Biallelic mismatch repair deficiency (bMMRD) is a cancer predisposition syndrome affecting primarily individuals from consanguinous families resulting in multiple childhood cancers including high grade gliomas (HGG). This is the first study to assess the prevalence of bMMRD among patients with HGG in countries where consanguinity is high. We collected molecular and clinical information on all children diagnosed with HGG and supratentorial primitive neuroectodermal tumors (sPNET) between 2003 and 2013 at King Hussein Cancer Center, Jordan. Comparison was made to a similar cohort from Toronto. Clinical data regarding presence of café au lait macules(CAL), family history of cancer, consanguinity, pathology and treatment were collected. Tumors were centrally reviewed and tested for MMRD by immunohistochemistry of the corresponding proteins. Forty‐two patients fulfilled the inclusion criteria, including 36 with HGG. MMRD was observed in 39% of HGG of whom79% also lost MMR staining in the corresponding normal cells suggestive of bMMRD. P53 dysfunction was highly enriched in MMR deficient tumors (p = 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p = 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p = 0.005 and 0.05,respectively) but family history of cancer didn't. HGG with all three bMMRD risk factors had evidence of MMRD and all children affected by multiple bMMRD related cancers had identical gene loss by immunohistochemical staining. In Jordan, the frequency of clinical and immunohistochemical alterations suggestive of bMMRD in pediatric HGG is high. Genetic testing will enable appropriate counseling and cancer screening to improve survival of these patients.

Pragmatic ways to apply molecular innovation to childhood brain cancer diagnosis and therapy in LMICs

PURPOSE: Medulloblastoma is composed of four clinically and prognostically distinct molecular subgroups (WNT, SHH, group 3, and group 4). However, the clinical implications of these subgroups in the context of the unique challenges of low- to middle-income countries are rarely reported. METHODS: We assembled an institutional cohort of children (3-18 years) diagnosed with medulloblastoma and treated in Jordan between 2003 and 2016. Tumors were subgrouped by NanoString and correlated with clinical and radiologic characteristics. RESULTS: Eighty-eight patients were identified (63% male); median age was 6.9 years (interquartile range 4.8-9.2) and median symptom duration was 6 weeks (interquartile range 4-11). Radiotherapy was implemented as standard-risk in 41 patients (47%) and high-risk in 47 patients (53%). Subgrouping revealed 17 WNT (19%), 22 SHH (25%), 21 group 3 (24%), and 28 group 4 tumors (32%). Median time between craniotomy and radiotherapy was 45 days (17-155); 44% of them > 49 days. Median duration of radiotherapy was 44 days (36-74). Seventy-two patients (82%) received chemotherapy afterward. With a median follow-up of 4.6 years (0.2-14.9), 5-year progression-free survival (PFS) and overall survival were 73.5% and 69.4%, respectively, with no statistically significant survival difference between standard-risk and high-risk patients. Metastasis was significant for overall survival ( P = .011). Patients with SHH and group 4 tumors had very good PFS (83.4% and 87.0%, respectively) and those with group 3 tumors had dismal outcomes (PFS 44.9%), whereas WNT tumors had less-than expected PFS (70.5%). PFS was statistically significant in patients with nonmetastatic tumors receiving radiotherapy ≤ 49 days ( P = .011), particularly group 3 tumors. CONCLUSION: Patients with SHH and group 4 medulloblastoma had excellent survival comparable with high-income countries. Compliance with treatment protocols and avoiding radiotherapy delays are important in achieving adequate survival in low- to middle-income country settings. Subgroup-driven treatment protocols should be considered in countries with limited resources.

Purpose: The management of central nervous system tumors is challenging in low- and middle-income countries. Little is known about applicability of twinning initiatives with high-income countries in neuro-oncology. In 2004, a monthly neuro-oncology video-teleconference program was started between King Hussein Cancer Center (Amman, Jordan) and the Hospital for Sick Children (Toronto, Ontario, Canada). More than 100 conferences were held and > 400 cases were discussed. The aim of this work was to assess the sustainability of such an initiative and the evolution of the impact over time. Methods: We divided the duration in to three eras according to the initial 2 to 3 years of work of three consecutive oncologists in charge of the neuro-oncology program at King Hussein Cancer Center. We retrospectively reviewed the written minutes and compared the preconference suggested plans with the postconference recommendations. Impact of changes on the patient care was recorded. Results: Thirty-three sets of written minutes (covering 161 cases) in the middle era and 32 sets of written minutes (covering 122 cases) in the last era were compared with the initial experience (20 meetings, 72 cases). Running costs of these conferences has dropped from $360/h to < $40/h. Important concepts were introduced, such as multidisciplinary teamwork, second-look surgery, and early referral. Suggestions for plan changes have decreased from 44% to 30% and 24% in the respective consecutive eras. Most recommendations involved alternative intervention modalities or pathology review. Most of these recommendations were followed. Conclusion: Video-teleconferencing in neuro-oncology is feasible and sustainable. With time, team experience is built while the percentage and the type of treatment modifications change. Commitment and motivation helped maintain this initiative rather than availability of financial resources. Improvement in patients’ care was achieved, in particular, with the implementation of a multidisciplinary team and the continuous effort to implement recommendations.

Pleomorphic xanthoastrocytoma is a rare brain tumor with unique high frequency of BRAF V600E mutation which is plausible for targeted therapy. The anaplastic variant has generally worse prognosis. We present an adolescent patient with a disseminated relapse of anaplastic pleomorphic xanthoastrocytoma following surgery, radiotherapy, and chemotherapy. She had a dramatic and prolonged response to a BRAF inhibitor (Dabrafinib) and later to addition of a MEK inhibitor (Trametinib) on tumor progression. With minimal side effects and a good quality of life, the patient is alive more than 2 years after initiation of targeted therapy. This experience confirms the potential role of targeted treatments in high-grade BRAF-mutated brain tumors.