A homogeneous treatment for non-DIPG diffuse midline glioma

Introduction: The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016, and confirmed in its fifth edition. The biological behavior and dismal prognosis of this tumor resemble diffuse intrinsic pontine gliomas (DIPG). Homogeneously-treated series are rarely reported. Methods: From 2016 onwards, we treated patients with DMG with radiotherapy and concomitant/adjuvant nimotuzumab/vinorelbine, plus re-irradiation at relapse, as already done for DIPG. Results: We treated nine patients, seven females, with a median age at diagnosis of 13 years. Tumor sites were: thalamic in five cases, pontocerebellar in two, pineal in one, and paratrigonal with nodular/leptomeningeal dissemination in one. Three patients were biopsied, and six had partial tumor resections. Central pathological review was always performed. The median time to local progression was 12.7 months, and the median overall survival was 17.8 months. Six patients died of tumor progression, one of cerebral bleeding at progression. Two were alive, one in continuous remission, the other after relapsing, at 38.6 and 46.3 months after diagnosis. Progression-free survival was 33.3% at one year. Overall survival was 88.9%, 33.3% and 22.2% at 1, 2 and 3 years, respectively. Conclusions: This is a small series of homogeneously-treated DMG patients. The results obtained are comparable with those of DIPG patients. Given the phenotypically- and molecularly-defined setting of DMG and severe outcome in this orphan population, they should be treated and included in registries and protocols of DIPG

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma

BACKGROUND: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports

Secreting Germ Cell Tumors of the Central Nervous System: A Long-Term Follow-up Experience

Simple Summary Nongerminomatous germ cell tumors of the central nervous system are rare tumours. Differently from germinomas, they have a severe prognosis above all when presenting with high alfafetoprotein levels. We report the results of a combined chemo- and radiotherapy approach in 28 patients affected by this disease with craniospinal irradiation and a boost tailored on the response to pre-radiant chemotherapy. Metastatic patients and high-risk disease are discussed as well. The 5 years overall survival and event-free survival were both 81% while at 10 years they were 81% and 76% respectively. Our series, even if small, concerns nongerminomatous germ cell tumors only (whereas in some papers they are mixed with pure germinomas), furthermore our patients had a very long follow-up (over 11 years) with encouraging survival data for localized and metastatic disease. Improving survival while trying to contain/avoid the long-term sequelae of chemotherapy and radiotherapy are the main goals of future studies. Introduction: Due to the rarity of nongerminomatous germ cell tumors (NGGCT) with non-standard treatment as yet, we report retrospectively our 30 year experience with chemotherapy followed by craniospinal irradiation (CSI), plus a boost of whole ventricular irradiation (WVI)/tumor bed (TB), tailored to pre-radiation chemotherapy response. Methods: Between 1988 and 2016, 28 patients received four cycles of PEB (cisplatin/etoposide/bleomycin), then CSI, and two further PEB cycles. Between 1988 and1994, CSI was 25.5 Gy for patients in complete remission (CR), 30 Gy if in partial remission (PR) or metastatic, with a boost to TB up to 45-54 Gy. In the period of 1995-2010, the boost included WVI and any extra-ventricular tumor sites up to 45 Gy. After 2010, CSI was reduced to 25.5 Gy for all non-metastatic patients, and a boost was given only to TB up to 40.5/45.5 Gy, depending on patients' CR/PR status. After 2003, patients with alfafetoprotein (alpha FP) > 1000 ng/mL received intensified treatment, also including autologous stem cell transplantation. Results: Among 28 patients (23 males; median age 12 years, 6 metastatic), 25 responded to PEB, and three progressed (PD) after one to four cycles; 26 received radiotherapy obtaining 13 CR, 7 PR and 5 stable disease (SD), 1 PD; 6 (21%) died (5 for disease, 1 for pneumonia while in CR). Five-year overall survival (OS) and progression-free survival (PFS) were both 81%; 10 year OS and PFS 81% and 76%, respectively (median follow-up 11 years). Conclusions: Survival for children with NGGCT, independently from disease extent, was encouraging. Further studies should elucidate which patients could benefit from reduced volume and dose irradiation

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Evolving of therapeutic strategies for CNS-PNET

Background: A protocol for the intensive treatment of non-cerebellar PNET (CNS-PNET) combining chemotherapy and radiotherapy was launched in 2000. Efforts were subsequently made to improve the prognosis and to de-escalate the treatment for selected patient groups. Procedure: Twenty-eight consecutive patients were enrolled for a high-dose drug schedule (methotrexate, etoposide, cyclophosphamide, and carboplatin±vincristine), followed by hyperfractionated accelerated CSI (HART-CSI) at total doses of 31-39Gy, depending on the patient's age, with two high-dose thiotepa courses following CSI. After the first 15 patients had been treated, craniospinal irradiation (CSI) was replaced with focal radiotherapy (RT) for selected cases (non-metastatic and not progressing during induction chemotherapy). Eight of the 28 children received the same chemotherapy but conventionally fractionated focal RT at 54Gy. Results: The 5-year progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) rates were 62%, 53%, and 52%, respectively, for the whole series, and 70%, 70%, and 87% for the eight focally irradiated children. Residual disease and metastases were not prognostically significant. In children with residual disease, response to RT was significant (5-year PFS 59% vs. 20%, P=0.01), while the total dose of CSI was not. There were three treatment-related toxic events. Relapses were local in seven cases (including two of the eight focally irradiated patients), and both local and disseminated in 2. Conclusions: This intensive schedule enabled treatment stratification for the purposes of radiation, thereby sparing some children full-dose CSI. Local control is the main goal of treatment for CNS-PNET. Pediatr Blood Cancer 2013;60:2031-2035. © 2013 Wiley Periodicals, Inc

Retrospective study of late radiation-induced damages after focal radiotherapy for childhood brain tumors.

PurposeTo study a robust and reproducible procedure to investigate a relation between focal brain radiotherapy (RT) low doses, neurocognitive impairment and late White Matter and Gray Matter alterations, as shown by Diffusion Tensor Imaging (DTI), in children.Methods and materialsForty-five patients (23 males and 22 females, median age at RT 6.2 years, median age at evaluations 11.1 years) who had received focal RT for brain tumors were recruited for DTI exams and neurocognitive tests. Patients' brains were parceled in 116 regions of interest (ROIs) using an available segmented atlas. After the development of an ad hoc, home-made, multimodal and highly deformable registration framework, we collected mean RT doses and DTI metrics values for each ROI. The pattern of association between cognitive scores or domains and dose or DTI values was assessed in each ROI through both considering and excluding ROIs with mean doses higher than 75% of the prescription. Subsequently, a preliminary threshold value of dose discriminating patients with and without neurocognitive impairment was selected for the most relevant associations.ResultsThe workflow allowed us to identify 10 ROIs where RT dose and DTI metrics were significantly associated with cognitive tests results (pConclusionThis analysis, despite being conducted on a retrospective cohort of children, shows that the identification of critical brain structures and respective radiation dose thresholds is achievable by combining, with appropriate methodological tools, the large amount of data arising from different sources. This supported the design of a prospective study to gain stronger evidence

Optimizing reirradiation for relapsed medulloblastoma: identifying the ideal patient and tumor profiles

Background: First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not standardized. We report here the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups. Methods: Patient's staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported. Results: 25 patients were included, with a median age of 11.4 years; 8 had metastases. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors(six TP53 mutated,one + MYC,one + NMYC amplification), 11 non-WNT/non-SHH (two with MYC/MYCN amplification).Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in nine, distant-DR in 14, LR + DR in two) was 26 months. Fourteen patients were re-operated, in five cases excising single DR-sites, thereafter three received CT, two after re-RT; out of 11 patients not re-operated, four had re-RT as first treatment and seven after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, craniospinal-CSI in five. Median post-relapse-PFS/after re-RT was 16.7/8.2 months, while overall survival-OS was 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. PD after re-RT was however significantly more frequent in SHH (with a suggestive association with TP53 mutation, p = 0.050). We did not observe any influence of biological subgroups on PFS from recurrence while SHH showed apparently worse OS compared to non-WNT/non-SHH group. Conclusions: Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to the SHH-subgroup