Trametinib Toxicities in Patients With Low-grade Gliomas and Diabetes Insipidus: Related Findings?

Low-grade gliomas (LGG) represent the most common form of primary central nervous system tumor arising in childhood. There is growing evidence to support the role of the mitogen-activated protein kinase pathway in driving tumor growth and MEK inhibitors are being investigated in clinical trials for refractory and unresectable LGGs. As MEK inhibitors progress through clinical trials, drug toxicities have been identified. We report on 2 pediatric patients with LGG and known diabetes insipidus who developed severe hyponatraemia associated with significant decreases in desmopressin doses after starting trametinib. We review potential mechanisms for this sodium imbalance by examining the interaction between MEK inhibition and aquaporin channel physiology. We recommend close monitoring of serum sodium levels and clinical status in patients with diabetes insipidus who have optic-hypothalamic gliomas and are started on treatment with MEK inhibitors.

[Weekly Vinblastine in Pediatric Optic Pathway/Hypothalamic Glioma:2 Cases Report].

It is reported that vinblastine monotherapy has promising activity in patients with pediatric optic pathway/hypothalamic glioma(OPHG)who experienced treatment failure after initial treatment with standard chemotherapy. However, there have been no reports on vinblastine monotherapy against OPHG in Japan. Since vinblastine is an unauthorized drug under the Ministry of Health and Welfare, we used it after completing an in-hospital institutional review board application for each case. In the first case, a 6-year-old boy with recurrent OPHG with hydrocephalus was referred to our hospital. Weekly vinblastine was started at a dose of 6mg/m2 and was then reduced to 5mg/m2 and 4mg/m2 sequentially due to hematotoxicity. After 11 cycles of vinblastine, improvement in hydrocephalus was observed. After 22 cycles of vinblastine, the best response was observed, and we continued treatment up to 35 cycles. Progression of the disease was observed after 47 cycles and then we changed treatment to another regimen after 48 cycles of vinblastine. In the second case, a 6-year-old boy with chemotherapy-naïve recurrent OPHG underwent chemotherapy with vincristine and carboplatin. After 9 treatment cycles with carboplatin, hypersensitivity was observed. Subsequently, he was treated using weekly vinblastine as per the same protocol as that in our first case. A moderate response was observed after 18 cycles of vinblastine. After 48 cycles of vinblastine, the best response was observed, and we completed treatment. In both cases, severe adverse events were not observed and the treatment was well-tolerated. Vinblastine administered once per week is well-tolerated and maintains quality of life in children with OPHG.

Monitoring optic chiasmatic-hypothalamic glioma volumetric changes by MRI in children under clinical surveillance or chemotherapy.

PURPOSE: Optic pathway gliomas represent 5% of pediatric brain tumors and are typically low-grade lesions. Because of their unpredictable clinical course, adequate treatment approaches have been controversial, involving surveillance, surgery, chemotherapy, and radiotherapy. In this study, we use volumetric imaging to compare evolution of optic chiasmatic-hypothalamic gliomas (OCHG) treated with and without chemotherapy, analyzing tumor volume variation during the overall period. METHODS: A total of 45 brain MRI were retrospectively analyzed for 14 patients with OCHG. Volumetric assessment of the lesions was performed by a neuroradiologist, using software DISPLAY. OCHG patients were allocated into two groups: group 1 (n = 8) who underwent chemotherapy and group 2 (n = 6) who did not receive chemotherapy. Outcome analysis was performed comparing tumor volume evolution of these two groups. RESULTS: The results showed a reduction of 4.4% of the volume of the lesions for group 1 after the end of chemotherapy, with an increase of 5.3% in volume in the late follow-up examination. For group 2, we found a slight reduction (5%) of the overall volume of the lesions, both with no statistical significance (p > 0.05). CONCLUSIONS: From the limited series analyzed in this study, no significant differences were observed in relation to the volume change of lesions treated or not treated with chemotherapy. Larger prospective clinical trials are needed to better evaluate the effect of chemotherapy and radiological response of OCHG.

Report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric response.

Brain tumors are the most common solid tumor in childhood, and astrocytomas account for the largest proportion of these tumors. Increasing sophistication in genetic testing has allowed for the detection of specific mutations within tumor subtypes that may represent targets for individualized tumor treatment. The mitogen-activating protein kinase (MAPK) pathway and, more specifically, BRAF mutations have been shown to be prevalent in pediatric pilocytic astrocytomas and may represent one such area to target. Herein, the authors describe 2 cases of inoperable, chemotherapy-resistant pediatric pilocytic astrocytomas with a documented response to trametinib, an MAPK pathway inhibitor. While these cases were not treated in the setting of a clinical trial, their data support further ongoing clinical trial investigation to evaluate the safety and efficacy of this agent in pediatric low-grade gliomas.

Long-tunnelled external ventricular drain as a long-term treatment option for hydrocephalus in a child with an unresectable low-grade supratentorial tumor: case report.

The authors report a case of a child with hypothalamic-origin pilocytic astrocytoma and hydrocephalus, which was refractory to treatment with a ventriculoperitoneal shunt due to high CSF protein content. With parental education, the child's hydrocephalus was managed long-term in the community with a long-tunnelled external ventricular drain, which was maintained by his parents. To the authors' knowledge this is the first report of this management option as a long-term measure. No harm has come to the patient. The authors propose long-term, long-tunnelled external ventricular drain as a viable treatment option for such patients.

[Growing teratoma syndrome in a patient with intracranial germ cell tumor].

A six-year-old patient with non-germinomatous germ cell tumor of the chiasmatic-sellar area developed polyuria and polydipsia as the first symptoms of the disease. Then there were signs of precocious puberty and vision impairment. MRI examination revealed a shiasmatic sellar tumor and occlusive hydrocephalus. Tumor marker levels in blood serum were elevated. The alpha-fetoprotein level was increased 5-fold; human chorionic gonadotropin 20-fold. These levels increased over time. The patient received 2 cycles of PEI multiagent chemotherapy (Ifosfamide 1.5 g/m(2), Cisplatin 20 mg/m(2), Etoposide 100 mg/m(2)) during 5 days and 1 cycle of second-line multiagent chemotherapy (Cisplatin 100 mg/m(2) for 1 day and Endoxan 1500 mg/m(2) for 2 days). Despite the decrease in tumor marker levels to normal values, the patient's vision still deteriorated. MRI examination revealed that tumor size increased and its structure changed. Total tumor resection led to vision improvement and regression of intracranial hypertension. Histological analysis of tumor tissue only revealed a mature teratoma. This phenomenon, known as growing teratoma syndrome, is very rare among patients with intracranial non-germinomatous germ cell tumors.

The role of surgery in optic pathway/hypothalamic gliomas in children.

OBJECT: Optic pathway/hypothalamic gliomas (OPHGs) are generally benign tumors situated in an exquisitely sensitive brain region. The location and natural history of OPHGs has led to much debate about optimal treatment. This paper revisits the role of and optimal timing of debulking surgery in OPHG. METHODS: This paper presents a series of cases managed by the neuro-oncology team at Alder Hey Children's Hospital and a single surgeon. Data were collected retrospectively for periods prior to 2009 and prospectively thereafter. Tailored treatment strategies were used, including observation and combinations of surgery, chemotherapy, and radiotherapy. Tumor control rates and outcomes are reviewed. RESULTS: Forty-two patients were treated between 1998 and 2011. Their median age at diagnosis was 5 years 7 months. Nineteen patients were positive for neurofibromatosis Type 1 (NF1) and 23 patients were negative for NF1. The median duration of follow-up was 77 months (range 21.8-142.3 months). Presenting symptoms included visual impairment (in 50% of cases), headache (in 24%), and hypothalamic/pituitary dysfunction (in 29%). Twenty-two debulking procedures were performed in 21 patients. Four biopsies (3 open, 1 endoscopic) were also performed. The histological diagnosis was pilocytic astrocytoma in 21 patients and pilomyxoid astrocytoma in 2 patients. Ten patients (Group 1) had primary surgical debulking alone and were then observed. Four patients (Group 2) had surgical debulking, plus planned chemotherapy within 3 months. Seven patients (Group 3) required surgical debulking for progressive disease following a variety of treatments. Patient age had the greatest impact on subsequent tumor progression. In total, 13 patients received chemotherapy, 4 on initial presentation, 4 in combination with surgery, and 5 for further tumor progression. Five patients were treated with radiotherapy, 3 prior to referral to Alder Hey. Eleven patients required shunt insertion for hydrocephalus. Vision was stabilized for 74% of patients. The number of patients with hypothalamic/pituitary dysfunction increased from 12 at presentation to 16 by the end of treatment. The overall survival rate was 93%. Three patients died-1 from tumor progression, 1 from infective complications from tumor biopsy, and 1 from a spontaneous posterior fossa hemorrhage. NF1 was associated with improved outcome-fewer patients required active intervention and rates of visual impairment and/or or hypothalamic/pituitary dysfunction were lower. CONCLUSIONS: Good long-term survival and functional outcomes can be achieved in children with OPHG. Tumor control was achieved through an individualized approach using surgery, chemotherapy, or radiotherapy in varied combinations. The authors aim to limit radiotherapy to cases involving older children in whom other therapies have failed, due to the well-described and often devastating late effects associated with midline cranial irradiation. Surgery has a clear role for diagnosis, tumor control, and relief of mass effect. In particular, primary surgical debulking of tumor (without adjuvant therapy) is safe and effective. Recent advances in intraoperative MRI may add value and need further assessment.

Platinum compounds and sodium metabolism in children with diencephalic glioma.

In this brief report we have described eight children affected by optic pathway/hypothalamus gliomas and treated with carboplatin and/or cisplatin, which developed a derangement of sodium and water metabolism, due to diabetes insipidus (DI) or to syndrome of inappropriate antidiuretic hormone secretion (SIADH) after surgical resection. In four out of these eight patients the treatment with platinum compounds produced prolonged haematological toxicity and in five out of them it caused neurosensorial bilateral hypoacusia. In addition cisplatin worsened electrolytes disturbances. Hence children with DI or SIADH should be carefully monitored before, during and after the treatment with platinum compounds.

Optic pathway gliomas in adolescence--time to challenge treatment choices?

BACKGROUND: Optimal management of optic pathway/hypothalamic glioma (OPHG) remains an ongoing challenge. Little is known about the natural history, management strategies, and outcomes in adolescents. Carboplatin-based chemotherapy is a useful modality in younger children, delaying radiation to their immature brains. National trials have focused on younger children and excluded adolescents from studies evaluating the role of chemotherapy. METHODS: This retrospective study describes clinical characteristics, treatment regimens, and outcomes in adolescents (aged ≥ 10 years) with OPHG (diagnosis during 1990-2006). Progression-free survival was compared with that in a cohort of younger children (aged <10 years). RESULTS: Thirty-three adolescents (19 females, 6 with neurofibromatosis type 1) with OPHG were identified within 2 Canadian pediatric oncology institutions. The majority presented with visual symptoms (82%). More than 55% (18 of 33) involved the posterior tract and/or hypothalamus (modified Dodge classification 3/4). Seventeen were initially observed; 8 remained progression free. Of the 25 of 33 adolescents who required active treatment, 9 (36%) needed second-line therapy. The progression-free survival for any first active treatment at age <10 years (52 of 102) or ≥ 10 years (25 of 33) was similar (46.9 vs 46.8 months; P = .60). In those who received chemotherapy as first-line treatment or after prior nonchemotherapy treatment failure, the progression-free survival trend was superior (62.9 vs 38.9 months) in those aged ≥ 10 years although not statistically significant (P = .16). CONCLUSIONS: Chemotherapy is a valuable treatment modality for the achievement of disease control even in adolescents; their progression-free survival compares favorably with that in younger children. We propose that chemotherapy be considered as a first-line modality in adolescents, avoiding potential radiation-associated morbidities.

Sustained response to weekly vinblastine in 2 children with pilomyxoid astrocytoma associated with diencephalic syndrome.

Diencephalic syndrome (DS) related to hypothalamic/chiasmatic region tumor has mainly been reported with low-grade glioma. We described 2 young children with DS related to pilomyxoid astrocytoma. Despite the recognized more agressive clinical behavior of this histologic subtype, we report successful resolution of DS and sustained tumor response with prolonged use of single-agent vinblastine.

Treatment with glucagon-like Peptide-1 agonist exendin-4 in a patient with hypothalamic obesity secondary to intracranial tumor.

BACKGROUND/AIMS: Patients with hypothalamic tumors frequently experience severe obesity, and its treatment with diet, exercise, and/or pharmacologic treatment has had limited effect. Glucagon-like peptide-1 agonist exenatide (exendin-4), used for treatment of type 2 diabetes, causes persistent weight loss via signaling in the brainstem. METHODS: We report the case of a 17-year-old patient with obesity resulting from a hypothalamic germ cell tumor. He was treated by chemoradiotherapy and exenatide at a dose of 5 µg subcutaneously twice daily. RESULTS: Exenatide resulted in a 29-kg weight loss (BMI reduction from 37.1 to 29.1) after 2.5 years of treatment; significant weight gain occurred shortly after exenatide was discontinued. CONCLUSION: Exenatide resulted in considerable reduction of body weight in a patient with severe hypothalamic obesity. This novel observation requires follow-up clinical studies for establishing the effects of exenatide in patients with disrupted hypothalamic energy regulatory pathways.

Successful treatment with a low-dose cisplatin--etoposide regimen for patients with diencephalic syndrome.

Diencephalic syndrome (DS) is a rare but rapidly fatal condition, usually occurring during the first year of life, as a result of a hypothalamic/chiasmatic tumor. The purpose of this study was to induce an objective tumor response and to achieve rapid weight recovery by using ten three-day courses of reduced-dose cisplatin-etoposide. Between 2004 and 2009, eight pediatric patients with DS as a result of an hypothalamic tumor and with a median age at diagnosis of 6.5 months (range 4-60 months) received 10 monthly courses of cisplatin (25 mg/m(2)/day on days 1-3) and etoposide (100 mg/m(2)/day on days 1-3). Under chemotherapy, rapid weight recovery was observed for all patients; tumor response was observed for six (75 %; partial response in four and minimum response in two). The other two had stable disease at completion of treatment. Mean time to weight recovery was 6 months (range 5-7 months) for pilomyxoid astrocytoma patients, and 3.3 months (range 3-4 months) for those with pilocytic astrocytoma. For DS patients who received nutritional support (enteral or parenteral nutrition) the mean time for weight recovery was 5 months (range 3-7 months) whereas children who were able to orally ingest a high-energy diet had a mean time for weight recovery of 8.66 months (range 3-19 months). After follow-up ranging from 22 to 89 months (median 38 months) all patients are alive. A low-dose cisplatin-etoposide regimen is highly effective regarding tumor response and treatment of DS symptoms/cachexia without causing significant side-effects.

Hypothalamic obesity syndrome: rare presentation of CNS+ B-cell lymphoblastic lymphoma.

Hypothalamic obesity syndrome can affect brain tumor patients following surgical intervention and irradiation. This syndrome is rare at diagnosis in childhood cancer, but has been reported with relapse of acute lymphoblastic leukemia. Here we present a case of hypothalamic obesity syndrome as the primary presentation of a toddler found to have CNS+ B-cell lymphoblastic lymphoma. Cytogenetic studies on diagnostic cerebrospinal fluid revealed MLL gene rearrangement (11q23). Hyperphagia and obesity dramatically improved following induction and consolidation chemotherapy. We describe a novel presentation of hypothalamic obesity syndrome in CNS B-cell lymphoblastic lymphoma, responsive to chemotherapy.

Precocious puberty produced by an osteolipoma of the tuber cinereum.

Central precocious puberty (CPP) is fairly common in girls. In most girls, the etiology for the CPP is unknown. Among the more rare causes of CPP in girls are central nervous system tumors and hamartomas. Osteolipoma of the tuber cinereum, which is the most commonly diagnosed at autopsy, has been reported as a cause of CPP. We describe an 8-year-old girl with central precocious puberty in whom MRI demonstrated a lesion compatible with osteolipoma. Her symptom was breast development that begun at age 7 years and 9 months. Her case history, laboratory studies and imaging are presented. Her puberty was rapidly progressive. She was treated successfully with a GnRHa (Triptorelin 3.75 mg IM q 4 weeks). Her case brings to the forefront the need to perform an MRI in children with rapidly progressing puberty.

Impaired aerobic exercise adaptation in children and adolescents with craniopharyngioma is associated with hypothalamic involvement.

OBJECTIVE: Many patients treated for craniopharyngioma (CP) complain of a relative incapacity for physical activity. Whether this is due to an objective decrease in adaptation to exercise is unclear. We assessed exercise tolerance in children with surgically treated CP and appropriate pituitary hormone replacement therapy compared with healthy controls and we examined the potential relationships with hypothalamic involvement, GH replacement, and the catecholamine deficiency frequently observed in these subjects. DESIGN AND METHODS: Seventeen subjects (12 males and five females) with CP and 22 healthy controls (14 males and eight females) aged 15.3±2.5 years (7.3-18 years) underwent a standardized cycle ergometer test. Maximum aerobic capacity was expressed as the ratio of VO(2max) to fat-free mass (VO(2max)/FFM), a measure independent of age and fat mass in children. RESULTS: VO(2max)/FFM was 20% lower in children with CP compared with controls (P<0.05), even after adjustment for gender. Children with hypothalamic involvement (n=10) had a higher percentage of fat mass (P<0.05) than those without hypothalamic involvement (n=7) and lower VO(2max)/FFM (P<0.05), whereas children without hypothalamic involvement had VO(2max)/FFM close to that of controls (P>0.05). GH treatment was associated with a significant positive effect on aerobic capacity (P<0.05) only in the absence of hypothalamic involvement. No relationship was found between exercise capacity parameters and daily urine epinephrine excretion or epinephrine peak response to insulin-induced hypoglycemia. CONCLUSIONS: Children with CP have a decrease in aerobic capacity mainly related to hypothalamic involvement. The hypothalamic factors altering aerobic capacity remain to be determined.

Combined central precocious puberty and primary gonadal failure after treatment of childhood malignancy in two boys: a diagnostic and therapeutic conundrum.

Central precocious puberty and primary gonadal failure are known sequelae of childhood cancer or its treatment. Here we report two boys with coexistent central precocious puberty and primary gonadal failure after treatment for childhood malignancies.

Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update.

To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3-16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3-20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival.