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Primary lung carcinoma is an exceptionally rare childhood tumour, as per definition of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT), with an incidence of 0.1-0.2/1,000,000 per year. Little is known about the clinical characteristics of children with primary lung carcinoma, a gap which this joint analysis of the EXPeRT group aimed to fill.We performed a retrospective case series of children (aged 0-18 years) with primary lung carcinoma, as collected through the EXPeRT databases between 2000 and 2021. We recorded relevant clinical characteristics including treatment and outcome.Thirty-eight patients were identified with a median age of 12.8 years at diagnosis (range: 0-17). Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 20), followed by adenocarcinoma (n = 12), squamous cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and small-cell lung cancer (n = 1). Patients with MEC presented rarely with lymph node metastases (2/20 cases). Overall, 19/20 patients achieved long-lasting remission by surgical resection only. Patients with other histologies often presented in advanced stages (14/18 TNM stage IV). With multimodal treatment, 3-year overall survival was 52% ± 13%. While all patients with squamous cell carcinoma died, the 12 patients with adenocarcinoma had a 3-year overall survival of 64% ± 15%.Primary lung carcinomas rarely occur in children. While the outcome of children with MEC is favourable with surgery alone, patients with other histotypes have a poor prognosis, despite aggressive treatment, highlighting the need to develop new strategies for these children, such as mutation-guided treatment.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.Significance:The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659

Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Very rare pediatric tumors (VRTs) pose a challenge for treating physicians as little is known about the best diagnostic assessment and therapeutic decision-making in these malignancies. A large proportion of these cancers occur in adolescence. Therefore, the established structures of pediatric oncology including cancer registration may partly be circumvented. This may lead to an underregistration in clinical cancer registries of yet unclear extent. The aim of this study is to increase the knowledge on the occurrence of VRTs in pediatric patients in Germany. Pseudonymized data of cases recorded in the Bavarian Cancer Registry (BCR) between 2002 and 2014 were retrieved. VRTs according to the definition of the European Cooperative Study Group for Pediatric Rare Tumors were identified using the ICD and ICD-O classification. The numbers of registered patients were compared to those reported to the German Childhood Cancer Registry (GCCR). 6.3% (n = 290) of all malignancies (n = 4615) in the age below 18 years were classified as VRTs. Median age at diagnosis was 15 years (range 0–17 years). The most common tumor types included malignant melanoma, skin carcinoma, and gonadal tumors. During the same period, 49 pediatric patients from Bavaria with matchable VRTs were reported to the GCCR, accounting for 17% of cases reported to the BCR.Conclusions: The frequency of VRTs in Germany is underestimated in the national GCCR. With this study, we present population-based data on the incidence of VRTs in Germany for the first time. In order to gain additional knowledge about these malignancies, registration of VRTs must be improved through enhanced data exchange between the GCCR, the public cancer registries, and the clinical Registry for Rare Pediatric Tumors (STEP). What is Known:• Rare pediatric tumors pose a challenge for treating physicians as limited knowledge is available on these malignancies for diagnostic and therapeutic decision-making.• Little is known about the frequency of these rare tumors in pediatric patients. What is New:• The frequency of rare pediatric tumors in Germany is distinctly underestimated in the German Childhood Cancer Registry.• We present population-based data on the incidence of these rare pediatric cancers for the first time.

PURPOSE Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB. METHODS Patients age 1-21 years underwent T-/B-cell–depleted haplo-SCT followed by DB and scIL2. The primary end point ‘success of treatment’ encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD. RESULTS Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1−6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; P = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred. CONCLUSION DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.

Nuclear protein of the testis (NUT) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology.The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external "experts." No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, "strength" of recommendations were categorized by grading (grade A to E).Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology (NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B).This project leads to a consensus strategy based on international experience with this very rare disease.

(1) Background: Gastric carcinoma is an exceptionally rare tumor in childhood. Little is known about the etiology, epidemiology, and clinical features of pediatric gastric carcinomas. This analysis aimed to fill this gap by increasing knowledge about the occurrence of gastric carcinoma in childhood. (2) Material and methods: Data from gastric carcinoma cases diagnosed between 2000 and 2017/2018 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) and the German Center for Cancer Registry Data. Data from patients

Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour-normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families.We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data.We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance (ATM, BRCA2, CHEK2 and BRCA1). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53, ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases.Tumour-normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour-normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families.

Primary lung malignancies are a heterogeneous group of cancers that occur very rarely in childhood. Due to limited knowledge of their epidemiologic and clinical features, these tumors present a challenge to the treating physicians. This study aimed to increase the knowledge about the occurrence of primary lung malignancies in childhood in Germany.Pseudonymized data of cases recorded at the German Center for Cancer Registry Data (ZfKD) between 1990 and 2017 were retrieved. Primary lung malignancies were identified using the ICD- and ICD-O classification. Numbers were compared to those reported to the German Childhood Cancer Registry (GCCR). Crude incidence rates were calculated using the ZfKD database.A total of 168 patients diagnosed with primary lung malignancies in the age below 19 years were identified from the ZfKD. The median age at diagnosis was 13 years. The most common tumor entities were lung carcinoids (n = 49), lung carcinoma (n = 36), and pleuropulmonary blastoma (n = 14). An unexpected accumulation of lung cancer cases was noted in the first year of life without a clearly specified histopathological diagnosis. A substantial discrepancy in the numbers of primary lung malignancies between ZfKD and GCCR was found.We present population-based data on the occurrence of primary childhood lung malignancies in Germany, which were more frequent than previously anticipated but likely remained underreported. For better understanding and optimal treatment of these entities, cancer registration needs to be improved through mandatory reporting to the GCCR and regular data sharing between GCCR, population-based and clinical cancer registries.

Im Vergleich zu den Krebserkrankungen bei Erwachsenen sind alle kinderonkologischen Erkrankungen selten. Dennoch wurden fur die klassischen kinderonkologischen Tumorentitaten im Rahmen kooperativer Therapieoptimierungsstudien erfolgreiche Therapiekonzepte entwickelt und die Prognose erheblich verbessert. Die besonders seltenen Tumorerkrankungen stellen die Behandler vor besondere Herausforderungen; sie sind als Gruppe sehr heterogen, es gibt weder Referenzinstitutionen, noch liegen validierte Therapiestrategien vor. Wegen ihrer geringen Inzidenz und der Unmoglichkeit, klinische Studien durchzufuhren, stellen besonders seltene Tumorerkrankungen klassische „orphan diseases“ dar. Um diesem Bedarf zu entgegnen und die Behandlungsqualitat zu verbessern, sind nationale Arbeitsgruppen fur seltene Tumoren gegrundet worden. In Deutschland wurde das Register Seltene Tumorerkrankungen in der Padiatrie (STEP) implementiert, in dem kinderonkologische Patienten mit besonders seltenen Tumoren erfasst werden. Das STEP-Register bietet eine klinische Beratung an und eroffnet den Zugang zu Referenzinstitutionen der Kinderonkologie. Bis Ende 2018 wurden die Erkrankungen von mehr als 600 Patienten im STEP-Register bei einer aktuellen jahrlichen Erfassungsrate von fast 100 Patienten dokumentiert. Durch die zunehmende internationale Vernetzung sind fur einige Erkrankungen Therapieempfehlungen abgestimmt worden, die in diesem Artikel fur einige Entitaten skizziert werden. Als Gesamtgruppe sind die seltenen Tumoren vergleichbar haufig wie andere klassische kinderonkologische Tumoren. Die Patienten profitieren von den zentralen Beratungsstrukturen und dem Zugang zu abgestimmten Therapieempfehlungen. Zukunftige wissenschaftliche Schwerpunkte mussen in der Erforschung einer moglichen genetischen Tumorpradisposition bei seltenen Tumoren und der Implementierung von zielgerichteten Therapien bei prognostisch ungunstigen Tumoren liegen.

Little is known about risks associated with germlineTo study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germlineOverall, 117/172 (68%)Germline

BACKGROUND Eye-preserving therapy in retinoblastoma comprises systemic chemotherapy, but studies analyzing the efficacy of different chemotherapy regimens are scarce. METHODS The efficacy and side effects of two different eye-preserving chemotherapy regimens containing either vincristine, etoposide, and carboplatin (VEC) or cyclophosphamide, vincristine, etoposide, and carboplatin (CyVEC) were compared in a prospective non-interventional observational study including children diagnosed with retinoblastoma between 2013 and 2019 in Germany and Austria. Event-free eye survival (EFES) and overall eye survival (OES) of all 164 eyes treated with both regimens and risk factors were investigated. RESULTS The EFES after VEC (2-year EFES 72.3%) was higher than after CyVEC (2-year EFES 50.4%) (plogrank

BackgroundLittle is known about risks associated with germlineSUFUpathogenic variants (PVs) known as a cancer predisposition syndrome.MethodsTo study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germlineSUFUPV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives withSUFUPV (89 patients) using the Nelson-Aalen estimator.ResultsOverall, 117/172 (68%)SUFUPV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entireSUFUgene and inherited in 73% of cases in which inheritance could be evaluated.ConclusionGermlineSUFUPV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.

Background: Adrenocortical tumors (ACTs) encompassing the adrenocortical adenoma (ACA), carcinoma (ACC), and tumors of undetermined malignant potential (ACx) are rare endocrine neoplasms with a poor prognosis. We report on pediatric ACT patients registered with the Malignant Endocrine Tumor studies and explore the EXPeRT recommendations for management. Patients: Data from the ACT patients (

Background Very rare tumors (VRT) in children and adolescents have such a low incidence that until recently, they have not been integrated into the clinical and scientific network of pediatric oncology. Data is very limited and consistent treatment strategies are missing. Thus, VRTs are classic orphan diseases. To counteract this problem, the Arbeitsgemeinschaft für Seltene Tumorerkrankungen in der Pädiatrie (STEP) was founded. Here we report on patient recruitment during the first 10 years. Patients Patients aged up to 18 years and not included in any other clinical trial or GPOH registry were included in this analysis. Methods Data was collected from 2008 to 2018 by means of a standardized form. The recorded diagnoses were descriptively analyzed focusing on histology, localization, and year of report. Results A total of 623 patients with VRTs were registered. During 2008-2014, the annual number of registrations was around 40 and is around 90 since 2015. Most frequent diagnoses included tumors of the skin (n=150), tumors of the gastrointestinal tract (n=102), tumors of the gonads (n=77), the ENT region (n=68), and miscellaneous tumors (n=107). Discussion With the establishment of central structures for clinical consultation and documentation of VRTs, the number of registrations increased. Comprehensively, VRTs are as common as other classic pediatric oncology tumors, but extremely heterogeneous in terms of localization, histology, and prognosis. By a centralized and complete registration and analysis of VRTs, also in collaboration with international partners, it is possible to develop treatment strategies and thus greatly increase treatment quality.Hintergrund Seltene Tumoren (VRT) im Kindes- und Jugendalter haben eine so niedrige Inzidenz, dass sie bisher nicht in das klinische und wissenschaftliche Netzwerk der Kinderonko-logie integriert waren. Die Datenlage ist sehr begrenzt und einheitliche Behandlungsstrategien fehlen. Somit sind VRT klassische Orphan Diseases. Um dieser Problematik entgegen zu wirken, wurde die Arbeitsgemeinschaft für Seltene Tumorerkrankungen in der Pädiatrie (STEP) gegründet. Hier berichten wir über die Patientenrekrutierung während der ersten 10 Jahre.Patienten Einschlusskriterien waren ein Patientenalter bis zum 18. Lebensjahr und eine Nichterfassung in anderen Therapieoptimierungsstudien oder Registern der GPOH. Methoden Die Erfassung erfolgte von 2008 bis 2018 anhand eines standardisierten Dokumentationsbogens. Die Meldungen wurden deskriptiv bezüglich Histologie, Lokalisation und Meldejahr ausgewertet. Ergebnisse Es wurden insgesamt 623 Patienten mit VRT registriert. Zwischen 2008-2014 schwankte die jährliche Meldezahl um 40, seit 2015 liegt sie bei ca. 90. Am häufigsten wurden Tumoren der Haut (n=150), Tumoren des Gastrointestinaltraktes (n=102), der Gonaden (n=77), des HNO-Bereichs (n=68) sowie verschiedene Tumoren (n=107) gemeldet. Diskussion Durch zentrale Strukturen für die klini-sche Beratung und Dokumentation von VRT steigt die Zahl erfasster seltener Tumoren. Insgesamt sind VRT vergleichbar häufig wie andere klassische kinderonkologische Tumoren, hinsichtlich Lokalisation, Histologie und Prognose aber extrem heterogen. Durch die zentrale und vollständige Erfassung und Analyse von VRT, gemeinsam mit internationalen Partnern, kann es gelingen, Behandlungsstrategien zu entwickeln und damit die Behandlungsqualität erheblich zu verbessern.

Histological classification of atypical spitzoid tumours (ASTs) is unreliable, and categorisation of these lesions into benign and malignant is poorly reproducible. Here, we classified ASTs based on histology and chromosomal aberrations and explored the prognostic significance of genomic aberrations in a prospective cohort with a long-term follow-up.Histologically equivocal ASTs from 76 patients were analysed by array comparative genomic hybridisation (aCGH). Tumours were histologically assessed by a panel of dermatopathologist before and after aCGH and classified as benign, ambiguous or malignant. Chromosomal aberrations were correlated with an outcome.Chromosomal aberrations were detected in 45 (59%) of 76 ASTs (median age: 16 years, range: 0-74; median follow-up: 90 months, range: 13-153). The initial histological diagnosis was changed upon presentation of aCGH results in 36 of 76 cases (47%). The final diagnostic interpretation classified 61% of the lesions as benign, 18% as ambiguous and 21% as malignant. Positive sentinel lymph node biopsies (6+/29) occurred at similar rates in all diagnostic groups (P = 0.83) and were not associated with an unfavourable outcome. Two patients had local recurrences, but none of the patients developed metastasis beyond the sentinel lymph node.All ASTs had an excellent prognosis, even in cases with worrisome morphology and chromosomal aberrations. With no distant metastasis or death in long-term follow-up of 76 patients, no correlation between chromosomal aberrations and prognosis was possible. However, it seems likely that in larger cohorts, metastases would arise in cases with complex aberrations and these patients should undergo clinical follow-up.

More comprehensive genetic diagnostics in children with cancer, enabled by modern sequencing techniques have shown that germline variants causing genetic cancer predisposition can be detected in an increasing proportion of patients. Many individuals carrying a predisposing germline variant exhibit distinct characteristics regarding family history, tumor type, age at manifestation and therapy toxicity. However, comprehensive phenotypic characterization and automated electronic documentation in searchable databases are essential to fully integrate genetic and clinical features. Therefore, we have developed a structured Paediatric Cancer Predisposition Tool – PERCEPT to facilitate more accurate documentation of even subtle clinical features of patients with or with suspected germline cancer predisposition or suspected germline cancer predisposition. It improves the comparability in multicentre studies and the automated recognition of phenotypic patterns in international searchable databases.

Although all tumours are rare in childhood, there are some particularly rare paediatric cancers which have not benefited from advances made by the international paediatric oncology network. To establish a shared definition and produce a list of these entities, the European Union Joint Action on Rare Cancers (JARC) promoted a consensus effort. The definition was based on the incidence rates estimated using the information network on rare cancers (RARECAREnet) database, pooling data from 94 population-based cancer registries and 27 countries. The RARECAREnet list of cancers was used to estimate the incidence rates. This list groups cancers by combining the International Classification of Diseases for Oncology, third edition, morphology and topography codes. According to the consensus, very rare paediatric cancers were identified as those with an annual incidence 2/1000000 (i.e. thyroid and testicular cancers and skin melanoma), but the consensus experts considered them as ‘very rare’ according to their clinical needs (e.g. shortage of knowledge and clinical expertise as the other rare paediatric cancers). The JARC consensus produced a definition and a list of very rare paediatric cancers which may represent a starting point for prioritising research on these tumours, based on data and patients’ clinical needs.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare tumor disease, which affects children and adolescents without history of primary liver disease. Beside surgical resection established treatment options are lacking for FL-HCC. Recently, the DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in 100% of FL-HCC patients. Here, we investigated the role of the DNAJB1-PRKACA fusion protein as a source for immunogenic neoepitopes and showed first immunotherapeutic application of these antigens in a FL-HCC patient.HLA class I- and class II-presented neoantigens derived from the DNAJB1-PRKACA fusion protein were predicted in silico using NetMHCpan 4.1 and SYFPEITHI 1.0, or NetMHCIIpan 4.0, respectively. With this workflow nine binding cores of nine amino acid length for a total of 1290 different HLA class II alleles, as well as 13 HLA class I ligands for the 20 most frequent HLA class I allotypes (European population, iedb.org) were identified. Cellular processing and HLA presentation of DNAJB1-PRKACA-derived peptides was proven by liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) of DNAJB1-PRKACA-transduced HCC cell lines. Immunogenicity of DNAJB1-PRKACA-derived peptides was assessed for the HLA class II peptide (PII-1) and the HLA-A*24 peptide (PA*24) by in vitro priming experiments which showed an induction of multifunctional peptide-specific CD4+ and CD8+ T cells, respectively, with expression of CD107a, IFNγ, and TNF upon peptide-pulsing. Furthermore, PA*24-specific T cells showed antigen-specific lysis of autologous peptide-loaded target cells and single-cell next-generation sequencing (10x Genomics) of PA*24-specific CD8+ T cells further enabled the identification of DNAJB1-PRKACA-reactive T cell receptors. Based on these preclinical data we applied a peptide vaccine, consisting of three HLA class I ligands (PA*02, PB*44, and PC*05) and PII-1 spanning the DNAJB1-PRKACA fusion region, to a 15-year old patient with histologically confirmed FL-HCC, who experienced multiple tumor relapses after early liver transplant due to unresectable FL-HCC not responsive to chemotherapy. After two vaccinations in vivo induction of multifunctional CD4+ T cells targeting PII-1 and PB*44 was observed by IFNγ ELISPOT. Single-cell RNA sequencing of vaccine-induced CD4+ T cells revealed distinct gene expression clusters of T cell activation and high TCR clonality. DNAJB1-PRKACA-specific T cells persisted in peripheral blood and were accompanied by relapse free survival of the patient until now, more than one year post vaccination. These findings identified the DNAJB1-PRKACA fusion transcript as novel prime source for broadly applicable neoepitopes and corresponding TCRs and provide first evidence for their application in cancer immunotherapy of FL-HCC. Citation Format: Jens Bauer, Natalie Köhler, Yacine Maringer, Philip Bucher, Tatjana Bilich, Melissa Zwick, Severin Dicks, Annika Nelde, Marissa Dubbelaar, Jonas Scheid, Marcel Wacker, Jonas J. Heitmann, Sarah Schroeder, Jonas Rieth, Monika Denk, Marion Richter, Reinhild Klein, Irina Bonzheim, Julia Luibrand, Ursula Holzer, Martin Ebinger, Ines B. Brecht, Michael Bitzer, Melanie Boerries, Helmut R. Salih, Hans-Georg Rammensee, Stephan Hailfinger, Juliane S. Walz. The oncogenic fusion protein DNAJB1-PRKACA can be actively targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2008.

Simple Summary Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare neoplasm that most commonly develops within maxilla in infants. It usually has a benign clinical course and is treated with only surgery. However, patients with large, inoperable, metastatic or multiply recurring MNTI may require systemic treatment. The role of pre- and post-surgery chemotherapy (CHT) in the management of MNTI is unclear. Here, we have presented the disease courses and outcomes of four infants treated with multidrug CHT due to inoperable/recurrent MNTI. Additionally, a systematic literature review was performed which revealed 38 similar cases in the last 42 years. Most children with primarily inoperable MNTI responded to CHT, which allowed physicians to perform complete, non-mutilating delayed surgery. However, it is still uncertain whether CHT administered after incomplete resection of MNTI prevents recurrence. This study aimed to contribute to the establishment of standards of management in patients with inoperable, metastatic or persistently recurring MNTIs, which are currently lacking. Abstract Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare pediatric neoplasm of neural crest origin. In most cases, it develops in infants as a localized tumor of the maxilla, and surgery is usually curative. In less than 10% of patients with inoperable, metastatic or persistently recurring MNTI, chemotherapy (CHT) may be considered; however, its role is still unclear. The aim of our study was to assess the efficacy of CHT in children with large, inoperable, metastatic and/or recurrent MNTI. Four such infants, treated with CHT in Polish and German centers of pediatric oncology, were presented. Additionally, a systematic literature search of the PubMed/MEDLINE, Scopus and Web of Science databases was performed, yielding 38 similar cases within the last 42 years. Neoadjuvant CHT, based mainly on the protocols for neuroblastoma, was often effective, allowing for complete delayed surgery in most cases. However, the role of adjuvant CHT in preventing recurrences after incomplete resection of MNTI remains unclear. Disseminated inoperable MNTI was almost universally associated with poor response to CHT and unfavorable outcome. Further investigations to elaborate standards of management in patients with inoperable, metastatic or persistently recurring MNTIs are necessary to improve outcomes.

Chemotherapy; Childhood cancer; Radiotherapy Quimioterapia; Cáncer infantil; Radioterapia Quimioteràpia; Càncer infantil; Radioteràpia Introduction Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Results Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers. Open access funding enabled and organized by Projekt DEAL.

Thymic tumors are epithelial tumors arising from the anterior mediastinum and constitute 0.2-1.5% of all adult malignancies but are exceptional in pediatric population. Thymic epithelial tumors (TETs) encompass a variety of histologic subtypes associated with different clinical outcomes. Due to its rarity in children, TETs' management requires a multidisciplinary approach. However, prognosis remains still poor, especially among patients with thymic carcinoma. This study presents the internationally recognized recommendations for the diagnosis and treatment of thymic tumors in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU-funded project Paediatric Rare Tumours Network - European Registry (PARTNER).

Pleuropulmonary blastoma (PPB) is a rare cancer occurring mainly during early childhood and often associated with germline DICER1 mutations. It is classified by the macroscopic appearance into three interrelated clinico-pathologic entities on a developmental continuum. Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy. Optimal modalities of neo- or adjuvant treatments can be challenging taking into account potential long-term toxicities in this young population. This paper presents the recommendations for diagnosis and treatment of children and adolescents with PPB elaborated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the European Union-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).

Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm affecting typically young children. Signs related to advanced upper-abdominal tumor accompanied by elevated serum α-fetoprotein levels in a young child suggest PBL, however histopathological examination is required for diagnosis. The mainstay of treatment is a complete surgical resection. Inoperable and/or metastatic PBL may become amenable to complete, delayed surgery after neo-adjuvant chemotherapy. This manuscript presents the internationally consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER (Paediatric Rare Tumors Network – European Registry) project.

As part of the European Union-funded project designated PARTN-ER, the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is continuously developing consensus recommendations in order to harmonize standard care for very rare solid tumors of children and adolescents. This paper presents the internationally recognized recommendations for the diagnosis and treatment of sex cord stromal tumors (SCST). The clinical approach to sex cord stromal tumors of the testis (TSCST) and ovary (OSCST) depends on histological differentiation and tumor stage. Virtually all TSCSTs present as localized non-metastatic tumors, with excellent prognosis after complete resection. In contrast, the prognosis of OSCSTs may be adversely affected by tumor spillage during surgery or presence of metastases. In these cases, cisplatin-based chemotherapy is recommended. Of note, some SCSTs may develop in the context of tumor predisposition syndromes e.g. DICER-1, so that specific follow-up is indicated. SCSTs should be diagnosed and treated according to standardized recommendations that include reference pathology, genetic testing for tumor predisposition syndromes in selected cases, and stratified adjuvant chemotherapy in patients with unfavorable risk profile. To ensure high quality of diagnosis and therapy, patients should be enrolled into prospective registries.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. Significance: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes. See related commentary by Eggermont et al., p. 2677 . This article is highlighted in the In This Issue feature, p. 2659

The PARTNER project (Paediatric Rare Tumours Network - European Registry) was launched in 2016. PARTNER aims to create a European Registry dedicated to children and adolescents with very rare tumors (VRT). It links existing national registries and provides a registry for those countries in which a VRT registry has not yet been created. This consortium is composed of the various national cooperative groups and their respective member institutions. The strategic value of this project is based on the Europe-wide data collection concerning the treatment of VRTs. These data are provided to experts and constitute the basis for new clinical practice guidelines for use by ERN (European Reference Network) and non-ERN institutions. The proposed tasks and milestones will increase collaboration in the field of pediatric oncology among member states and will also facilitate the inclusion of low health expenditure average rate (LHEAR) countries in this process. In addition, this project creates a platform for VRTs that may represent a model on how to elaborate a comprehensive approach (case registration, international case consultation and treatment recommendations, and website to provide information for parents/patients) for rare diseases.

As part of the European Union-funded project designated Paediatric Rare Tumours Network - European Registry (PARTNER), the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is continuously developing consensus recommendations in order to harmonize standard care for very rare solid tumors of children and adolescents. This paper presents the internationally recognized recommendations for the diagnosis and treatment of sex cord stromal tumors (SCST). The clinical approach to sex cord stromal tumors of the testis (TSCST) and ovary (OSCST) depends on histological differentiation and tumor stage. Virtually all TSCSTs present as localized nonmetastatic tumors, with excellent prognosis after complete resection. In contrast, the prognosis of OSCSTs may be adversely affected by tumor spillage during surgery or presence of metastases. In these cases, cisplatin-based chemotherapy is recommended. Of note, some SCSTs may develop in the context of tumor predisposition syndromes, for example, DICER-1, so that specific follow-up is indicated. SCSTs should be diagnosed and treated according to standardized recommendations that include reference pathology, genetic testing for tumor predisposition syndromes in selected cases, and stratified adjuvant chemotherapy in patients with unfavorable risk profile. To ensure high quality of diagnosis and therapy, patients should be enrolled into prospective registries.

Primary lung carcinomas are very rare paediatric tumours with an incidence of 2/1.000.000 per year. They are clinically and histologically heterogeneous, and there are no therapeutic guidelines for this age group. Therefore, they represent a challenge for treating physicians. This analysis was performed to expand knowledge on characteristics, treatment and prognosis of primary lung carcinoma in paediatric patients.Between 2009 and 2019, twelve children and adolescents with lung carcinoma were identified in the prospective German registry for rare paediatric tumours (STEP). Data were analysed for histopathological entities, symptoms, diagnostics, therapy, clinical course and outcome.Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 7), followed by adenocarcinoma (n = 2), squamous cell carcinoma (SCC; n = 2) and adenosquamous carcinoma (n = 1). Patients presented with non-specific symptoms and often, they were initially mistreated for airway infections. Patients with MEC showed no metastases and were successfully treated with complete resection. Patients with adenocarcinoma and SCC were older than 16 years of age at diagnosis. While patients with SCC presented with distant metastases and died within one year after diagnosis, those with adenocarcinoma and adenosquamous carcinoma achieved complete remission after multimodal treatment.Presenting symptoms of lung carcinomas are unspecific and therefore, diagnostic evaluation and treatment are difficult. In the absence of carcinogen exposure, etiology seems to differ from adult lung carcinoma. Children diagnosed with MEC face a favourable outcome. In contrast, patients with prognostically unfavourable adenocarcinoma and SCC might benefit from molecular profiling and targeted therapies. International collaboration for the establishment of treatment protocols adjusted for distinct features of primary lung carcinoma in childhood is essential.

Colorectal cancer is a very rare disease in children and associated with a high frequency of tumor preposition syndromes. Multimodal treatment resulted in considerable improvement of survival although related with late and long-term risk of toxicity. Oxaliplatin-induced neuropathy is frequently observed and may take years to completely resolve, particularly in the treatment of children. Molecular mechanisms are described as well as potential protective measures. Bowel dysfunction depends on the surgical procedure with long-term data available particularly on ostomy. Late toxicities of radiotherapy need to be considered due to substantial improvement of outcome thru neoadjuvant chemoradiotherapy protocols for the treatment of rectal cancer. All of the above treatment modalities can affect quality of life in colorectal cancer survivors with mental, physical as well as social aspects being addressed in detail. Late effects related to tumor predisposition syndromes include second malignancies thus underlining the necessity of enrolment in surveillance programs. Different screening procedures depend on the underlying genetic disposition and are further described in detail.