRODUCTION: Rhabdomyosarcoma is a soft tissue malignant musculoskeletal tumor frequent in children. Biliary duct localization is extremely rare, but it is the most common cause of malignant obstructive jaundice in pediatric patients. METHODS: This report describes a series of 10 patients under 18 years of age with biliary tract rhabdomyosarcoma who were enrolled, from 1979 to 2004, in 3 consecutive Italian pediatric cooperative protocols that had been drawn up by the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). RESULTS: Considering initial and delayed surgery, tumor resection was achieved in 7 cases, 3 complete with free margins (2 liver transplants) and 4 with microscopic residual disease. Chemotherapy was given to all patients and radiotherapy to 3. At present, 5 patients survive in complete remission 90-200 months after diagnosis while 4 died of disease progression or relapse and 1 of liver transplant-related complications. CONCLUSIONS: Better outcomes in this series were associated with the feasibility of conservative surgery due to the favorable location of the tumor, in particular in the common bile duct. Chemotherapy and radiotherapy might obviate the need for demolitive surgery or liver transplant, which were linked to worse outcomes in our series.

Long-term results in children with head and neck rhabdomyosarcoma: A report from the Italian Soft Tissue Sarcoma Committee.

BACKGROUND: Rhabdomyosarcoma (RMS) occurring at nonparameningeal head and neck (NPM-HN) sites carries a better prognosis than parameningeal RMS and some other sites. We analyzed the treatments administered and results obtained in patients with localized NPM-HN RMS, included in the protocols coordinated by the Italian Soft Tissue Sarcoma Committee (STSC), in an effort to identify prognostic factors that could facilitate the tailoring of treatment. METHODS: Sixty-six patients up to 18 years of age with previously untreated, localized NPM-HN RMS were prospectively registered in three consecutive protocols: RMS79, RMS88, and RMS96. Primary surgery was recommended when complete tumor resection was deemed feasible without mutilations. In other cases, only a biopsy was performed, followed by chemotherapy and delayed surgery and/or radiotherapy (RT). RESULTS: NPM-HN RMS showed favorable characteristics: 72.7% were <5 cm, 72.7% were T1, and 80.3% were N0. With a median follow-up of 16 years (range 7-27), the 10-year progression-free survival and overall survival for the whole group were 65.1% (confidence interval [CI]: 52.3-75.3) and 74.2% (CI: 61.8-83.1). Progressive improvement has been seen in the successive protocols. Age and RT emerged as independent prognostic factors. The group of young children (age

Gastrointestinal tract carcinoma in pediatric and adolescent age: The Italian TREP project experience.

BACKGROUND: Gastrointestinal (GI) carcinomas are very rare in the pediatric and adolescent age range. We report the clinical features, treatment, and outcome of a series of children and adolescents with GI carcinoma prospectively registered in the Italian Tumori Rari in Età Pediatrica (TREP) project. METHODS: The TREP project developed diagnostic and therapeutic guidelines based on recommendations currently in use for adults. Clinical data were centrally registered and reviewed. RESULTS: Fifteen patients were registered over the years 2000-2016. Most of the tumors were colorectal carcinomas (12 cases). All but one patient had advanced-stage disease (American Joint Committee on Cancer stages III-IV), and the majority of patients had aggressive histological subtypes, i.e. poorly differentiated (G3) (five patients), mucinous (four patients), and signet ring (two patients) adenocarcinomas. Surgery was performed in 13 of 15 patients, and was radical in nine of 13 patients. Only one patient received postoperative radiotherapy. All patients received chemotherapy, with the addition of bevacizumab in two cases. Nine patients were still alive at the time of the present report, but two of them had only just completed their treatment program and one patient is still on treatment. Six patients died due to disease progression. CONCLUSIONS: This prospective report on pediatric GI tract carcinomas confirms the rarity and biological aggressiveness of these diseases in pediatric and adolescent age. Further prospective studies are needed to explore the distinct biology of tumor in this age group in order to find new therapeutic targeted agents.

Pediatric nonrhabdomyosarcoma soft tissue sarcomas arising at visceral sites.

BACKGROUND: Pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) may rarely occur in visceral tissues, and little is known about their clinical history. The present study retrospectively analyzed a group of patients prospectively registered in Italian pediatric protocols conducted between 1979 and 2004. METHODS: Inclusion criteria for the study were as follows: a pathological diagnosis of "adult-type NRSTS," arising at visceral sites (lung-pleurae, liver, kidney, and mesentery-bowel); age under 18 years; no previous treatment except for primary surgery; available clinical data; and written consent. RESULTS: Thirty cases with visceral NRSTS were collected and analyzed. Sites of origin were as follows: mesentery-bowel in 12 cases, lung-pleurae in 11, liver in 5, and kidney in 2. According to the Intergroup Rhabdomyosarcoma Study (IRS) surgical grouping system, patients were classified as follows: nine IRS group I, three group II, 12 group III, and six group IV. Patients were treated with a multimodal approach including surgery, radiotherapy, and/or chemotherapy, according to their characteristics. For the series as a whole, the 5-year event-free and overall survival rates were 33.3% and 40.0%, respectively. The IRS group (reflecting the feasibility of initial complete resection) emerged as the main prognostic factor. Survival rates also correlated with tumor size and local invasiveness, histological subtype, and tumor sites (the worst outcome was seen for tumors arising in the lung and pleurae). CONCLUSIONS: This study confirmed that visceral NRSTS are aggressive tumors carrying a worse prognosis than pediatric NRSTS arising in soft tissues of the extremities. Local treatment remains the main challenge for these tumors.

Response to pazopanib in two pediatric patients with pretreated relapsing synovial sarcoma.

Pazopanib is an oral multikinase inhibitor that has proved effective in adults treated for relapsing soft tissue sarcoma and synovial sarcoma in particular. Two cases are reported here of pediatric patients with pretreated relapsing synovial sarcoma whose tumors showed a prolonged response to pazopanib given on compassionate grounds. These results suggest that new agents found effective in adult patients might achieve similar results in adolescents with the same disease. Facilitating the availability of new drugs for children and adolescents is a major challenge for pediatric oncologists.

Prognostic factors in children undergoing salvage surgery for bladder/prostate rhabdomyosarcoma.

BACKGROUND: Prognostic factors have been studied in patients with rhabdomyosarcoma in general, but little is known about prognostic factors in the subgroup of patients with bladder/prostate rhabdomyosarcoma (BP-RMS) requiring salvage surgery after failure of chemotherapy ± radiotherapy to achieve local control. We reviewed the 28-year Italian experience with BP-RMS requiring salvage surgery after failure of nonsurgical management indicated by evidence of disease persistence after chemotherapy ± radiotherapy. Our hypothesis was that the same variables identified as prognostic factors in the general population with RMS could have prognostic value in this subgroup. METHOD: Between 1986 and 2014, 108 patients with a histological diagnosis of BP-RMS were registered into three consecutive protocols. Patients undergoing salvage surgery after failure of chemotherapy ± radiotherapy and follow-up >5 years were considered for study. Variables related to the patient, to treatment, and to the surgical specimen were compared using the log-rank test in patients who achieved and failed to achieve 5-year progression-free survival (5-yr PFS). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for significant variables. RESULTS: Of the 108 patients enrolled in the protocols, 33 (30.6%) underwent salvage surgery and 26 matched study criteria. Seventeen patients were disease-free after a median follow-up of 125 months (range 65.5-311.7 months), 5-yr PFS 65.4%. Nine events were registered after a median follow-up of 5.4 months (range 1.9-27.5 months). Among the variables assessed (Table), only an undifferentiated histology proved to be significantly associated with a poorer 5-yr PFS, whereas a tumor size above 5 cm in the removed specimen approached significance. The OR (95% CI) for failure of 5-yr PFS was 28 (2.4-326.8) and 8.3 (1.03-67.1), respectively. CONCLUSION: 5-yr PFS proved unrelated to excision margins of the surgical specimen, that is on whether there was evidence of microscopic residues left behind during surgery. These data suggest that the outcome is more influenced by the biological properties of the tumor. If small foci of differentiated cells are left behind, these probably do not compromise final prognosis. In our patients requiring salvage bladder-prostate surgery after failure of chemotherapy ± radiotherapy, long-term progression-free survival seemed unrelated to patient/tumor characteristics at presentation and preoperative management. Regarding the characteristics of the removed specimen, instead, an undifferentiated tumor histology and a diameter of the removed tumor >5 cm negatively influenced prognosis, whereas the presence of positive excision margins did not.

A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is very rare in childhood. It differs from its adult counterpart in the prevalence of the nonkeratinizing, undifferentiated subtype and by an advanced clinical stage at onset and better chances of survival. The risk of long-term treatment-related toxicity also may be a more important issue in younger individuals. METHODS: A prospective chemoradiotherapy protocol for pediatric NPC was started in Italy in 2000 within the framework of the Rare Tumors in Pediatric Age (TREP) project. Three courses of cisplatin/5-fluorouracil induction chemotherapy were followed by radiotherapy (doses up to 65 grays) with concomitant cisplatin. RESULTS: Forty-six patients (ages 9-17 years) were considered eligible for the study over a 10-year period. The ratio of observed to expected cases based on epidemiological data was approximately 1 for both children and adolescents. All but 1 patient had lymph node involvement, and 5 patients had distant metastases. The rate of response to primary chemotherapy was 90%. The 5-year overall and progression-free survival rates were 80.9% and 79.3%, respectively (median follow-up, 62 months). The only statistically significant prognostic variable was the presence or absence of distant metastases. A 65% incidence of late sequelae was reported. CONCLUSIONS: This study demonstrates the feasibility and efficacy of a prospective protocol even for such rare tumors as pediatric NPC. The use of lower radiotherapy doses than those used in adults did not affect locoregional failure rates. Long-term follow-up will be needed to obtain more information on both survival and treatment sequelae. The next objective will be to establish broader, international prospective cooperation schemes.

Loss of 10q26.1-q26.3 in association with 7q34-q36.3 gain or 17q24.3-q25.3 gain predict poor outcome in pediatric medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. We have investigated for novel chromosomal imbalances and prognostic markers of pediatric MB. Forty MBs out of 64, were analyzed using high resolution prometaphase comparative genomic hybridization. Chromosome 10q26.1-q26.3 loss combined with 17q24.3-q25.3 gain and/or 7q34-q36.3 gain in tumors predicted poor patient's survival. A minimal deleted region of 14.12cM at 10q26.1-q26.3 was refined by LOH analysis. We propose a new prognostic marker for pediatric MB patient risk stratification based on the presence of 10q26.1-q26.3 loss plus 17q24.3-q25.3 gain and/or 7q34-q36.3 gain associations.

Neonatal hepatoblastoma in a newborn with severe phenotype of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome is an overgrowth disorder characterized by neonatal macrosomia, abdominal wall defects, macroglossia, renal anomalies, organomegaly, hypoglycemia, and cancer predisposition. Hepatoblastoma is the second most frequent tumor and periodic serum alpha-fetoprotein (αFP) dosage is the cornerstone of the tumor surveillance for its early detection. In this report, we describe the outstanding case of a Beckwith-Wiedemann syndrome (BWS) newborn with severe phenotype and paternal chromosome 11 uniparental disomy (UPD11) associated with a high tumor risk. Based on the clinical picture and previous reports, a close monitoring of αFP was commenced. The marker was normal immediately after birth, but rapidly raised in 20 days, leading to the diagnosis of an extremely aggressive hepatoblastoma. The latter was successfully treated with pre-surgical reductive chemotherapy, gross total mass resection, and subsequent chemotherapy. Based on this observation, the tumor surveillance routinely suggested every 3 months should be more intense and with closer time intervals in newborns with severe BWS phenotype. We suggest monitoring neonatal αFP every 20 days in such cases.

Chromosome 9q and 16q loss identified by genome-wide pooled-analysis are associated with tumor aggressiveness in patients with classic medulloblastoma.

Medulloblastoma (MB) is one of the most aggressive pediatric brain tumor. We report genome-wide pooled-analysis of classic MB variant of patients over 3 years of age at diagnosis. We combined array comparative genomic hybridization (aCGH) results from experimental analysis (31 cases) with two public databases (55 cases) in a final evaluation of 86 MBs. The most common chromosome structural aberrations were gains of 17q (45.3%), 1q (22.1%), and losses of 8p (15.1%), 10q (19.8%), 17p (37.2%), and 16q (16.3%). Isochromome (17q) was observed in 29.1% MBs. A significant association between poor patients survival and losses of 9q (p < 0.0023), 10q (p < 0.012), and 16q (p < 0.036) was observed. Univariate analysis showed association of 9q loss (p < 0.008) and 16q loss (p = 0.05) with adverse overall survival (OS). Chromosome 6 monosomy was a protective event although statistically borderline (p = 0.066). After adjusting for confounding factors, a poor OS was found for patients whose tumor has 9q loss [hazard ratio (HR) = 3.97; p < 0.006) or 16q loss (HR = 2.41; p = 0.038). Our results highlight the importance of genomic studies in different MB histological variants and indicate a genotype-phenotype correlation.

Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma.

AIM: The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma. PATIENTS AND METHODS: Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered. RESULTS: Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years. CONCLUSION: Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma.