Primary Gamma Knife Radiosurgery for pineal region tumors: A systematic review and pooled analysis of available literature with histological stratification.

Pineal region tumors (PTs) represent extremely rare pathologies, characterized by highly heterogeneous histological patterns. Most of the available evidence for Gamma Knife radiosurgical (GKSR) treatment of PTs arises from multimodal regimens, including GKSR as an adjuvant modality or as a salvage treatment at recurrence. We aimed to gather existing evidence on the topic and analyze single-patient-level data to address the efficacy and safety of primary GKSR. This is a systematic review of the literature (PubMed, Embase, Cochrane, Science Direct) and pooled analysis of single-patient-level data. A total of 1054 original works were retrieved. After excluding duplicates and irrelevant works, we included 13 papers (n = 64 patients). An additional 12 patients were included from the authors' original series. A total of 76 patients reached the final analysis; 56.5% (n = 43) received a histological diagnosis. Confirmed lesions included pineocytoma WHO grade I (60.5%), pineocytoma WHO grade II (14%), pineoblastoma WHO IV (7%), pineal tumor with intermediate differentiation WHO II/III (4.7%), papillary tumor of pineal region WHO II/III (4.7%), germ cell tumor (2.3%), neurocytoma WHO I (2.3%), astrocytoma WHO II (2.3%) and WHO III (2.3%). Presumptive diagnoses were achieved in the remaining 43.5% (n = 33) of cases and comprised of pineocytoma (9%), germ cell tumor (6%), low-grade glioma (6%), high-grade glioma (3%), meningioma (3%) and undefined in 73%. The mean age at the time of GKSR was 38.7 years and the mean lesional volume was 4.2 ± 4 cc. All patients received GKSR with a mean marginal dose of 14.7 ± 2.1 Gy (50% isodose). At a median 36-month follow-up, local control was achieved in 80.3% of cases. Thirteen patients showed progression after a median time of 14 months. Overall mortality was 13.2%. The median OS was not reached for all included lesions, except high-grade gliomas (8mo). The 3-year OS was 100% for LGG and pineal tumors with intermediate differentiation, 91% for low-grade pineal lesions, 66% for high-grade pineal lesions, 60% for germ cell tumors (GCTs), 50% for HGG, and 82% for undetermined tumors. The 3-year progression-free survival (PFS) was 100% for LGG and pineal intermediate tumors, 86% for low-grade pineal, 66% for high-grade pineal, 33.3% for GCTs, and 0% for HGG. Median PFS was 5 months for HGG and 34 months for GCTs. The radionecrosis rate was 6%, and cystic degeneration was observed in 2%. Ataxia as a presenting symptom strongly predicted mortality (odds ratio [OR] 104, p = .02), while GCTs and HGG histology well predicted PD (OR: 13, p = .04). These results support the efficacy and safety of primary GKSR treatment of PTs. Further studies are needed to validate these results, which highlight the importance of the initial presumptive diagnosis for choosing the best therapeutic strategy.

[Participation of pineal gland in antistressor activity of adaptogenic drugs].

Chronic stress produces some morphological changes in rats, including thymus weight reduction, adrenal hypertrophy, and peptic ulcers in stomach. Repeated administration of phytoadaptogenic drugs (ginseng and bilobil) decreased these stress-induced disorders. The antistressor activity of drugs was attenuated upon by removal of the pineal gland. Histochemical and morphometric investigation of pineal tissues in stressed animals showed that that the pharmacological effect was accompanied by increasing functional activity of the pineal gland. It is suggested that pineal mobilization may participate in antistressor activity of phytoadaptogenic drugs.

[Effect of moxibustion on quantity of pinealocytes and pineal HSP 70 expression in subacute aging rats].

OBJECTIVE: To study the mechanism of moxibustion in postponing the process of aging. METHODS: Thirty Wistar rats were equally randomized into control, model and moxibustion groups. The subacute aging model was established by hypodermic injection of 25% D-galactose (125 mg/kg). Moxibustion was applied to bilateral "Shenshu" (GV 23) and "Pishu" (GV 20) once everyday for 6 weeks. After slicing, the pineal gland tissue was stained with HE and insitu hybridization methods respectively for detecting the quantity of pinealocytes and the expression of heat shock protein (HSP 70). RESULTS: Compared with the control group, both the quantity of pinealocytes and the expression of HSP 70 in the pineal gland in the model group were downregulated significantly (P < 0.001, P < 0.01). Compared with model group, the quantity of pinealocytes and of HSP 70 mRNA in the pineal gland of moxibustion group were upregulated significantly (P < 0.01, P < 0.05). CONCLUSION: Moxibustion can suppress aging induced decrease of pinealocyte number and HSP 70 expression in subacute aging rats, which may contribute to its effect in postponing aging.

An historical view of the pineal gland and mental disorders.

Since Classical Antiquity numerous authors have linked the origin of some mental disorders to physical and functional changes in the pineal gland because of its attributed role in humans as the connection between the material and the spiritual world. The pineal organ was seen as a valve-like structure that regulated the flow of animal spirits through the ventricular system, a hypothesis that took on more vigour during the Middle Ages and the Renaissance. The framework for this theory was "the three cells of the brain", in which the pineal gland was even called the "appendix of thought". The pineal gland could also be associated with the boom, during this period, of certain legends about the "stone of folly". But the most relevant psychopathological role of this organ arrived with Descartes, who proposed that it was the seat of the human soul and controlled communications between the physical body and its surroundings, including emotions. After a period of decline during which it was considered as a mere vestigial remnant of evolution, the link between the pineal gland and psychiatric disorders was definitively highlighted in the 20th century, first with the use of glandular extracts in patients with mental deficiency, and finally with the discovery of melatonin in 1958. The physiological properties of melatonin reawakened interest in the relationship between the pineal gland and mental disorders, fundamentally the affective and sleep disorders, which culminated in the development of new pharmacological agents acting through melatonergic receptors (ramelteon and agomelatine).

Feasibility of neuroendoscopic biopsy of pediatric brain tumors.

PURPOSE: The purpose of this study was to investigate the potential value of neuroendoscopic biopsies in pediatric patients with peri- or intraventricular tumors. METHODS: From 2001 to 2008, 49 pediatric patients (mean age, 12.16 years) with tumors located in the intraventricular or paraventricular areas underwent neuroendoscopic biopsy, with or without simultaneous endoscopic third ventriculostomy. Neuroendoscopic biopsies were performed to verify the histological diagnosis of neoplasms and to establish pathological diagnoses necessary for planning appropriate treatment strategies. RESULTS: In 45 of 49 patients (91.8%) neuroendoscopic biopsy specimens were appropriate for diagnosis and revealed 27 germinomas, 11 astrocytomas, and one ependymoma, etc. The tumor location included the pineal gland (n = 28), thalamus (n = 7), intraventricle (n = 3), hypothalamus (n = 3), suprasellar area (n = 2), and diffuse multifocal area (n = 3). In two patients (4.1%) biopsy specimens were informative but not diagnostic. Tumor tissue specimens were undiagnostic in two patients (4.1%). There were eight transient morbidities, including four EOM limitations, two central DI, one EVD infection, and one CSF leakage. One patient experienced postoperative tumor bleeding requiring emergent operation. There was no case of operative mortality. CONCLUSION: Neuroendoscopic biopsy can be considered as the first choice for tissue sampling of periventricular and intraventricular tumors with acceptable risks.

Peri-operative quality of life assessment in endoscopically treated patients with pineal region tumours.

BACKGROUND: Therapeutic modalities for pineal region tumours are still matter of debate. Endoscopic treatment is a minimally invasive approach. The aim of this study was to assess the quality of life of patients with pineal region tumours who underwent endoscopic procedures. MATERIALS AND METHODS: Eight patients (male:3, female 5) were included in this study. Post-operative evaluation of surgical outcome in terms of quality of life (QoL) was performed using the Quality of Life Questionnaire (QLQ-C30). The patient's outcome scores were compared with normative outcome values of the German population. Pre-operative and post-operative global QoL and symptoms such as headache, visual disturbance, gait disturbance, cognitive function and unconsciousness were documented. Descriptive and explorative statistics were performed. RESULTS: There were no significant differences between the normal German population and the endoscopically treated patients in different health domains and measures of QLQ-C30 (physical functioning 87.5%, emotional functioning 50%, cognitive functioning 50%, social functioning 62.5%; percentage represents regular functioning). Improved quality of life could be demonstrated in short-term (3-12 months, n = 3) and long-term (21-29 months, n = 5) follow-up. Global QoL improved significantly (p < 0.001; t-test) post-operatively. The following changes between pre-operative and post-operative clinical symptoms were found (headache 87.5%/62.5%, visual disturbance 50%/25%, gait disturbance 87.5%/25%, cognitive functioning 75%/37.5%, unconsciousness 25%/-). CONCLUSION: Endoscopic treatment of patients with pineal region tumours produces improved post-operative quality of life in all health domains. Therefore, the endoscopic approach should be considered as an alternative treatment in patients with newly diagnosed pineal tumours and/or related hydrocephalus.

Pineal germinoma presenting as anorexia nervosa: Case report and review of the literature.

OBJECTIVE: Tumors of the hypothalamic-pineal region may present with a wide variety of symptoms, including disturbed eating. We present a case where such a tumor was misdiagnosed as anorexia nervosa. METHOD: We describe a case of pineal germinoma invading the hypothalamus, which was initially diagnosed as anorexia nervosa. RESULTS: Clinical features included weight loss, vomiting, pyrexia, hypernatraemia, and visual disturbance and the typical psychopathology of anorexia nervosa was absent. CONCLUSION: Organic disorder should always be considered before making a diagnosis of anorexia nervosa, particularly if the presentation is atypical.

Increased REM sleep associated with melatonin deficiency after pinealectomy: a case study.

The objectives of the investigation were to assess hypersomnia, which progressively appeared in a young patient after a pinealectomy, chemotherapy, and radiotherapy for a typical germinoma, as well as the potential benefit of melatonin administration in the absence of its endogenous secretion. 24 h ambulatory polysomnography and the Multiple Sleep Latency Test (MSLT) were performed; in addition, daily plasma melatonin, cortisol, growth hormone, prolactin, and rectal temperature profiles were determined before and during melatonin treatment (one 2 mg capsule given nightly at 21:00 h for 4 weeks). MSLT showed abnormal sleep latency and two REM sleep onsets. Nighttime total sleep duration was lengthened, mainly as a consequence of an increased REM sleep duration. These parameters were slightly modified by melatonin replacement. Plasma melatonin levels, which were constantly nil in the basal condition, were increased to supraphysiological values with melatonin treatment. The plasma cortisol profile showed nycthemeral variation within the normal range, and the growth hormone profile showed supplementary diurnal peaks. Melatonin treatment did not modify the secretion of either hormone. The plasma prolactin profile did not display a physiological nocturnal increase in the basal condition; however, it did during melatonin treatment, with the rise coinciding with the nocturnal peak of melatonin concentration. A 24 h temperature rhythm of normal amplitude was persistent, though the mean level was decreased and the rhythm was dampened during melatonin treatment. The role of radiotherapy on the studied parameters cannot be excluded; the findings of this case study suggest that the observed hypersomnia is not the result of melatonin deficiency alone. Overall, melatonin treatment was well tolerated, but the benefit on the sleep abnormality, especially on daytime REM sleep, was minor, requiring the re-introduction of modafinil treatment.

Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study.

Using PET with the opioidergic ligand [11C]diprenorphine, the authors demonstrate decreased tracer binding in the pineal gland of cluster headache patients vs healthy volunteers. Opioid receptor availability in the hypothalamus and cingulate cortex depended on the duration of the headache disorder. Therefore, the pathophysiology of cluster headache may relate to opioidergic dysfunction in circuitries generating the biologic clock.

Interphotoreceptor retinoid-binding protein (IRBP)-deficient C57BL/6 mice have enhanced immunological and immunopathogenic responses to IRBP and an altered recognition of IRBP epitopes.

Experimental autoimmune uveitis (EAU) and pinealitis (EAP) can be induced in susceptible mice by immunization with immunologically privileged retinal antigens. In the present study, we analyzed the immunologic and immunopathologic responses of mice deficient in the retinal autoantigen interphotoreceptor retinoid-binding protein (IRBP). The consequences of IRBP deficiency on the T-cell repertoire were also investigated. IRBP+/+, IRBP+/- and IRBP-/- mice on the C57BL/6 background were immunized with IRBP or with a pathogenic epitope, IRBP(1-20) peptide in adjuvant, and were evaluated for disease severity and immunological responses. C57BL/6 IRBP-/- mice were completely resistant to EAU and EAP, and had enhanced immunological responses to IRBP and to its pathogenic peptide 1-20, as compared to their IRBP+/+ counterparts. IRBP-/- mice exhibited an altered IRBP epitope recognition. T cell epitope mapping revealed a response to IRBP peptide 271-290 in IRBP-/- mice, that was absent in the wild type. Primed T cells of IRBP-/- mice transferred an exacerbated form of EAU to nai;ve wild type recipients. A gene-dose effect was evident in that C57BL/6 IRBP+/- mice, exhibited intermediate immunological responses and lower disease scores compared to wild type. We conclude that expression of IRBP in target tissues is a necessary prerequisite for disease induction, excluding other retinoid-binding or vision-related proteins as surrogate targets. Furthermore, endogenous expression of IRBP is directly responsible for lowering the threshold of susceptibility to uveitic disease.

Nonresective treatment of pineoblastoma: a case report.

BACKGROUND: Stereotactic biopsy followed by cytoreductive surgery and/or radiation are the standard treatment for pineoblastoma. We are reporting a patient with a relatively large pineoblastoma, who was treated with a combination of nonresective treatment modalities. METHOD: The patient is a 20-year-old woman who presented with signs and symptoms of raised intracranial pressure. Magnetic resonance imaging (MRI) showed a large tumor in the pineal region and hydrocephalus. She was emergently treated by placement of a ventriculoperitoneal shunt. Three days later she underwent a stereotactic biopsy, which showed the tumor to be pineoblastoma. She was then further treated with the following treatment modalities: permanent implantation of high activity I125 seeds, external radiation, and chemotherapy. RESULTS: At 10 months' follow-up, MRI showed complete disappearance of the tumor. At 18 months' follow-up, the patient is asymptomatic, neurologically intact, and her MRI scans show no evidence of intracranial or intraspinal tumor. CONCLUSIONS: Though the follow-up is relatively short, the results of the nonresective approach in this patient have been excellent.

Recoverin is highly uveitogenic in Lewis rats.

PURPOSE: Recoverin, a calcium-binding protein that selectively localizes to the retina and pineal gland, has been identified as the target for the putative pathogenic autoimmune process of cancer-associated retinopathy (CAR). The present study was aimed at testing the capacity of recoverin to induce experimental autoimmune uveoretinitis and pinealitis in Lewis rats. METHODS: Lewis rats were immunized against recombinant myristoylated recoverin by a single footpad injection of the protein, at various doses, emulsified in complete Freund's adjuvant. Development of uveoretinitis was monitored by clinical and histologic examinations, whereas pinealitis was detected by histologic examination. RESULTS: Immunization with recoverin induced severe panuveitic changes that closely resemble those induced by S-antigen (arrestin). The effect was dose-dependent, with 10 micrograms/rat the lowest immunopathogenic dose. Rats immunized with recoverin also developed pineal inflammation. CONCLUSION: Recoverin is highly immunopathogenic in Lewis rats. Although the ocular changes induced in rats differ from those seen in CAR, the data recorded here are in line with the concept that recoverin can initiate pathogenic autoimmune processes in the eye.

Germ cell tumor in the hypothalamo-neurohypophysial region: clinical features and treatment.

Twenty-one patients with germ cell tumors (17 germinomas and 4 teratomas) involving the hypothalamic-neurohypophysial (HN) region were reviewed retrospectively. Eleven patients were males and 10 females, and their ages ranged from 7 to 45 years (average 18.5 years). Diabetes insipidus was the initial and the most prominent symptom in most germinomas; in teratomas the most prominent symptom was visual disturbance. Fifteen patients with germinomas were treated by radiotherapy, and 4 with teratomas were treated by surgical resection alone. Two recent germinoma patients with extensive CSF dissemination were treated with systemic chemotherapy consisting of anticancer platinum drugs and etoposide, which resulted in a complete disappearance of the tumors. Patients with germinoma treated after the introduction of CT scanning had a greatly improved mortality rate, and their actual survival rate was 87.5% over 10 years. On the basis of this review, the authors consider that diagnosis at an early stage of the disease and chemotherapy, which can be an effective therapeutic alternative to radiation therapy, may improve not only the mortality rate but also the quality of life of patients with HN germ cell tumors.

Experimental autoimmune uveoretinitis and pinealitis induced by interphotoreceptor retinoid-binding protein and S-antigen: induction of intraretinal and subretinal neovascularization.

Experimental autoimmune uveoretinitis (EAU) and pinealitis were induced in Lewis rats following hind foot pad injection of interphotoreceptor retinoid-binding protein (IRBP) or S-antigen. A comparison is made in this study of the in vivo and histological changes in uveoretinitis and pinealitis induced by administering similar doses of highly-purified IRBP and S-antigen emulsified in complete Freund's adjuvant (CFA). The time of onset of ocular inflammation after inoculation was slightly later in S-antigen (14-18 days) as compared with IRBP-inoculated animals (10-14 days), while the severity of the inflammation was lower in the latter group. The distribution of inflammation in the anterior segment was similar in both the S-antigen and IRBP sensitized animals but there was major variation in the location of the posterior segment disease. Vasculitis was a predominant feature of IRBP induced disease while chorioretinitis and photoreceptor destruction was more prominent in the S-antigen sensitized animals. A striking feature of this study is that both antigens induced intraretinal and subretinal neovascularization, an observation which has not been reported previously. Inflammation was induced in all pineal glands and as with EAU the severity was closely related to the type of antigen inoculated.

Induction of experimental autoimmune uveoretinitis and pinealitis by IRBP. Comparison to uveoretinitis induced by S-antigen and opsin.

Microgram quantities bovine IRBP (interphotoreceptor retinoid binding protein) injected in Freund's complete adjuvant induced severe autoimmune uveoretinitis and pinealitis in Lewis rats. At low doses the onset was accelerated and intensified by co-injection of Hemophilus pertussis bacteria. Wistar, BN and PVG rats were less susceptible, while the eyes of athymic, nude rats did not respond. The disease developed similar to but faster than S-antigen-induced uveoretinitis, while its onset was one day earlier and the reactions were slightly more severe. As distinct from these two types of uveoretinitis, opsin (in much higher doses) caused milder reactions in the anterior segment, while retinitis dominated. In each type of inflammation the photoreceptor cell layer was totally destroyed. All three ocular diseases were inhibited by cyclosporine treatment, which indicates that T cell-dependent mechanisms are essential for the development.

The role of the pineal gland in stress.

A short survey of the results of our previous research into the protective role of the pineal gland against stress is given. The neuroendocrine aspect of a chronic auditory stress and the neuroendocrine aspect of ulcer disease in man were studied. Auditory stress: hypertrophy and hyperplasia of pinealocytes, hyperplasia of the STH, FSH, LTH and TSH cells, hypertrophy of the nuclei and nucleoli of the neuroglandular cells of the supraoptic and paraventricular nuclei, pronounced hyperplasia of the cells of the reticular zone of the adrenal gland, involution of the seminal epithelium, hyperplasia of the Leydig cells. Ulcer disease: numerous glial plates, cavities and acervuli in the pineal gland, numerous granules and vacuoles in the FSH cells, large and eccentrical nuclei in the LH cells, hyperplasia of the cells of the reticular zone of the adrenal gland, presence of the seminal tubules marked by signs of involution, hyperplasia of the Leydig cells. The results obtained point to the secretion of androgens and the insufficiency of the antiandrogenic function of the pineal gland both in auditory stress and ulcer disease. The anticancerogenic effect of the pineal gland would be based on its antiandrogenic function.

Computed tomography: evaluation of the posterior third ventricle.

The normal computed tomography (CT) appearances of the posterior third ventricle and related structures are presented. Seventy-six patients with lesions directly involving this ventricle were studied by CT, and results of other neuroradiological procedures evaluated. Primary tumors, metastases, hematomas, infarcts, and cysts may be reliably distinguished by CT, particularly if contrast enhancement is utilized. Size and density resolution limit the direct visualization of the aqueduct of Sylvius; stenosis however may be inferred. Small infarcts may be difficult to demonstrate by the use of CT scans without contrast enhancement, yet be shown by isotope scans.