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Supplementary Data from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation.Significance:We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic.This article is highlighted in the In This Issue feature, p. 587

Background Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Methods Patients (N = 166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. Results As of January 13, 2021, median OS (80% CI) was 11.7 (10.3–16.5) and 10.8 (9.1–15.8) months with NIVO and NIVO + IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO + IPI was 1.7 (1.4–2.7) and 1.3 (1.2–1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2–1.4) and 2.8 (1.5–4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4–2.6) and 4.6 (1.4–5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1–1.3) and 1.6 (1.3–3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO + IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. Conclusions NIVO ± IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.

Background: National advisory panels (NAPs) have been established for the care of children and young people (CYP) with cancer in the United Kingdom since 2011, with an increase in panel number in recent years. Their practice has not previously been reviewed; therefore, we sought to evaluate the role, practice and impact of six selected NAPs offering expertise in ependymoma, histiocytosis, leukaemia, neuroblastoma, renal tumours and sarcoma. Procedure: This service evaluation used mixed methodology, including review of NAP documentation, semi-structured interviews with the NAP chairs and an analysis of the cases referred for discussion. Results: Total 1110 referrals were analysed. Results demonstrated the significant scope and amount of work undertaken by the NAPs, largely testament to the commitment of the panel members. Specific roles fulfilled have been highlighted, and NAP recommendations have been shown to influence clinical decision-making and be implemented in the majority of cases. Despite widespread good practice, areas to address have been identified; these include clarity regarding NAP membership, consistency in recommendations, the consideration of holistic information to promote personalised management and the exploration of wider multidisciplinary team roles. Conclusions: In the context of increasing demand and the escalating number of NAPs, it is timely to consider how service improvement can be facilitated. Best practice guidelines have been formulated as a product of this study, to promote a sustainable and effective model for NAPs. Review and benchmarking national panel performance against these guidelines will drive high standards of care going forward and they should be embedded as standard practice.

Cobimetinib; Pediatrics; Refractory Solid Tumors Cobimetinib; Pediatria; Tumors sòlids refractaris Cobimetinib; Pediatría; Tumores sólidos refractarios Background: The MAPK pathway is an emerging target across a number of adult and pediatric tumors. Targeting the downstream effector of MAPK, MEK1, is a proposed strategy to control the growth of MAPK-dependent tumors. Objective: iMATRIX-cobi assessed the safety, pharmacokinetics, and anti-tumor activity of cobimetinib, a highly selective MEK inhibitor, in children and young adults with relapsed/refractory solid tumors. Patients and methods: This multicenter Phase I/II study enrolled patients aged 6 months to < 30 years with solid tumors with known/expected MAPK pathway involvement. Patients received cobimetinib tablet or suspension formulation on Days 1-21 of a 28-day cycle. Dose escalation followed a rolling 6 design. The primary endpoint was safety; secondary endpoints were pharmacokinetics and anti-tumor activity. Results: Of 56 enrolled patients (median age 9 years [range 3-29]), 18 received cobimetinib tablets and 38 cobimetinib suspension. Most common diagnoses were low-grade glioma (LGG; n = 32, including n = 12 in the expansion cohort) and plexiform neurofibroma within neurofibromatosis type 1 (n = 12). Six patients (11 %) experienced dose-limiting toxicities (including five ocular toxicity events), which established a pediatric recommended Phase II dose (RP2D) of 0.8 mg/kg tablet and 1.0 mg/kg suspension. Most frequently reported treatment-related adverse events were gastrointestinal and skin disorders. Steady state mean exposure (Cmax, AUC0-24) of cobimetinib at the RP2D (1.0 mg/kg suspension) was ~ 50 % lower than in adults receiving the approved 60 mg/day dose. Overall response rate was 5.4 % (3/56; all partial responses in patients with LGG). Conclusions: The safety profile of cobimetinib in pediatrics was similar to that reported in adults. Clinical activity was observed in LGG patients with known/suspected MAPK pathway activation. Cobimetinib combination regimens may be required to improve response rates in this pediatric population.

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation. Significance: We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587

BACKGROUND: Limited data exist regarding checkpoint inhibitor efficacy for pediatric CNS malignancies. METHODS: CheckMate 908 is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in 5 cohorts of pediatric patients previously treated with standard-of-care (NCT03130959). Patients received NIVO-3mg/kg Q2W or NIVO-3mg/kg + IPI-1mg/kg Q3W (4 doses) followed by NIVO-3mg/kg Q2W. Primary endpoints included OS (newly diagnosed DIPG) and PFS (other CNS cohorts); secondary endpoints included other efficacy metrics/safety. Exploratory endpoints included pharmacokinetics/biomarker analyses. Comparisons between treatments/cohorts were not planned. RESULTS: At data cutoff (13-Jan-2021), 166 patients received NIVO (n=85) or NIVO+IPI (n=81) at median (m) ages of 10.0yrs (range, 1-21) and 11.0yrs (1-21), respectively. In newly diagnosed DIPG, mOS (80% CI) was 11.7mos (10.3-16.5) with NIVO (n=23) and 10.8mos (9.1-15.8) with NIVO+IPI (n=22). In recurrent/progressive HGG, mPFS (80% CI) was 1.7mos (1.4-2.7) with NIVO (n=16) and 1.3mos (1.2-1.5) with NIVO+IPI (n=15). In relapsed/resistant medulloblastoma, mPFS (80% CI) was 1.4mos (1.2-1.4) with NIVO (n=15) and 2.8mos (1.5-4.5) with NIVO+IPI (n=15). In relapsed/resistant ependymoma, mPFS (80% CI) was 1.4mos (1.4-2.6) with NIVO (n=12) and 4.6mos (1.4-5.4) with NIVO+IPI (n=10). In other recurrent/progressive CNS tumors, mPFS (95% CI) was 1.2mos (1.1-1.3) with NIVO (n=19) and 1.6mos (1.3-3.5) with NIVO+IPI (n=19). Median treatment duration was 2.1mos (range, 0-41.7+ [NIVO]/0-29.6+ [NIVO+IPI]). Grade 3/4 treatment-related AEs occurred in 14.1% (NIVO) and 27.2% (NIVO+IPI) of patients. NIVO and IPI first dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor PD-L1 expression was not associated with survival. Tumor mutational burden was high in 1 patient (NIVO+IPI) with HGG (OS=11.0mos). CONCLUSIONS: NIVO±IPI demonstrated no clinical benefit in pediatric patients with high-grade CNS malignancies, consistent with available historical data. The safety profiles were manageable.

BackgroundThe National Institute for Health and Care Excellence (NICE) guidance for referral of children with suspected cancer was first published in 2005 and updated in 2015. The updated version relied on sparse primary care evidence and published without input from key stakeholders, for example, acute general paediatricians and paediatric haematologists/oncologists. This led to a document that fell short as a practical guide for referring physicians managing children with potentially life-threatening conditions. Following discussions between the Children’s Cancer and Leukaemia Group (CCLG, the UK multidisciplinary professional body for healthcare professionals caring for children with cancer) and NICE, it was agreed that a practical supplement should be produced for the 2015 guidance. A prerequisite was evidence gathering from tertiary care to balance the existing primary care evidence, and a Delphi consensus method was therefore convened.MethodsA CCLG NICE Guidance Committee formulated 25 draft statements for review. The CCLG emailed its paediatric haematologist/oncologist membership (n=179) and 88 responded (49%). To achieve consensus, statements required ≥70% agreement from ≥60% of actual respondents, from the denominator (n=88).ResultsFifteen of 25 original statements were accepted at the first round of voting. Three of 25 statements where >50% did not support were rejected outright. One statement could not be revised without replicating a previously accepted statement. The six remaining statements were revised and a second round of voting undertaken; all six revised statements were accepted. Overall, 21 of 25 statements (84%) met consensus criteria.ConclusionsThis expert opinion should help streamline suspected cancer referral in children and help optimise subsequent outcomes.

Introduction High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. Methods Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study. Results From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4–18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6–33.3) and 4.9 months (range: 0.7–28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study. Conclusion These results call for new treatment approaches for patients with HR stage IV WT.

While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan-containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate-risk (CR and PR) and blastemal-type histologies (PR). Two patients were alive at last follow-up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.

Background Topotecan has been variably incorporated in the treatment of patients with relapsed Wilms tumour (WT) who failed initial treatment with three or more effective drugs. Our objective was to describe outcome and to retrospectively investigate the potential role of topotecan in relapsed WT patients. Methods Children who were treated with topotecan as part of their chemotherapeutic regimens for relapsed WT were identified and included in our retrospective study. Patient charts were reviewed for general patient characteristics, histology and stage at initial diagnosis, number and type of relapse, salvage treatment schedules, toxicity, response to treatment and outcome. Results From 2000 to 2012, 30 children (median age at relapse 5.5 years, range 1.6–14.5 years) were identified to have received topotecan as part of their salvage regimens (primary progressive disease n = 3, first, second and third relapse n = 13, 9 and 2 respectively, partial response n = 3). Topotecan was administered as a single agent (12 patients) or in combination with other drugs (18 patients). Sixteen patients had high-risk histology according to the SIOP classification, 15 died within 12 months because of progressive disease. Fourteen patients had SIOP intermediate-risk histology of which four patients displayed objective responses to topotecan. Overall, 6 out of 14 intermediate-risk patients survived (median follow up of 6 years), however, three of whom (stage V) had bilateral nephrectomy after topotecan treatment. Conclusions Topotecan does not seem to show effectiveness in the treatment of relapsed WT patients with initial high-risk histology. In patients with intermediate-risk histology, the role of topotecan might deserve further attention, to prove its efficacy.

NS-18. ROLE OF METFORMIN IN THE TREATMENT OF HYPOTHALAMIC OBESITY SYNDROME (HOS) Arundoss Gangadharan1, Aliki Bogiatzopoulou1, Joanne Blair1, Barry Pizer2, Lisa Howell2, James Hayden2, Conor Mallucci3, Benedetta Pettorini3, and Mohammed Didi1; Department of Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK; Department of Oncology, Alder Hey Children’s Hospital,Liverpool, UK; Department of Neurosurgery,Alder HeyChildren’s Hospital, Liverpool, UK BACKGROUND: HOS in children with structural hypothalamic lesions is characterised by weight gain refractory to standard lifestyle interventions. Disruption of hypothalamic function results in hyperphagia, hyperinsulinemia and possible reduction of energy expenditure. Metformin induces anorectic effects, but its role in these patients has not been studied. OBJECTIVE: To compare BMI of patients with HOS before and after treatment with Metformin. METHOD: BMI of 6 children with HOS unresponsive to demonstrable change in lifestyle measures was compared before and after treatment with metformin by converting BMI to BMI standard deviation scores (SDS). Tolerance to metformin was assessed. RESULTS: There were 6 females. [Hypothalamic hamartoma (N 1⁄4 2), craniopharyngioma (N 1⁄4 2), hypothalamic astrocytoma (N 1⁄4 2)]. Treatment included surgery (N 1⁄4 5), primary fractionated radiotherapy (N 1⁄4 1), additional proton beam radiotherapy (N 1⁄4 1) and chemotherapy (N 1⁄4 1). Results are given as median (range). Age at diagnosis was 10.1years (1.3-13.8). Metformin was introduced at 12.5years of age (4.5-18.1). The change in BMI SDS was +0.42/year (+0.06 to +3.6) after 4.3 years (0.2 to 7.1). The change in BMI SDS between commencement of metformin and the final assessment was +0.15/ year (-0.31 to +0.22) after follow up of 1.9 years (1.3-5.4). The rate of change in BMI SDS before and after introduction of metformin is statistically significant (p1⁄4 0.043). CONCLUSION: Use of metformin in addition to lifestyle change is associated with control of obesity in patients with HOS and structural disease where lifestyle change alone was not successful. A prospective study is warranted to rigorously examine its role in this difficult group of patients. Neuro-Oncology 18:iii127–iii134, 2016. doi:10.1093/neuonc/now078.18 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Hypercalcaemia is a rare life-threatening complication of paediatric cancer that is commoner in haematological than solid malignancies and associated rarely with acute renal failure. Often refractory to medical therapy, control of hypercalcaemia in children with solid tumours may necessitate excision of localised tumours or urgent chemotherapy for metastatic ones. We present a child with refractory hypercalcaemia, bulky chemosensitive metastatic tumours and acute renal failure in whom chemotherapy posed high-risk of tumour lysis syndrome (TLS). Resection of the metastatic tumours successfully normalised the hypercalcaemia and represents a practical alternative control strategy in cases at high risk of TLS.

This pilot study examines the efficacy of a group memory notebook intervention. Five individuals with very mild dementia and 4 spouses who served as coaches attended 14 group treatment sessions. Therapists use educational strategies and learning activities packets to teach memory notebook use. At posttreatment, coaches report fewer symptoms of depression, and participants with very mild dementia report greater confidence in ability to obtain support. Modified laboratory memory testing reveals that participants with dementia demonstrate improved posttreatment memory scores because of increased note-taking behavior and more frequent referencing of notes. Although more frequent everyday memory strategies use is reported at posttreatment, this does not translate into reports of fewer everyday memory failures or greater everyday independence for the participants with dementia. This study demonstrates that a multidyad group intervention can successfully be used to teach patients with very mild dementia to use a memory notebook, with beneficial effects for both members of the care dyad.

We report a 6-year-old male with left-sided ptosis, aniscoria and an initially missed slow growing left-sided neck mass, which was surgically excised when he was 9 years old and confirmed to be a paraganglioma. Seven years later he developed recurrent symptoms and was found to have a recurrence in the anterior mediastinum. We also report on all cases of cervical paragangliomas registered with the Manchester Children's Tumour Registry (MCTR) for the 50-year period 1954-2004. Paragangliomas are very rare tumours in the head and neck but should be considered in the differential diagnosis of neck masses especially when presenting with Horner syndrome. Recurrent symptoms and signs of hypertension herald recurrence. As these tumours can form part of a familial syndrome, long-term follow-up is necessary. Family members should be screened for early detection.

One of the most important tasks faced by adolescents and young adults is the formation of romantic relationships. Little is known, however, about the developmental timing of early relational experiences. This study investigated the age at which an ethnically diverse sample of young adults (N = 683) experienced their very first date, love, serious relationship, kiss, and act of intercourse. Most had experienced each event by the end of high school, with first dates and kisses occurring at earlier ages than falling in love or intercourse. Gender and ethnic differences were found. For example, young men began dating at earlier ages than did young women. Asian American participants were less sexually and romantically experienced, and had their very first sexual experiences at an older age, than African American, Latino/Hispanic, and Caucasian/non-Hispanic White participants. Interestingly, there were no differences in first romantic love experience. Almost all men and women within each ethnic group had fallen in love at least once, typically around age 17; this suggests that romantic love is a common human life event and that it first occurs during the developmental period spanning late adolescence and early adulthood.

Wilms' tumor (WT) is a common childhood renal cancer. A 25-year single center UK experience is reported. During 1985-2010, 97 children underwent immediate nephrectomy or delayed resection of tumor after chemotherapy. Survival, morbidity, and late effects following treatment are described. Tumor distribution was: Stage I, 25.7% (n = 25); Stage II, 24.7% (n = 24); Stage III, 26.8% (n = 26); Stage IV, 17.5% (n = 17); and Stage V, 5.2% (n = 5). Immediate nephrectomy was performed in 39% (n = 38) patients with elective delayed resection in 61% (n = 59) cases. Ten patients had cavotomy to excise tumor involving vena cava territory. Two cases required cardiopulmonary bypass. Tumor rupture was recorded in eight (8.5%) total operated cases-after immediate (n = 5/37), 13.5% vs delayed nephrectomy-(n = 3/57), 5.2%; X(2) P = .154. From 2001 onwards, one case of tumor rupture was recorded at this center after the universal adoption of UKW3 and SIOP guidelines advocating preoperative chemotherapy and delayed nephrectomy for all WT. Three treatment-related deaths occurred-hepatic veno-occlusive disease (n = 2) with actinomycin D and a single WT fatality due to vascular injury. Overall survival was 84.5% (82/97 cases). Two patients developed "late malignancies" -thyroid cancer and a basal cell carcinoma. This study demonstrates excellent survival for WT comparable with national outcomes and international cooperative studies. Adverse events with chemotherapy and surgery, including "late onset," second malignancies deserve special consideration.

Phaeochromocytoma is a rare clinical entity in children. Contrary to traditional teaching, which suggested that 10% of phaeochromocytomas are "familial", a germline mutation has been identified in up to 59% (27/48) of apparently sporadic phaeochromocytomas presenting at 18 years or younger and in 70% of those presenting before 10 years of age. The inherited predisposition may be attributable to a germline mutation in the Von Hippel-Lindau gene, the genes encoding the subunits B and D of succinate dehydrogenase, the RET proto-oncogene predisposing to multiple endocrine neoplasia type 2, or the neurofibromatosis type 1 gene. Of these, the Von Hippel-Lindau gene is the most commonly mutated gene in children presenting with a phaeochromocytoma. Genetic counselling is recommended before gene testing and investigation of the wider family. This review provides guidance on the aetiology, investigation, management, histopathology, genetics and follow-up of children with a phaeochromocytoma.

This exploratory study examined frequency of self-reported cervical and breast cancer screening rates in a multiethnic sample of 331 female university students. In general, rates of lifetime screening were fairly low, with only 41% reporting having ever had a PAP examination and 44% reporting having undergone at least one clinical breast examination. Screening rates differed by ethnicity. Non-Hispanic White and African-American women had higher screening rates than Asian/Pacific Islander and Latina women. The significantly lower rate of screening among the latter groups is of particular concern given the higher cancer mortality rates typically observed in those groups.

BACKGROUND Frequent follow-up and regular investigation are routine in pediatric oncology. However, there is little evidence regarding their value in the detection of recurrent disease. METHODS The authors carried out a retrospective study of the follow-up of 186 children with solid tumors who were diagnosed between 1992 and 1996. The numbers of clinic visits, follow-up investigations, and (if appropriate) the mode of recurrence detection were recorded. RESULTS The mean follow-up was 5.9 years. During this time, 37 recurrences were detected, symptomatically in 54% of patients, by routine investigation in 30% of patients, and at routine clinic appointment in 16% of patients. It was calculated that routine magnetic resonance imaging detected 1 recurrence for every 42 scans performed, routine computed tomography detected 1 recurrence for every 129 scans performed, and routine chest radiography detected 1 recurrence for every 257 films. CONCLUSIONS The current results raise questions regarding the usefulness of such follow-up in children with solid tumors. Cancer 2005. © 2005 American Cancer Society.

We report a case of Peutz-Jeghers syndrome (PJS) in a 2-year old with precocious puberty secondary to a Sertoli-Leydig cell tumour. Family history of PJS and other neoplasms were discovered. The tumour was excised and the STK11 gene deletion identified in both patient and father. Screening revealed hamartomatous gastric polyps, which were removed. Current recommendations for screening of children with PJS begin at age 8 years, based on reported occurrence of complications 1. This report illustrates the importance of considering early screening, along with close clinical review and patient/parent education, for detection of life threatening neoplasms and complications.

On March 7, 2017, Canadian Senator Lynn Beyak stood up in the Red Chamber and delivered a lengthy speech urging Canadians to recognise the positive aspects of the Indian Residential Schooling system that the Truth and Reconciliation Commission had failed to acknowledge. In their positions as settler teacher educators, the authors examine how Senator Beyak’s statements expose the depth of systemic settler colonialism, anti-Indigenous racisms, and unsettling beneficiary narratives here in Canada. The authors call on teacher educators to examine these systemic anti-Indigenous racisms in relation to how they can confront and disrupt settler Canadian colonialism and historical settler consciousness within teacher education and school curricula. Drawing on recent research done by educational researchers at Faculties of Education across Canada, the authors maintain that settler colonial benevolence and colonial systemic anti-Indigenous racisms can be unlearned and learned through ethical relationality, truth, and a critical praxis of reconciliation., Le 7 mars 2017, la sénatrice canadienne Lynn Beyak s’est levée dans la Chambre rouge et a prononcé un long discours dans lequel elle incitait les Canadiens à reconnaître les aspects positifs du système des pensionnats indiens que la Commission de vérité et réconciliation n’avait pas reconnus. Comme enseignants et enseignantes descendants des colons, les auteurs de cette communication examinent comment les déclarations de la sénatrice Beyak mettent en évidence la profondeur du colonialisme de peuplement systémique, des racismes anti-autochtones et des récits troublants des conquérants du Canada. Les auteurs demandent aux enseignants et aux éducateurs d’examiner ces racismes systémiques anti-autochtones en relation avec la façon dont ils peuvent confronter et déconstruire le colonialisme de peuplement et la conscience historique des colons dans les programmes scolaires et de formation des enseignants. En s’appuyant sur des recherches récentes effectuées par des chercheurs des Facultés d’éducation du Canada, les auteurs soutiennent que la bienveillance des colons et les racismes coloniaux systémiques anti-autochtones peuvent non seulement être déconstruits, mais aussi que les antiracismes peuvent aussi être reconstruits par l’entremise des relations éthiques, de la vérité et d’une pratique critique visant la réconciliation.