Perioperative multidisciplinary management of endoscopic transsphenoidal surgery for sellar lesions: practical suggestions from the Padova model.

Perioperative management of patients with sellar lesion submitted to endoscopic transsphenoidal neurosurgery (TSS) lacks standardization and therefore it is committed to each center clinical practice. Although neurosurgical procedure remains the same for all sellar lesions, perioperative approach can require different measures depending on the underlying disease. With the aim of standardizing our perioperative procedures and sharing our experience with other centers involved in the management of pituitary disease, we developed a clinical care path for patients with sellar lesions candidate to endoscopic TSS. For the drafting of the following protocol, the national and international guidelines published in the last 5 years have been evaluated and integrated with our center experience accumulated in decades of clinical practice. A steering committee including medical doctors involved in management of patients with pituitary masses at the Padua Hospital reviewed current knowledge on this topic. The committee developed a first draft which was shared with a broader group of medical doctors to reach a preliminary consensus; when it was reached, the clinical care assistance pathway was confirmed, validated, and published in the local web-based health service. We want to present and share our experience with colleagues involved in the perioperative management of pituitary diseases in other centers.

A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal.

The 2017 World Health Organization (WHO) classification proposes to type and subtype primary adenohypophyseal tumours according to their cell lineages with the aim to establish more uniform tumour groups. The definition of atypical adenoma was removed in favour of high-risk adenoma, and the assessment of proliferative activity and invasion was recommended to diagnose aggressive tumours. Recently, the International Pituitary Pathology Club proposed to replace adenoma with the term of pituitary neuroendocrine tumour (PitNET) to better reflect the similarities between adenohypophyseal and neuroendocrine tumours of other organs. The European Pituitary Pathology Group (EPPG) endorses this terminology and develops practical recommendations for standardised reports of PitNETs that are addressed to histo- and neuropathologists. This brief report presents the results of EPPG's consensus for the reporting of PitNETs and proposes a diagnostic algorithm.

Adjuvant chemotherapy in adult medulloblastoma: is it an option for average-risk patients?

The standard treatment in children with average-risk medulloblastoma (MB) is reduced-dose radiotherapy (RT) followed by chemotherapy. However, in adults, there is no agreement on the use of adjuvant chemotherapy. We performed a retrospective analysis of adult MB patients with average-risk disease, defined as no postsurgical residual (or ≤1.5 cm(2)) and no metastatic disease (M0). Main inclusion criteria were: age >16 years, post-surgical treatment with craniospinal irradiation with or without adjuvant chemotherapy (cisplatin and etoposide ± cyclophosphamide). From 1988 to 2012 were accrued 43 average-risk MB patients treated with surgery and adjuvant RT. Fifteen (34.9 %) patients received also chemotherapy: 7 before RT, 5 after RT, and 3 before and after RT. Reasons to administer chemotherapy were presence of residual disease (even if ≤1.5 cm) and delay in RT. After a median follow up time of 10 years (range: 8-13), median survival was 18 years (95 % CI 9-28) in patients who receive RT alone, and was not reached in patients treated with RT plus chemotherapy. The survival rates at 5, 10 and 15 years were 100 %, 78.6 % (95 % CI 60.0-97.2 %) and 60.2 % (95 % CI 36.9-83.5 %), in patients treated with RT alone, and 100, 100 and 100 %, in patients treated with RT plus chemotherapy (p = 0.079). Our findings suggest a role for adjuvant chemotherapy in the treatment of average-risk MB adult patients. Further improvements might drive to add chemotherapy in average-risk setting with less favourable biological signatures (i.e., non-WNT group).

Identification of new flavonols in hybrid grapes by combined liquid chromatography-mass spectrometry approaches.

Grape flavonols are involved in the phenomenon of copigmentation in red wines. These compounds are characterised by nutraceutical properties, have antioxidant activity and are studied for chemotaxonomy of grapes. In general, hybrid grapes are characterised by presence of polyphenols often qualitatively and quantitatively different from Vitis vinifera varieties. In this work, flavonols of 34 hybrid grape varieties (22 red and 12 white) produced by crossing of V. vinifera, Vitis riparia, Vitis labrusca, Vitis lincecumii and Vitis rupestris species, were studied. Compounds were characterised by combining different liquid chromatography/mass spectrometry (LC/MS) methods: precursor-ion and neutral-loss multiple-reaction-monitoring (MRM), and high-resolution mass spectrometry. Twenty-four glycoside flavonols were identified, including 4 quercetin, 5 myricetin, 4 kaempferol, 3 isorhamnetin, 2 laricitrin, 3 syringetin and 3 dihydroflavonol derivatives; myricetin hexoside-glucuronide, myricetin O-di-hexoside, syringetin O-di-hexoside, isorhamnetin rutinoside and kaempferol rutinoside were found in grape for the first time. Statistical analysis (PCA and cluster analysis) divided the samples in four groups on the basis of their flavonol profiles.

Assessing response using 99mTc-MIBI early after interstitial chemotherapy with carmustine-loaded polymers in glioblastoma multiforme: preliminary results.

Introduction. Early signs of response after applying wafers of carmustine-loaded polymers (gliadel) are difficult to assess with imaging because of time-related imaging changes. (99m)Tc-sestamibi (MIBI) brain single-photon emission tomography (SPET) has reportedly been used to reveal areas of cellularity distinguishing recurrent neoplasm from radionecrosis. Our aim was to explore the role of MIBI SPET in assessing response soon after gliadel application in glioblastoma multiforme (GBM). Methods. We retrospectively reviewed the charts on 28 consecutive patients with a radiological diagnosis of GBM who underwent MIBI SPET/CT before surgery (with intracavitary gliadel placement in 17 patients), soon after surgery, and at 4 months. The area of uptake was selected using a volume of interest that was then mirrored contralaterally to obtain a semiquantitative ratio. Results. After adjusting for ratio at the baseline, the effect of treatment (gliadel versus non-gliadel) was not statistically significant. Soon after surgery, however, 100% of patients treated with gliadel had a decreased ratio, as opposed to 62.5% of patients in the non-gliadel group (P = 0.0316). The difference between ratios of patients with radical versus partial resection reached statistical significance by a small margin (P = 0.0528). Conclusions. These data seem to suggest that the MIBI ratio could be a valuable tool for monitoring the effect of gliadel early after surgery.

Alström syndrome is associated with short stature and reduced GH reserve.

INTRODUCTION: Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called 'ciliopathies' and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thus far no study has specifically investigated this aspect in a large population. MATERIAL AND METHODS: Twenty-three patients with ALMS (age, 1-52 years; 11 males, 12 females) were evaluated for anthropometric parameters (growth charts and standard deviation score (SDS) of height, weight, BMI), GH secretion by growth hormone-releasing hormone + arginine test (GHRH-arg), bone age, and hypothalamic-pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized. RESULTS: The length-for-age measurements from birth to 36 months showed normal growth with most values falling within -0·67 SDS to +1·28 SDS. A progressive decrease in stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (>16-20 years; mean SDS, -2·22 ± 1·16). The subset of 12 patients with ALMS tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154·7 ± 10·6 cm vs 162·9 ± 4·8 cm, P = 0·009) and a mild increase in BMI (Kg/m(2) ) (27·8 ± 4·8 vs 24·1 ± 2·5, P = 0·007). Peak GH after GHRH-arg was significantly lower in patients with ALMS in comparison with controls (11·9 ± 6·9 µg/l vs 86·1 ± 33·2 µg/l, P < 0·0001). Severe GHD was evident biochemically in 50% of patients with ALMS. The 10 adult ALMS patients with GHD showed a reduced height in comparison with those without GHD (149·7 ± 6·2 cm vs 161·9 ± 9·2 cm, P = 0·04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases. CONCLUSIONS: Our study shows that 50% of nonobese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion.

Study of anthocyanic profiles of twenty-one hybrid grape varieties by liquid chromatography and precursor-ion mass spectrometry.

The anthocyanins of 21 hybrid red varieties produced by crossing V. vinifera, V. riparia, V. labrusca, V. lincecumii and V. rupestris species, the profiles for which have not yet been reported, were studied. Profiles were determined by LC/DAD, and identification of single anthocyanins was confirmed by LC/MS precursor-ion analysis. Anthocyanidin precursors (pelargonidin at m/z 271, dephinidin at m/z 303, cyanidin at m/z 287, petunidin at m/z 317, peonidin at m/z 301, and malvidin at m/z 331) and precursors of monoglucoside compounds allowed 24 different compounds to be identified. Analysis of precursor ions of monoglucoside anthocyanins at low capillary voltage revealed the signals of diglucosides only, providing a very selective method for analysis of diglucoside anthocyanins in grape. According to anthocyanin profile, the samples were subdivided into two groups: one characterized by the substantial presence of diglucoside compounds (particularly Seyve Villard 23-399 and Seyve Villard 23-369) and one by the scarce presence or practical absence of diglucosides (Seibel 10878, Burdin 4077, and Galibert 238-35). Particularly interesting for producing anthocyanin for the natural colorant industry were the varieties Siebel 8357, Bacò 30-12 and Terzi 100-31.

Diffuse leptomeningeal glioneuronal tumours: clinico-pathological follow-up.

Glioneuronal tumours are a group of primary brain neoplasms of relatively recent acquisition in the World Health Organization (WHO) Classification of the Central Nervous System tumours. In diagnostic practice it is still possible to encounter glioneuronal tumours that cannot be placed into any of the well-defined WHO categories despite a growing list of entities. We have recently published four paediatric cases of diffuse leptomeningeal tumours that cannot be easily classified in the currently used CNS WHO classification, but which have histological and immunohistochemical criteria to be considered as glioneuronal tumours. The clinical, neuroradiological and pathological long-term follow-up of an unusual diffuse leptomeningeal glioneuronal tumour is presented herein.

TP53, ß-Catenin and c-myc/N-myc status in embryonal tumours with ependymoblastic rosettes.

BACKGROUND: The primitive neuroectodermal tumours of central nervous system (CNS-PNET) are a heterogeneous group of neoplasms, occurring in the CNS and composed of undifferentiated or poorly differentiated neuroepithelial cells which may display divergent differentiation along neuronal, astrocytic and ependymal lines. The WHO classification includes in this group of tumours also ependymoblastomas and medulloepitheliomas. Several groups have reported examples of CNS-PNET with combined histological features of ependymoblastoma and neuroblastoma, defined as 'embryonal tumour with abundant neuropil and true rosettes'. The presence of the amplification of chromosome region 19q13.42, common in both ependymoblastoma and embryonal tumour with abundant neuropil and true rosettes, suggests that they represent a histological spectrum of a single biological entity. METHODS: We examined 24 cases of ependymoblastoma/embryonal tumour with abundant neuropil and true rosettes (EPBL/ETANTR) for the presence of mutations of TP53 and ß-Catenin and for amplification of c-myc/N-myc. RESULTS: The single strand conformation polymorphism-mutational screening did not identify any mutation in exons 5 to 8 of the TP53 gene. However, we found a point mutation affecting codon 34 (GGA → GTA) of ß-Catenin gene resulting in a Glycine → Valine substitution. No cases presented c-myc/N-myc amplification. CONCLUSIONS: EPBL/ETANTRs show molecular features different from other CNS-PNET and medulloblastomas. The presence of alterations in the ß-Catenin/WNT pathway seems to be noteworthy due to the close relationship between this pathway and miR-520g encoded in chromosome 19q13.42 region amplified in these tumours.

Internal auditory canal metastasis.

Metastasis of the inner auditory canal is a really rare event. Clinically, it usually presents with rapid worsening cranial nerve palsy. Authors present a review of the literature reporting clinical features, radiological findings, intraoperative aspects of an illustrative case. A 56-year-old female patient presented with a peripheral facial nerve palsy. MRI showed two left p-fossa tumors whose one into the inner canal. Rapid worsening of facial damage despite corticosteroid treatment and the possibility to remove both tumors in the same surgical step suggested authors to operated on the patient. Intraoperatively, inner canal tumor looked totally involving the VII-VIII nerve complex so surgical extirpation was only partially feasible. Posterior wall drilling of the meatus was performed which improved facial palsy. Leptomeningeal spinal seeding occurred and spinal irradiation was performed. The case highlights the importance of maintaining a high degree of awareness of the auditory canal metastasis in patients with a previous history of malignancy who develop a rapid progressive peripheral VII nerve palsy. Furthermore, our case and literature data suggest that inner canal metastasis is a distinct entity from temporal bone and ponto-cerebellar angle metastasis on the base of the peculiarity of clinical features, prognosis, therapeutic strategies. In fact, inner canal metastases usually arise in patients apparently cured, and they imply a better prognosis even if with an higher risk of leptomeningeal seeding. Moreover, surgery rarely allows the removal of the lesion, also if symptoms relief may be achieved, as in our case.

Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

BACKGROUND: Standardized salvage treatment has not yet proved effective in glioblastoma multiforme (GBM) patients who receive prior standard radiotherapy plus concomitant and adjuvant temozolomide. METHODS: Patients with progressive GBM after radiotherapy plus concomitant and/or adjuvant temozolomide received three-weekly doses (100-75 mg m(2)) of fotemustine followed, after a 5-week rest, by fotemustine (100 mg m(2)) every 3 weeks for < or =1 year. RESULTS: Forty-three patients (29 M, 14 F; median age 51 years, range 34-68; median KPS 90) were enrolled. Progression-free survival at 6 months (PFS-6) was 20.9% (95% CI: 9-33%); three patients (7.1%) had partial response (PR); 15 (34.9%), disease stabilization (SD). The median survival was 6 months (95% CI: 5-7). MGMT promoter status was methylated in 8 (18.6%) and unmethylated in 26 (60.5%) and not assessable in 9 (20.9%) patients, respectively. Disease control was 75% versus 34.6% in methylated and unmethylated MGMT patients (P = 0.044); no significant difference was found between groups for PFS-6 and survival. Grade 3 and 4 thrombocytopenia and neutropenia were observed in 20.9 and 16.3% of patients, during the induction phase, and in 0 and 9.5% patients during the maintenance phase, respectively. CONCLUSIONS: The findings of the present trial, that evaluate fotemustine in a homogeneous population, may represent a new benchmark for nitrosourea activity. Moreover, this is the first study to evaluate correlation between MGMT promoter status and outcome of fotemustine for relapsing GBM previously treated with radiotherapy and temozolomide.

Intraventricular hemorrhage caused by peripheral anterior choroidal artery aneurysm rupture. A case report.

Intraventricular hemorrhage is a severe ictal event secondary to several pathological conditions (anticoagulation therapies, hypertension, post-surgical, traumatic, neoplastic, vascular malformations), leading to blockage of CSF flow and possible hydrocephalus, often justifying surgical intervention. We describe an uncommon source of intraventricular hemorrhage in a 54-year-old woman caused by a peripheral anterior choroidal artery aneurysm rupture.

Haemorrhagic presentation of low-grade glioma in adults.

Intracranial bleeding is rare in patients with low-grade gliomas, above all in adult population. We reviewed the literature of such cases and reported another case of a haemorrhagic low-grade glioma in a 54-year-old woman presenting with a left hemiparesis. Computer tomography (CT) images showed a right basal ganglia haemorrhage with no mass effect. Vascular malformations were ruled out by angiography. Eighteen fluoro-fluoro deossiglucosio (18F-FDG) positron emission tomography (PET/CT) showed a large hypometabolic area corresponding to the lesion. We waited for patient's improvement. Late magnetic resonance images revealed a low-grade glioma at the bleeding site. Tumour was removed and histopathologic examination revealed a WHO grade II mixed glioma. The authors emphasize that this evidence has to be kept in mind since it has important therapeutic implications.

Peroxisome proliferator-activated receptor gamma in the human pituitary gland: expression and splicing pattern in adenomas versus normal pituitary.

Pituitary adenomas are slow-growing tumours arising within the pituitary gland. If secreting, they give rise to well-known syndromes such as Cushing's disease or acromegaly; when hormonally inactive, they come to clinical attention often with local mass effects or pituitary deficiency. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor with a key role in fat and glucose metabolism, but also involved in several neoplasia, has recently been detected in pituitary adenomas. In the present study, we evaluated the occurrence and splicing profile of PPARgamma in 43 cases of pituitary adenoma of different subtypes and compared it to 12 normal pituitary glands. By real-time polymerase chain reaction, PPARgamma was expressed as much in adrenocorticotrophic hormone (ACTH)-secreting and ACTH-silent adenomas as in controls, with a moderate underexpression in somatotrophinomas and prolactinomas and overexpression in 54% of nonfunctioning pituitary adenomas (NFPA). There was no apparent qualitative change in the splicing profile of pathological pituitary glands, nor was the presence of specific isoforms with dominant negative effects against PPARgamma detected. Western blotting revealed similar expression levels in the different subgroups of pituitary adenomas and normal glands. Immunohistochemistry confirmed PPARgamma expression in approximately one-half of analysed samples. The intra- and intergroup differences observed in pituitary adenomas may represent new elements in the process of understanding the different clinical responses of Cushing's and Nelson patients to PPARgamma-ligand treatment. Moreover, the higher level of PPARgamma expression detected in the NFPA subgroup may suggest its possible role as a molecular target in these pituitary adenomas, paving the way for investigations on the effectiveness of treatment with thiazolidinediones in such patients.

The usefulness of combined biochemical tests in the diagnosis of Cushing's disease with negative pituitary magnetic resonance imaging.

OBJECTIVE: The etiological diagnosis of ACTH-dependent Cushing's syndrome is often a problem. In fact, no endocrine or radiological examination can conclusively distinguish the ectopic from the pituitary source of disease. The aim of our study was to evaluate the role of stimulation and suppression endocrine tests in the diagnostic and therapeutic approach of patients with Cushing's disease (CD) and negative pituitary magnetic resonance imaging (MRI), considering their post-surgical outcome in comparison with patients with CD and positive MRI. PATIENTS AND METHODS: We retrospectively analyzed 31 patients (25 women and 6 men, median age 40 +/- 15 years) with a confirmed diagnosis of CD who underwent transsphenoidal pituitary surgery by the same neurosurgeon between 2001 and 2005. Preoperative endocrine assessment included corticotropin-releasing hormone (CRH), desmopressin (dDAVP), and overnight 8 mg dexamethasone suppression tests (8-DST) in all patients. Fifteen patients had a normal pituitary MRI and sixteen had a clearly evident pituitary microadenoma. Bilateral inferior petrosal sinus sampling (BIPSS) was performed in patients with discordant biochemical results or with signs and symptoms highly suggestive of an ectopic source of ACTH. Post-surgical median follow-up was 38.4 +/- 22.0 months. RESULTS: Among patients with negative MRI, 60% had concordant positive endocrine tests and underwent neurosurgery without other examinations. BIPSS was performed in three other patients prompted by discordant endocrine tests (negative dDAVP) and in two patients with clinical suspicion of ectopic disease. Among patients with positive MRI, 87% underwent neurosurgery without BIPSS that was performed in two patients because of negative concomitant response to dDAVP and CRH tests. A pituitary adenoma, confirmed by pathological examination, was found in 40 and 81% of patients with negative and positive MRI respectively (P<0.05), corticotroph hyperplasia resulted more frequent in the group with negative MRI. Remission rate was not different between patients with negative and positive MRI (73 and 75% respectively; P=0.61) and between patients with negative MRI who did not undergo BIPSS and patients with positive MRI (P=0.56). The recurrence rate was also similar between groups (P=0.64), but higher, although not statistically different (P=0.07) in patients with corticotroph hyperplasia at histology. CONCLUSIONS: An accurate evaluation of presurgical endocrine tests results enabled us to reduce the number of BIPSS in patients with a negative MRI without any fallout on their post-surgical outcome. In the hands of an expert pituitary surgeon, the outcome after surgeryand the subsequent recurrence rate are much the same in patients with negative or positive MRI.

Clinical and pathological characteristics of patients presenting with biochemical progression after radical retropubic prostatectomy for pathologically organ-confined prostate cancer.

INTRODUCTION: To identify risk factors for biochemical failure after radical prostatectomy (RP) in men with pathologically organ-confined (OC) prostate cancer (PCa). MATERIALS AND METHODS: Clinical and pathological features of 350 consecutive patients with pathologically OC PCa treated only with RP and bilateral pelvic lymphadenectomy were analyzed, retrospectively, to identify predictor parameters of prostate-specific antigen (PSA) failure (PSA>or=0.4 ng/ml). The median follow-up was 58.6 months (range: 3.9-183 months). All pathological specimens were step sectioned at 4-mm intervals. Kaplan-Meier progression-free survival rates and chi2 test were adopted for statistical analyses. Multivariate Cox proportional hazard regression models were used to test the association between pathological Gleason score and surgical margin status. RESULTS: 67 patients (19.1%) failed at a median follow-up of 40.2 months (range 1.9-123.3). Age and preoperative PSA failed to reveal significance also in patients with serum PSA>or=20 ng/ml (p=0.46). Patients with T3 clinical stage had a higher progression rate compared to T1C and T2 (43.5 vs. 27.8 and 17.3%, respectively) even if no high statistical significance was pointed out. Presence of perineural infiltration (p=0.04) and prostatic apex infiltration (p=0.74) in the prostatectomy specimens failed to reveal significance. A high pathological Gleason score (>or=7; p=0.0003) and surgical margin status (p<0.0001) were shown to be the most powerful predictive parameters of biochemical progression. CONCLUSIONS: In patients with pathologically OC PCa the presence of a high pathological Gleason score and positive surgical margins appear to represent the most important factors for prediction of outcome following RP.

Is protracted low-dose temozolomide feasible in glioma patients?

The authors investigated the safety of 75 mg/m2 temozolomide for 21 days every 28 days in glioma patients. This schedule could lead to DNA repair enzyme O6-alkylguanine-DNA alkyltransferase depletion, contributing to overcoming drug resistance. Although Phase III studies are forthcoming, no data are available on the long-term toxicity of temozolomide, which, in this series, incurred prolonged, cumulative lymphopenia, which leads to a high incidence of infections.

Photofrin as a specific radiosensitizing agent for tumors: studies in comparison to other porphyrins, in an experimental in vivo model.

The use of ionizing radiation for tumor treatment represents a well established therapeutic modality. The efficiency and selectivity of radiotherapeutic protocols can be often enhanced by the addition of specific chemical compounds that optimise the response of the tumor to the incident radiation as compared with peritumoral tissue districts. The results of this study showed that Photofrin, a porphyrin derivative which is presently used as a tumor-photosensitizing agent in photodynamic therapy (PDT), can also act as an efficient tumor radiosensitizer. To test this possibility, we used nude mice subcutaneously implanted with human bladder cancer RT4. The mice were injected with different porphyrin-type photosensitizing agents, including Photofrin, 5-aminolevulinic acid, chlorin e(6), haematoporphyrin, protoporphyrin, Zn-tetrasulphophtalocyanine, and irradiated with 5 and 15 Gy using a Siemens X-ray device. Even though all the porphyrins accumulated in significant amounts in the neoplastic lesion, only Photofrin significantly improved the response of the tumor to irradiation by increasing the doubling time of the tumor volume from 6.2 days in the untreated control group to 10.9 days in the 5 and 15 Gy-irradiated groups. The tumor response was maximal with injected Photofrin doses of 7.5 mg/kg, and was not further enhanced by injection of higher doses. Our hypothesis is, that the radiosensitizing effect of Photofrin seems to be due to some oligomeric constituents which could specifically react with radiogenerated-radicals thereby amplifying the effect of the X-ray radiation.