Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup?

Introduction: Advances in molecular diagnostics led to improved targeted interventions in the treatment of pediatric CNS tumors. However, the capacity to test for these is limited in LMICs, and thus their value needs exploration. Methods: We reviewed our experience with NGS testing (TruSight RNA Pan-Cancer-seq panel) for pediatric CNS tumors at KHCC/Jordan (March/2022-April/2023). Paraffin blocks' scrolls were shipped to the SickKids laboratory based on the multidisciplinary clinic (MDC) recommendations. We reviewed the patients' characteristics, the tumor types, and the NGS results' impact on treatment. Results: Of 237 patients discussed during the MDC meetings, 32 patients (14%) were included. They were 16 boys and 16 girls; the median age at time of testing was 9.5 years (range, 0.9-21.9 years). There were 21 samples sent at diagnosis and 11 upon tumor progression. The main diagnoses were low-grade-glioma (15), high-grade-glioma (10), and other histologies (7). Reasons to request NGS included searching for a targetable alteration (20) and to better characterize the tumor behavior (12). The median turnaround time from samples' shipment to receiving the results was 23.5 days (range, 15-49 days) with a median laboratory processing time of 16 days (range, 8-39 days) at a cost of US$1,000/sample. There were 19 (59%) tumors that had targetable alterations (FGFR/MAPK pathway inhibitors (14), checkpoint inhibitors (2), NTRK inhibitors (2), and one with PI3K inhibitor or IDH1 inhibitor). Two rare BRAF mutations were identified (BRAFp.G469A, BRAFp.K601E). One tumor diagnosed initially as undifferentiated round cell sarcoma harbored NAB2::STAT6 fusion and was reclassified as an aggressive metastatic solitary fibrous tumor. Another tumor initially diagnosed as grade 2 astroblastoma grade 2 was reclassified as low-grade-glioma in the absence of MN1 alteration. NGS failed to help characterize a tumor that was diagnosed histologically as small round blue cell tumor. Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7). Conclusion: In this highly selective cohort, a high percentage of targetable mutations was identified facilitating targeted therapies. Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to "new drugs" continue to be a challenge in LMICs.

SIOP PODC-adapted treatment guidelines for craniopharyngioma in low- and middle-income settings.

Pediatric craniopharyngioma is a rare tumor with excellent survival but significant long-term morbidities due to the loco-regional tumor growth or secondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage, and behavioral changes are among the main challenges. This tumor should be managed under the care of a multidisciplinary team to determine the optimum treatment within the available resources. This is particularly important for low middle-income countries where resources are variable. This report provides risk-stratified management guidelines for children diagnosed with craniopharyngioma in a resource-limited setting.

Feasibility of treating pediatric intracranial germ cell tumors in a middle-income country: The Jordanian experience.

BACKGROUND: Pediatric intracranial germ cell tumors (iGCT) are rare, with limited data available from Arabic countries. METHODS: We retrospectively reviewed the medical charts of children <18 years diagnosed with iGCT at King Hussein Cancer Center/Jordan (January 2003 to December 2020) for clinical characteristics, treatment, and morbidities. RESULTS: Sixteen patients had germinoma; median age was 6.9 years and median symptoms duration 8 months. Nine tumors were suprasellar, five pineal, and two bifocal. Four were metastatic. Eight patients had slightly elevated beta subunit human chorionic gonadotropin and 11 patients had resection/biopsy. Fifteen patients received chemotherapy; mostly carboplatin (450 mg/m2 )/etoposide, which had low toxicity. All patients received radiotherapy (different doses and fields). At median follow-up of 7.7 years, one tumor recurred (progression-free survival: 91% ± 8%). Twelve patients who continued follow-up had stable visual and endocrine deficits to their initial presentation. Five finished or are finishing diploma and seven had poor school performance (four left school). Six patients were diagnosed with nongerminomatous germ cell tumor; median symptom duration was 1 month. Three tumors were pineal, two suprasellar, and one at quadrigeminal plate. Three were metastatic. Five tested patients had high tumor markers and four had resection/biopsy. All patients received chemotherapy, and then five received craniospinal radiation. Two patients are alive, two died with tumor progression, one died in remission with electrolyte imbalance, and one developed leukemia and died with septic shock. CONCLUSIONS: We achieved excellent survival in treating germinoma using a feasible protocol for low middle-income countries. However, patients encountered significant morbidities exacerbated by delayed diagnosis and unnecessary surgical interventions despite abnormal tumor markers. Raising awareness on iGCT symptomatology and diagnosis may help limit these morbidities.

Molecular Subgroup Is the Strongest Predictor of Medulloblastoma Outcome in a Resource-Limited Country.

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.

Molecular correlates of cerebellar mutism syndrome in medulloblastoma.

BACKGROUND: Cerebellar mutism syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS. METHODS: We assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from 5 sites globally, including Great Ormond Street Hospital, Christian Medical College and Hospital, the Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children's Hospital. Age at diagnosis, sex, tumor volume, and CMS development were assessed in addition to molecular subgroup. RESULTS: Overall, 23.8% of patients developed CMS. CMS patients were younger (mean difference -2.05 years ± 0.50, P = 0.0218) and had larger tumors (mean difference 10.25 cm3 ± 4.60, P = 0.0010) that were more often midline (odds ratio [OR] = 5.72, P < 0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumor volume, Wingless (adjusted OR = 4.91, P = 0.0063), Group 3 (adjusted OR = 5.56, P = 0.0022), and Group 4 (adjusted OR = 8.57 P = 9.1 × 10-5) tumors were found to be independently associated with higher risk of CMS compared with sonic hedgehog tumors. CONCLUSIONS: Medulloblastoma subgroup is a very strong predictor of CMS development, independent of tumor volume and midline location. These findings have significant implications for management of both the tumor and CMS.

Video-Teleconferencing in Pediatric Neuro-Oncology: Ten Years of Experience.

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.

Sustained Response to Targeted Therapy in a Patient With Disseminated Anaplastic Pleomorphic Xanthoastrocytoma.

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.

Review of management and morbidity of pediatric craniopharyngioma patients in a low-middle-income country: a 12-year experience.

BACKGROUND: Management of craniopharyngioma in children is challenging, and their quality of life can be significantly affected. Series describing this from low-middle income countries (LMIC) are few. PATIENTS AND METHODS: The study provides a retrospective chart review of pediatric patients <18 years old, diagnosed with craniopharyngioma between 2003 and 2014, and treated at King Hussein Cancer Center, Jordan. RESULTS: Twenty-four patients (12 males) were identified. Median age at diagnosis was 7.4 years (0.9-16.4 years). Commonest symptoms were visual impairment and headache (71%). Review of seventeen preoperative MRIs showed hypothalamic involvement in 88% and hydrocephalus in 76%. Thirteen patients (54%) had multiple surgical interventions. Five patients (21%) had initial gross total resection. Eleven patients (46%) received radiotherapy and six (25%) intra-cystic interferon. Five years' survival was 87 ± 7% with a median follow-up of 4.5 years (0.3-12.3 years). Four patients (17%) died; one after post-operative cerebral infarction and three secondary to hypothalamic damage. At their last evaluation, all but one patient required multiple hormonal supplements. Ten patients (42%) had best eye visual acuity (VA) >20/40, and four (16%) were legally blind. Eleven patients (46%) were overweight/obese; one had gastric bypass surgery. Seven patients had hyperlipidemia, and eight developed fatty liver infiltration. Eleven patients (65%) were attending schools and one at college. Nine of the living patients (53%) expressed difficulty to engage in the community. CONCLUSIONS: Management of pediatric craniopharyngioma is particularly complex and demanding in LMIC. Multidisciplinary care is integral to optimize the care and minimize the morbidities. A management outline for LMIC is proposed.

High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan.

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 whom 79% 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.

Synchronous glioblastoma and medulloblastoma in a child with mismatch repair mutation.

Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m(2)/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome.

Central nervous system tumors in the first year of life: a clinical and pathologic experience from a single cancer center.

PURPOSE: This study aims to review our experience with central nervous system (CNS) tumors occurring during the first year of life and to report differing features found in our series. METHODS: This is a retrospective study of infants with CNS tumors diagnosed at our institution from 2006 to 2011. RESULTS: A total of 19 cases were identified, with a median age of 232 days and predominance of male gender. Males were younger than females at the time of diagnosis (p value = 0.039). There were 13 low-grade tumors, glial tumors being the most common (11/13, p value = 0.003) and six high-grade tumors, atypical teratoid rhabdoid tumor being the most common (4/6). Low-grade tumors predominated in the supratentorial region, while high-grade tumors were seen in the infratentorial area (p value = 0.035). Males had a predilection to have more supratentorial tumors (p value = 0.058). Four patients underwent gross total resection, and eight received chemotherapy; none received radiotherapy. Two patients had spinal cord tumors; both were of pilomyxoid astrocytoma histology. Rare tumors included hemangiopericytoma (n = 1) and atypical choroid plexus tumor (n = 1), both occurring in the supratentorial area and affecting the youngest patients in this group; they were diagnosed prenatally and at 107 days, respectively. The median progression-free and overall survivals were 269 and 667 days, respectively. Among all tested parameters, only the grade of the tumor affected the outcome. CONCLUSIONS: Diagnosis and management of infant's CNS tumors remain challenging. Pathologists should be aware of the diversity of histological types. Assigning appropriate tumor grade is fundamental in predicting the outcome.

Brain stem gliomas: a clinicopathological study from a single cancer center.

Brain stem gliomas (BSG) are rare tumors occurring predominantly in childhood. They are mostly of astrocytic origin and are divided into infiltrative versus circumscribed types, with different prognoses. The diagnosis is mainly based on MRI findings, and biopsy is rarely performed. This is a retrospective study of BSG with available biopsies diagnosed at our center over 6-year period. Fifteen cases were identified, with a predominance of females. The median age was 7 years, and the mean duration of symptoms was <6 weeks in 58.3% (n = 7) of cases. MRI was typical of diffuse pontine gliomas in 64.3% (n = 9) of cases. Radiotherapy was the commonest modality of treatment, and the median overall survival was 21.7 months. Twelve cases were consistent with infiltrative astrocytoma of various grades (2 grade II, 7 grade III and 3 grade IV). Entrapped normal neurons and mitosis were the commonest findings indicating infiltrative growth and high grade, respectively, and those correlated significantly with immunostaining for neurofilament protein and Ki-67 of ≥3%. Overall survival correlated only with the duration of symptoms and tumor grade on biopsies. A limited panel of immunostains might be useful in undetermined cases to decide on the growth pattern and grade.

Embryonal tumor with abundant neuropil and true rosettes: a report of three cases of a rare tumor, with an unusual case showing rhabdomyoblastic and melanocytic differentiation.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is an increasingly recognized entity that belongs to the family of embryonal tumors of the CNS. The authors present three cases of this rare tumor that were encountered at King Hussein Cancer Center, Amman, Jordan. Discussion of the clinicopathological findings is presented along with a recent literature review. Sixteen-, 57- and 30-month-old children presented with tumors located in the pineal gland, the right fronto- parieto-temporal region and the cerebellum, respectively. The findings of hypocellular neuropil as well as the characteristic ependymoblastic rosettes were seen. In addition the third case showed an abnormal combination of patterns including melanocytic and rhabdomyoblastic differentiation. The tumors stained positively for synaptophysin in the neuropil and small cell component, while the ependymoblastic rosettes stained for vimentin only. Epithelial membrane antigen and CD99 were negative in all components. One of the cases showed tetraploidy of chromosome 2. All cases exhibited an aggressive course. This is a rare and recently recognized tumor with dismal outcome, and reporting of additional new cases should help in gaining more knowledge about it.

Mondini malformation associated with diastematomyelia and presenting with recurrent meningitis.

The authors report the case of 5-year-old girl who presented with 4 episodes of recurrent meningitis. Her initial workup revealed a lumbosacral dermoid sinus associated with diastematomyelia and a tethered cord. Therefore, a surgical repair to correct the anomaly was performed. However, another episode of meningitis occurred after surgery, and a subsequent temporal bone scan revealed the presence of left Mondini dysplasia. To the authors' knowledge, this is the first report of Mondini dysplasia in association with diastematomyelia.

Descriptive epidemiological analysis, MRI signals intensity and histopathological correlations of meningiomas.

OBJECTIVES: To present our experience in operated meningioma cases regarding their prevalence, anatomical location, multiplicity, presenting signs and symptoms, and the possible correlation between MRI signal intensity and histological grades to set criteria for radio-pathological diagnosis. METHODS: In this retrospective study, operated meningioma cases in the Department of Neurosurgery, Jordan University Hospital (JUH), Amman, Jordan between January 1997 and January 2007 were reviewed. Our study included 90 cases, and their medical records, histopathological reports, and neuroimages were analyzed thoroughly. RESULTS: Meningioma was more common in females than males with a ratio of 2.2:1. Para-sagittal meningiomas were the most common (23.3%). Multiple intracranial meningiomas were found in 4.4% of the cases. Most cases were of benign histopathology and exhibited iso-intense signals on T1 and T2, and appeared with hyper-intense signals on FLAIR with vivid enhancement. CONCLUSION: The prevalence of meningioma among genders and its anatomical location at JUH corresponds to the published medical literature worldwide. There was no correlation between signal intensities (as seen on T1WI, T2WI, and FLAIR sequences), enhancement pattern on one side, and histological grades on the other side.

Closing the survival gap: implementation of medulloblastoma protocols in a low-income country through a twinning program.

Successful twinning initiatives have been reported in childhood leukemia. Pediatric neuro-oncology requires a complex multidisciplinary approach and the feasibility of similar twinning programs is unknown. Twinning between King Hussein Cancer Center in Amman and the Hospital for Sick Children in Toronto started with e-mail communications, and subsequently included monthly videoconferences and exchanges between institutions. The outcome of 35 newly diagnosed medulloblastoma patients (22 high-risk and 13 average-risk) treated during this period is reported. The 3-year overall survival for average risk and high-risk patients was 100 and 81%, respectively. This experience suggests that twinning may facilitate the implementation of multidisciplinary neuro-oncology programs in low-income countries. Videoconferencing allows interactive exchanges with a significant learning impact.

Impact of telemedicine on pediatric neuro-oncology in a developing country: the Jordanian-Canadian experience.

BACKGROUND: Telemedicine is widely used in industrialized countries for educational purposes. Twinning experiences using telemedicine between institutions in industrialized and developing countries (DC) have been limited. Pediatric neuro-oncology is a complex multidisciplinary discipline that is underserved in most of DC and provides a model to test the feasibility of such tool for twinning purposes. METHODS: A computer, an EMLO visual presenter HV-7600SX document camera, and a TANDBERG 6000 model videoconference unit were used to present data. For connectivity, we used a six-channel ISDN telephone line. Each channel is 64 megabytes/sec. RESULTS: Between December 2004 and May 2006, 20 sessions of videoconference were held between King Hussein Cancer Center and the Hospital for Sick Children to discuss 72 cases of 64 patients with various brain tumors (5 patients were discussed twice and 1 patient four times). In 23 patients (36%), major changes from original plan were recommended on different aspects of the care. In 21 patients (91%), those recommendations were followed, with potentially significant positive impact on patients' care. CONCLUSIONS: Videoconferencing is a feasible and practical twinning tool in pediatric neuro-oncology with a potentially major impact on patient care.

Ataxia-telangiectasia complicated by craniopharyngioma--a new observation.

Ataxia-telangiectasia is a rare autosomal recessive neurodegenerative disorder with high incidence of malignancy including leukemias, lymphomas, and solid tumors. Central nervous system tumors in ataxia telangiectasia include medulloblastomas and gliomas. We describe a 13-year-old girl with ataxia telangiectasia who developed craniopharyngioma and non-Hodgkin's lymphoma. To our knowledge, this is the first case of ataxia telangiectasia complicated by craniopharyngioma in the English literature.