Mission impossible: chemotherapy in the intensive care for pineal region germ cell tumor.

Pineal region tumors are rare and a heterogenous group of primary central nervous system tumors which are primarily classified as germ cell tumors and non-germ cell tumors. Chemotherapy and radiotherapy as the primary treatment modalities have been reported to result in good outcomes. We discuss the case of a young girl who presented to our emergency department in an unconscious state and had a large lesion in the posterior third ventricular region, but without any associated hydrocephalus which could explain her stuporous state. Given the rapid decline in her sensorium, we were faced with the difficult choice between surgical decompression of the tumor and a trial of rescue chemotherapy following histopathological confirmation through biopsy. She underwent an open biopsy followed by chemotherapy in a neurosurgical intensive care unit despite her poor Karnofsky performance score. She improved after chemotherapy and her tumor decreased in size significantly over time. We highlight the role of chemotherapy administered in the neurosurgical ICU to an unconscious patient with a large chemoresponsive tumor leading to rapid shrinkage of the lesion and gradual improvement in the sensorium of the patient.

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy.

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

Upfront chemotherapy followed by response adaptive radiotherapy for intracranial germinoma: Prospective multicenter cohort study.

PURPOSE: To assess the efficacy of upfront chemotherapy followed by response-adapted reduced-dose/reduced-volume radiotherapy (RT) for intracranial germinoma. MATERIALS AND METHODS: Ninety-one patients from five institutions were registered in the KSPNO G051/G081 Protocol. Germinomas were classified as solitary or multiple/disseminated diseases, and upfront chemotherapy was administered. For all patients with multiple or disseminated disease, and patients with partial response after chemotherapy, 19.5-24 Gy of craniospinal irradiation plus 10.8-19.8 Gy of tumor bed boost were planned. For patients with complete response (CR), reduced-dose RT (30.6 Gy) was planned, along with a reduced field for solitary lesions. RESULTS: The median patient age was 14 (range, 3-30) years. Sixty-five patients (71.4%) had a solitary lesion. The median follow-up duration was 67.9 (range, 6.6-119.3) months. Recurrence was not observed in 32 patients in the protocol compliant group. Four patients (4.4%) in the protocol non-compliant group experienced relapse after CR and one patient died of the disease. The 5-year and 7-year overall survival rates were 98.8% and 98.8%, while the corresponding event-free survival rates were 96.6% and 93.8%, respectively. All three patients with basal ganglia germinomas who were treated with local RT experienced recurrence outside the RT field. Among the 23 patients with pineal or suprasellar lesions who received whole-ventricle RT, there was no recurrence. CONCLUSIONS: Currently used upfront chemotherapy followed by reduced-dose, reduced-volume RT appears acceptable, when whole-ventricle RT for pineal or suprasellar tumors and, at minimum, whole-brain RT for basal ganglia/thalamus lesions are applied.

A Case Report of Adult Pineoblastoma Occurring in a Pregnant Woman.

BACKGROUND/AIM: Pineoblastoma of the adult age is an uncommon tumor with only 200 cases reported. A standardized approach for an optimal adjuvant strategy is currently lacking. The case presented herein also deals with the issue of central nervous system tumors in pregnancy. CASE REPORT: A 21-year-old pregnant woman presented with massive hydrocephalus due to a mass in the pineal region detected with MRI. After positioning an urgent ventricular derivation, a cesarean section was performed. During a third ventriculocisternostomy, a biopsy revealed a pineoblastoma. After a maximal safe resection, postoperative craniospinal irradiation for a total dose of 36 Gy plus a sequential boost to the tumor bed to 54 Gy, and adjuvant chemotherapy with CDDP plus CCNU plus vincristine were performed. After one year, the patient is alive with no evidence of disease. CONCLUSION: The use of adjuvant radio-chemotherapy provided excellent outcomes in our case. The advanced gestational age facilitated the choice of the therapeutic strategy.

Minimal disseminated disease evaluation and outcome in trilateral retinoblastoma.

Trilateral retinoblastoma (TRb) presents a management challenge, since intracranial tumours are seldom times resectable and quickly disseminate. However, there are no risk factors to predict the final outcome in each patient. OBJECTIVE: To evaluate minimal disseminated disease (MDD) in the bone marrow (BM) and the cerebrospinal fluid (CSF) at diagnosis and during follow-up and reviewing its potential impact in the outcome of patients with TRb. METHODS AND ANALYSIS: We evaluated MDD in five patients with TRb, detecting the mRNA of CRX and/or GD2, in samples from BM and CSF, obtained at diagnosis, follow-up and relapse. RESULTS: Treatment involved intensive systemic chemotherapy in four patients, one did not receive this treatment and died of progression of the disease. Two patients underwent stem cell rescue. Three patients had leptomeningeal relapse and died. One patient remains disease-free for 84 months. RB1 mutations were identified in the five patients, all of them were null mutations. At diagnosis, one patient had tumour cells in the CSF, and none had the BM involved. Only one case of four presented MDD during follow-up in the CSF, without concomitant detection in the BM. On leptomeningeal relapse, no case had MDD in the BM. In all these cases, cells in the CSF were positive for GD2 and/or CRX. CONCLUSION: CSF dissemination always concluded in the death of the patient, without concomitant systemic dissemination denoting the importance of increasing treatment directed to the CSF compartment. The MDD presence could indicate a forthcoming relapse.

Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors.

The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short-term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2-3, dentate gyrus (DG)-CA4, stratum radiatum-lacunosum-moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short-term verbal associative memory was performed in a subset of brain tumor survivors (N = 11) and typically developing children (N = 16), using the Children's Memory Scale or Wechsler's Memory Scale-third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG-CA4, CA1, CA2-3, and stratum radiatum-lacunosum-moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG-CA4, CA1, and stratum radiatum-lacunosum-moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood.

Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data.

Background: Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods: Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results: Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age ≥4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients <4 years old, 5-year PFS/overall survival (OS) were 11 ± 4%/12 ± 4%. Two patients survived after chemotherapy only, while 3 of 16 treated with craniospinal irradiation (CSI) with boost, and 3 of 5 treated with high-dose chemotherapy (HDCT) and local radiotherapy survived. In 78 patients aged ≥4 years, PFS/OS were 72 ± 7%/73 ± 7% for patients without metastases, and 50 ± 10%/55 ± 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion: Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients.

Treatment Results for Pineal Region Tumors: Role of Stereotactic Biopsy Plus Adjuvant Therapy vs. Open Resection.

AIM: Pineal tumors represent uncommon intracranial tumors with highly diverse histologic subtypes. There still exists a controversy in literature about what influences overall survival and outcome. MATERIAL AND METHODS: We present the results of 48 patients with pineal tumor treated either by stereotactic biopsy followed by adjuvant therapy (23 patients) or open surgical resection without (18 patients) or with (7 patients) adjuvant therapy in Shohada Tajrish Hospital, Iran (1993-2008). RESULTS: Unremarkable pathology yield was 3/23 in the biopsy and 1/25 in the surgical group. Perioperative mortality and morbidity were 4.3% and 0% in the biopsy group and 32.0% and 4.0% in the surgical group. Analysis showed that age, gender, cranial nerve deficit, motor deficit, preoperative Karnofsky Performance Score (KPS), midbrain involvement, and brain stem involvement had no effect on neither perioperative mortality nor long-term survival, while local invasion and pineocytoma pathology increased perioperative mortality and presence of hydrocephalus and pineoblastoma pathology significantly decreased long-term survival. Hospitalization length was shorter in the stereotactic biopsy plus adjuvant therapy group. CONCLUSION: The results of the study suggests that although gross total resection is the standard of care in most pineal tumors nowadays, stereotactic biopsy followed by adjuvant therapy may still be a safe and viable option.

Parinaud «plus¼ syndrome in a patient with dysgerminoma. / Síndrome de Parinaud «plus¼ en paciente con disgerminoma.

CLINICAL CASE: A 33-year-old male diagnosed with Parinaud's syndrome, exotropia and post-papillary oedema optic atrophy in his left eye. A pineal germinoma was diagnosed after performing neuroimaging scans and a stereotactic biopsy. He was treated with chemotherapy and radiotherapy, showing a complete pathological response. The Parinaud's syndrome persists one year after diagnosis and the patient has refused to have strabismus surgery. DISCUSSION: Parinaud's syndrome consists of a supranuclear vertical gaze palsy resulting from damage to the midbrain tectum. The involvement of adjacent structures leads to the «Parinaud-plus¼ syndrome. When a Parinaud's syndrome is accompanied by diplopia («Parinaud-plus¼ syndrome), extension of the injury into adjacent areas must be considered.

Treatment of children with central nervous system primitive neuroectodermal tumors/pinealoblastomas in the prospective multicentric trial HIT 2000 using hyperfractionated radiation therapy followed by maintenance chemotherapy.

PURPOSE: The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4. METHODS AND MATERIALS: After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine). RESULTS: Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (± standard error [SE]) were each 58% (± 10%) for the entire cohort: CNS-PNET was 53% (± 13); pinealoblastoma was 64% (± 15%; P=.524 and P=.627, respectively). CONCLUSIONS: Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.

[Endoscopic approach to ventricular atrium for biopsy of pineal region tumour: case report]. / Abordaje endoscópico al atrio ventricular para toma de biopsia de tumor de la región pineal: a propósito de un caso.

INTRODUCTION: The usual endoscopic approach in the management of pineal region tumours consists of inserting the scope into the frontal horn of the lateral ventricle and advancing it through the foramen of Monro into the third ventricle. We report the case of a patient with a pineal tumour on whom we used an endoscopic approach through the ventricular atrium to obtain a biopsy by opening the choroidal fissure. CLINICAL CASE: This young 25-year-old man presented with headache and double vision. Papilloedema and Parinaud's syndrome were found on physical examination. Cranial magnetic resonance revealed a pineal mass and hydrocephalus. We initially performed a third ventriculostomy and a tumour biopsy through a frontal burr hole. The tissue sample was not useful for pathological diagnosis and we decided to perform a second endoscopic biopsy. CONCLUSIONS: The endoscopic approach to pineal region masses, reaching the ventricular atrium through a parietal burr hole and opening the choroidal fissure, makes it possible to take a biopsy using a single endoscopic approach without needing to cross other ventricular structures.

Assessing therapy response of secreting pineal germ cell tumor on simultaneous 18F-choline PET/MRI.

An 18-year-old man presented with 6 weeks' history of diplopia, early morning headaches, and blurred vision; on ophthalmologic examination, Parinaud syndrome was revealed. Brain MRI scan showed a calcified pineal mass. Brain simultaneous PET/MRI with 18F-choline showed an avid enhancing mass occupying the pineal region with restricted diffusion. A second examination after chemotherapy demonstrated reduction in both size and radiotracer activity of the mass. Our study emphasizes the potential of simultaneous 18F-choline PET/MRI being a useful tool for contribution in the diagnosis and treatment assessment in a convenient way with minimal radiation exposure and reduced throughput patient time.

Primary pineal tumors: outcome and prognostic factors--a study from the Rare Cancer Network (RCN).

PURPOSE: To better define outcome and prognostic factors in primary pineal tumors. MATERIALS AND METHODS: Thirty-five consecutive patients from seven academic centers of the Rare Cancer Network diagnosed between 1988 and 2006 were included. Median age was 36 years. Surgical resection consisted of biopsy in 12 cases and resection in 21 (2 cases with unknown resection). All patients underwent radiotherapy and 12 patients received also chemotherapy. RESULTS: Histological subtypes were pineoblastoma (PNB) in 21 patients, pineocytoma (PC) in 8 patients and pineocytoma with intermediate differentiation in 6 patients. Six patients with PNB had evidence of spinal seeding. Fifteen patients relapsed (14 PNB and 1 PC) with PNB cases at higher risk (p = 0.031). Median survival time was not reached. Median disease-free survival was 82 months (CI 50 % 28-275). In univariate analysis, age younger than 36 years was an unfavorable prognostic factor (p = 0.003). Patients with metastases at diagnosis had poorer survival (p = 0.048). Late side effects related to radiotherapy were dementia, leukoencephalopathy or memory loss in seven cases, occipital ischemia in one, and grade 3 seizures in two cases. Side effects related to chemotherapy were grade 3-4 leucopenia in five cases, grade 4 thrombocytopenia in three cases, grade 2 anemia in two cases, grade 4 pancytopenia in one case, grade 4 vomiting in one case and renal failure in one case. CONCLUSIONS: Age and dissemination at diagnosis influenced survival in our series. The prevalence of chronic toxicity suggests that new adjuvant strategies are advisable.

Expression of O6-methylguanine DNA methyltransferase (MGMT) and immunohistochemical analysis of 12 pineal parenchymal tumors.

Pineal parenchymal tumors (PPTs) are rare neoplasms which occupy less than 1% of primary CNS tumors. Because of their rare incidence, previous reports on PPTs are limited in number and the useful molecular markers for deciding histological grading and even selecting chemotherapy are undetermined. In this study, we conducted immunohistochemical analysis of 12 PPT specimens, especially for expression of O6-methylguanine DNA methyltransferase (MGMT) to assess whether temozolomide (TMZ) could serve as a possible alternative therapy for PPTs. We analyzed 12 PPTs, consisting of three pineocytomas, six PPTs of intermediate differentiation (PPTIDs), and three pineoblastomas. Immunohistochemical analysis was performed using antibodies against MGMT, synaptophysin, neurofilament protein (NF), p53, and neuronal nuclear antigen (NeuN). Immunohistochemically, 11 out of 12 cases were positive for MGMT. The mean MIB-1 labeling index was less than 1% in pineocytoma, 3.5% in PPTID, and 10.5% in pineoblastoma. All 12 cases were positive for synaptophysin and 11 cases, except one PPTID case, showed positive for NF. Nuclear staining of NeuN was negative in all cases although cytoplasmic staining of NeuN was observed in five cases. No case was positive for p53. Eleven out of 12 cases of PPTs demonstrated MGMT expression, suggesting chemoresistancy to TMZ treatment. This is the first report showing MGMT expression in PPTs. In addition, MIB-1 labeling index correlated with WHO grade, although the immunoreactivity of synaptophysin, NF, NeuN and p53 did not correlate with the histological grade.

Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature.

PURPOSE: Bifocal germinoma (BFG) is a rare intracranial neoplasm for which the choice of radiation therapy (RT) field is controversial. Some believe that BFG represents disseminated disease requiring craniospinal irradiation (CSI), whereas others believe that BFG represents localized disease and advocate for more limited fields. METHODS AND MATERIALS: We analyzed 20 BFG patients at our institutions with classic bifocal lesions (pineal gland and suprasellar region). In addition, we identified 60 BFG patients from the literature. The RT fields, use of chemotherapy and extent of disease were recorded and analyzed for each patient. RESULTS: There were 55 patients with bifocal lesions only (Group I), and 25 with bifocal lesions plus ventricular and/or CSF positive disease (Group II). The 5-year progression-free survival was 95% for Group I and 80% for Group II. In Group I, there were no failures in patients receiving CSI (n = 11), two spinal failures in those treated with more limited RT fields without chemotherapy (n = 17), and one spinal failure with chemotherapy (n = 23). In Group II, there were no failures in patients receiving CSI (n = 11), but four spinal failures were observed in patients receiving more limited RT fields with chemotherapy (n = 13); 1 patient who received whole-brain RT without chemotherapy experienced failure in the spine and brain. CONCLUSIONS: CSI is associated with excellent PFS in BFG. In Group I BFG patients, omission of spinal irradiation appears to be a reasonable approach, especially when chemotherapy is used. Patients with Group II BFG are best treated with CSI.

Adjuvant temozolomide chemotherapy for treatment of papillary tumor of the pineal region.

BACKGROUND: We present a personal case of papillary pineocytoma in a 42-year-old woman. METHODS: The lesion was first treated surgically both for diagnostic aims and for resolution of the mass effect causing hydrocephalus and correlated neurological disturbances. Because the tumor recurred after surgery and radiotherapy, we decided to further treat the patient with chemotherapy, in particular with temozolomide. RESULTS: Currently, almost 9 years after the first treatment, the patient is symptom-free and follow-up magnetic resonance imaging shows no tumor recurrence. CONCLUSION: Although surgery should be considered the first-choice therapy, we think that temozolomide can be a valid option in case of recurrence of these rare tumors.

Papillary tumor of the pineal region in a 15-month-old boy.

The papillary tumor of the pineal region (PTPR) is a distinct entity that is particularly rare in the pediatric population. The authors document the youngest reported patient with this clinicopathological entity to date. A case of PTPR in a 15-month-old boy is described. Initially thought to be a tectal glioma, the tumor was later identified as a pineal region tumor after demonstrating growth on routine imaging. Diagnosis of PTPR was established by histopathological evaluation of biopsy samples, which revealed papillary, cystic, and solid tumor components. The patient's postoperative course was complicated by tumor growth despite several debulking procedures and chemotherapy, as well as persistent hydrocephalus requiring 2 endoscopic third ventriculostomies and eventual ventriculoperitoneal shunt placement. After a 15-month follow-up period, the patient has received proton-beam therapy and has a stable tumor size. The PTPR is a recently described tumor of the CNS that must be included in the differential diagnosis of pineal region masses. The biological behavior, prognosis, and appropriate treatment of PTPR have yet to be fully defined.