Raoull Hoogendijk

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation.

Summary No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22 + blasts was 72% (range 40–100%, n = 9). The median dose in the first course was 1.74 mg/m 2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)‐positive patient became MRD‐negative. Six‐month overall survival was 47% (95% confidence interval [CI] 27–80%). Two patients developed veno‐occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.

Abstract Pediatric classical Hodgkin's lymphoma (cHL) is characterized by Hodgkin Reed‐Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active crosstalk between these cells. One promising biomarker in adult cHL patients is “thymus‐and‐activation‐regulated chemokine” (TARC). The objectives of this study were to define normal TARC values in non‐cHL children and to investigate and correlate pretherapy TARC as diagnostic marker in pediatric cHL. In this multicenter prospective study, plasma and serum samples were collected of newly diagnosed cHL patients before start of treatment (n = 49), and from randomly selected non‐cHL patients (n = 81). TARC levels were measured by enzyme‐linked immunosorbent assay. The non‐cHL patients had a median plasma TARC value of 71 pg/mL (range: 18‐762), compared to 14 619 pg/mL (range: 380‐73 174) in cHL patients ( P < .001). TARC values had a high discriminatory power (AUC = .999; 95% confidence interval, .998‐1). A TARC cutoff level of 942 pg/mL maximized the sum of sensitivity (97.9%) and specificity (100%). TARC plasma levels were associated with age, treatment level, bulky disease, B‐symptoms, and erythrocyte sedimentation rate. TARC was found to be a highly specific and sensitive diagnostic marker for pediatric cHL. This noninvasive marker could be of great value as screening test in the work‐up for pediatric patients with lymphadenopathy.

Introduction: Survival of children with central nervous system (CNS) tumors varies largely between countries. For the Netherlands, detailed population-based estimation of incidence, survival, and mortality of pediatric CNS tumors are lacking but are needed to evaluate progress. Methods: All CNS tumors diagnosed in patients <18 years during 1990-2017 were selected from the Netherlands Cancer Registry. Other than pilocytic astrocytomas, nonmalignant tumors were included since 2000. Incidence and mortality trends were evaluated by average annual percentage change (AAPC). Changes over time in the five-year observed survival (5-year OS) were evaluated by Poisson regression models adjusted for follow-up time. Results: Between 1990 and 2017, 2057 children were diagnosed with a malignant CNS tumor and 885 with a pilocytic astrocytoma. During 2000-2017, 695 children were diagnosed with other nonmalignant CNS tumors. Incidence rates of malignant tumors remained stable, while pilocytic astrocytomas and other nonmalignant tumors increased by 2.0% and 2.4% per year, respectively. The 5-year OS rates improved for all groups; however, improvement for malignant tumors was not constant over time. The contribution of malignant tumors located at the optic nerve tumors was 1% in 2000-2009. However, shifting from pilocytic astrocytomas, increased to 6% in 2010-2017, impacting survival outcomes for malignant tumors. Conclusion: Survival rates of CNS tumors improved over time but were not accompanied by a decreasing mortality rate. The observed temporary survival deterioration for malignant tumors appears to be related to changes in diagnostics and registration practices. Whether differences in treatment regimens contribute to this temporary decline in survival needs to be verified.

<h3>BACKGROUND AND PURPOSE:</h3> T2-FLAIR mismatch is a highly specific imaging biomarker of <i>IDH</i>-mutant diffuse astrocytoma in adults. It has however also been described in <i>MYB/MYBL1</i>–altered low grade tumors. Our aim was to assess the diagnostic power of the T2-FLAIR mismatch in <i>IDH</i>-mutant astrocytoma and <i>MYB/MYBL1</i>–altered low-grade tumors in children and correlate this mismatch with histology. <h3>MATERIALS AND METHODS:</h3> We evaluated MR imaging examinations of all pediatric patients, performed at the Princess Máxima Center for Pediatric Oncology and the University Medical Center Utrecht between January 2012 and January 2023, with the histomolecular diagnosis of <i>IDH</i>-mutant astrocytoma, diffuse astrocytoma <i>MYB/MYBL1</i>–altered, or angiocentric glioma, and the presence of T2-FLAIR mismatch was assessed. Histologically, the presence of microcysts in the tumor (a phenomenon suggested to be correlated with T2-FLAIR mismatch in <i>IDH</i>-mutant astrocytomas in adults) was evaluated. <h3>RESULTS:</h3> Nineteen pediatric patients were diagnosed with either <i>IDH</i>-mutant astrocytoma (<i>n</i> = 8) or <i>MYB/MYBL1</i>–altered tumor (<i>n</i> = 11: diffuse astrocytoma<i>, MYB-</i> or <i>MYBL1</i>-altered <i>n</i> = 8; or angiocentric glioma <i>n</i> = 3). T2-FLAIR mismatch was present in 11 patients, 3 (38%) in the <i>IDH</i>-mutant group and 8 (73%) in the <i>MYB/MYBL1</i> group. No correlation was found between T2-FLAIR mismatch and the presence of microcysts or an enlarged intercellular space in either <i>IDH</i>-mutant astrocytoma (<i>P </i>= .38 and <i>P </i>= .56, respectively) or <i>MYB/MYBL1</i>–altered tumors (<i>P </i>= .36 and <i>P </i>= .90, respectively). <h3>CONCLUSIONS:</h3> In our pediatric population, T2-FLAIR mismatch was more often found in <i>MYB/MYBL1</i>–altered tumors than in <i>IDH</i>-mutant astrocytomas. In contrast to what has been reported for <i>IDH</i>-mutant astrocytomas in adults, no correlation was found with microcystic changes in the tumor tissue. This finding challenges the hypothesis that such microcystic changes and/or enlarged intercellular spaces in the tissue of these tumors are an important part of explaining the occurrence of the T2-FLAIR mismatch.