Central Nervous System Germ Cell Tumors Research Articles

12p gain is predominantly observed in non-germinomatous germ cell tumors and identifies an unfavorable subgroup of central nervous system germ cell tumors.

Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs. Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH). A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs. 12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT.

Multimodality treatment for Central Nervous System Germ Cell Tumors: Disease spectrum and management strategies - A tertiary care center experience from India

ObjectiveIntracranial germ cell tumors (GCTs) are relatively rare neoplasms, representing 2–3 % of paediatric brain tumors in Western countries and 8–15 % in East Asia. Here, we discuss the clinical features and treatment outcomes in patients with central nervous system (CNS) GCTs treated at our institute. MethodsMedical records of all primary CNS GCT patients were retrieved retrospectively from 2007 to 2019. Demographic, clinical, treatment and follow up details were entered in a predesigned proforma. Overall survival (OS) and progression-free survival was computed using Kaplan-Meier method and Log-Rank test. Effect of various prognostic factors on survival outcomes was assessed by univariate and multivariate analysis. ResultsA total of 28 CNS GCT patients were included in this analysis. Median age at presentation was 17 years (range, 7–45 years) with a male to female ratio of 1.8:1. Pineal region was the commonest location, encountered in 15 patients (53.6 %). Pure germinoma was the most frequent histology observed, seen in 19 patients (67.9 %). Male gender and germinoma histology were highly associated with pineal location (p = 0.043 and p = 0.052, respectively). Fourteen patients underwent surgical intervention and nine patients underwent biopsy for diagnostic purpose or to relieve the obstructive symptoms. Only 23 patients (82.1 %) received chemotherapy. However, all patients received radiotherapy (Craniospinal irradiation/whole brain radiotherapy/whole ventricular radiotherapy/ or local radiotherapy). After a median follow-up of 53 months (range, 7–150), 23 patients (82.1 %) were alive. OS was significantly affected by histology (89 % in germinoma vs. 60 % in non-germinomatous, p = 0.054) and location (93 % in pineal region vs. 64.2 % in other location, p = 0.042). Age, gender and surgery did not have any impact on the survival outcomes. ConclusionCNS GCTs are relatively rare and heterogeneous neoplasms commonly seen in pineal and suprasellar locations. A combination of chemotherapy and radiotherapy had shown excellent outcomes.

GCT-06. DIAGNOSIS OF A RARE CASE OF RECURRENT GERM CELL TUMOR BY CSF PLACENTAL ALKALINE PHOSPHATASE PRESENTING WITH DIFFUSE INTRAAXIAL ABNORMALITY IN THE LOWER BRAINSTEM

INTRODUCTIONGerm cell tumors in the central nervous system (CNS) typically arise either at suprasellar and/or pineal region, and occasionally at basal ganglia. We report a case of diagnostically challenging, recurrent germ cell tumor presented with diffuse intraaxial abnormality in and across the lower brainstem, which was diagnosed by the elevated placental alkaline phosphatase (PLAP) level in cerebrospinal fluid (CSF). CASE DESCRIPTION: A 28-year-old man had been treated by chemoradiotherapy at the previous hospital for bifocal suprasellar and pineal lesions with the provisional diagnosis of germinoma without histological confirmation. Three years later, he presented with progressive weakness of bilateral extremities for weeks. Magnetic resonance imaging showed a diffuse, bilaterally symmetric high intensity lesion on T2-weighted image with slight contrast enhancement across the ventral side of the medulla oblongata to the upper cervical spinal cord. Serum and CSF hCG, hCG-β, and AFP were all negative. Since the image findings were atypical for recurrent germ cell tumor, some kind of myelitis was initially suspected. Therefore, steroid pulse therapy was administered. However, the patient’s symptom was still gradually progressing. Then, the CSF PLAP turned out to be positive, indicating the recurrence of germinoma. Accordingly, platinum-based chemotherapy was administered, and the imaging findings, patient’s symptoms, and CSF PLAP began to improve. The patient is to be treated with radiotherapy following chemotherapy.CONCLUSIONWe report a rare case of CNS germ cell tumor that presented with diffuse intraaxial lesion in the lower brainstem in which examination of CSF PLAP was extremely useful.

GCT-56. ACUTE MYELOID LEUKEMIA FOLLOWING CHEMORADIOTHERAPY FOR INTRACRANIAL GERMINOMA: A CASE REPORT

INTRODUCTIONTherapy-related acute myeloid leukemia (t-AML) is known as possible complication of chemotherapy, especially topoisomerase Ⅱ inhibitor, alkylating agents, and platinum agents. Although there are many reports of therapy-related leukemia associated with gonadal germ cell tumor, few cases have been reported on central nervous system (CNS) germ cell tumor. CASE REPORT: A 35-year old gentleman presented with diplopia. CT and MR imaging showed enhancing nodules on his right hypothalamus and around fourth ventricle, and differential diagnoses included sarcoidosis and germinoma. Biopsy for fourth ventricle lesion was performed via transvermian approach, and histopathological diagnosis was germinoma. He was treated by 3 cycles of CARE chemotherapy (carboplatin and etoposide) followed by craniospinal irradiation (CSI, 24Gy). After completion of chemoradiotherapy, he was followed up every half year by MRI, and there had been no evidence of tumor recurrence. Two years after chemoradiotherapy, however, the patient presented with bleeding tendency, which led to the diagnosis of AML. Based on the history of chemoradiotherapy and the presence of t(16;21)(q24; q22), t-AML was diagnosed. Complete remission was successfully achieved by chemotherapy consisting of idarubicin and cytarabine.DISCUSSIONt-AML was diagnosed after chemoradiotherapy in a patient with CNS germinoma probably due to the administration of topoisomerase II inhibitor, etoposide. The prognosis of t-AML is known to be poorer as compared with de novo AML. Therefore, intensive therapy such as allogeneic stem cell transplantation should be considered in younger patients.CONCLUSIONA possibility of t-AML should be kept in mind following chemotherapy for CNS germ cell tumors.

Cerebrospinal fluid ctDNA and metabolites are informative biomarkers for the evaluation of CNS germ cell tumors

Serum and cerebrospinal fluid (CSF) levels of α-fetoprotein and β-subunit of human chorionic gonadotropin are used as biomarkers for the management of central nervous system (CNS) germ cell tumors (GCTs). However, additional discriminating biomarkers are required. Especially, biomarkers to differentiate non-germinomatous germ cell tumors (NGGCTs) from germinomas are critical, as these have a distinct prognosis. We investigated CSF samples from 12 patients with CNS-GCT patients (8 germinomas and 4 NGGCTs). We analyzed circulating tumor DNA (ctDNA) in CSF to detect mutated genes. We also used liquid chromatography-mass spectrometry to characterize metabolites in CSF. We detected KIT and/or NRAS mutation, known as frequently mutated genes in GCTs, in 3/12 (25%) patients. We also found significant differences in the abundance of 15 metabolites between control and GCT, with unsupervised hierarchical clustering analysis. Metabolites related to the TCA cycle were increased in GCTs. Urea, ornithine, and short-chain acylcarnitines were decreased in GCTs. Moreover, we also detected several metabolites (e.g., betaine, guanidine acetic acid, and 2-aminoheptanoic acid) that displayed significant differences in abundance in patients with germinomas and NGGCTs. Our results suggest that ctDNA and metabolites in CSF can serve as novel biomarkers for CNS-GCTs and can be useful to differentiate germinomas from NGGCTs.

Symptom interval and treatment burden for patients with malignant central nervous system germ cell tumours

ObjectivePatients with central nervous system germ cell tumours (CNS-GCTs) commonly initially present to primary care or general paediatricians. Prolonged symptom intervals (SI) are frequently seen in CNS-GCTs and have been...

Intensity-modulated ventricular irradiation for intracranial germ-cell tumors: Survival analysis and impact of salvage re-irradiation.

Background and purposeThe roles of surgery, chemotherapy, and parameters of radiation therapy for treating very rare central nervous system germ cell tumors (CNS-GCT) are still under discussion. We aimed to evaluate the survival and recurrence patterns of patients with CNS-GCT treated with chemotherapy followed by whole ventricle irradiation with intensity-modulated radiation therapy.Materials and methodsWe reviewed the clinical outcomes of 20 consecutive patients with CNS-GCT treated with chemotherapy and intensity-modulated radiation therapy from 2004 to 2014 in two partner institutions.ResultsTwenty children with a median age of 12 years were included (16 males). Sixteen tumors were pure germinomas, and 4 were non-germinomatous germ cell tumors (NGGCT). All patients were treated with intensity-modulated radiation therapy guided by daily images, and 70% with volumetric intensity-modulated arc radiotherapy additionally. The median dose for the whole-ventricle was 25.2 Gy (range: 18–30.6 Gy) and 36 Gy (range: 30–54 Gy) for the tumor bed boost. The median post-radiation therapy follow-up was 57.5 months. There were 3 recurrences (2 NGGCT and 1 germinoma that recurred as a NGGCT), with 1 death from the disease and the other 2 cases each successfully rescued with chemotherapy and craniospinal irradiation. The overall survival at 5 years was 95% and disease-free survival was 85%.ConclusionsThe results of this study suggest that the combined use of chemotherapy followed by whole ventricle irradiation with intensity-modulated radiation therapy is effective for CNS-GCTs, especially pure germinomas. Even being rescued with craniospinal irradiation, the NGGCT cases have markedly worse prognoses and should be more rigorously selected for localized treatment.

Descriptive epidemiology of germ cell tumors of the central nervous system diagnosed in the United States from 2006 to 2015.

Germ cell tumors (GCT) in the central nervous system (CNS) are rare tumors that occur with highest frequency in males, Asian populations, and children less than age 20years. Due to the rarity of these tumors, their patterns of incidence are not well-described. The aim of this study is to provide the most up-to-date data on incidence and survival patterns for CNS GCT by sex, race, and age at diagnosis. The Central Brain Tumor Registry of the United States (CBTRUS) is the largest aggregation of population-based incidence data on primary brain and other CNS tumors in the United States, containing incidence data from 51 central cancer registries and representing 100% of the US population. The current study used the CBTRUS analytic file to examine incidence (IR) of CNS GCT from 2006 to 2015, as well as registry data from the Surveillance, Epidemiology, and End Results (SEER) program to examine survival. Males had greater IR than females in all CNS GCT histologies examined. Asian and Pacific Islanders had a significantly greater IR of CNS GCT than the other race categories. We confirmed that CNS GCT IR was greatest for those age 10-14years and male. Overall survival rates were high for malignant CNS GCT, germinoma, mixed GCT, and malignant teratoma. There is significant variation in CNS GCT incidence by sex, race, and age at diagnosis. Ascertaining accurate incidence and survival rates of CNS GCT provides vital information usable in real time for clinicians, public health planners, patients, and their families.

Bifocal germinoma in a patient with 16p11.2 microdeletion syndrome.

SummaryIntracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background.Learning points:Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism.The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation.Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology.16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders.Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion.Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.

Primary Central Nervous System Germ Cell Tumors: A Review and Update.

Primary central nervous system (CNS) germ cell tumors (GCT) are a heterogeneous group of tumors that are still poorly understood. In North America, GCTs comprise approximately 1% of primary brain tumors in pediatric and young adult patients. GCTs can occur as pure or mixed subtypes; they are divided into germinomas, which are the most common subtype, and non-germinomatous germ cell tumors (NGGCTs), which consist of approximately one-third of GCTs and include teratomas, embryonal carcinomas, choriocarcinomas, and yolk sac tumors. While the etiology of primary CNS GCT is not entirely clear, the various subtypes are lineage-related and may involve progenitor germ cells that fail to migrate and become trapped in midline locations. Primary CNS GCT most commonly arises in the pineal region but also occur in other areas. Presenting symptoms can include headache, Parinaud syndrome, diabetes insipidus, precosious puberty, ataxia, or hemiparesis. Diagnosis of primary CNS GCTs can be difficult and is often delayed. Various imaging studies and tumor markers can assist in specific diagnosis. Treatment plans differ depending on the subtype of GCT and may vary among physicians and institutions. Germinomas have a favorable prognosis with a greater than 90% overall survival, while NGGCTs only have survival rates ranging from 40-70%. Germinomas seem to be most effectively treated with chemotherapy and radiation, while NGGCT usually require surgical resection, chemotherapy, and radiation with the exception of mature teratomas frequently curable with surgery alone. Gamma knife radiosurgery is a promising treatment that may be an effective additional treatment option. Cytogenic and molecular analyses are attempting to further specify the different GCT subtypes and are helping to direct the development of distinct therapeutic targets to improve treatment and prognosis.

Global DNA methylation analysis reveals miR-214-3p contributes to cisplatin resistance in pediatric intracranial nongerminomatous malignant germ cell tumors.

Pediatric central nervous system germ cell tumors (CNSGCTs) are rare and heterogeneous neoplasms, which can be divided into germinomas and nongerminomatous germ cell tumors (NGGCTs). NGGCTs are further subdivided into mature teratomas and nongerminomatous malignant GCTs (NGMGCTs). Clinical outcomes suggest that NGMGCTs have poor prognosis and survival and that they require more extensive radiotherapy and adjuvant chemotherapy. However, the mechanisms underlying this difference are still unclear. DNA methylation alteration is generally acknowledged to cause therapeutic resistance in cancers. We hypothesized that the pediatric NGMGCTs exhibit a different genome-wide DNA methylation pattern, which is involved in the mechanism of its therapeutic resistance. We performed methylation and hydroxymethylation DNA immunoprecipitation sequencing, mRNA expression microarray, and small RNA sequencing (smRNA-seq) to determine methylation-regulated genes, including microRNAs (miRNAs). The expression levels of 97 genes and 8 miRNAs were correlated with promoter DNA methylation and hydroxymethylation status, such as the miR-199/-214 cluster, and treatment with DNA demethylating agent 5-aza-2'-deoxycytidine elevated its expression level. Furthermore, smRNA-seq analysis showed 27 novel miRNA candidates with differential expression between germinomas and NGMGCTs. Overexpresssion of miR-214-3p in NCCIT cells leads to reduced expression of the pro-apoptotic protein BCL2-like 11 and induces cisplatin resistance. We interrogated the differential DNA methylation patterns between germinomas and NGMGCTs and proposed a mechanism for chemoresistance in NGMGCTs. In addition, our sequencing data provide a roadmap for further pediatric CNSGCT research and potential targets for the development of new therapeutic strategies.

Loco-regional extensions of central nervous system germ cell tumors: a retrospective radiological analysis of 100 patients.

The current staging system of central nervous system (CNS) germ cell tumors (GCT) includes a binary classification in "localized" or "metastatic" disease based on the absence or presence of leptomeningeal dissemination. Loco-regional tumor dissemination has been barely described whereas its accurate definition might be useful in terms of prognosis and treatment, especially for radiation therapy planning. Our purpose was therefore to describe MR patterns and prevalence of loco-regional extensions of these tumors. One hundred consecutive patients (median age 16.3years, range 7-41years, sex ratio 7:1) with a histologically or biologically proven CNS GCT were retrospectively included. Brain and spinal MRI at diagnosis were reviewed by two neuroradiologists focusing on MR patterns of primaries and loco-regional extensions. When available, follow-up MR exams were analyzed. Pure germinoma represented 84/100 cases. Primaries were unifocal pineal (n=49/100), bifocal pineal and supra-sellar (n=27/100), isolated supra-sellar (n=21/100), isolated basal ganglia (n=2/100) or trifocal pineal, supra-sellar, and basal ganglia (n=1/100). Metastatic disease occurred in 6/100 patients (depicted by MRI in two and CSF cytology in four). Loco-regional extensions were observed in all patients and classified as follows: third ventricle (n=88/100), thalamus (n=47/100), midbrain (n=42/100), distant sub-ependymal areas (n=19/100), optic pathways (n=19/100), lateral ventricles (n=7/100), cavernous sinus (n=6/100), corpus callosum (n=4/100), and fourth ventricle (n=3/100). CNS GCT present with specific loco-regional extensions at diagnosis. Improving their recognition will be helpful to further understand their prognostic value and potentially to optimize the treatment.

Nationwide Population-Based Incidence and Survival Rates of Malignant Central Nervous System Germ Cell Tumors in Korea, 2005-2012.

PurposeMalignant central nervous system (CNS) germ cell tumors (GCTs), although rare, are thought to occur more frequently among Asians. However, a recent population-based study revealed no differences in GCT incidence between Asians and Caucasians. Therefore, this study was conducted to determine the incidence and survival rates of CNS GCTs using the national cancer incidence database, and to compare these rates to those in the United States and Japan.Materials and MethodsWe extracted CNS GCT patients diagnosed between 2005 and 2012 from the Korea Central Cancer Registry database. Age-standardized rates (ASRs), annual percentage change, and the male-female incidence rate ratios (IRRs) were calculated. To estimate the survival rate, we used data for patients diagnosed between 2005 and 2010 and followed their cases until December 31, 2013.ResultsThe ASR for CNS GCT between 2005 and 2012 was 0.179 per 100,000 (95% confidence interval, 0.166 to 0.193), with an overall male-to-female (M:F) IRR of 2.95:1. However, when stratified by site, the M:F IRR was 13.62:1 for tumors of the pineal region and 1.87:1 for those located in nonpineal regions. The most frequent histologic type was germinoma (76.0%), and the most frequent location was the suprasellar region (48.5%). The 5-year survival rate of germinoma patients was 95.3%.ConclusionThe incidence rate of CNS GCTs in Korea during 2005-2012 was 0.179 per 100,000, which was similar to that of the Asian/Pacific Islander subpopulation in the United States. Moreover, the CNS GCT survival rate in Korea was similar to rates in Japan and the United States.

Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors.

Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.

Psychiatric manifestations as initial presentation for pediatric CNS germ cell tumors, a case series.

Central nervous system (CNS) germ cell tumors account for 3% of all pediatric brain tumors in the USA. Presenting symptoms are typically location based with pineal tumors presenting with obstructive hydrocephalus and suprasellar tumors with hypothalamic/pituitary dysfunction and ophthalmologic abnormalities. Psychiatric manifestations such as psychosis and behavioral changes are atypical presentations of CNS germ cell tumors, with only 11 previously reported cases. This is a retrospective case series describing patients with CNS germ cell tumors with an atypical presentation including psychiatric manifestations. Information regarding clinical presentation, treatment course, and outcome were obtained. We report seven patients who presented with psychiatric symptoms consisting of psychomotor delay as well as behavioral and mood changes. Six of the seven patients were diagnosed ≥6months after onset of psychiatric symptoms. All of the seven are alive but five continue to have neurologic and psychiatric issues post treatment. Atypical presentations of CNS germ cell tumors can delay diagnosis and treatment and may be secondary to atypical locations as well as endocrine dysfunction manifesting as psychiatric symptoms. Delayed diagnosis did not appear to affect survival but earlier diagnosis may potentially be associated with better neurologic and psychiatric outcome. Patients who present with these symptoms and atypical neuroimaging should have a thorough evaluation for CNS germ cell tumors including serum and CSF markers. Clinicians should be aware of these less common presentations to aid in prompt diagnosis and treatment.

Expression and mutation of c-Kit in intracranial germ cell tumors: A single-centre retrospective study of 30 cases in China.

Although primary central nervous system (CNS) germ cell tumors (GCTs) are one of the most treatable types of malignant brain tumor, a subset of patients remain resistant to standard chemotherapy. Gain-of-function mutations of the c-Kit gene, and KIT protein expression, have been observed in a number of GCTs, including testicular seminoma, ovarian dysgerminoma and mediastinal seminoma in various ethnic groups. Although a small number of studies have reported the role of c-Kit in CNS GCTs, few have focused on Chinese patients exhibiting CNS GCTs. In the present study, the frequency and location of c-Kit mutations and KIT protein expression levels in CNS GCTs were investigated in 30 patients, between January 1994 and October 2014. Immunohistochemical assays suggested that KIT protein expression was present in 59.1% patients (66.7% in males and 42.9% in females); however, no statistically significant correlation was identified between KIT protein expression and patient clinicopathological features. By performing PCR amplification and direct sequencing, 4 mutational hot spots of the c-Kit gene (exons 9, 11, 13 and 17) were examined, and c-Kit gene mutation was identified in 1/17 (5.9%) CNS germinoma cases. This mutation was located in exon 11 at codon 557–558 WK (Tryptophan-Lysine). No c-Kit gene mutations were detected in non-germinomatous GCTs. Imatinib, a tyrosine kinase inhibitor, may be an effective treatment against standard chemotherapy-resistant CNS germinoma patients exhibiting c-Kit mutations.

Relapse and outcome patterns of patients with central nervous system mixed malignant germ cell tumors treated without irradiation: Findings from the Third International Central Nervous System (CNS) Germ Cell Tumor (GCT) Study

To evaluate patterns of relapse and outcome in patients newly diagnosed with CNS Mixed Malignant GCT (MMGCT) treated initially with chemotherapy alone. A retrospective chart review was conducted using all 25 patients enrolled on the International CNS GCT Study III, with at least 7 years follow-up for all surviving patients. Thirteen patients at diagnosis had CNS MMGCT by pathology and tumor markers (n = 11), or tumor markers alone (n = 2). Twelve received chemotherapy alone, one additionally receiving focal irradiation prior to relapse. Six patients (46%) relapsed (mean of 30.5 months; range 6-59 months), two beyond and four within the primary site alone. Three patients relapsed early (6-23 months from diagnosis), two with alpha-fetoprotein elevations and one without tumor markers assessed; all three expired of progressive disease at 2-10 months following initial relapse. Three patients relapsed late (37-59 months) without AFP elevations, one with pathologically pure germinoma, two with mild beta-human chorionic gonadotropin elevations; these patients survive disease-free at 86+, 94+, and 126+ months following additional treatment. Patients with CNS MMGCT relapsing following chemotherapy alone display two distinct patterns of recurrence and outcome; patients relapsing early possess MMGCT elements and have a dismal prognosis, while patients relapsing late do so with pure germinomatous elements and have an excellent outcome. Current cooperative group studies utilizing more localized fields of irradiation should monitor closely the patterns of relapse and outcome; late recurrences with germinomatous elements might be avoided by initial use of low-dose larger field irradiation in select patients.

Prediction of radiosensitivity in primary central nervous system germ cell tumors using dynamic contrast-enhanced magnetic resonance imaging.

To evaluate the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting tumor response to radiotherapy in patients with suspected primary central nervous system (CNS) germ cell tumors (GCTs). DCE-MRI parameters of 35 patients with suspected primary CNS GCTs were obtained prior to diagnostic radiation, using the Tofts and Kermode model. Radiosensitivity was determined in tumors diagnosed 2 weeks after radiation by observing changes in tumor size and markers as a response to MRI. Taking radiosensitivity as the gold standard, the cut-off value of DCE-MRI parameters was measured by receiver operating characteristic (ROC) curve. Diagnostic accuracy of DCE-MRI parameters for predicting radiosensitivity was evaluated by ROC curve. A significant elevation in transfer constant (K(trans)) and extravascular extracellular space (Ve) (P=0.000), as well as a significant reduction in rate constant (Kep) (P=0.000) was observed in tumors. K(trans), relative K(trans), and relative Kep of the responsive group were significantly higher than non-responsive groups. No significant difference was found in Kep, Ve, and relative Ve between the two groups. Relative K(trans) showed the best diagnostic value in predicting radiosensitivity with a sensitivity of 100%, specificity of 91.7%, positive predictive value (PPV) of 95.8%, and negative predictive value (NPV) of 100%. Relative K(trans) appeared promising in predicting tumor response to radiation therapy (RT). It is implied that DCE-MRI pre-treatment is a requisite step in diagnostic procedures and a novel and reliable approach to guide clinical choice of RT.

Variations in treatment practices among pediatric solid tumor patients in Japan.

e17656 Background: Care of pediatric cancer patients is only mildly centralized in Japan, and it is not known whether this has led to variations in treatment practices for pediatric solid tumor patients. We aimed to investigate where practice variations exist among pediatric solid tumor patients, by evaluating the treatments patients received in eight pediatric solid tumors that have Japanese clinical guidelines. Methods: Using a database linking hospital-based cancer registry and administrative claims data obtained from 210 cancer treatment hospitals, we identified 20 hepatoblastoma (HB), 68 neuroblastoma (NB), 28 retinoblastoma (RB), 24 nephroblastoma (WT), 20 rhabdomyosarcoma (RMS), 14 Ewing’s sarcoma, 32 osteosarcoma, and 56 central nervous system germ cell tumor (CNSGCT) patients who were diagnosed from 69 hospitals in 2012. We reviewed each patient’s chemotherapy regimens, radiation therapy schedules, and surgical procedures using administrative claims data from September 2011 to December 2013. Results: Most pediatric solid tumor patients received treatment in concordance with clinical guidelines for their first course of treatment. For instance, first-line chemotherapy for HB were cisplatin (CDDP) + pirarubicin (66%) and CDDP + doxorubicin (DXR) ± carboplatin (33%). However, treatment practices varied greatly for both primary and recurrent CNSGCT patients, as well as patients receiving second and third-line chemotherapies. About a quarter of CNSGCT patients received resection or radiation alone as their first treatment, but a greater proportion of patients received surgery followed by various adjuvant chemotherapies or radiation therapy, and neoadjuvant chemotherapy followed by radiation. Regimens for recurrent tumors varied greatly, such that all recurrent RMS patients received different chemotherapy regimens. Conclusions: Despite lack of centralization of care among pediatric solid tumor patients, our study showed that the majority of patients were receiving treatments in concordance with clinical guidelines. However, practice variations existed in CNSGCTs and patients receiving second and third-line chemotherapies, which suggest that centralization of care may be necessary for these patients.

The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors.

Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.