Hypopituitarism after gamma knife radiosurgery for pituitary adenoma.

PURPOSE: The aim of the study was to investigate the incidence of and risk factors for hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenoma. MATERIALS AND METHODS: We conducted a retrospective analysis of the pituitary function of 90 patients who underwent GKRS for pituitary adenoma at the University Hospital Centre Zagreb between 2003 and 2014. Twenty seven of them met the inclusion criteria and the others were excluded from the study due to pituitary insufficiency which was present before GKRS. Eighteen patients had non-functioning and 9 patients had secretory adenomas. Median patients' age was 56 years (24-82). GKRS was performed using the Leksell gamma knife Model C. The median prescription radiation dose was 20 Gy (15-25) and the median tumor volume size was 3.4 cm3 (0.06-16.81). New onset hypopituitarism was defined as a new deficit of one of the three hormonal axes (corticotroph, thyreotroph, or gonadotroph) ≥3 months following GKRS. SPSS was used for statistical analysis, with the significance level at P<0.05. RESULTS: During the median follow-up period of 72 months (range 6-144), 30% of patients developed new hypopituitarism after GKRS. This corresponds to incidence of one new case of hypopituitarism per 15 patient-years. Age, gender, tumor function, tumor volume, suprasellar extension, prescription dose of radiation, as well as dose-volume to the pituitary gland, stalk and hypothalamus were not predictive factors for the development of hypopituitarism. CONCLUSIONS: In our cohort of patients with pituitary tumors who underwent GKRS, 30% developed new hypopituitarism during the follow-up period.

Usefulness of an ad hoc questionnaire (Acro-CQ) for the systematic assessment of acromegaly comorbidities at diagnosis and their management at follow-up.

PURPOSE: To determine the validity of a self-administered questionnaire (Acro-CQ) developed to systematically assess the presence, type and time of onset of acromegaly comorbidities. METHODS: This is a cross-sectional study; 105 acromegaly patients and 147 controls with other types of pituitary adenoma, referred to a specialized Italian Center, autonomously compiled Acro-CQ in an outpatient clinical setting. To test its reliability in a different setting, Acro-CQ was administered via mail to 78 patients with acromegaly and 100 with other pituitary adenomas, referred to a specialized US Center. Data obtained from questionnaires in both settings were compared with medical records (gold standard). RESULTS: Demographics of patients and controls from both countries were similar. In both settings, >95 % of the questionnaires were completely filled; only one item was missed in the others. Concordance with medical record was excellent (k > 0.85) for most of the items, independently from the way of administration, patient age, gender and nationality, pituitary adenoma type and disease activity. CONCLUSIONS: Acro-CQ is an inexpensive, highly accepted from patients and reliable tool recommended to expedite systematic collection of relevant clinical data in acromegaly at diagnosis, to be replicated at follow-ups. This tool may guide a targeted, cost-effective management of complications. Moreover, it could be applied to retrieve data for survey studies in both acromegaly and other pituitary adenomas, as information is easily and rapidly accessible for statistical analysis.

Adenovirus-mediated retinoblastoma gene therapy suppresses spontaneous pituitary melanotroph tumors in Rb+/- mice.

The retinoblastoma gene (RB) is the prototypic tumor suppressor. Studies to date have demonstrated cancer suppression with tumor cells reconstituted with RB ex vivo and implanted into immunodeficient mice, as well as with germline transmission of a human RB transgene into tumor-prone Rb +/- mice. To mimic the therapy of cancer more closely, spontaneous pituitary melanotroph tumors arising in immunocompetent Rb +/- mice were treated with a recombinant adenovirus carrying RB cDNA. Intratumoral RB gene transfer decreased tumor cell proliferation, reestablished innervation by growth-regulatory dopaminergic neurons, inhibited the growth of tumors, and prolonged the life spans of treated animals.

[Ectopic relapse of an operated craniopharyngioma. Case report and review of the literature]. / Recidiva a distancia de craneofaringioma intervenido. Caso clínico y revisión de laliteratura.

INTRODUCTION. Craniopharyngioma is an embrionary tumor of the sellar and/suprasellar region derived from fusiform cells of Rathke´s cleft. Although locoregional relapse is the way classically proposed for relapse after treatment, it has been described, in a few cases, the possibility of ectopic relapse out of the sellar-suprasellar region, by direct seeding of cells during surgery on the surgical field, or by cell dissemination in the cerebrospinal fluid (CSF). It is proposed to report the case of a patient with relapse of a craniopharyngioma in the frontal lobe, who was previously operated ten years after, as well as to review the similar cases reported in the literature to the date. RESULTS. A systematic review of the literature has allowed to find 21 cases previously reported. Direct cellular seeding was the most frequent implantation mechanism. In all cases, the preferred treatment was radical surgical removal when this was possible. The time of latency between first surgery and relapse differed from 1 to 21 years. CONCLUSIONS. It is interesting, in the differential diagnosis, to bear in mind the possibility of ectopic relapse of craniopharyngioma in patients who have been operated because of this type of tumor and who present a new mass in nervous central system (CNS). In view of the long time of latency that can pass between the resection of a craniopharyngioma and his relapse, there becomes necessary a long follow-up of these patients by periodic imaging tests.

Modification of mortality and tumorigenesis by tocopherol-mono-glucoside (TMG) administered after X irradiation in mice and rats.

The effects of TMG [2-(alpha-d-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol], a water-soluble vitamin E derivative, administered after irradiation on the mortality of X-irradiated mice and on the development of tumors in the mammary and pituitary glands in rats were investigated. When TMG (650 mg/kg) was administered intraperitoneally (i.p.) to C3H mice immediately after whole-body exposure to 7 Gy radiation, the 30-day survival was significantly higher than that of the control mice. The i.p. administration of TMG at 4 h after irradiation significantly improved survival compared to that of the controls, but administration 8 h after irradiation did not have a significant effect. Subcutaneous administration of TMG immediately after irradiation also decreased mortality significantly. When dams of lactating Wister rats were exposed to 1.5 Gy of X rays at day 21 after parturition and were then treated with diethylstilbestrol as a tumor promoter, the incidence of mammary tumors and pituitary tumors was increased compared to that in the nonirradiated control group. The administration of TMG (600 mg/kg, i.p.) after irradiation significantly reduced the incidence of mammary tumors and pituitary tumors. The number of rats that were free of both mammary and pituitary gland tumors was enhanced fourfold by TMG. These results suggest that TMG is effective in preventing radiation-induced bone marrow death in mice and in reducing mammary and pituitary tumors in rats even when it is administered after irradiation.

mPRs represent a novel target for PRL inhibition in experimental prolactinomas.

Membrane progesterone receptors are known to mediate rapid nongenomic progesterone effects in different cell types. Recent evidence revealed that mPRα is highly expressed in the rat pituitary, being primarily localized in lactotrophs, acting as an intermediary of P4-inhibitory actions on prolactin secretion. The role of mPRs in prolactinoma development remains unclear. We hypothesize that mPR agonists represent a novel tool for hyperprolactinemia treatment. To this end, pituitary expression of mPRs was studied in three animal models of prolactinoma. Expression of mPRs and nuclear receptor was significantly decreased in tumoral pituitaries compared to normal ones. However, the relative proportion of mPRα and mPRß was highly increased in prolactinomas. Interestingly, the selective mPR agonist (Org OD 02-0) significantly inhibited PRL release in both normal and tumoral pituitary explants, displaying a more pronounced effect in tumoral tissues. As P4 also regulates PRL secretion indirectly, by acting on dopaminergic neurons, we studied mPR involvement in this effect. We found that the hypothalamus has a high expression of mPRs. Interestingly, both P4 and OrgOD 02-0 increased dopamine release in hypothalamus explants. Moreover, in an in vivo treatment, that allows both, pituitary and hypothalamus actions, the mPR agonist strongly reduced the hyperprolactinemia in transgenic females carrying prolactinoma. Finally, we also found and interesting gender difference: males express higher levels of pituitary mPRα/ß, a sex that does not develop prolactinoma in these mice models. Taken together, these findings suggest mPRs activation could represent a novel tool for hyperprolactinemic patients, especially those that present resistance to dopaminergic drugs.

Exosome-Transmitted lncRNA H19 Inhibits the Growth of Pituitary Adenoma.

CONTEXT: Our previous study demonstrated that the expression of long noncoding RNA (lncRNA) H19 was frequently downregulated in human primary pituitary adenomas and negatively correlated with tumor progression. However, the role of exosomal lncRNA H19 in the inhibition of pituitary tumor growth remains unclear. OBJECTIVE: To investigate whether exosomal H19 could be transported across the cell membrane to exert its inhibitory effect on pituitary tumor growth. DESIGN: Empty lentivirus GH3 cells with or without H19 overexpression were used to establish a xenograft model. Isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking, and Western blotting. The expression levels of serum exosomal H19 from 200 healthy subjects and 206 patients with various subtypes of pituitary tumors were detected by ultracentrifugation and quantitative real-time PCR. RESULTS: The growth of distal tumor cells was inhibited by transferring exosomal H19, which could be transported through cell membrane and exert its inhibitory effect. Cabergoline increased H19 expression and played a synergic therapeutic effect with exosomal H19. Exosomal H19 inhibited phosphorylation of the mTORC1 substrate 4E-BP1. Of note, the expression level of exosomal H19 in the patients with all subtypes of pituitary tumors was significantly lower than that in the healthy subjects. The change of plasma exosomal H19 level may be correlated with the prognosis or drug response of the patients. CONCLUSION: Exosomal H19 inhibits the growth of distal pituitary tumors through inhibiting 4E-BP1 phosphorylation. Plasma exosomal H19 may serve as an important biomarker for predicting medical responses of patients with prolactinomas.

Physiologic Growth Hormone-Replacement Therapy and Craniopharyngioma Recurrence in Pediatric Patients: A Meta-Analysis.

OBJECTIVE: A systematic review and meta-analysis were conducted to examine the effect of growth hormone-replacement therapy (GHRT) on the recurrence of craniopharyngioma in children. METHODS: PubMed, Embase, and Cochrane databases were searched through April 2017 for studies that evaluated the effect of GHRT on the recurrence of pediatric craniopharyngioma. Pooled effect estimates were calculated with fixed- and random-effects models. RESULTS: Ten studies (n = 3487 patients) met all inclusion criteria, including 2 retrospective cohorts and 8 case series. Overall, 3436 pediatric patients were treated with GHRT after surgery and 51 were not. Using the fixed effect model, we found that the overall craniopharyngioma recurrence rate was lower among children who were treated by GHRT (10.9%; 95% confidence interval 9.80%-12.1%; I2 = 89.1%; P for heterogeneity <0.01; n = 10 groups) compared with those who were not (35.2%; 95% confidence interval 23.1%-49.6%; I2 = 61.7%; P for heterogeneity = 0.11; n = 3); the P value comparing the 2 groups was <0.01. Among patients who were treated with GHRT, subgroup analysis revealed that there was a greater prevalence of craniopharyngioma recurrence among studies conducted outside the United States (P < 0.01), single-center studies (P < 0.01), lower impact factor studies (P = 0.03), or studies with a lower quality rating (P = 0.01). Using the random-effects model, we found that the results were not materially different except for when stratifying by GHRT, impact factor, or study quality; this led to nonsignificant differences. Both Begg's rank correlation test (P = 0.7) and Egger's linear regression test (P = 0.06) indicated no publication bias. CONCLUSIONS: This meta-analysis demonstrated a lower recurrence rate of craniopharyngioma among children treated with GHRT than those who were not.

Influence of GH substitution therapy in deficient adults on the recurrence rate of hormonally inactive pituitary adenomas: a case control study.

OBJECTIVE: Several studies documented metabolic and psychological benefits of GH substitution in deficient adults, most of them suffering from benign pituitary adenomas. Since GH substitution is considered to promote tumour regrowth, adequate treatment is performed with some reservation. Therefore, we aimed to elucidate the effect of GH replacement therapy on tumour recurrence following surgery. METHODS: In patients with hormonally inactive pituitary adenomas undergoing tumour surgery, a retrospective case-control study was performed. Pre- and postoperative magnetic resonance (MR) images of GH-treated and untreated patients were matched for best fit by two independent observers. The treated patients were retrieved from the surveillance programme of the German KIMS database and the untreated from the database of the Department of Neurosurgery, University of Erlangen. A total of 55 matched pairs were followed for at least 5 years. Tumour recurrence and progression rates were determined according to the postoperative MR. RESULTS: There were 16 tumour progressions in the treatment group and 12 in the control group. Statistical analysis revealed no significant increase in either recurrence (P = 0.317) or progression (P = 0.617) within the follow-up period of 5 years when GH was adequately replaced. CONCLUSIONS: This study provides further observational data of substitution therapy in GH-deficient adults with pituitary adenomas. Comparing long-term surgical results, we found no evidence that GH substitution should be withheld in deficient patients. Even residual tumour does not constitute a contraindication to GH replacement. However, since pituitary tumours are slow growing, an observational period of 5 years may not have been long enough to verify any absolute influence on recurrence potential.

E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas.

The E2F transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor. We have previously shown that E2F3 plays a critical role in mediating the mitogen-induced activation of E2F-responsive genes and contributes to both the inappropriate proliferation and the p53-dependent apoptosis that arise in pRB-deficient embryos. Here we show that E2F3 also has a significant effect on the phenotype of tumor-prone Rb(+/-) mice. The absence of E2F3 results in a significant expansion in the life spans of these animals that correlates with a dramatic alteration in the tumor spectrum. E2F3 loss suppresses the development of the pituitary tumors that normally account for the death of Rb(+/-) mice. However, it also promotes the development of medullary thyroid carcinomas yielding metastases at a high frequency. This increased aggressiveness does not seem to result from any change in p53 levels or activity in these tumors. We show that, instead, E2F3 loss leads to an increase in the rate of tumor initiation. Finally, analysis of Rb(+/-); E2f3(+/-) mice shows that this tumor-suppressive function of E2F3 is dose dependent.

Mutations of N-terminal regions render the retinoblastoma protein insufficient for functions in development and tumor suppression.

To assess biological roles of the retinoblastoma protein (RB), four independent transgenic mouse lines expressing human RB with different deletions in the N-terminal region (RBdeltaN) were generated and compared with mice expressing identically regulated, full-length RB. Expression of both RB and RBdeltaN caused developmental growth retardation, but the wild-type protein was more potent. In contrast to wild-type RB, the RBdeltaN proteins were unable to rescue Rb-/- mice completely from embryonic lethality. Embryos survived until gestational day 18.5 but displayed defects in the terminal differentiation of erythrocytes, neurons, and skeletal muscle. In Rb+/- mice, expression of the RBdeltaN transgenes failed to prevent pituitary melanotroph tumors but delayed tumor formation or progression. These results strongly suggest that N-terminal regions are crucial for embryonic and postnatal development, tumor suppression, and the functional integrity of the entire RB protein. Furthermore, these transgenic mice provide models that may begin to explain human families with low-penetrance retinoblastoma and mutations in N-terminal regions of RB.

Management of hormone-secreting pituitary adenomas.

Pituitary adenomas are one of the most common primary central nervous system tumors and have an estimated prevalence of 17%. Approximately half of pituitary adenomas secrete distinct pituitary hormones (most often prolactin, growth hormone, or adrenocorticotropic hormone). While these tumors are histologically benign, they have potent endocrine effects that lead to significant morbidity and shortened lifespan. Because of their pathophysiologic endocrine secretion and anatomic location near critical neural/vascular structures, hormone-secreting pituitary adenomas require defined management paradigms that can include relief of mass effect and biochemical remission. Management of hormone-secreting pituitary adenomas involves a multidisciplinary approach that can incorporate surgical, medical, and/or radiation therapies. Early and effective treatment of hormone-secreting pituitary adenomas can reduce morbidity and mortality. Consequently, understanding clinical features as well as therapeutic options in the context of the specific biological features of each type of hormone-secreting pituitary adenoma is critical for optimal management.

Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas.

OBJECTIVES: Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. DESIGN: Multicenter retrospective study by members of the French Society of Endocrinology. METHODS: Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. RESULTS: The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. DISCUSSION: Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Inhibitory effect of antiestrogen on hepatic tumorigenesis in WF rats treated with diethylstilbestrol alone or in combination with N-nitrosobutylurea.

Four groups of inbred male WF rats were castrated and received sc implantations of diethylstilbestrol [(DES) CAS: 56-53-1; alpha,alpha'-diethyl-4,4'-stilbenediol] at 40 days of age. Group I was given no further treatment; groups II and IV were treated with antiestrogen (AntiE) clomiphene citrate simultaneously with DES treatment. At 50-55 days of age, groups III and IV were given drinking water containing N-nitrosobutylurea [(NBU) CAS: 869-01-2; 1-butyl-1-nitrosourea] for 30 days. Castrated male rats or rats castrated and treated with NBU alone developed neither hepatic tumors (HT) nor pituitary tumors (PT). When AntiE was administered, incidences of HT and PT, size and the total number of HT, and mean pituitary weight were significantly reduced in rats given DES alone and in rats given DES with NBU. AntiE treatment changed the distribution in the histologic classification of hepatocellular lesions: Neoplastic nodules, instead of hepatocellular carcinomas, were predominant. The results indicate that AntiE was effective in the inhibition of hepatic and pituitary tumorigenesis associated with DES treatment. Our previous study has shown that prolactin was not involved in this hepatic tumorigenesis. Therefore, these studies provide evidence that the carcinogenic effect of DES on the liver cell is direct and that HT are regulated in development and growth by AntiE treatment.

Inhibition by 3-amino-1H-1,2,4-triazole of hepatic tumorigenesis induced by diethylstilbestrol alone or combined with N-nitrosobutylurea in WF rats.

Six groups of inbred male WF rats were castrated at 40 days of age. Group 1 was given no further treatment; groups 3-6 received sc implantations of 5.0 mg diethylstilbestrol [(DES) CAS: 56-53-1]. At 50-55 days of age, groups 5 and 6 were given drinking water containing 5.0 mg N-nitrosobutylurea [(NBU) CAS: 869-01-2] per day for 30 days. After the termination of NBU treatment, groups 2, 4, and 6 were given 3-amino-1H-1,2,4-triazole (AT), considered an inhibitor of hydroperoxidases, in the drinking water throughout the experiment. Castrated male rats or rats castrated and treated with AT alone developed neither hepatic tumors nor pituitary tumors. The hepatic tumor incidence, the size and total number of hepatic tumors, and the mean liver weight were significantly reduced in rats given the DES-NBU combination and slightly reduced in rats given DES alone when AT was administered. In contrast, AT treatment did not change the pituitary tumor incidence and the mean pituitary weight. The thyroid gland weights were approximately 7-44 times greater in AT-treated groups than those in each corresponding control group. These data indicate that AT inhibited hepatic but not pituitary tumorigenesis and caused enlargement of the thyroid gland. The present study, therefore, provides evidence that the metabolic activation of DES by oxidation is involved in rat liver carcinogenesis.

Growth hormone replacement therapy reduces risk of cancer in adult with growth hormone deficiency: A meta-analysis.

The risk of growth hormone on cancer in adult with growth hormone deficiency remains unclear. We carried out a meta-analysis to evaluate the risk of cancer in adult with and without growth hormone replacement therapy. We searched PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases up to 31 July 2016 for eligible studies. Pooled risk ratio (RR) with 95% confidence interval (CI) was calculated using fixed-or random-effects models if appropriate. The Newcastle-Ottawa Scale was used to assess the study quality. Two retrospective and seven prospective studies with a total of 11191 participants were included in the final analysis. The results from fixed-effects model showed this therapy was associated with the deceased risk of cancer in adult with growth hormone deficiency (RR=0.69, 95%CI: 0.59-0.82), with low heterogeneity within studies (I2=39.0%, P=0.108). We performed sensitivity analyses by sequentially omitting one study each time, and the pooled RRs did not materially change, indicating that our results were statistically stable. Begger's and Egger's tests suggested that there was no publication bias (Z=-0.63, P=0.520; t=0.16, P=0.874). Our study suggests that growth hormone replacement therapy could reduce risk of cancer in adult with growth hormone deficiency.

Mucin 1 and poly I:C activates dendritic cells and effectively eradicates pituitary tumors as a prophylactic vaccine.

Pituitary tumors are the most common type of cancer within the central nervous system. In the present study, the expression levels of mucin 1 (Muc1) were examined in invasive and non­invasive pituitary tumor samples, and the results of immunohistochemical staining and Western blot analysis demonstrated marked positive expression of Muc1. In addition, Muc1 + polyinosinic:polycytidylic acid (poly I:C) was found to stimulate the expression levels of the surface molecules cluster of differentiation (CD)40, CD83 and CD80, and HLA­DRm and decreased the expression of CD14 in the dendritic cells, determined using fluorescence­activated cell sorting. The secretions of interleukin (IL)­6, tumor necrosis factor­α and IL­1ß cytokines were also significantly induced, in a dose­dependent manner. In in vivo experiments, a higher percentage of CD3+CD4+ T lymphocytes was detected, and the levels of interferon­Î³ and IL­2 in the splenocytes were also upregulated. Furthermore, the combination treatment of Muc1 with poly I:C increased anti­Muc1 IgM and anti­Muc1 IgG titers, and altered the balance of IgG2a and IgG1, all of which increased the T helper (Th)1 polarized immune response. Thus, the tumor antigen, Muc1, with poly I:C may produce potent protective effects, which polarize immune responses towards Th1, and elicit antitumor immunity to inhibit the progression of pituitary tumors.

Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction.

A reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is associated with an extension of lifespan in laboratory rodents. Several phenotypes of such animal models resemble those induced by caloric restriction (CR). Using a transgenic male Wistar rat model whose GH-IGF-1 axis was moderately suppressed by overexpression of the antisense GH transgene (tg), we elucidated a relationship between the effects of a reduced GH-IGF-1 axis and CR for some biomarkers of aging, lifespan, and pathologies. Heterozygous (tg/-) rats fed ad libitum (AL) had a dwarf phenotype similar to that of control nontransgenic (-/-) rats subjected to 30% CR from 6 wk of age. Both the reduced GH-IGF-1 axis and CR extended lifespan to a similar extent, although the effect of CR seemed to be greater. There was an additive effect of CR to lifespan extension when tg/- rats were subjected to CR. Pathologic analyses indicated that the preventive effect of CR on selected diseases was greater than that of the reduced GH-IGF-1 axis. The present study suggests that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effects partly through the reduced GH-IGF-1 axis.

Radiosurgery and the prevention of regrowth of incompletely removed nonfunctioning pituitary adenomas.

OBJECT: The authors studied the efficacy of gamma knife radiosurgery (GKS) in the prevention of regrowth of nonfunctioning pituitary adenomas (NPA). METHODS: One hundred nineteen patients were included in this study and were divided into two groups. All patients had undergone surgery in our department and recurrent or residual adenoma was demonstrated on postoperative MR imaging. Group A consisted of 68 patients who were followed without additional treatment. Group B was composed of 51 patients who received GKS within 1 year after microsurgery. There was no significant demographic difference between the two groups. In Group B the mean margin dose was 16.5 +/- 0.3 Gy (range 13-21 Gy). Fifty one and one tenth percent of patients in Group A were recurrence free at 5 years and 89.8% in Group B (p < 0.001). In Group B patients, tumor volume decreased from a baseline value of 2.4 +/- 0.2 cm3 to 1.6 +/- 0.2 cm3 at last follow up (p < 0.001). CONCLUSIONS: The results of this study suggest that GKS is effective in controlling growth of residual NPA for at least 5 years following initial maximal surgical debulking compared with no radiation therapy. Thus, GKS is recommended after microsurgery when visible tumor can be detected on imaging studies.

Deprenyl reinitiates estrous cycles, reduces serum prolactin, and decreases the incidence of mammary and pituitary tumors in old acyclic rats.

The purpose of this study was to investigate the effects of long term treatment with deprenyl, a monoamine oxidase-B inhibitor, on estrous cyclicity, serum PRL, incidence of mammary and pituitary tumors, and monoamine metabolism in the medial basal hypothalamus (MBH) and striatum (ST) of old female rats. Acyclic female Sprague-Dawley rats (15-16 months old) were treated sc with 0, 0.25, or 2.5 mg deprenyl/kg BW.day for more than 8 months. Body weight and food intake were measured every week, and the estrous cycles and development of mammary tumors were monitored throughout the treatment period. At the end of the treatment period, the concentrations of catecholamines, serotonin, and their metabolites in the MBH and ST were determined by HPLC with electrochemical detection. The wet weights of the pituitary, heart, liver, lung, kidney, adrenals, uterus, and ovaries were recorded. Trunk blood was collected for measurement of serum PRL concentrations by RIA. Deprenyl treatment temporarily reestablished estrous cycles in most of the rats. The incidence of pituitary and mammary tumors was markedly reduced in the deprenyl-treated rats compared with that in the saline-treated control rats. Deprenyl had no significant effect on the weights of internal organs. The high dose of deprenyl (2.5 mg/kg) decreased serum PRL concentrations significantly. There were no significant differences in body weight or food intake between the control and deprenyl-treated groups. Deprenyl decreased the concentrations of the monoamine metabolites, dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid, in both the MBH and ST. It had no effect on the concentrations of norepinephrine and dopamine in the MBH, but significantly increased norepinephrine concentrations in the ST and serotonin concentrations in both the MBH and ST (P < 0.05). It is concluded that deprenyl treatment exerted these effects via suppression of monoamine metabolism.