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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.

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/m 2 and was then reduced to 5mg/m 2 and 4mg/m 2 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.

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.

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.

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.

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.

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.

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.

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.

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.

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., (Copyright © 2011 Wiley Periodicals, Inc.)

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.

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.

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., (Copyright © 2012 S. Karger AG, Basel.)

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.

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.

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., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objective: Optic pathway/hypothalamic astrocytomas (OPHA) in young children often show accelerated growth and require rather intensive induction chemotherapy., Methods: Fifteen children (median age: 3 years) with a large OPHA were treated. All of them presented with progressive disease, and the tumor size was larger than 34 mm. Pilocytic astrocytoma was confirmed histologically in 10 patients. Eleven patients had visual disturbance, six had diencephalic syndrome and four had hydrocephalus., Results: The children received six to eight cycles of cisplatin (20 mg/m(2): days 1-5) and vincristine (1.4 mg/m(2): days 1, 8, 15), every 4 weeks. Objective response was obtained in 11 patients (73%); one complete response, eight partial responses and two minor responses. Although the remaining four cases were evaluated as stable disease, all tumors decreased in volume. All children tolerated the chemotherapy well under careful audiological monitoring., Conclusion: Although the present series was small, this chemotherapy is a useful regimen for induction therapy in children with an aggressive deep-seated pilocytic astrocytoma.

Parasellar and hypothalamic metastases are uncommon. Their principal clinical manifestation is diabetes insipidus. Associated hypopituitarism is very rare. We report the case of a 54-year-old man with small cell lung cancer and hypopituitarism. A brain magnetic resonance imaging scan revealed a mass in the anterior region of the third ventricle with no clear etiology. The patient began chemotherapy treatment and the mass disappeared, which confirmed the diagnosis of secondary hypopituitarism caused by hypothalamic metastasis from small cell lung cancer.

Background: Hypothalamic-chiasmatic gliomas (HCG) account for up to 20% of tumors in patients under the age of 3 years. While most children respond to chemotherapy, alternative treatment approaches are needed for those with progressive disease refractory to chemotherapy., Procedure: Six patients (median age: 5.5 years) with progressive HCG were treated with imatinib for 3-29 months at a median daily oral dose of 270 mg/m(2). All patients initially presented with extensive tumors during infancy and had undergone two to three surgical resections and two to three prior chemotherapies with multiple agents., Results: The best response achieved was stable disease in all six patients. Disease control lasted from 5 to 46 months and was sustained longer in comparison to their last prior chemotherapy. Toxicities possibly related to imatinib included edema, elevated liver enzymes and bowel problems. Immunohistochemistry in our patients' tumor cells revealed focal expression of arg and PDGFR-alpha in one patient, in the remaining five patients no expression of any of the five known targets of imatinib could be detected. Expression of PDGFR-alpha and PDGFR-beta was detected in endothelial cells of tumor capillaries of all six patients., Conclusions: We conclude that imatinib has possible activity in progressive HCG and may present an additional therapeutic option for patients who are too young or whose tumor is too extensive to receive radiotherapy. However, the optimal use of imatinib in this disease, its mechanism of action, and possible long-term effects remain unclear and will require additional study., (Copyright 2008 Wiley-Liss, Inc.)

Studies on adults with cancer, with or without CNS involvement, have shown that chemotherapy (CT) can affect cognitive functions. Two studies on children with optic pathway gliomas, involving the hypothalamus in some cases, and treated with CT according to various protocols reported the children maintaining a good IQ (no other cognitive abilities were tested). Among 18 children with chiasmatic-hypothalamic tumors (CHT) given front-line CT treatment at our institute using the same protocol (cisplatin and etoposide), we screened eight children for cognitive sequelae, correlating their test performance with several clinical variables (age at diagnosis and at time of treatment, time elapsing since treatment, and tumor volume reduction). The neuropsychological evaluation involved measuring IQ in all eight children and cognitive flexibility in three before CT (T1), then testing IQ, attention, memory and executive functions after CT (T2). The group as a whole showed no signs of any decline in IQ from T1 to T2, except for some WISC items, but IQ deteriorated severely in three patients with NF1 (only suspected in one case). At T2, the whole sample performed within normal range, except for two children showing a significantly worse result in two specific tests. The parents of the other 10 children, reported no substantial changes in their children's behavior and intellectual vivacity in a semistructured telephone interview conducted in cooperation with the children's teachers. CT alone as front-line treatment for CHT does not appear to have a negative effect on IQ and numerous neuropsychological tests. Some skills were more affected than others in our sample (albeit with a very low statistical significance of the impairment), and some patients seemed to be more vulnerable than others after CT. The multifactorial origin of such cognitive impairments is discussed. This type of study needs to be repeated in larger, but nonetheless carefully selected groups of patients.

Optic pathway/hypothalamic pilocytic astrocytomas in children are usually treated with chemotherapy following a surgical biopsy. In this report, we retrospectively considered the role of surgical intervention. In a series of 25 patients without neurofibromatosis type 1, the median age at initial treatment was 3.1 years (range, 0-15 years). Twenty cases were verified by histology, and five cases were diagnosed by MRI findings. Twenty-three patients received chemotherapy. All patients were alive at median follow-up of 66 months. Aims of surgery at the initiation of treatment were biopsy in 12 cases (1 stereotactic and 11 craniotomies) and debulking in 7 cases. The 11 open biopsies revealed pilocytic astrocytoma; however, noticeable complications occurred in five children after the biopsies. Review of preoperative MRIs showed that all had typical findings indicating pilocytic astrocytoma. The open biopsy offered no noteworthy benefit for the patients despite surgical risk and delay of chemotherapy. The extent of the seven resection surgeries was 70% or less removal, and postoperative adjuvant therapy was needed for six of the seven patients. The remaining six children who did not undergo surgery obtained remission with chemotherapy alone. After relapse in nine patients, 15 bulk-reduction surgeries were performed. Surgical resection was not curative in any patient. In five patients, mostly older children, cystic expansion of tumor was partially resected, resulting in additional remission. In conclusion, considering the risk of open surgery and the effectiveness of chemotherapy, the role of surgical intervention is restricted to bulk-reduction surgery only when it is inevitable, especially at relapse after chemotherapy.

Radical resection of chiasmatic-hypothalamic glioma (CHG) carries a significant risk of morbidity and the optimum treatment remains undecided. The authors reported 9 children with CHG, who were treated with surgical resection with or without postoperative chemotherapy. Age at the time of diagnosis ranged from 4 months to 7.7 years (mean 3.1 years), and no patient had evidence of neurofibromatosis type 1. Surgical resections of the tumors were performed in all patients because of severe visual impairment or intracranial hypertension caused by large tumors. All of the surgical interventions resulted in partial resections. Pathological examination revealed pilocytic astrocytomas in 7 patients, low grade astrocytoma in 1 and anaplastic astrocytoma in 1. Seven patients with residual tumors received postoperative chemotherapy consisting of cisplatin, cyclophosphamide, etoposide and vincristine. Reduction in tumor size was noticed in 5 patients, although 2 patients had no response and switched to local radiotherapy. Although minor complications of chemotherapy were noticed in 5 patients, severe sequelae such as neuropsychological deficits or endocrinopathies did not occur, and all patients completed chemotherapy programs. Additional treatments are recommended in case of incomplete tumor resections, because our experience demonstrates that the majority of the residual tumors have potential to progress. Our present data suggests that the chemotherapy of the aforementioned regimen is effective in controlling CHGs after partial resections and is relatively well tolerated even in young children who are vulnerable to radiotherapy.

Background: Diencephalic syndrome (DS) is a rare cause of failure to thrive in early childhood. It is associated with neoplastic lesions of the hypothalamic-optic chiasmatic region. Treatment options consist of surgical resection, radiation therapy (RT) and chemotherapy. We describe the clinical course of two children suffering from diencephalic syndrome due to unresectable hypothalamic gliomas and emphasize the importance of chemotherapy as a first-line treatment., Patients and Methods: We report about two children, at the age of 21 months and 13 months at diagnosis, who presented with severe dystrophy at 12 months and 6 months respectively. Imaging of the brain showed a suprasellar mass, identified histologically as low grade pilocytic astrocytoma. Both patients were treated with chemotherapy which induced tumor regression and stable disease., Results: The two children gradually gained weight and improved remaining in stable remission., Conclusions: Diencephalic syndrome caused by a hypothalamic/chiasmatic astrocytoma is a rare cause of failure to thrive in children so that diagnosis is frequently delayed. It should be considered as differential diagnosis in any child with dystrophy despite adequate caloric intake. Since most of these tumors in that specific anatomic site are regarded to be unresectable, chemotherapy including carboplatin and vincristine may reveal clinical improvement in these patients.

Purpose: Obesity is a common consequence in patients with tumors of the hypothalamic region and of related treatment in children. Much less information is available on adult patients and long-term survivors. The aims of this study were to estimate the prevalence of obesity in adult patients with acquired structural hypothalamic damage and to define the characteristics of patients at greatest risk of obesity., Methods: A retrospective study was conducted of 52 patients (25 women; median age at diagnosis, 44 years; range, 17 to 78 years) with tumors involving the hypothalamic region. These included 22 craniopharyngiomas, 24 pituitary adenomas, and six other hypothalamic tumors. Changes in body mass index were determined, magnetic resonance imaging scans were scored by a radiologist for tumor size and the extent of involvement of the hypothalamus, and current hormone replacement therapy was recorded, to identify possible features associated with new or worsened obesity (defined as a body mass index > or =30 kg/m(2) at the latest follow-up, which had increased by at least 2 kg/m(2) since diagnosis of the tumor)., Results: Serial body mass index data from diagnosis to the latest follow-up were available for 42 patients. After a median of 5 years (range, 1 to 19 years) of follow-up, most patients with hypothalamic damage were obese (52% [n = 22] vs. 24% [n = 10] at the time of diagnosis, P < 0.0001). In a multivariate model, use of desmopressin (odds ratio [OR] = 13; 95% confidence interval [CI]: 2.0 to 86; P = 0.007) and growth hormone replacement (OR = 7.6; 95% CI: 1.1 to 51; P = 0.04) were associated with new or worsened obesity during follow-up. No correlation was found between the initial size or location of the tumor and subsequent weight gain., Conclusion: Obesity is highly prevalent in adult survivors of hypothalamic tumors. Use of desmopressin and growth hormone therapy, but not size or location of the tumor, were associated with weight gain and obesity following diagnosis. These findings may be helpful in identifying patients at increased risk of obesity, to whom earlier intervention could be offered.

Hypothalamic/chiasmatic gliomas (H/CG) in children are commonly accompanied by endocrine dysfunction due to mass effects of the tumor itself or as a consequence of tumor therapy, with GH deficiency (GHD) being the most common disorder. We report the height outcomes of GH-treated H/CG patients with GHD. We reviewed the records of 14 GHD patients with H/CG who were treated with human GH. A comparison group of non-GH-treated H/CG patients was also identified. Heights were expressed as sd scores (SDS). For GH-treated patients, the mean initial height was -0.7 +/- 0.3 (+/-se). Their mean final height was -0.3 +/- 0.3. The mean change in height SDS for the GH-treated group was +0.4. The mean initial and final height SDS for the non-GHD patients were 0.6 (se = 0.4) and 0.0 (se = 0.4), respectively. The mean change in height SDS was -0.6. The GHD patients had significantly lower initial height SDS compared with the non-GHD patients (P = 0.01) and had a significantly greater change in their height SDS (P = 0.04). GH treatment for H/CG patients restores much of their growth potential and improves adult height to within normal limits.

We report a 13-month-old boy with diencephalic syndrome (DS) due to an optico-hypothalamic juvenile pilocytic astrocytoma (JPA). Massive neuroaxis dissemination was identified at diagnosis. He received 6 courses of combined conventional-dose chemotherapy consisting of carboplatin (CBDCA), etoposide (VP-16), and cyclophosphamide (CPA) followed by high-dose chemotherapy with CBDCA, CPA, and ranimustine (MCNU) and peripheral blood stem cell transplantation (PBSCT). This treatment produced tumor regression in both intracranial and spinal lesions and remarkable improvement of DS. The rare combination of DS and symptomatic neuroaxis dissemination of JPA at diagnosis suggests that the behavior of some of these tumors is more aggressive and resistant to conventional-dose chemotherapy than is that of JPA without DS manifestation and dissemination.

Background: The management of children with hypothalamic (H) and/or chiasmatic (C) tumors remains controversial. We evaluated the impact of clinical and neuroimaging parameters and primary therapy on overall (OS) and progression-free (PFS) survival and on neuroendocrine and neurocognitive outcome in children with H and/or C tumors., Methods: Records were reviewed for 73 children with H and/or C tumors treated at St. Jude Children's Research Hospital between October 1981 and December 1999., Results: Thirty-six patients received irradiation or chemotherapy immediately postdiagnosis and 37 were observed. The 6-year OS and PFS rates were 86 +/- 5%; and 36 +/- 7%, respectively. The 6-year PFS rates for the irradiation, chemotherapy, and observation groups were 69 +/- 16%, 12 +/- 11%, and 37 +/- 9%, respectively. In multivariate analysis, intracranial NF1 lesions (P = 0.015) and initial irradiation (P = 0.056) led to better PFS rates. There was no difference in OS between those initially treated or observed. Mean serial intelligence quotient (IQ) scores were 86 and 86 at diagnosis and at 6 years later, respectively. Patients younger than 5 years old had a lower mean IQ score at diagnosis (79.1) than older patients (96.3; P = 0.003). Patients who were irradiated at diagnosis had a significantly higher cumulative incidence of endocrinopathy at 3 years (P = 0.008)., Conclusions: Overall survival for children with H and/or C tumors is excellent. Initial treatment with radiation and the presence of intracranial NF1 lesions were positive predictors of PFS. Mean IQ is significantly compromised at diagnosis, but does not change over time or with irradiation. Overall survival is not affected by initial observation. We recommend observation in asymptomatic patients, platinum-based chemotherapy in younger patients, and irradiation in older symptomatic patients., (Copyright 2003 American Cancer Society)

Hypothalamic tumors are difficult to treat surgically, and chemotherapy and/or radiation are given based on the histology and the neuraxis staging of the tumors. We have developed flexible neuroendoscopes (Yamadori-type 8 and 9) which have excellent image quality and maneuverability as well as capabilities for biopsy and electrocoagulative debulking of the cystic tumors. We report the successful application of the neuroendoscopes to 10 children with hypothalamic tumors diagnosed with computed tomography or magnetic resonance imaging. Histologic diagnosis was obtained from all the patients. Cystic tumors were evacuated, hydrocephalus managed with endoscopic operations, and some benign tumors were removed totally. The relatively non-invasive approach reported here would represent a significant technical advance in the diagnosis and management of hypothalamic and other ventricular tumors.

An eight-year-old girl presented with vision loss and optic atrophy. Neuro-imaging revealed a sellar mass, which when biopsied proved to be a chiasmatic/hypothalamic glioma. The differential diagnosis of a sellar mass in childhood is discussed, and the presentation and management of chiasmatic/hypothalamic gliomas is reviewed.

Background and Purpose: Optic pathway and/or hypothalamic astrocytomas in children are often quiescent, but in some cases, more aggressive tumors may cause progressive visual, endocrine, and neurologic deterioration. The initial treatment of these gliomas includes surgery and IV chemotherapy. Radiotherapy is not recommended in young children because of its severe adverse effects on cognitive and neuroendocrine function. This report suggests a new approach using combined intraarterial and IV carboplatin-based chemotherapy for patients for whom first line treatment has already failed., Methods: Six children (mean age, 57 months) with the diagnosis of optic pathway hypothalamic gliomas, who had tumor progression after surgery and underwent IV chemotherapy, were treated monthly with intraarterially administered carboplatin, intraarterially administered etoposide phosphate, and IV administered Cytoxan. Four of the children had histologically verified pilocytic astrocytomas, and in two cases, diagnosis was made on the basis of clinical findings. Administration of the intraarterial chemotherapy required catheter placement in both internal carotid arteries at the level of C2-C3 and into one of the vertebral arteries at the level of C6-C7, with the patient under general anesthesia., Results: Four of six patients had partial radiographic response, one had stable disease, and one had progressive disease after one cycle. Three patients showed clinical improvement. There were no serious complications associated with the angiographic procedures. Toxicities included bronchospasm that resolved after 3 to 4 minutes in one patient. One patient showed mild ototoxicity, and four patients needed platelet transfusion because of hematologic toxicity of drugs., Conclusion: These results suggest that this modality of chemotherapy (administered after failure of systemic [ie, IV] chemotherapy), of progressive optic-hypothalamic astrocytomas in young children may be an effective treatment prior to radiotherapy.

Objectives: Optic pathway/hypothalamic gliomas (OPHGs) tend to occur in young children. Treatment options consist of surgical resection, radiation therapy (RT) and chemotherapy. Due to complications induced by surgery and RT, chemotherapy has gained significant recognition for the treatment of OPHG in young children. Chemosensitivity of OPHG in very young children under 3 years of age has not been well documented. We analyzed 14 patients who were treated with chemotherapy with or without surgery., Materials and Methods: Fourteen children younger than 3 years (median age of 10 months) with OPHG were treated between 1988 and 1998. Magnetic resonance imaging was obtained in all cases. Hydrocephalus was present in 8 patients and diencephalic syndrome was noted in 6. Only 3 of these had evidence of neurofibromatosis-1. Five patients had partial tumor resection and 4 had endoscopic biopsy at the time of ventriculoperitoneal shunt placement. Pathological examination revealed low-grade astrocytoma in 5 and juvenile pilocytic astrocytoma in 4. All patients received chemotherapy: carboplatin in 8, a combination of carboplatin and vincristine in 4 and a combination of other agents in 2., Results: Eight (57%) of 14 patients had a sustained reduction of tumor during the follow-up time between 15 months and 8 years. The 5-year progression-free survival was 63%. These tumor reductions were often accompanied by clinical improvements. Diencephalic syndrome responded to chemotherapy alone in 4 of 6 patients. However, 5 others had progressive disease; 3 during the treatment and 2 following the treatment (9 months and 2 years, respectively). All these 5 patients had a partial tumor resection prior to chemotherapy., Conclusion: A majority of OPHGs responds to chemotherapy. Due to slow progression of these tumors and adverse effects of other therapeutic modalities, we recommend chemotherapy as a primary treatment for OPHGs. Our present data indicates that partial surgical resection does not enhance chemotherapy effectiveness for OPHGs in infants or children younger than 3 years., (Copyright 2000 S. Karger AG, Basel)

Chemotherapy is an increasing component of the management of diencephalic gliomas. It can result in tumor shrinkage and significant disease control in some patients. However, decisions concerning the institution of treatment should be based on the goals of treatment. Factors include: (1) age of the patient; (2) whether the child has neurofibromatosis type 1; (3) tumor size and location; (4) the potential sequelae of radiotherapy, and (5) the acute and long-term toxicity of the chemotherapeutic approach utilized. The erratic natural history of diencephalic tumors confounds evaluation of efficacy of the regimen chosen.

Children who have received chemotherapy and radiation therapy for treatment of thalamic/hypothalamic tumors are at risk for late effects, specifically endocrine dysfunction. Evaluation of growth and pubertal development, thyroid function and integrity of the hypothalamic-pituitary-adrenal axis should be undertaken in a prospective manner. Issues of metabolic disturbances such as obesity, altered body composition/bone density as well as ultimate fertility also need to be addressed by ongoing prospective evaluations., (Copyright 2000 S. Karger AG, Basel.)

Hypothalamic/visual pathway astrocytomas in children are usually quiescent, but certain cases contain aggressive neoplasms that cause progressive neurological and visual deterioration. Radiotherapy is not recommended in young children because of its adverse effects later in life. This report describes the efficacy of a chemotherapeutic regimen. Four young children with hypothalamic/visual pathway astrocytoma, with a mean of 18 months of age at diagnosis, were treated with chemotherapy. Three patients had diencephalic syndrome at the disease's onset. Three patients with pilocytic astrocytoma were histologically verified, and another infant was clinically diagnosed. A combination chemotherapy using cisplatin and vincristine was administered in a total of 8 cycles in 3 children and 4 in one child. One patient who demonstrated renal insufficiency after 4 cycles of this regimen was treated with additional 4 cycles using carboplatin instead of cisplatin. The acute and subacute hematologic and otologic toxicities were mild, and a transient renal insufficiency in a child during chemotherapy improved. After chemotherapy, tumor regression was documented in 3 patients, and the disease was observed to be stable in one patient with an evidence of intratumoral necrosis on MRI. Three patients showed neurological and endocrinological improvements. These results suggest that this regimen is feasible in young children and may be useful as a first-line treatment for hypothalamic/visual pathway astrocytomas, which in turn may allow potentially deleterious irradiation on the maturing brain to be deferred until the disease progresses.

The management of a 12-year-old boy with hypothalamic anaplastic astrocytoma is reported herein. The pediatric patient underwent a subtotal removal of his brain tumor, and subsequently received multimodal treatment comprising radiotherapy (30.6 Gy to the whole brain and 50.4 Gy to the local lesion) and immunochemotherapy with MCNU (80 mg/m2, day 1), VP 16 (50 mg/day, days 2 to 6), and interferon-beta (3 x 10(6) units/day, initiating on day 2 for 4 weeks). The immunochemotherapy was given as of 4 weeks after radiotherapy. The administration of anti-cancer drugs caused severe nausea and vomiting, the intra-carotid infusion of MCNU being particularly emetogenic. The multi-modal treatment was then discontinued for a few weeks. A partial response was obtained, and the patient subsequently received 3 courses of maintenance therapy at six-month intervals using the same protocol as for the initial immunochemotherapy. During maintenance therapy, granisetron (40 micrograms/kg) was given intravenously 30 minutes before and one day after the injection of MCNU. Owing to the anti-emetic management of this patient, there were no complications throughout the chemotherapy. The patient has now survived for more than 3 years with a good quality of life, showing a Karnofsky performance score of 90.

Purpose: Chiasmatic-hypothalamic gliomas are not amenable to surgical resection and therefore are treated with either radiotherapy or chemotherapy. Here we report the use of etoposide (VP-16) administered on a chronic oral schedule as a novel chemotherapeutic approach., Patients and Methods: Fourteen patients, aged 2 to 15 years, were treated with VP-16 after clinical and neuroradiographic tumor progression. Thirteen patients had received prior radiotherapy, and 12 received prior nitrosourea-based chemotherapy. VP-16 was administered orally, each cycle consisting of 50 mg/m2/d on day 1 through 21 and 36 through 57. Clinical and neuroradiographic evaluations were performed during days 58 through 72 before initiation of each cycle of therapy. Complete blood counts were performed weekly., Results: Treatment-related complications included the following: partial alopecia (seven patients); diarrhea (six); weight loss (five); neutropenia (four); and thrombocytopenia (four). Three patients required transfusion (three RBC; two platelet), and one patient required antibiotic treatment of neutropenic fever. There were no treatment-related deaths. Fourteen patients were assessable, five of whom demonstrated a radiographic response (one complete and four partial); and three patients demonstrated stable disease, with a median duration of response of 8 months., Conclusion: Chronic oral VP-16 is well tolerated, produces modest toxicity, and has apparent activity in this small cohort of patients with recurrent chiasmatic-hypothalamic gliomas.

In recent years the health problems of adults with growth hormone deficiency (GHD) and the benefits of GH replacement therapy have received considerable attention. However, the reliability of conventional GH tests in the assessment of pituitary GH reserve in this group of patients is still controversial. In this study, we assessed GH secretion after the combined administration of GH-releasing hormone (GHRH) (1 microgram/kg iv) and GH-releasing peptide 6 (GHRP-6, 1 microgram/kg iv) in adult patients diagnosed with GHD by conventional GH testing, and correlate this response with insulin-like growth factor I levels. Twenty-one subjects (13 male, 8 female) with long-standing diagnosis of GHD aged 21-54 years were studied. In 13 subjects GH responses to GHRH plus GHRP-6 were markedly reduced (peak GH response < 10 mU/l), whereas in the remaining eight the response was greater (range 11-100 mU/l). In conclusion, our data show that combined administration of GHRH plus GHRP-6 elicited a significant increase in plasma GH levels in about 40% of patients diagnosed with GHD by conventional GH testing.

Background: Chiasmatic-hypothalamic gliomas are not amenable to surgical resection and therefore are treated with either radiotherapy or chemotherapy. Etoposide (VP-16), administered on a long-term oral schedule, represents a novel chemotherapeutic approach., Patients and Methods: Fourteen patients (age range, 2 to 15 years) were treated with etoposide following tumor progression as determined by clinical and neuroradiographic examinations. Thirteen patients had received prior radiotherapy, and 12 received prior nitrosourea-based chemotherapy. Etoposide was administered orally; each cycle consisted of 50 mg/m2 per day on days 1 to 21 and days 36 to 57. Clinical and neuroradiographic examinations were performed from days 58 to 72 prior to the start of each cycle of therapy. Complete blood cell counts were performed weekly., Results: Treatment-related complications included partial alopecia (n = 7), diarrhea (n = 6), weight loss (n = 5), neutropenia (n = 4), and thrombocytopenia (n = 4). Three patients required a transfusion (ie, red blood cell [n = 3] and platelet [n = 2] transfusions), and one patient required antibiotic treatment of neutropenic fever. There were no treatment-related deaths. Fourteen patients were evaluable; in eight of these 14 patients, a response was demonstrated radiographically (complete response [n = 1], partial response [n = 4], and stable disease [n = 3]), with a median duration of response of 8 months., Conclusions: Long-term treatment with oral etoposide was well tolerated by the patients in this study, and etoposide was a relatively nontoxic chemotherapeutic agent with apparent activity in this small cohort of patients who had recurrent chiasmatic-hypothalamic gliomas.

Six patients with optic pathway gliomas who were previously managed with surgery and/or chemotherapy were treated with carboplatin (560 mg/sq m) after radiographic evidence of disease progression. The median age at diagnosis was 2 years (range 4 months to 7 years), and the interval between diagnosis and carboplatin therapy ranged between 7 months and 6.5 years (median 1.8 years). Treatment was given at 4-week intervals and continued until unacceptable toxicity supervened, the disease progressed, or the disease was stable for 12 months. All patients demonstrated disease stability at the outset of the third cycle and continued to do so at the time of this writing. Two patients are 16 and 32 months from initial carboplatin therapy and have been off treatment for 5 and 14 months, respectively; two patients are still receiving therapy at 7 and 11 months after their initial treatment. During the study, two patients developed hypersensitivity to the drug, requiring its discontinuation. Toxicity was minimal, consisting mainly of thrombocytopenia, requiring a one-dose reduction in four of the six treated patients. No platelet transfusions were needed. These results suggest that carboplatin can arrest growth of progressive optic pathway gliomas in children and can allow delay of radiotherapy. A larger trial will be required to define the optimal use of carboplatin in the treatment of low-grade gliomas in children.

Five children, three girls and two boys, were treated for precocious puberty secondary to hypothalamic hamartoma by resection of the hamartoma. The patients' ages at onset of pubertal development ranged from 6 to 19 months. The hamartomas ranged in size from 6 to 10 mm; four were pedunculated, one was sessile, and all were located below the tuber cinereum. The hamartomas were excised via a right subtemporal approach, with transection at the inferior surface of the hypothalamus; two were adherent posteriorly to the basilar artery and brain stem, and the adhesions were divided. Postoperatively, three children exhibited a transient oculomotor paresis and one other child required eye-muscle surgery. The symptoms and signs of precocious puberty completely regressed postoperatively in all patients. Preoperative hormone assays of testosterone, luteinizing hormone, and follicle-stimulating hormone were within the pubertal range in all five children; postoperative assays fell to prepubertal levels. The children have been followed for 0.5 to 10.5 years (mean 5.0 years) postoperatively, without evidence of recurrence of precocious puberty. One child has begun spontaneous puberty at a normal age. It is concluded that complete resection of hypothalamic hamartomas causing precocious puberty is curative.

PP therapy, combination therapy with Cis-platinum (CDDP) and tetrahydropyranyladriamycin (THP-ADR), were performed on a case of recurrent medulloblastoma. CDDP and THP-ADR involve agents difficult to pass the blood brain barrier (BBB), but can pass BBB on the metastatic lesion. PP therapy is considered to be one of the most effective agents for the treatment of recurrent malignant brain tumor.