Optimal radiotherapy target volumes in intracranial nongerminomatous germ cell tumors: Long-term institutional experience with chemotherapy, surgery, and dose- and field-adapted radiotherapy.

PURPOSE: To evaluate patterns of failure after multimodality treatment of nongerminomatous germ cell tumors (NGGCTs). MATERIALS AND METHODS: We retrospectively reviewed records of 34 patients diagnosed with primary intracranial NGGCT between 1988 and 2014. RESULTS: Thirty-four patients received induction chemotherapy followed by radiation with or without surgery. Median follow-up was 11.1 years (0.8-23.3). Outcomes were significantly improved in these 34 patients (5-year overall survival [OS]: 88% versus 50%, P = 0.0092), so analysis is restricted to that subset. Disease-free survival (DFS) was 67, 60, and 54% at 5, 10, and 15 years, respectively. Elevated cerebrospinal fluid-α-fetoprotein (CSF-AFP) at diagnosis was associated with poorer DFS (37 vs. 89% at 10 years; P = 0.01). There was no statistically significant difference in OS, or DFS, or patterns of failure for limited radiotherapy volumes versus larger volumes; however, patients receiving initial local radiotherapy had 32% distant central nervous system (CNS) recurrence at 10 years compared to 0% for those receiving initial larger field irradiation (P = 0.09). Fifteen patients recurred. All four patients who relapsed in the spine had received local radiotherapy and had elevated serum and CSF-AFP at baseline. All three patients with ventricular relapse received local radiation therapy. CONCLUSIONS: NGGCT patients continue to relapse beyond 5 years. Late ventricular relapse occurred even in patients without clear evidence of germinoma component. Elevated CSF-AFP at diagnosis is associated with poor DFS and risk for distant CNS relapse. Patients with residual radiographic disease after chemotherapy or residual malignant histologies after second-look surgery have inferior outcomes. Our data support consideration of treatment intensification for these patients.

A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours.

BACKGROUND: The current biomarkers alpha-fetoprotein and human chorionic gonadotropin have limited sensitivity and specificity for diagnosing malignant germ-cell tumours (GCTs). MicroRNAs (miRNAs) from the miR-371-373 and miR-302/367 clusters are overexpressed in all malignant GCTs, and some of these miRNAs show elevated serum levels at diagnosis. Here, we developed a robust technical pipeline to quantify these miRNAs in the serum and cerebrospinal fluid (CSF). The pipeline was used in samples from a cohort of exclusively paediatric patients with gonadal and extragonadal malignant GCTs, compared with appropriate tumour and non-tumour control groups. METHODS: We developed a method for miRNA quantification that enabled sample adequacy assessment and reliable data normalisation. We performed qRT-PCR profiling for miR-371-373 and miR-302/367 cluster miRNAs in a total of 45 serum and CSF samples, obtained from 25 paediatric patients. RESULTS: The exogenous non-human spike-in cel-miR-39-3p and the endogenous housekeeper miR-30b-5p were optimal for obtaining robust serum and CSF qRT-PCR quantification. A four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p): (i) showed high sensitivity/specificity for diagnosing paediatric extracranial malignant GCT; (ii) allowed early detection of relapse of a testicular mixed malignant GCT; and (iii) distinguished intracranial malignant GCT from intracranial non-GCT tumours at diagnosis, using CSF and serum samples. CONCLUSIONS: The pipeline we have developed is robust, scalable and transferable. It potentially promises to improve clinical management of paediatric (and adult) malignant GCTs.

Potential role of ventricular tumor markers in CNS germ cell tumors.

BACKGROUND: There is increasing reliance on oncoprotein assays such as the ß-subunit of human chorionic gonadotropin (ß-hCG) and alpha-fetoprotein (AFP) for diagnosis or confirmation of histology of central nervous system (CNS) germ cell tumors (GCT), but the relative diagnostic sensitivity and reliability of assays from serum (S), lumbar (L), and ventricular (V) cerebrospinal fluid (CSF) are uncertain. PROCEDURE: A total of 86 patients with CNS GCT were identified from our database. Fourteen patients had contemporaneous ß-hCG and/or AFP measurements from serum, ventricular, and lumbar CSF at diagnosis (n = 13) or relapse (n = 1), constituting the subjects for this report. Their primary tumor sites were: pineal (n = 8), suprasellar (n = 1), or both (n = 5). Their mean age at diagnosis was 16.0 years (range 9.1-25.9). The male:female sex ratio was 13:1. RESULTS: For the germinoma-treated patients (n = 8), the median (range) ß-hCG values (S, V, L) were 0 (0-6.9), 7.0 (0-57.4), 8.3 (0-34.0) mIU/ml. For patients managed as mixed malignant GCT (MMGCT) (n = 6), the median (range) ß-hCG values (S, V, L) were 3.9 (0-58.0), 3.6 (0-147.0), 61.8 (0-358.0) mIU/ml. The median (range) AFP values were 7.5 (0-27,400.0), 2.0 (0-2,981.0), 3.0 (0-14,015.0) ng/ml. Lumbar CSF ß-hCG values were equal or greater than those in ventricular CSF or serum in 12 of 13 cases (92.3%). All patients with MMGCT had lumbar AFP equal or greater than the ventricular CSF values, while serum AFP values remained highest. CONCLUSIONS: Ventricular CSF values cannot be considered a replacement for lumbar CSF. Lumbar CSF is the most reliable source of tumor markers to establish baseline and follow-up diagnostic endpoints.

Intracranial germ cell tumours. A review with special reference to endocrine manifestations.

EPIDEMIOLOGY: Intracranial germ cell tumours (icGCTs) represent 3-15% of primary paediatric intracranial neoplasms with a considerable geographical variation in incidence. Ninety percent of patients diagnosed with icGCTs are under 20 years of age. PATHOLOGY: Histologic characteristics and investigation of the tumour markers ß-human chorionic gonadotropin (ß-hCG) and alpha-fetoprotein (AFP) help define the different categories of icGCTs. The tumours are divided into two major groups called germinomas and non-germinomatous GCTs (NGGCTs). CLINICAL PRESENTATION: The clinical symptoms depend on the size and location of tumour in the brain, which is most commonly in the pineal or suprasellar region. Pineal GCTs often present with neurological symptoms because of their tendency to cause increased intracranial pressure. Suprasellar GCTs are often accompanied by endocrine abnormalities such as diabetes insipidus (DI), growth retardation and precocious or delayed puberty. DIAGNOSIS: A combination of clinical findings, endocrine and tumour marker evaluation, spinal fluid cytology, magnetic resonance imaging (MRI) and biopsy helps verifying the diagnosis of an icGCT. A summary of published data (n = 97) revealed that >90% of patients at diagnosis had at least one endocrine abnormality, DI being the most common (>80%). TREATMENT: Classification of tumour is important for choice of treatment and for prognosis. A combination of chemotherapy and radiotherapy is often used, since most icGCTs have a great sensitivity to these treatment modalities. CONCLUSION: Endocrine symptoms are very frequently appearing in patients with icGCTs and they can present long before neuroimaging verification of tumour is possible. It is of the outmost importance to have the diagnosis of icGCTs in mind when children, adolescents and young adults are presenting with endocrine irregularities, because most icGCTs are very sensitive to radiotherapy and chemotherapy, and early onset of treatment is important in order to minimize morbidity and mortality.

CSF and serum AFP in patients without gestational or neoplastic AFP-secretion.

BACKGROUND: The measurement of alpha-fetoprotein (AFP) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumors. The current study was performed to establish reference values for AFP in CSF and to explore the relationship of CSF AFP and serum AFP in patients. MATERIAL AND METHODS: CSF samples were obtained from 351 inpatients admitted because of various neurological diseases, excluding those who were pregnant, had active liver disease, or who had trophoblastic or other malignant tumors. In 256 of the 351 patients, paired samples of CSF and serum were obtained. Both CSF AFP and serum AFP were measured. The 97.5th percentile and maximum value of CSF AFP were obtained. The CSF AFP and serum AFP concentrations in each of the 256 paired samples were compared. RESULTS: The 97.5th percentile and maximum value of CSF AFP concentration for overall participants were 1.042 and 1.950 g/L, respectively. The CSF AFP concentration was found to be higher than the simultaneous serum AFP concentration only in 1.6% (4/256) of participants. CONCLUSIONS: The reference value determined in this study for CSF AFP is significantly lower than that usually used in clinical practice. A CSF AFP concentration higher than the simultaneous serum AFP concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal AFP-secretion.

Induction Chemotherapy Reduces Radiation Therapy Dose and Volume in the Treatment of Intracranial Germinoma: Results of the SMC-G13 Trial.

PURPOSE: We performed a prospective single-arm trial (NCT02782754) to explore the feasibility of reducing radiation therapy (RT) dose when induction chemotherapy is combined in the treatment of intracranial germinoma with beta-human chorionic gonadotropin levels <200 mIU/mL. METHODS AND MATERIALS: All patients aged 3 to 35 years from November 2012 to June 2018 were eligible for this study. Four cycles of induction chemotherapy were given before RT. Carboplatin/etoposide and cyclophosphamide/etoposide regimens were used in alternation every 3 weeks. A dose of 18 Gy of craniospinal RT for metastatic tumors, whole brain RT for basal ganglia tumors, or otherwise whole ventricular RT followed by 12.6 Gy of boost RT to the primary tumor bed was administered after induction chemotherapy. The primary endpoint of this study was progression-free survival. RESULTS: A total of 41 consecutive patients were enrolled (location: suprasellar in 12, pineal in 12, both suprasellar and pineal in 11, and basal ganglia in 6 patients). Eleven patients had leptomeningeal seeding. Toxicity during chemotherapy was mild, except for bone marrow suppression. Tumor status after induction chemotherapy was complete response in 33 patients and partial response in 8. All but 2 patients completed the scheduled treatment. All patients but 1 remained event free during a median follow-up of 3.4 (range, 0.3-7.0) years from diagnosis. The 1 patient experienced relapse and died of tumor bleeding. Late effects were not significant except for neuroendocrine dysfunction already present at diagnosis. Vertical growth and cognitive function were not significantly disturbed by treatment. CONCLUSIONS: This study showed the feasibility of reducing RT dose/volume with induction chemotherapy in pathologically pure germinoma with elevated beta-human chorionic gonadotropin levels up to 200 mIU/mL.

Intracranial Germ Cell Tumors in Adolescents and Young Adults: A 40-Year Multi-Institutional Review of Outcomes.

PURPOSE: The aim of this study was to determine the practice patterns and outcomes of intracranial germ cell tumors (IGCT) in adolescents and young adults according to different therapeutic approaches. METHODS AND MATERIALS: One-hundred twelve patients with IGCT aged 15 to 39 years were managed at either XX or the XY center from 1975 to 2015. The charts were retrospectively reviewed and data collected. RESULTS: Median duration of follow-up was 8.3 years. Ninety-four patients had germinomas, and 18 had nongerminomatous germ cell tumors (NGGCT). The primary disease sites were pineal gland (37 of 94 germinoma, 14 of 18 NGGCT) and suprasellar region (23 of 94 germinoma, 2 of 18 NGGCT). Eleven patients with germinoma (12%) and 2 patients with NGGCT (11%) had radiographic spinal metastases or positive lumbar cerebrospinal fluid cytology. Event-free survival (EFS) was 84% and overall survival (OS) was 90% at 10 years for germinoma; EFS was 71% and OS was 86% at 10 years for NGGCT. For patients with germinoma, 10-year EFS was 100% after craniospinal radiation therapy (CSRT) with chemotherapy (N = 10); 100% after whole-ventricular radiation therapy (WVRT), whole-brain radiation therapy (WBRT), or focal radiation therapy (FRT) with chemotherapy (N = 22); 90% after CSRT alone (N = 46); and 41% after WVRT, WBRT, or FRT alone (N = 16) (P < .0005). Ten-year OS was 100%, 100%, 90%, and 72%, respectively (P = .032). For patients with NGGCT, 10-year EFS was 80% after CSRT, WBRT, or WVRT plus chemotherapy (N = 10) versus 58% after FRT plus chemotherapy (N = 8) (P = .31); 10-year OS was 90% versus 58%, respectively (P = .16). CONCLUSIONS: We report excellent overall outcomes according to treatment approach in the largest study of IGCT in adolescents and young adults to our knowledge. EFS and OS were inferior after non-CSRT without chemotherapy in germinoma.

The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors.

BACKGROUND: To determine the impact of diagnostic serum and/or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (b-HCG) elevations on survival in newly diagnosed patients with central nervous system germ cell tumors (CNS GCT) treated with chemotherapy with the intent to avoid irradiation. PROCEDURE: Seventy-five patients with newly diagnosed CNS GCT enrolled in two sequential internationally conducted clinical trials with serum and CSF AFP and b-HCG levels available from initial diagnosis were retrospectively analyzed. Subjects received platinum based chemotherapy and were followed with serial imaging and tumor marker evaluations. RESULTS: The 5-year overall survival (OS) and event free survival (EFS) for patients with normal tumor markers compared with those with elevated markers at diagnosis was 78% (95% CI 51-91%) versus 60% (95% CI 46-72%) (P = 0.08) and 22% (95% CI 7-43%) versus 28% (95% CI 16-40%) (P = 0.68). The hazard ratio of death for patients with elevated markers was 1.9 times as high as that for those with normal markers (95% CI 0.58-6.5) after adjusting for other baseline characteristics. There was no observed difference in survival among patients with histologically confirmed germinomas, irrespective of level of b-HCG. CONCLUSIONS: Patients with elevated tumor markers appear to have poorer OS independent of tumor histology, although these differences do not reach statistical significance (P < or = 0.05). No differences were observed in EFS between groups likely due to the poor response of chemotherapy only approach to patients with normal markers. b-HCG elevations in biopsy proven germinomas do not seem to alter a patient's prognosis.

Pineal region teratoma with high serum and CSF alpha-fetoprotein levels.

We report a patient with an immature teratoma of the pineal region with high levels of alpha-fetoprotein (AFP) in serum and cerebrospinal fluid. This is very rare and to the best our knowledge, the second case reported in the literature.

An update on the clinical diagnostic value of ß-hCG and αFP for intracranial germ cell tumors.

BACKGROUND: Pathological examination combined with tumor markers has become a standard for the diagnosis of intracranial germ cell tumors (ICGCTs), but the current concept of 'secreting germ cell tumors' and three empirically highly specific diagnostic criteria (ß-hCG ≥ 50 IU/L or αFP ≥ 10 ng/mL; ß-hCG ≥ 100 IU/L or αFP ≥ 50 ng/mL; ß-hCG > 50 IU/L or αFP > 25 ng/mL) are not based upon pathology examination or CSF cytology. Further investigation is needed to re-evaluate their value. METHODS: A multidisciplinary diagnostic team was created. Valid ß-hCG/αFP data were collected from cases of ICGCTs confirmed by pathology and CSF cytology (n = 58) between 1991 and 2012, and from suspected ICGCTs cases (n = 17) between 2011 and 2012 as controls [Langerhans cell histiocytosis (LCH), n = 12; and other intracranial tumor (ICT), n = 5]. The cut-off points for ß-hCG and αFP were calculated using receiver operating characteristic (ROC) curves. RESULTS: This study clarifies the relative rationality of one criteria (ß-hCG > 50 IU/L and αFP > 25 ng/mL); confirms new ß-hCG diagnostic cut-off points: CSF ß-hCG ≥ 8.2 IU/L and serum ß-hCG ≥ 2.5 IU/L (sensitivity of 47 and 34%, respectively, specificity of 100%, both; P < 0.05); and empirically adjusts the criteria for αFP to ≥ 3.8 ng/mL in CSF and to ≥ 25 ng/mL in serum. The total diagnostic sensitivity for ICGCTs finally increased from 34.6 to 65.4% (P < 0.05, diagnostic value of CSF ß-hCG exceeds 90%). Subtype diagnosis improved with αFP in 16.7% of non-geminomatous germ cell tumor cases. CONCLUSION: New evidence-based criteria of ß-hCG and αFP can help improving early and formal diagnosis of ICGCTs, and is of great clinical significance.

Interpretation of alpha-fetoprotein concentrations in cerebrospinal fluid of infants.

BACKGROUND: There are no published reference intervals for concentrations of alpha-fetoprotein (AFP) in the cerebrospinal fluid (CSF) of normal infants. The presence of abnormal concentrations of AFP in plasma or CSF may indicate the presence of a teratoma or a germ cell tumour with yolk sac elements. We measured CSF AFP in infants who did not have malignancy in order to determine its reference intervals. METHODS: AFP was measured in the CSF and/or plasma in 128 infants. Of these, 91 infants had CSF AFP measurements, 94 infants had plasma AFP measurements and in 60 infants AFP concentrations were determined in paired CSF and plasma samples. The patients ranged in age from 1 to 110 days. Both CSF and plasma AFP concentrations were measured by a microparticle enzyme immunoassay using an AxSYM analyser. RESULTS: Using ages corrected for prematurity, the median CSF AFP concentration for babies -69 to 31 days old was 61 kIU/L (5th-95th centile: 2-889 kIU/L), while the median CSF AFP concentration for infants 32 to 110 days was 1.2 kIU/L (5th-95th centile: 0.1-12.5 kIU/L). By age 6 weeks, the concentrations were close to those found in adult plasma and all CSF AFP concentrations from infants with a corrected age over 2 months were <3 kIU/L. CONCLUSION: We have defined reference intervals for CSF AFP concentrations in infants. These results may assist in the diagnosis of CNS tumours, particularly congenital CNS tumours containing yolk sac elements.

Fetuin in the developing neocortex of the rat: distribution and origin.

Immunocytochemical distribution of the fetal protein fetuin in the neocortex of developing rat brain and the presence of its mRNA, as detected by using reverse transcriptase-polymerase chain reaction analysis, was studied in fetuses at embryonic day 15 (E15) through E22, in neonates at postnatal day 0 (P0) through P20, and in adults. Quantitative estimates of fetuin in cerebrospinal fluid (CSF) and plasma were obtained over the same period. Exogenous (bovine) fetuin injected intraperitoneally into fetal and postnatal rats was used to study the uptake of fetuin into CSF and brain and its distribution compared with endogenous fetuin; bovine albumin was used as a control. Fetuin was identified immunocytochemically in the cortical plate and subplate cells of the developing neocortex. In the rat fetus, fetuin first was apparent at E17, mainly in cell processes, but a few subplate cells also were positive. By E18, there was strong staining in subplate neurons and in inner cells of the cortical plate. At E21, these inner cells of the cortical plate were beginning to differentiate into layer VI neurons, many of which were positive for fetuin. By P0-P1, more layer VI neurons and some layer V neurons had become positive for fetuin. Fetuin immunoreactivity generally was weaker at P1, and, by P2-P3, it had disappeared from all of the layers of the developing neocortex. Bovine fetuin (but not albumin), probably taken up through CSF over the neocortical dorsal surface, had a cytoplasmic distribution; endogenous rat fetuin was both cytoplasmic and membrane bound. Thus, much of this fetuin can be accounted for by uptake, although the presence of fetuin mRNA indicates that in situ synthesis may also contribute.

Intracranial germinoma: the case for lower dose radiation therapy.

PURPOSE: To determine the optimal dose and treatment outcome of patients treated with radiation for intracranial germinoma. METHODS AND MATERIALS: Between 1975 and 1995, 40 patients with the diagnosis of intracranial germinoma were treated with radiation (RT) to the central nervous system. All patients received whole-brain (WB) RT (median dose: 32.4 Gy, range: 15-44.37 Gy) and a boost to the tumor volume (median total tumor volume dose: 52 Gy, range: 45-59.5 Gy). Thirty patients received RT to the spine (median dose: 26 Gy, range: 18.75-37.5 Gy). Four patients were treated with cisplatin-based chemotherapy and WB RT with a boost to the tumor volume (dose range: 51-54 Gy). A low-dose RT only group was defined as < or = 25.5 Gy to the WB (9 patients); < 50 Gy to the primary site (14 patients); and < 22 Gy to the spine (9 patients). Seventeen tumors were biopsy-proven germinoma, and 17 patients presented with multiple midline germinomas (MMG). Among 26 patients who had tumor markers measured, 27% had elevation of beta-human chorionic gonadotropin and by definition, no patient had an elevation of AFP. Twenty-four percent of 26 patients who had spine imaging or cerebral spinal fluid cytology had evidence of tumor seeding at diagnosis. The male to female ratio was 1.9:1. Median age at diagnosis was 14 years for male patients and 9.5 years for female patients (p = 0.02), (overall age ranges: 0.5-31 years). Median follow-up was 62 months (range: 3-226 months). Late effects of 29 patients with follow-up of > or = 20 months and adequate documentation in their medical records were analyzed. RESULTS: The 5-year actuarial rate of disease-free survival (DFS) and overall survival (OS) for biopsy-proven germinomas and presumed germinomas was 97%. No patient died of germinoma. There were no local failures regardless of the dose of RT, elevation of HCG tumor marker, or CSF dissemination at presentation. At presentation 22 patients had evidence of at least one endocrine abnormality. At follow-up there were no new patients diagnosed with an endocrine abnormality; however, 13 out of 22 patients had an increase in the number of endocrine deficiencies requiring hormone replacement. At presentation, 14 patients showed evidence of growth retardation. At follow-up there were no new cases of growth failure in the remaining patients. CONCLUSIONS: Germinomas are highly curable with RT alone. Lower doses of RT to the craniospinal axis without chemotherapy appear to produce equally effective DFS and OS as do higher doses of RT or combination chemotherapy and RT. Craniospinal RT may be indicated for patients with MMG or patients with evidence of spinal seeding. Long-term effects of growth retardation, and other endocrine deficiencies appear to be correlated with disease at presentation rather than solely with treatment.

Evaluation of an intrathecal immune response in amyotrophic lateral sclerosis patients implanted with encapsulated genetically engineered xenogeneic cells.

A phase I/II clinical trial has been performed in 12 amyotrophic lateral sclerosis (ALS) patients to evaluate the safety and tolerability of intrathecal implants of encapsulated genetically engineered baby hamster kidney (BHK) cells releasing human ciliary neurotrophic factor (CNTF). These patients have been assessed for a possible intrathecal or systemic immune response against the implanted xenogeneic cells. Hundreds of pg CNTF/ml could be detected for several weeks in the cerebrospinal fluid (CSF) of 9 out of 12 patients, in 2 patients up to 20 weeks after capsule implantation. Slightly elevated leukocyte counts were observed in 6 patients. Clear evidence for a delayed humoral immune response was found in the CSF of only 3 patients out of 12 (patients #4, #6, and #10). Characterization of the antigen(s) recognized by the antibodies present in these CSF samples allowed to identify bovine fetuin as the main antigenic component. The defined medium used for maintaining the capsules in vitro before implantation contains bovine fetuin. Fetuin may therefore still be adsorbed to the surface of the cells and/or the polymer membrane, or be present in the medium surrounding the encapsulated cells at the time of implantation. Because of the insufficient availability of CSF samples, as well as the relatively poor sensitivity of the assays used, a weak humoral immune response against components of the implanted cells themselves cannot be excluded. However, the present study demonstrates that encapsulated xenogeneic cells implanted intrathecally can survive for up to 20 weeks in the absence of immunosuppression and that neither CNTF nor the presence of antibodies against bovine fetuin elicit any adverse side effects in the implanted patients.

Protein composition of cerebrospinal fluid in the developing chick embryo.

Proteins from cerebrospinal fluid of chick embryos at 4-19 days of development were qualitative and quantitatively analyzed. The total protein concentration and the relative concentration of each protein fraction were calculated for each day. The main proteins found along development were immunoglobulin G, transferrin, alpha-fetoprotein, serum albumin, ovalbumin, prealbumin, and an unidentified component. alpha-Fetoprotein was found to be the major protein at 4-16 days, and serum albumin at 17-19 days of development. The unidentified fraction was present from 4 to 11 days; at day 5 it represented 28% of the total cerebrospinal fluid protein concentration.

Fetuin in neurons of the retina and cerebellum during fetal and postnatal development of the rat.

Although long known to be a liver-derived fetal plasma glycoprotein, fetuin has more recently been shown to be present in sub-populations of neurons in the developing nervous system of a number of mammalian species. We have extended these observations to examine the fetuin immunoreactivity (IR) in developing rat retina and cerebellum. Fetuin-IR was first seen in the retina on embryonic day (E)19 in a sub-population of cells in the retinal ganglion cell layer and a small proportion of cells in the neuroblastic layer. The proportion of cells in the ganglion layer exhibiting fetuin-IR increased until postnatal day (P)10 when all cells in this layer were strongly immunoreactive. From P14 onwards fetuin-IR was absent or very weak and restricted to a small proportion of ganglion cells. In the developing cerebellum, the outer and inner granule cell layers, the deep nuclei and cells in the sub-cortical white matter exhibited fetuin-IR from E19 to P10. There was little fetuin-IR in the cerebellum at ages P14 and older, and Purkinje cells did not exhibit fetuin-IR at any time. The results show that fetuin appears in many neurons in the retina and cerebellum that are differentiating during the period from E19 to P10. The concentration of fetuin in cerebrospinal fluid is at its highest in this same period which suggests that some sub-populations of neurons could obtain fetuin from extracellular fluid during this period; however, the lack of fetuin-IR in other neuronal populations suggests that fetuin uptake is not a general property of developing neurons.

Alpha-fetoprotein in human fetal cerebrospinal fluid.

Alpha-fetoprotein (AFP) is a fetal glycoprotein. It has been ascribed a regulatory function of growth factor responses and immune functions. The concentrations of AFP and albumin (ALB) are highly variable in fetal serum and CSF and change with gestational age. The AFP index=[AFP(CSF)/AFP(SERUM)]/[ALB(CSF)/ALB(SERUM)] was determined in six normal fetuses at gestational age 17-23 weeks and found to be independent of gestational age and close to unity, mean 0.90+/-0.11 (S.D.). The ratio of CSF-serum concentrations of AFP and ALB both decreased significantly (p<0.05) with gestational age. The mean fraction of AFP being non-reactive with concanavalin A was 1.7% in serum and 1.9% in CSF, suggesting a common hepatic origin of AFP in both compartments. In conclusion, the concentration of AFP in CSF seems to be determined largely by the serum-CSF concentration gradient in normal fetuses. This finding, combined with the remarkable constancy of the AFP index compared to the highly variable absolute concentrations of AFP in both serum and CSF should make the AFP index the marker of choice when analyzing for intrathecal AFP synthesis during development and in pathological conditions.

Cerebrospinal fluid markers in central nervous system metastases from testicular carcinoma.

Serum values of alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) have been used to monitor disseminated testicular carcinoma. Serial measurements of these markers have been used to monitor the response to therapy, to follow the progress of disease, and to detect subclinical recurrences. With increasingly effective chemotherapy for systemic disease, central nervous system (CNS) metastases in testicular carcinoma are becoming increasingly important as a cause of treatment failure. Cerebrospinal fluid (CSF) values of AFP and HCG seem to be important ancillary acids in the neurosurgical management of CNS metastases from testicular cancer. Our preliminary experience with three cases suggests that these CSF markers (plus computerized tomograhic scanning) should be evaluated in patients with this disease.

Endodermal sinus tumor of the pineal region: case report.

A 13-year-old boy presented with symptoms and signs of a posterior 3rd ventricle tumor associated with raised levels of serum and cerebrospinal alpha-fetoprotein. The patient underwent subtotal resection of the tumor followed by craniospinal radiation. Histopathological examination revealed a pure endodermal sinus tumor. Endodermal sinus tumors represent a rare type of germ cell tumor, only 13 intracranial cases having been reported in the literature.