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.

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.

[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.

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.

Trilateral retinoblastoma: potentially curable with intensive chemotherapy.

BACKGROUND: Trilateral retinoblastoma has been lethal in virtually all cases previously reported. We describe a series of 13 patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. PROCEDURE: Induction chemotherapy generally included vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide. Hematopoietic stem cells typically were harvested after the first or second cycle of induction chemotherapy, usually from peripheral blood. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan and cyclophosphamide (n = 3). RESULTS: Trilateral sites were pineal (n = 11) and suprasellar (n = 2); 7 patients had localized (M-0) disease and six had leptomeningeal dissemination (M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intra-ocular retinoblastoma; eight later developed trilateral disease at a median of 35 months (range 3-60 months) following diagnosis of intra-ocular retinoblastoma. One patient died of toxicity (septicemia and multi-organ system failure) during induction and three developed disease progression prior to high-dose chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months (range 4-9) post-diagnosis of trilateral disease. Five patients survive event-free at a median of 77 months (range 36-104 months) and never received external beam radiation therapy. Four of seven patients with M-0 disease survive event-free versus only one of six patients with M-1+ disease. CONCLUSIONS: Intensive chemotherapy is potentially curative for some patients with trilateral retinoblastoma, especially those with M-0 disease.

Successful treatment of trilateral retinoblastoma with conventional and high-dose chemotherapy plus radiotherapy: a case report.

Trilateral retinoblastoma (TRB) is a rare condition characterized by an intracranial neuroblastic tumor associated with bilateral or unilateral retinoblastoma (RB). The outcome is almost always fatal. An 18-month-old patient with familial bilateral RB was referred for a pineal lesion detected on a screening by magnetic resonance imaging. The child, considered inoperable by 2 different neurosurgical teams, was treated with conventional chemotherapy (methotrexate, vincristine, vepeside, cyclophosphamide, and carboplatin) plus tandem transplantation (vepeside/carboplatin and thiotepa/mephalan) followed by local radiotherapy. At 80 months from the diagnosis of TRB, the patient is alive and in complete remission, with no neuropsychologic consequences. An early and aggressive treatment may improve the prognosis of TRB.

What's growing on? The growing teratoma syndrome.

BACKGROUND: The growing teratoma syndrome (GTS) consists of a mature teratoma paradoxically enlarging during or after chemotherapy for malignant nongerminomatous germ cell tumors. METHODS AND RESULTS: We report two cases of GTS occurring in association with NSGCT of the pineal gland. Although an unusual event, clinicians and radiologists should be aware of its natural history. CONCLUSIONS: When normalized tumor markers after chemotherapy are associated with imaging features of a growing mass, the hypothesis of GTS must be taken in consideration. When early diagnosed, GTS can be managed surgically with good results.

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.

Response of an adult patient with pineoblastoma to vorinostat and retinoic acid.

We report the case of an adult patient with pineoblastoma (PBL) who had a complete radiographic response following treatment with vorinostat and retinoic acid. This regimen was used to treat bulky residual tumor that persisted despite radiation therapy (RT) and two cycles of cytotoxic chemotherapy. Vorinostat and retinoic acid were chosen as an alternative to cytotoxic chemotherapy, which our patient was unable to tolerate, based on preclinical data suggesting efficacy of this combination. MRI demonstrated a complete response to this regimen, which continues to remain stable without evidence of recurrence.

Synchronous mixed germ cell tumor of the pineal gland and suprasellar region with a predominant angiomatous component: a diagnostic challenge.

We present a case of synchronous involvement of the pineal and suprasellar regions by a mixed germ cell tumor comprising germinoma and yolk sac tumor components, with a predominant angiomatous component. To our knowledge, it is the first case of this nature to be reported in the literature. Usually, synchronous lesions of this kind are pure germinomas, and some clinicians will forgo a biopsy and assume a germinoma histology if the serum beta-human chorionic gonadotrophin (HCG) is <50 IU/l and the alpha-fetoprotein (AFP) is within normal limits. Secondly, if a biopsy is performed on a lesion that has a prominent angiomatous component, the diagnostic germ cell tumor may be missed at the time of the biopsy. In order to alert clinicians and pathologists to this rare entity, the case is discussed with particular reference to difficulties that were encountered in rendering an accurate diagnosis, and the associated management implications.

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.

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.

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.

Recurrent intracranial germinoma along the endoscopic ventriculostomy tract. Case report.

The authors report a case of a recurrent intracranial germinoma along the site of an endoscopic third ventriculostomy (ETV) after complete local tumor control using 3D conformal radiation therapy. A 13-year-old girl presented with sudden left upward gaze limitation for 4 days. A pineal region tumor and obstructive hydrocephalus were noted on magnetic resonance (MR) images. An ETV and tumor biopsy procedure were performed, which revealed the lesion to be a germinoma. The patient's visual symptoms and hydrocephalus disappeared postoperatively. Chemotherapy using cisplatin, etoposide, vincristine, and cyclophosphamide was initiated on postoperative Day 10. An MR image obtained 10 weeks after surgery and 2 weeks after chemotherapy revealed a significant (> 50%) reduction of the lesion. Radiation therapy was administered at 50.4 Gy to the target and 36 Gy to the periphery. Ten months after surgery, an MR image revealed further shrinkage of the tumor mass. One year after surgery, follow-up MR imaging demonstrated a small mass lesion at the entry site of the ETV, measuring 1.0 x 1.4 x 1.5 cm. An operation was performed to remove the small lesion, and pathological findings revealed it to be of the same histology as the primary tumor.

Late intrathoracic relapse of pineal germinoma connected to intraspinal canal.

Extraneural metastases of intracranial germinoma are rarely reported. The authors describe the first case of metastatic lung germinoma of the thoracic spine. A 27-year-old man presented with right shoulder pain and right upper limb weakness. He had a history of repetitive radiation therapy - nine (whole-abdomen; 15Gy), 12 (whole brain; 30Gy, whole spine 42Gy) and 14 years ago (local; 32Gy) - for abdominal metastasis, temporal and fourth ventricle metastasis and spinal dissemination and metastatic pineal germinoma, respectively. Magnetic resonance imaging revealed a lung mass invading the thoracic spine that was diagnosed as a germinoma by tumor biopsy. He was treated by irradiation with 54Gy and two cycles of chemotherapy with cisplatin and etoposide. He did not have any sign of tumor eight years later.

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.

Postoperative adjuvant treatment for pineal parenchymal tumour of intermediate differentiation.

Pineal parenchymal tumour of intermediate differentiation (PPTID) in adults is rare and a treatment strategy for this condition has not yet been established. We present a case of an elderly patient treated with postoperative adjuvant therapy using radio- and chemotherapy. This 60-year-old man presented with a 3-month history of memory disturbance, gait instability and double vision. Computed tomography and magnetic resonance imaging demonstrated a mass in the pineal region that suggested a malignant tumour. Partial removal of the tumour was undertaken via the right occipital transtentorial approach. The histological diagnosis was PPTID. Postoperative radio- and chemotherapy were administered, with a good response. Little is known about the clinical behaviour of PPTID in adults. Our treatment plan indicates one effective option for the management of such tumours.

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.