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Introduction: Treatment for childhood-onset craniopharyngioma (cCP) has shifted from complete to limited resection aiming to avoid additional hypothalamic morbidity. Up to 90% of cCP patients develop growth hormone deficiency (GHD). GH replacement therapy (GHRT) is of high importance for linear growth and metabolic state. Hardly any studies evaluated the optimal time to start GHRT in relation to tumor progression or recurrence. Our aim was to assess the effect of GHRT in cCP on tumor progression/recurrence. Methods: Patients with cCP diagnosed between 2001 and 2022, with at least one year of follow-up were included. Tumor progression/recurrence was defined as tumor progression/recurrence requiring intervention. Kaplan Meier and multivariable cox regression analyses were estimated for tumor progression/recurrence. Comparison was made between cCP patients with GHRT and without GHRT. Of the cCP patients receiving GHRT, those given GHRT ≤ 1 year of cCP diagnosis were compared to those given GHRT >1 year after cCP diagnosis. Results: Of 59 cCP patients, 52 were diagnosed with GHD and 51 (86.4%) received GHRT. Sixteen cCP patients (31.4%) developed tumor progression/recurrence during GHRT compared to four cCP patients (50.0%) without GHRT. Mean progression free survival (PFS) did not differ between cCP patients with or without GHRT (GHRT: 5.55 years 95% CI 3.74 - 7.36 vs. no GHRT: 3.69 years 95% CI 1.44 - 5.93). Of cCP patients who started GHRT ≤1 year after cCP diagnosis, 36.4% developed tumor progression/recurrence compared to 27.6% of cCP patients who received GHRT > 1 year after diagnosis (PFS: 8.45 years CI 95% 5.54 – 11.36 vs. 7.99 years CI 95% 6.03 – 9.94). Limited surgery was associated to tumor progression/recurrence (HR 6.99 CI 95% 2.10 – 23.25). Conclusion: GHRT does not seem to influence tumor progression/recurrence in cCP. These results support early initiation of GHRT in cCP patients to optimize linear growth and metabolic outcome.

OBJECTIVES: To produce an efficient and practically implementable method, based on primary care data exclusively, to identify patients with complex care needs who have problems in several health domains and are experiencing a mismatch of care. The Johns Hopkins ACG System was explored as a tool for identification, using its Aggregated Diagnosis Group (ADG) categories. STUDY DESIGN: Retrospective cross-sectional study using general practitioners' electronic health records combined with hospital data. METHODS: A prediction model for patients with complex care needs was developed using a primary care population of 105,345 individuals. Dependent variables in the model included age, sex, and the 32 ADGs. The prediction model was externally validated on 30,793 primary care patients. Discrimination and calibrations were assessed by computing C statistics and by visual inspection of the calibration plot, respectively. RESULTS: Our model was able to discriminate very well between complex and noncomplex patients (C statistic = 0.9; 95% CI, 0.88-0.92), whereas the calibration plot suggests that the model provides overestimates of complex patients. CONCLUSIONS: With this study, the ACG System has proven to be a useful tool in the identification of patients with complex care needs in primary care, opening up possibilities for tailored interventions of care management for this complex group of patients. Utilizing ADGs, the prediction model that we developed had a very good discriminatory ability to identify those complex patients. However, the of the model still needs improvement.

[EN] BACKGROUND: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of incidence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contemporary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. METHOD AND PATIENTS: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Information on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. RESULTS: Newly diagnosedpatients with ALL (n=5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence interval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. CONCLUSION: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. BSPHO: none. CoALL: none. DCOG: none. DFCI: none. NOPHO: The authors BKA and KS would like to thank the Danish Cancer Society and the Danish Childhood Cancer Society for supporting this study. LAL/SEHOP-PETHEMA: Author ELL would like to thank all involved hospitals for data collection. UKALL: Author AV would like to thank Amy Kirkwood, UKALL 2011 statistician, for collecting the UK data.

Purpose The purpose of this study was to determine and compare the percentage of completely healed meniscal tears after arthroscopic repair combined with anterior cruciate ligament reconstruction (ACLR) for the different vascular zones of the meniscus. Methods PubMed, Embase, Web of Science, Cochrane library and Emcare were searched on 19 May 2020 for articles reporting healing rates after arthroscopic meniscal repair with concomitant ACLR for the different meniscal vascular zones as assessed by second-look arthroscopy. Data on meniscal tears were extracted as located in zones 1, 2 or 3, according to the Cooper classification. Studies were graded in quality using a modified Newcastle–Ottawa Scale. Pooled analyses were performed utilizing a random-effects model. Meta-analyses were performed using R version 3.6.2 and SPSS statistical software version 25.0. The study was registered with PROSPERO (ID:CRD42020176175). Results Ten observational cohort studies met the inclusion criteria, accounting for 758 meniscal tear repairs in total. The pooled overall proportion of healing was 78% (95% CI 72–84%). The mean weighted proportion of healing was 83% (95% CI 76–90%) for studies (n = 10) reporting zone 1 tears and 69% (95% CI 59–79%) for studies (n = 9) reporting zone 2 tears. No study reported healing rates for zone 3 tears. The pooled overall odds ratio was 2.5 (95% CI 1.00−6.02), indicating zone 1 tears as 2.5 times more likely to heal than zone 2 tears. Conclusion This study demonstrates that meniscal tears localized in vascular zone 1 were more likely to heal than those in zone 2. Level of evidence IV.

PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1- associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pig mentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA ( P = .069) or V4e isopter seeing retinal areas ( P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up ( P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies. (Am J Ophthalmol 2021;234: 37-48. (C) 2021 The Authors. Published by Elsevier Inc.

Patients with Barcelona Clinic Liver Cancer intermediate stage hepatocellular carcinoma (HCC) theoretically are an excellent group to consider downstaging using locoregional therapy (LRT) since they do not have extrahepatic spread or vascular invasion. Once successful, this can change the treatment strategy from palliative to curative intention. Although downstaging therapy is suggested in guidelines, it is still not widely accepted. Moreover, studies on downstaging are mainly performed in high-incidence HCC countries. Therefore, our aim was to gain insight in therapeutic strategies in patients with intermediate stage HCC and their impact on intention-to-treat survival in a real-life setting in a low-incidence HCC country. We retrospectively analyzed data from the national Dutch HCC registry. From this database, consisting of 1409 patients with a diagnosis of HCC between 2005-2013 in 5 Dutch tertiary referral centers, we identified 165 patients with intermediate stage HCC. Out of these patients, 63 (38%) were not offered LRT, whereas 102 (62%) did receive LRT. Subsequently, 50 (49%) of the 102 patients who received LRT were successfully downstaged. Eleven patients (22% of successfully downstaged patients) eventually underwent liver transplantation. Cox regression analysis showed that a lower MELD score, an AFP value

Background: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era.Methods: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model.Findings: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59.1% (95% CI 50.5-69.1), 5-year overall survival was 76.1% (68.6-84.5), and the 5-year cumulative incidence of relapse was 31.0% (95% CI 22.4-40.1). MRD at the end of induction therapy was high (>= 10(-2) cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10(-2) cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of >= 10(-2) vs those with a MRD of