Gamma knife radiosurgery is effective in patients with thyrotropin-secreting pituitary adenomas.

PURPOSE: Thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) is a rare cause of TSH-dependent hyperthyroidism. The first therapeutic option is surgery. Medical treatment with somatostatin analogs is also effective. To obviate the need for lifelong drug therapy, gamma knife radiosurgery (GKRS) might be considered in selected patients. We report the largest series of patients with TSHoma treated by GKRS at a single center. METHODS: This study was a retrospective analysis of 18 consecutive patients with TSHoma treated by GKRS between 1994 and 2022. Normalization of hyperthyroidism, when present at the time of surgery, and control of tumor growth were the main outcomes of the study. RESULTS: The median follow-up after GKRS treatment was 114 months (IQR, 57-213 months; range 17-285 months). No patients had growth of the residual tumor after GKRS. Remission of hyperthyroidism occurred in 9 of the 11 (81.8%) patients who were hyperthyroid before GKRS. The probability of hyperthyroidism remission three years after GKRS was 59.1% (95% CI 27.9-90.3%). No major side effects occurred after GKRS. One patient out of the 15 patients (6.7%) with normal baseline adrenal function and follow-up longer than 3 years developed new onset hypoadrenalism, while hypogonadism did not occur in the 13 patients with baseline normal function. CONCLUSION: Our study shows that GKRS is an effective and safe adjuvant treatment for selected patients with residual or recurring TSHoma. The option of GKRS as an alternative treatment to lifelong medical treatment with somatostatin analogs should be thoroughly discussed with the patients.

Gamma knife radiosurgery in patients with Nelson's syndrome.

PURPOSE: Nelson's syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with Cushing's disease. The best therapeutic strategy in NS has not been well defined. Gamma knife radiosurgery (GKRS) is very effective to stop the growth of the pituitary adenoma, which is the main goal of the treatment of patients with NS. We report the largest series of patients with NS treated by GKRS at a single center. METHODS: The study was an observational, retrospective analysis of 28 consecutive patients with NS treated by GKRS in our department between 1995 and 2019. All patients had a growing ACTH-secreting pituitary adenoma. The main outcome of the study was to assess by the Kaplan-Meier method the risk of tumor progression after GKRS. RESULTS: The median follow-up after GKRS treatment was 98 months (IQR 61-155 months, range 7-250 months). Two patients (7.1%) had a recurrence of disease during follow-up. The 10-year progression-free survival was 91.7% (95% CI 80.5-100%). No patient had deterioration of visual function or oculomotor function after GKRS. New onset of hypogonadism and hypothyroidism occurred in 18.8% and 14.3% of the patients at risk. CONCLUSION: Our study confirms that GKRS may stop the tumor growth in the majority of patients with NS, even though very aggressive adenomas may ultimately escape this treatment. Safety of GKRS was good in our experience, but due attention must be paid to planning the distribution of radiation to critical structures, especially in patients previously treated by radiation.

The emerging role of hearing loss rehabilitation in patients with vestibular schwannoma treated with Gamma Knife radiosurgery: literature review.

Stereotactic radiosurgery (SRS) is currently the most common treatment for small- to medium-size vestibular schwannoma (VS). Despite favorable outcome, hearing deterioration still remains an underestimated problem, and the role of hearing rehabilitation is an underinvestigated topic. Among available technologies, cochlear implant (CI) should represent a valid alternative in sporadic VS with single-sided deafness and in neurofibromatosis (NF2) with bilateral profound hearing loss. A literature review of the current clinical data was performed searching scientific literature databases. From all of the articles found, 16 papers were selected. Forty-four subjects treated with radiosurgery (18 male, 19 female, and in 7 cases, sex were not specified; 43 NF2 and 1 sporadic VS) were included in the analysis. Epidemiological, clinical, tumor, treatment, and audiological data were collected. Clinical outcome at last follow-up showed an audiological improvement in 25 of the 44 patients. The audiological outcome was unchanged in 16 cases. Audiological deterioration was recorded in 3 cases. Severity of NF2 phenotype, long history of ipsilateral profound deafness before implantation, progressive tumor growth, and high radiation dose (20 and 40 Gy) were found in patients with a worst audiological outcome. Hearing rehabilitation can improve audiological results for VS patients following SRS in selected cases. Hearing rehabilitation with cochlear implant (CI) in SSD leads to partial restoration of binaural hearing with an improvement in speech comprehension in noise and in sound localization, and partial suppression of subjective incapacitating tinnitus. SRS followed by CI may represent in selected cases a potential emerging option in the management of these patients, aimed at improving their quality of life. Possible implications for the follow-up of these patients are still present, although partially resolved.

Procedure for the systematic orientation of digitised cranial models. Design and validation.

Comparison of bony pieces requires that they are oriented systematically to ensure that homologous regions are compared. Few orientation methods are highly accurate; this is particularly true for methods applied to three-dimensional models obtained by surface scanning, a technique whose special features make it a powerful tool in forensic contexts. The aim of this study was to develop and evaluate a systematic, assisted orientation method for aligning three-dimensional cranial models relative to the Frankfurt Plane, which would be produce accurate orientations independent of operator and anthropological expertise. The study sample comprised four crania of known age and sex. All the crania were scanned and reconstructed using an Eva Artec™ portable 3D surface scanner and subsequently, the position of certain characteristic landmarks were determined by three different operators using the Rhinoceros 3D surface modelling software. Intra-observer analysis showed a tendency for orientation to be more accurate when using the assisted method than when using conventional manual orientation. Inter-observer analysis showed that experienced evaluators achieve results at least as accurate if not more accurate using the assisted method than those obtained using manual orientation; while inexperienced evaluators achieved more accurate orientation using the assisted method. The method tested is a an innovative system capable of providing very precise, systematic and automatised spatial orientations of virtual cranial models relative to standardised anatomical planes independent of the operator and operator experience.

Vestibular assessment in patients with vestibular schwannomas: what really matters?

Vestibular function is often underdiagnosed in vestibular schwannomas (VS). To evaluate it in a selected group of patients harbouring vestibular schwannomas, 64 patients were included in this study, recruited between March 2008 and June 2011 at our institution. All patients underwent Gd-enhanced MRI and complete neurotological evaluation before gamma knife surgery. Morphological measurements included Koos Classification and quantification of internal acoustic canal filling in length and diameter. Cochlear and vestibular functions were assessed considering pure tone and speech audiometry, bedside examination and caloric test by videonystagmography. A statistical analysis was performed to find possible correlations between morphological and cochleovestibular data. Patients with a higher intracanalicular length (ICL, mean value 8.59 and median 8.8 mm) of the tumour presented a higher value of UW than the subgroup with a lower length (51.9 ± 24.3% and 38.8 ± 18.1% respectively, p = 0.04), while no difference was detected for pure tone audiometry (PTA) values (50.9 ± 22.3 db and 51.1 ± 28.9 db respectively). Patients with a higher ICL also presented a higher rate of positive HIT (88% and 60% respectively, p = 0.006). Patients with a higher value of intracanalicular diameter (ICD, mean value 5.22 and median 5.15 mm) demonstrated higher values of UW (50.2 ± 29.1% and 39.3 ± 21% respectively, p = 0.03), but not different PTA (50.2 ± 29.1 db and 51.9 ± 29.9 db respectively). Finally, patients with a positive head impulse test (HIT) demonstrated significantly higher values of unilateral weakness (UW) (p = 0.001). Vestibular disorders are probably underdiagnosed in patients with VS. ICL and ICD seem to be the main parameters that correlate with vestibular function. Also, in case of small intracanalar T1 VS a slight increase of these variables can result in significant vestibular impairment. The data reported in the present study are not inconsistent with the possibility of proactive treatment of patients with VS.

Target-specific action of organochlorine compounds in reproductive and nonreproductive tissues of estrogen-reporter male mice.

Organochlorines are lipophylic molecules that accumulate in the fat where they remain for years. During weight loss, they are mobilized and their concentration increases in blood. The present work tests, in transgenic estrogen-reporter mice (ERE-tK-LUC), whether this increase is sufficient to modulate the estrogen receptors (ERs) in the whole body. Three weak estrogens were studied: p,p'DDT [1,1,1-trichloro2,2-bis(p-chlorophenyl) ethane], p,p'DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene], and betaBHC [beta-benzene-hexachloride]. Dose-dependent analysis of reporter expression (luciferase) were performed in tissues of acutely treated mice. A body map of ER activation was obtained. All these chemicals modulated the reporter, although with a different efficiency and depending upon the tissue analyzed. Induction was confirmed in the liver by determining the expression of the endogenous progesterone receptor (PR) gene, at the dose and time point at which the luciferase gene was maximally induced. After experimental accumulation in the fat tissue, followed by a 48-h period of fasting, we tested whether these compounds could be mobilized to reach sufficient levels to activate the ERs in selected reproductive and nonreproductive tissues (testicle, prostate, liver, and lung). This experimental setting produced results that were different than those obtained following acute treatments. In loaded mice, fasting induced betaBHC mobilization resulted in strong ER activation in the liver and the lung, which was blocked by ICI-182780. p,p'DDT mobilization had no effect in these tissues, but it acted efficiently in the prostate and testis. betaBHC inhibited the ERE-mediated reporter in the testicle and induced the reporter in the prostate. In this tissue, betaBHC action was not inhibited by the anti-estrogen ICI-182780. During fasting, betaBHC, p,p'DDT, and metabolite p,p'DDE increased in blood concentration, from 2.25 +/- 0.25, 0.51 +/- 0.09, and 0.38 +/- 0.06 microg/ml to 8.24 +/- 0.95, 4.52 +/- 0.68, and 5.06 +/- 0.57 microg/ml, respectively. The effect produced by these organochlorines in the liver correlates with the modulation of the ERalpha protein. We conclude that these organochlorines modulate differently the expression of estrogen-regulated genes in male mice. Their effect is tissue- and compound-specific and is dependent on the energetic balance.

[Is the technique used to collect urine important in avoiding contamination of samples?]. / 'Es importante la técnica de recogida de la orina para evitar la contaminación de las muestras?

OBJECTIVE: To appraise the efficacy of hygienic standards in preventing the contamination of urine samples. DESIGN: Randomised clinical trial. 515 women assigned at random: 279 to the Intervention group and 236 to Control. SETTING: Population registered with 4 doctors at 2 health centres. PARTICIPANTS: Women from 15 to 65 who attended the clinic for on-demand care. Criteria for exclusion from the trial were: permanent bladder catheter, anomalies in genito-urinary apparatus, antibiotic treatment in the 7 previous days and inability to understand instructions. INTERVENTION: Verbal instructions on hygienic standards for collecting the sample and explanatory leaflet, as against the customary guidelines. MAIN MEASUREMENTS: The main result was the combination of contamination levels and infection. Analysis by intention to treat. RESULTS: Irregularities in the urine culture in 113 (41%) patients from the Intervention group and in 133 (56%) from the Control group (P<.001), with RRR of 28% (95% CI, 14%-40%) and NNT of 6 (95% CI, 4-14). Taking only serious contamination or urinary infection, we had 14 in the Intervention group and 36 in the Control (P<.0001), with RRR of 67% (95% CI, 41%-82%) and NNT of 10 (95% CI, 6-20). CONCLUSIONS: Providing an explanatory leaflet and giving verbal instructions on hygienic standards for urine collection reduces contamination of the samples.

Effect of the single major proteic fractions of the liver perchloric extract UK101 on the development of oral tumours in Syrian hamsters.

Squamous cell carcinoma of the oral cavity continues to be a major clinical problem, with about 100,000 new deaths each year worldwide. There is therefore a need to search for new tools to aid oral cancer treatment. We tested the inhibitory activity on chemical carcinogenesis of the three principal protein fractions of about 50, 14, and 8.5 kDa of the mixture UK101 derived from goat liver. These are composed principally of a glycoprotein rich in mannose residues, a protein with analogy to the heat shock protein family, and ubiquitin, respectively. The animal model employed was dimethylbenzanthracene-induced hamster cheek pouch carcinoma. Number of tumours per animal, tumour mass per animal, and proliferating cell nuclear antigen (PCNA) in non-tumour mucosa were quantified: the 14-kDa fraction was the most active; this was also confirmed by testing its corresponding recombinant material. The 50-kDa fraction was inactive, while the ubiquitin showed only low inhibitory activity. It is possible that the technique described and the results obtained could lead to an interesting clinical approach to the treatment of oral cancer.

Corticosterone-dependent alterations in utilization of catecholamines in discrete areas of rat brain.

This study investigated the impact of chronic adrenalectomy (ADX), and subsequent corticosterone (CORT) replacement to ADX rats, on brain levels of norepinephrine (NE) and dopamine (DA) and their extent of depletion after alpha-methyl-p-tyrosine (alpha-MpT) administration. Seven discrete hypothalamic areas, namely, the paraventricular nucleus (PVN), medial preoptic nucleus (POM), dorsomedial nucleus (DMN), ventromedial hypothalamus (VMH), perifornical lateral hypothalamus (PLH), supraoptic nucleus (SON), and arcuate nucleus/median eminence (ARC-ME), were examined. The steady-state content of NE and DA in all areas remained essentially unaltered 7 days after ablation of the adrenal glands, as well as after subsequent CORT replacement therapy in ADX rats. However, ADX, which reduced circulating CORT levels to 0.3 microgram % as compared to greater than 3.0 micrograms % in sham rats, caused a significant increase in the depletion of NE following alpha-MpT treatment, in 4 out of the 7 brain sites examined (PVN, PLH, DMN and ARC-ME). In these brain sites, the NE turnover rate (K, pg/microgram protein/h) and rate constant (K, h-1) increased following ADX. The chronic subcutaneous CORT implant (200 mg), which raised circulating CORT levels of ADX rats to 11 micrograms %, prevented this enhancement of NE turnover in the PVN, PLH and ARC-ME, but not the DMN. Unlike NE, DA utilization in the 7 discrete hypothalamic areas of alpha-MpT-treated rats remained unaltered after ablation of the adrenal glands, as well as after the CORT replacement therapy in ADX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Light and electron microscopic studies on the localization of hyaluronic acid in developing rat cerebellum.

The hyaluronic acid-binding region was prepared by trypsin digestion of chondroitin sulfate proteoglycan aggregate from the Swarm rat chondrosarcoma, and biotinylated in the presence of hyaluronic acid and link protein. After isolation by gel filtration and HPLC in 4 M guanidine HCl, the biotinylated hyaluronic acid-binding region was used, in conjunction with avidin-peroxidase, as a specific probe for the light and electron microscopic localization of hyaluronic acid in developing and mature rat cerebellum. At 1 w postnatal, there is strong staining of extracellular hyaluronic acid in the presumptive white matter, in the internal granule cell layer, and as a dense band at the base of the molecular layer, surrounding the parallel fibers. This staining moves progressively towards the pial surface during the second postnatal week, and extracellular staining remains predominant through postnatal week three. In adult brain, there is no significant extracellular staining of hyaluronic acid, which is most apparent in the granule cell cytoplasm, and intra-axonally in parallel fibers and some myelinated axons. The white matter is also unstained in adult brain, and no staining was seen in Purkinje cell bodies or dendrites at any age. The localization of hyaluronic acid and its developmental changes are very similar to that previously found in immunocytochemical studies of the chondroitin sulfate proteoglycan in nervous tissue (Aquino, D. A., R. U. Margolis, and R. K. Margolis. 1984. J. Cell Biol. 99:1117-1129; Aquino, D. A., R. U. Margolis, and R. K. Margolis. J. Cell Biol. 99:1130-1139), and to recent results from studies using monoclonal antibodies to the hyaluronic acid-binding region and link protein. The presence of brain hyaluronic acid in the form of aggregates with chondroitin sulfate proteoglycans would be consistent with their similar localizations and coordinate developmental changes.

Changes in systemic and pulmonary vascular reactivity in hypertension following nifedipine and verapamil.

Excessive vascular tone and overresponsiveness to adrenergic stimuli characterize the hemodynamics of the greater and the lesser circulation in hypertension. We tested whether calcium entry blockade with verapamil (11 cases) or nifedipine (11 cases) may improve the vascular regulation in high blood pressure. Mental arithmetic and cold were used as adrenergic activators. The former stimulus produced obvious elevation of epinephrine plasma concentration, increase of cardiac output (CO), slight systemic vasodilatation, pulmonary vasoconstriction, and rise of blood pressure in both circuits. After calcium antagonists, the epinephrine reaction to the arithmetic test was significantly attenuated, variations in CO and systemic blood pressure were unchanged, pulmonary vasoconstriction was abolished, and the pressure rise in the lesser circuit was halved. The cold pressor test increased norepinephrine plasma concentration (NE pc), systemic and pulmonary blood pressure, and vascular resistance and did not alter CO. The attained NE pc during cold was unvaried after verapamil and significantly enhanced after nifedipine; pressure and resistance responses of the two circuits were almost unchanged after the former, whereas systemic and pulmonary vascular resistance rises were importantly attenuated after the latter compound, resulting in much lower pressure reactivity. A modulation of the sympathoadrenal reaction, per se, can explain changes in the systemic and in the pulmonary vasomotion with calcium blockade during arithmetic. It would seem that after verapamil the sympathetic system was still activated during cold to such an extent as to maintain the same vasoconstrictor potency. NE pc suggests that the sympathetic discharge was not reduced by nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin and 5-hydroxyindoleacetic acid levels in discrete hypothalamic areas of the rat brain: relation to circulating corticosterone.

We examined the influence of adrenalectomy (ADX), and chronic corticosterone (CORT) replacement, on serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels in discrete hypothalamic areas of the rat brain. A significant decrease in 5-HT (-25%) and 5-HIAA (-28%) content was observed in the paraventricular nucleus (PVN) 7 days following ADX. A similar decrease in 5-HT levels (-27%) was observed in the preoptic area (POM) following ADX. In contrast, 5-HT and 5-HIAA levels in the supraoptic nucleus (SON) were significantly elevated by 82% and 54%, respectively. Replacement therapy with subcutaneous CORT implants (200 mg) was effective in preventing these effects of ADX in some cases. These findings suggest that the pituitary-adrenal endocrine system may influence various physiological and behavioral functions via its action on serotonergic neurons within specific hypothalamic sites.

Two CEA cross-reacting antigens: differences in absorbing the same anti-CEA serum.

A factor that cross reacts with the carcinoembryonic antigen (CEA), which we call P factor, was isolated from normal human plasma. To demonstrate the difference between this P factor and the nonspecific cross-reacting antigen (NCA), the same anti-CEA serum was absorbed in an identical manner with both the antigens. Absorption was checked by immunohistochemistry by the beta-galactosidase procedure on sections of colonic adenocarcinoma and normal colonic mucosa. The unabsorbed antiserum recognizes both tissues; after absorption with NCA the staining becomes paler on both tissues, but maintains color on the normal colonic mucosa and granulocytes. Only absorption with the P factor will give an unstained field of normal colonic mucosa, thus revealing the tumor structure. Data obtained by us suggest that the NCA (tissue extract) is an antigen that is not suitable to the absorption of anti-CEA serum for immunocytochemistry techniques, whereas the P factor (plasma extract) appears to be utilizable with good results.

Anti-carcinoembryonic antigen sera acquiring higher tumor specificity by absorption with a plasma factor.

A factor reacting with antisera against carcinoembryonic antigen (CEA) was isolated from healthy donors' plasma. Ten different antiCEA sera were absorbed with this plasma factor (P-factor): the antiCEA activity was mostly, or completely, removed in 8 sera. Only 2 of these absorbed sera (here defined as type A) still presented a high CEA binding activity by radioimmunoassay and, on tissue sections, selectively stained most of the colonic adenocarcinomas and areas of severe dysplasia in neoplastic adenomas. Contrary to the behaviour of the antisera against the P-factor, of the unabsorbed antiCEA sera, of a commercially available antiserum and of a monoclonal antibody, the P-absorbed type A antiCEA sera appeared unreactive with normal colonic mucosa and granulocytes. Absorption with the P-factor allows us to obtain antiCEA sera with higher tumor specificity.

[Experience in educational information for diabetics and their families]. / Esperienza di informazione educativa per il diabetico ed i familiari.

Experience in health education programmes for diabetics is reported. Such education is considered a priority since it is an essential aspect of treatment. Only education can prevent acute attacks and reduce the consequences of later diabetic complications. Elsewhere education programmes have been organised by Anti-diabetic Centres or group meetings. The present health education programme however was conducted at the Day Hospital. The programme was " personalized " to allow for personal control of the disease taking place in the patients' environment and attended not only by diabetics, but also by their families, subjects at risk and non-diabetics interested in this problem.

BCA (breast cancer antigens): different purification extraction methods.

Various types of extraction were tested to increase the immunological yield of BCA, a CEA-like primary breast cancer associated carcinoma antigen. To allow a comparison, the different extraction techniques were applied to only one breast tumour. The comparison of the various systems was based on two parameters: protein yield and immunological activity, assayed in a RIA 125I CEA-anti CEA system. The following extraction methods were described and compared in this paper: 3M KCl; 1N HClO4; neutral pH extraction (PBS) in the absence and presence of various detergents (anionic, neutral and cationic), basic pH extraction (1N NaOH) and acid pH extraction (1.5M acetic acid) in the presence of urea and various detergents. The more significant systems were applied also to the extraction of CEA, from colonic adenocarcinoma liver metastases. The best results for both the antigens studied were obtained by using neutral detergents (1% NP 40) at neutral pH.

Extraction and partial purification of a CEA-like BCA from a pool of pre-selected breast carcinomas.

By exploiting the cross-reaction among the antigens associated with a pool of breast carcinomas, preselected according to their antigenic content, a CEA-like BCA, with a specific activity of 1400 U/micrograms has been extracted, by means of 3M KCl, and partially purified by means of ConA Sepharose affinity chromatography and bioabsorption, employing, for the latter, a cross-reacting antiserum (anti CEA). The subsequent labelling, after Sephadex G-200 gel filtration, points out an immunological activity at the apex of the first peak versus anti CBC (or C.BCA) and anti CEA.