Prognostic utility and characteristics of MIB-1 labeling index as a proliferative activity marker in childhood low-grade glioma: a retrospective observational study.

PURPOSE: The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity (TGV), aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in PLGG. METHODS: MIB-1 LI of a cohort of 172 nonependymal PLGGs were comprehensively characterized. Correlation to TGV, assessed by sequential MRI-based three-dimensional volumetry, and PFS was analyzed. RESULTS: Mean MIB-1 LI accounted for 2.7% (range: < 1-10) and showed a significant decrease to 1.5% at secondary surgery (p = .0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R2 = .55, p < .0001), while correlation to TGV remarkably decreased after incomplete resection (R2 = .08, p = .013). Log-rank test showed no association of MIB-1 LI and 5-year PFS after incomplete (MIB-1 LI > 1 vs ≤ 1%: 48 vs 46%, p = .73) and gross-total resection (MIB-1 LI > 1 vs ≤ 1%: 89 vs 95%, p = .75). CONCLUSION: These data confirm a correlation of MIB-1 LI and radiologically detectable TGV in PLGG for the first time. Compared with preoperative TGV, a crucially decreasing correlation of MIB-1 LI and TGV after surgery may result in limited prognostic capability of MIB-1 LI in PLGG.

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3.

BACKGROUND: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. METHODS: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. RESULTS: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. CONCLUSION: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

Redo nephron-sparing surgery in stage V pediatric renal tumors - A report from the SIOP/GPOH study group for renal tumors.

PURPOSE: Nephron-sparing Surgery (NSS) is the surgical treatment of choice in children with bilateral renal tumors or in syndromatic patients. With an increasing role of this surgical approach, there is also an increased number of tumor relapses after NSS. Aim of this study was to evaluate a second ("Redo-") NSS in children with relapsed renal tumors. MATERIALS AND METHODS: We retrospectively analysed patients undergoing Redo-NSS for relapsed kidney tumors between 2009 and 2021 at our institution, which represents a national reference center of the SIOP/GPOH renal tumor study group. RESULTS: Nine patients (5 girls, 4 boys) underwent Redo-NSS with resection of 15 lesions. Mean age at surgery was 58 months (12-137), mean operative time for Redo-NSS was 195 min (137-260). R0 resection status was achieved in all children. Two patients had second relapses, one of them was resected via NSS, the other child underwent tumor nephrectomy. Two patients with anaplastic relapses died from combined second relapses. Thus, 7/9 patients are alive without evidence of disease, an impaired renal function was observed in one child. Mean follow-up after Redo-NSS was 35 months (6-49). CONCLUSIONS: In renal tumor relapses, Redo-NSS can be performed with satisfactory oncological and functional results. Occurrence of diffuse anaplasia should possibly refrain from this approach. Further evaluation in international multicenter analyses are necessary for a definitive determination of Redo-NSS.

Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse.

Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1-21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m2/day × 5 days for 5-6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse.

Th1 cytokines in pediatric acute lymphoblastic leukemia.

Immune milieus play an important role in various types of cancer. The present study focuses on the effect of Th1 cytokines on pediatric acute lymphoblastic leukemia (ALL). The reaction of ALL cell lines and patient-derived xenografts (PDX) to the most important Th1 cytokines TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) is analyzed and correlated with the respective cytokine receptors and the intracellular signaling molecules. ALL cell lines and ALL PDX display a great heterogeneity in cell death after incubation with TNF-α and IFN-γ. Several samples show a dose-dependent and additive induction of cell death by both cytokines; others do not react at all or even display an increased viability. Apoptosis is the main type of cell death induced by Th1 cytokines in ALL cells. Over all leukemia cells analyzed, IFN-γ receptor (IFNGR) shows a higher expression than both TNF-receptors, resulting in higher phosphorylation of STAT1 (signal transducer and activator of transcription) compared to phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) in the TNF pathway. The activation of STAT1 correlates with the amount of cell death after stimulation with Th1 cytokines. TNF-α and IFN-γ lead to heterogeneous reactions in ALL cell lines and ALL PDX but are able to induce cell death by apoptosis in the majority of ALL blasts. The correlation of a high expression of IFNGR and following activation of STAT1 with cell death indicates an important role for IFN-γ signaling in this setting.

Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients.

The prevalence of pathogenic and likely pathogenic (P/LP) variants in genes associated with cancer predisposition syndromes (CPS) is estimated to be 8-18% for paediatric cancer patients. In more than half of the carriers, the family history is unsuspicious for CPS. Therefore, broad genetic testing could identify germline predisposition in additional children with cancer resulting in important implications for themselves and their families. We thus evaluated clinical trio genome sequencing (TGS) in a cohort of 72 paediatric patients with solid cancers other than retinoblastoma or CNS-tumours. The most prevalent cancer types were sarcoma (n = 26), neuroblastoma (n = 15), and nephroblastoma (n = 10). Overall, P/LP variants in CPS genes were identified in 18.1% of patients (13/72) and P/LP variants in autosomal-dominant CPS genes in 9.7% (7/72). Genetic evaluation would have been recommended for the majority of patients with P/LP variants according to the Jongmans criteria. Four patients (5.6%, 4/72) carried P/LP variants in autosomal-dominant genes known to be associated with their tumour type. With the immediate information on variant inheritance, TGS facilitated the identification of a de novo P/LP in NF1, a gonadosomatic mosaic in WT1 and two pathogenic variants in one patient (DICER1 and PALB2). TGS allows a more detailed characterization of structural variants with base-pair resolution of breakpoints which can be relevant for the interpretation of copy number variants. Altogether, TGS allows comprehensive identification of children with a CPS and supports the individualised clinical management of index patients and high-risk relatives.

Second-line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR).

BACKGROUND: Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance. METHODS: Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018) were retrospectively analyzed. RESULTS: Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively. CONCLUSION: Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.

Pediatric Patients with Stage IV Rhabdomyosarcoma Significantly Benefit from Long-Term Maintenance Therapy: Results of the CWS-IV 2002 and the CWS DOK IV 2004-Trials.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (n = 21, EFS 19%, p = 0.02, OS 24%, p = 0.002). The outcome of LTML was slightly improved compared to HDCT (n = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower.

Haploidentical hematopoietic stem cell transplantation as individual treatment option in pediatric patients with very high-risk sarcomas.

Background: Prognosis of children with primary disseminated or metastatic relapsed sarcomas remains dismal despite intensification of conventional therapies including high-dose chemotherapy. Since haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of hematological malignancies by mediating a graft versus leukemia effect, we evaluated this approach in pediatric sarcomas as well. Methods: Patients with bone Ewing sarcoma or soft tissue sarcoma who received haplo-HSCT as part of clinical trials using CD3+ or TCRα/ß+ and CD19+ depletion respectively were evaluated regarding feasibility of treatment and survival. Results: We identified 15 patients with primary disseminated disease and 14 with metastatic relapse who were transplanted from a haploidentical donor to improve prognosis. Three-year event-free survival (EFS) was 18,1% and predominantly determined by disease relapse. Survival depended on response to pre-transplant therapy (3y-EFS of patients in complete or very good partial response: 36,4%). However, no patient with metastatic relapse could be rescued. Conclusion: Haplo-HSCT for consolidation after conventional therapy seems to be of interest for some, but not for the majority of patients with high-risk pediatric sarcomas. Evaluation of its future use as basis for subsequent humoral or cellular immunotherapies is necessary.

Thoracoscopic Resection of Lung Nodules following CT-Guided Labeling in Children and Adolescents with Solid Tumors.

Resection of lung metastases in children with solid tumors is regularly hampered by limited intraoperative detectability and relevant operative trauma of the open surgical access. The aim of this study was to analyze thoracoscopic resection of lung metastases in children following CT-guided labeling with coil wires. We retrospectively analyzed data of children and adolescents undergoing this approach at our institution between 2010 and 2022 with regard to technical aspects as well as surgical and oncological data. Within this period, we performed this procedure on 12 patients wherein we resected 18 lesions (1-5 per patient). The median age of patients was 178 months (51-265). The median duration of coil wire placement was 41 min (30-173) and the median surgery time was 53 min (11-157). No conversions were necessary and no intraoperative complications occurred. Complete microscopic resection (R0) was achieved in all labeled lesions and malignant tumor components were found in 5/12 patients. Our study shows that with a careful patient selection, thoracoscopic resection of lung metastases after coil wire labeling is a safe and reproducible procedure in children. Using this approach, lesions that are expected to have a reduced intraoperative detectability during open surgery become resectable. Patients benefit from the minimally invasive surgical access and reduced operative trauma.

Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial.

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.

Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

BACKGROUND: A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsed/refractory (R/R) B-ALL. METHODS: Data from five trials of blinatumomab for R/R B-ALL were pooled for analyses. Patients were placed in one of three groups: group 1, ≥50% bBMBs; group 2, ≥25% to <50% bBMBs; group 3, ≥5% to <25% bBMBs. Response and survival outcomes were compared between groups. RESULTS: Data from 683 patients (166 pediatric, 517 adult) were analyzed. Collectively, patients in groups 2 and 3 had significantly higher odds of achieving a complete remission (CR) (odds ratio [OR], 3.50 [95% confidence interval (CI), 2.23-5.48] and 3.93 [95% CI, 2.50-6.18], respectively; p < .001) and minimal/measurable residual disease response (OR, 2.61 and 3.37, respectively; p < .001) when compared with group 1 (reference). Groups 2 and 3 had a 37% and 46% reduction in the risk of death (hazard ratio [HR], 0.63 and 0.54, respectively; p < .001) and a 41% and 43% reduction in the risk of an event (relapse or death) (HR, 0.59 and 0.57, respectively; p < .001) compared with group 1. No significant differences in response or survival outcomes were observed between groups 2 and 3. Seven of nine patients whose bBMB% was lowered to <50% with dexamethasone achieved CR with blinatumomab. CONCLUSION: Any bBMB% <50% was associated with improved efficacy following blinatumomab treatment for R/R B-ALL.

Evaluating the safety of perioperative dexamethasone treatment: A retrospective analysis of a single center pediatric low-grade glioma cohort.

In addition to surgical management, corticosteroids have proven to be beneficial in the management of acute symptoms related to CNS tumors, and have been widely used for many decades, with dexamethasone (DM) representing the most commonly used agent. However, lately published in vitro data possibly indicates a DM-induced suppression of oncogene-induced senescence (OIS) in a preclinical pediatric low-grade glioma (pLGG) model, which, alongside data associating perioperative DM treatment with reduced event-free survival in adult glioma, raises questions concerning the safety of DM treatment in pLGG. A total of 172 patients with pLGG were retrospectively analyzed concerning the impact of perioperative DM application on postoperative short- and long-term tumor growth velocity and progression-free survival (PFS). Three-dimensional volumetric analyses of sequential MRI follow-up examinations were used for assessment of tumor growth behavior. Mean follow-up period accounted for 60.1 months. Sixty-five patients (45%) were perioperatively treated with DM in commonly used doses. Five-year PFS accounted for 93% following gross-total resection (GTR) and 57% post incomplete resection (IR). Comparison of short- and long-term postoperative tumor growth rates in patients with vs without perioperative DM application showed no significant difference (short-term: 0.022 vs 0.023 cm3 /month, respectively; long-term: 0.019 vs 0.023 cm3 /month, respectively). Comparison of PFS post IR (5-year-PFS: 65% vs 55%, respectively; 10-year-PFS: 52% vs 53%, respectively) and GTR (5- and 10-years-PFS: 91% vs 92%, respectively) likewise showed similarity. This data emphasizes the safety of perioperative DM application in pLGG, adding further evidence for decision making and requested future guidelines.

Evaluation of functional and metabolic tumor volume using voxel-wise analysis in childhood rhabdomyosarcoma.

BACKGROUND: Cross-sectional imaging-based morphological characteristics of pediatric rhabdomyosarcoma have failed to predict outcomes. OBJECTIVE: To evaluate the feasibility and possible value of generating tumor sub-volumes using voxel-wise analysis of metabolic and functional data from positron emission tomography/magnetic resonance imaging (PET/MR) or PET/computed tomography (CT) and MRI in rhabdomyosarcoma. MATERIALS AND METHODS: Thirty-four examinations in 17 patients who received PET/MRI or PET/CT plus MRI were analyzed. The volume of interest included total tumor volume before and after therapy. Apparent diffusion coefficients (ADC) and standard uptake values (SUV) were determined voxel-wise. Voxels were assigned to three different groups based on ADC and SUV: "viable tumor tissue," "intermediate tissue" or "possible necrosis." In a second approach, data were grouped into three clusters using the Gaussian mixture model. The ratio of these clusters to total tumor volume and changes due to chemotherapy were correlated with clinical and histopathological data. RESULTS: After chemotherapy, the proportion of voxels in the different groups changed significantly. A significant reduction of the proportion of voxels assigned to cluster 1 was found, from a mean of 36.4% to 2.5% (P < 0.001). There was a significant increase in the proportion of voxels in cluster 3 following chemotherapy from 24.8% to 81.6% (P = 0.02). The proportion of voxels in cluster 2 differed depending on the presence or absence of tumor recurrence, falling from 48% to 10% post-chemotherapy in the group with no tumor recurrence (P < 0.05) and from 29% to 23% (P > 0.05) in the group with tumor recurrence. CONCLUSION: Voxel-wise evaluation of multimodal data in rhabdomyosarcoma is feasible. Our initial results suggest that the different distribution of sub-volumes before and after therapy may have prognostic significance.

Resection extent and BRAF V600E mutation status determine postoperative tumor growth velocity in pediatric low-grade glioma: results from a single-center cohort analysis.

PURPOSE: Despite excellent long-term overall survival rates, pediatric low-grade gliomas (pLGG) show high variety of clinical behavior regarding progress or senescence post incomplete resection (IR). This study retrospectively analyzes tumor growth velocity (TGV) of pLGG before surgery and after IR to investigate the impact of surgical extent, tumor location and molecular BRAF status on postoperative residual tumor growth behavior. METHODS: Of a total of 172 patients with pLGG receiving surgical treatment, 107 underwent IR (66%). Fifty-three vs 94 patients could be included in the pre- and post-operative cohort, respectively, and were observed over a mean follow-up time of 40.2 vs 60.1 months. Sequential three-dimensional MRI-based tumor volumetry of a total of 407 MRI scans was performed to calculate pre- and postoperative TGV. RESULTS: Mean preoperative TGV of 0.264 cm3/month showed significant deceleration of tumor growth to 0.085 cm3/month, 0.024 cm3/month and -0.016 cm3/month after 1st, 2nd, and 3rd IR, respectively (p < 0.001). Results remained significant after excluding patients undergoing (neo)adjuvant treatment. Resection extent showed correlation with postoperative reduction of TGV (R = 0.97, p < 0.001). ROC analysis identified a residual cut-off tumor volume > 2.03 cm3 associated with a higher risk of progress post IR (sensitivity 78,6%, specificity 76.3%, AUC 0.88). Postoperative TGV of BRAF V600E-mutant LGG was significantly higher than of BRAF wild-type LGG (0.123 cm3/month vs. 0.016 cm3/month, p = 0.047). CONCLUSION: This data suggests that extensive surgical resection may impact pediatric LGG growth kinetics post incomplete resection by inducing a significant deceleration of tumor growth. BRAF-V600E mutation may be a risk factor for higher postoperative TGV.

The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.

The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies. This study reports on the identification, characterization, and immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in fibrolamellar hepatocellular carcinoma. DNAJB1-PRKACA-derived HLA class I and HLA class II ligands induce multifunctional cytotoxic CD8+ and T-helper 1 CD4+ T cells, and their cellular processing and presentation in DNAJB1-PRKACA expressing tumor cells is demonstrated by mass spectrometry-based immunopeptidome analysis. Single-cell RNA sequencing further identifies multiple T cell receptors from DNAJB1-PRKACA-specific T cells. Vaccination of a fibrolamellar hepatocellular carcinoma patient, suffering from recurrent short interval disease relapses, with DNAJB1-PRKACA-derived peptides under continued Poly (ADP-ribose) polymerase inhibitor therapy induces multifunctional CD4+ T cells, with an activated T-helper 1 phenotype and high T cell receptor clonality. Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion.

Creating a data commons: The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT).

In this article, we will discuss the genesis, evolution, and progress of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), which aims to foster international research and collaboration focused on pediatric soft tissue sarcoma. We will begin by highlighting the current state of clinical research for pediatric soft tissue sarcomas, including rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. We will then explore challenges and research priorities, describe the development of INSTRuCT, and discuss how the consortium aims to address key research priorities.

Surgical Management of Pre-Chiasmatic Intraorbital Optic Nerve Gliomas in Children after Loss of Visual Function-Resection from Bulbus to Chiasm.

Optic pathway gliomas in children carry significant morbidity and therapeutic challenges. For the subgroup of pre-chiasmatic gliomas, intraorbital and intradural resection is a curative option after blindness. We present a two-center cohort using different surgical approaches. A retrospective analysis was performed, including 10 children. Mean age at surgery was 6.8 years. Interval between diagnosis and surgery was 1-74 (mean 24 ± 5.5, median 10) months. Indications for surgery were exophthalmos, pain, tumor progression, or a combination. Eight patients underwent an extradural trans-orbital-roof approach to resect the intra-orbital tumor, including the optic canal part plus intradural pre-chiasmatic resection. Gross total resection was achieved in 7/8, and none had a recurrence. One residual behind the bulbus showed progression, treated by chemotherapy. In two patients, a combined supra-orbital mini-craniotomy plus orbital frame osteotomy was used for intraorbital tumor resection + intradural pre-chiasmatic dissection. In these two patients, remnants of the optic nerve within the optic canal remained stable. No patient had a chiasmatic functional affection nor permanent oculomotor deficits. In selected patients, a surgical resection from bulb to chiasm ± removal of optic canal tumor was safe without long-term sequela and with an excellent cosmetic result. Surgery normalizes exophthalmos and provides an effective tumor control.

The genomic landscape of pediatric renal cell carcinomas.

Pediatric renal cell carcinomas (RCC) differ from their adult counterparts not only in histologic subtypes but also in clinical characteristics and outcome. However, the underlying biology is still largely unclear. For this reason, we performed whole-exome and transcriptome sequencing analyses on a cohort of 25 pediatric RCC patients with various histologic subtypes, including 10 MiT family translocation (MiT) and 10 papillary RCCs. In this cohort of pediatric RCC, we find only limited genomic overlap with adult RCC, even within the same histologic subtype. Recurrent somatic mutations in genes not previously reported in RCC were detected, such as in CCDC168, PLEKHA1, VWF, and MAP3K9. Our papillary pediatric RCCs, which represent the largest cohort to date with comprehensive molecular profiling in this age group, appeared as a distinct genomic subtype differing in terms of gene mutations and gene expression patterns not only from MiT-RCC but also from their adult counterparts.