Publications by authors named "Andrea Di Cristofori"

31 Publications

The "Parachute" Technique for the Endoscopic Repair of High-Flow Anterior Skull-Base CSF Leaks.

World Neurosurg 2021 May 8. Epub 2021 May 8.

Department of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; "Aldo Ravelli" Research Center, Milan, Italy; Department of Medical-Surgical Physiopathology and Transplantation, University of Milan, Milan, Italy.

Objective: This study aims to assess the feasibility and reliability of our endoscopic trans-nasal technique for the repair of cribriform and sellar high-flow cerebrospinal fluid (CSF) leaks.

Methods: A comparison between patients suffering from high-flow rhinorrhea and treated through a free grafting endoscopic technique or the "parachute" technique, our nasal packing proposal, was performed.

Results: Thirty-three patients were included. The mean age was 52 years (range: 36-68 years). The etiology of the CSF leaks was iatrogenic in 16 cases (48.5%), traumatic in 5 cases (15.2%), spontaneous in 11 cases (33.3%), and related to anterior skull base tumors in 1 case (3%). The bone defect affected the sphenoidal sinus in 20 cases (60.6%), the cribriform plate of the ethmoid in 10 cases (30.3%), and both the sphenoid and ethmoid in 3 cases (9.1%). The mean size of bone defects was 8.5 ± 3.9 mm. The median follow-up was 28 (64) months. A CSF leak recurrence occurred in no cases treated with the parachute technique and in 3 cases that underwent conventional endoscopic treatments. The CSF leak recurrences were associated with 2 iatrogenic and 1 post-traumatic fistula. All the CSF leak recurrences underwent the parachute technique, not showing second recurrences.

Conclusions: Our results suggest that the parachute technique is simple, safe, and effective. We recommend it as an alternative treatment to vascular flaps for the treatment of high-flow and recurrent fistulas.
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http://dx.doi.org/10.1016/j.wneu.2021.05.006DOI Listing
May 2021

Perspectives on (A)symmetry of Arcuate Fasciculus. A Short Review About Anatomy, Tractography and TMS for Arcuate Fasciculus Reconstruction in Planning Surgery for Gliomas in Language Areas.

Front Neurol 2021 10;12:639822. Epub 2021 Feb 10.

Neurosurgery Unit, San Gerardo Hospital, ASST Monza, Monza, Italy.

Gliomas are brain tumors that are treated with surgical resection. Prognosis is influenced by the extent of resection and postoperative neurological status. As consequence, given the extreme interindividual and interhemispheric variability of subcortical white matter (WM) surgical planning requires to be patient's tailored. According to the "connectionist model," there is a huge variability among both cortical areas and subcortical WM in all human beings, and it is known that brain is able to reorganize itself and to adapt to WM lesions. Brain magnetic resonance imaging diffusion tensor imaging (DTI) tractography allows visualization of WM bundles. Nowadays DTI tractography is widely available in the clinical setting for presurgical planning. Arcuate fasciculus (AF) is a long WM bundle that connects the Broca's and Wernicke's regions with a complex anatomical architecture and important role in language functions. Thus, its preservation is important for the postoperative outcome, and DTI tractography is usually performed for planning surgery within the language-dominant hemisphere. High variability among individuals and an asymmetrical pattern has been reported for this WM bundle. However, the functional relevance of AF in the contralateral non-dominant hemisphere in case of tumoral or surgical lesion of the language-dominant AF is unclear. This review focuses on AF anatomy with special attention to its asymmetry in both normal and pathological conditions and how it may be explored with preoperative tools for planning surgery on gliomas in language areas. Based on the findings available in literature, we finally speculate about the potential role of preoperative evaluation of the WM contralateral to the surgical site.
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http://dx.doi.org/10.3389/fneur.2021.639822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902861PMC
February 2021

Interplay Between V-ATPase G1 and Small EV-miRNAs Modulates ERK1/2 Activation in GBM Stem Cells and Nonneoplastic Milieu.

Mol Cancer Res 2020 11 4;18(11):1744-1754. Epub 2020 Aug 4.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

The ATP6V1G1 subunit (V1G1) of the vacuolar proton ATPase (V-ATPase) pump is crucial for glioma stem cells (GSC) maintenance and tumorigenicity. Moreover, V-ATPase reprograms the tumor microenvironment through acidification and release of extracellular vesicles (EV). Therefore, we investigated the role of V1G1 in GSC small EVs and their effects on primary brain cultures. To this end, small EVs were isolated from patients-derived GSCs grown as neurospheres (NS) with high (V1G1-NS) or low (V1G1-NS) V1G1 expression and analyzed for V-ATPase subunits presence, miRNA contents, and cellular responses in recipient cultures. Our results show that NS-derived small EVs stimulate proliferation and motility of recipient cells, with small EV derived from V1G1-NS showing the most pronounced activity. This involved activation of ERK1/2 signaling, in a response reversed by V-ATPase inhibition in NS-producing small EV. The miRNA profile of V1G1-NS-derived small EVs differed significantly from that of V1G1-NS, which included miRNAs predicted to target MAPK/ERK signaling. Mechanistically, forced expression of a MAPK-targeting pool of miRNAs in recipient cells suppressed MAPK/ERK pathway activation and blunted the prooncogenic effects of V1G1 small EV. These findings propose that the GSC influences the brain milieu through a V1G1-coordinated EVs release of MAPK/ERK-targeting miRNAs. Interfering with V-ATPase activity could prevent ERK-dependent oncogenic reprogramming of the microenvironment, potentially hampering local GBM infiltration. IMPLICATIONS: Our data identify a novel molecular mechanism of gliomagenesis specific of the GBM stem cell niche, which coordinates a V-ATPase-dependent reprogramming of the brain microenvironment through the release of specialized EVs.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642188PMC
November 2020

Role of aquaporins in hydrocephalus: what do we know and where do we stand? A systematic review.

J Neurol 2020 Aug 3. Epub 2020 Aug 3.

Unit of Neurosurgery, Ospedale San Gerardo, Azienda Socio Sanitaria Territoriale Monza, Via G. B. Pergolesi 33, 20900, Monza, MB, Italy.

Introduction: Glymphatic fluid circulation may be considered the lymphatic system of the brain and the main role of such system seems to be played by aquaporins (AQPs), a family of proteins which regulates water exchange, in particular AQP4 and 1. Alterations of glymphatic fluid circulation through AQPs variations are now emerging as central elements in the pathophysiology of different brain conditions, like hydrocephalus. This systematic review provides an insight about the role of AQPs in hydrocephalus establishment and compensation, investigating their possible role as diagnostic tools or therapeutic targets.

Methods: PubMed database was screened searching for the relevant existing literature in English language published until February 29th 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.

Results: A total of 40 articles met the inclusion criteria for our systematic analysis. AQP4 resulted the most studied water channel, followed by AQP1. The changes in cerebrospinal fluid (CSF), brain parenchyma and choroid plexus (CP) in different hydrocephalus type were analyzed. Moreover, important pharmacological interactions regarding AQP and molecules or conditions were discussed. A very interesting result is the general consensus on increase of AQP4 in hydrocephalic patients, unless in patients suffering from idiopathic normal pressure hydrocephalus, where AQP4 shows a tendency in reduction.

Conclusion: AQP seem to play a central role in the pathophysiology of hydrocephalus and in its compensation mechanisms. Further studies are required to definitively establish their precise roles and their quantitative changes to allow their utilization as diagnostic tools or therapeutic targets.
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http://dx.doi.org/10.1007/s00415-020-10122-zDOI Listing
August 2020

Long-term follow-up of neuropsychological functions in patients with high grade gliomas: can cognitive status predict patient's outcome after surgery?

Acta Neurochir (Wien) 2020 04 28;162(4):803-812. Epub 2020 Jan 28.

Unit of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35 (Padiglione Monteggia), 20122, Milan, Italy.

Background: Patients affected by a high-grade glioma (HGG) have a poor prognosis with a median survival of 12-16 months. Such poor prognosis affects the perception of the remaining life by patients and the neuropsychological status can strongly affect every-day functioning of these patients. Monitoring changes of neuropsychological functioning (NPF) overtime may provide better clinical information and optimize the neuro-oncological management. The aims of our work were (1) to investigate the feasibility of a complex neuropsychological battery in HGG patients before and during follow-up after surgery; (2) to study the neuropsychological profile of patients affected by HGGs and their relation with the disease status (relapse/death) across time after surgery.

Methods: One hundred two patients who received surgery for HGG between 2011 and 2017 were studied. All clinical data were prospectively recorded. NPF was assessed during the neuro-oncological follow-up through the Milano-Bicocca Battery (MIBIB). Statistical analysis was performed on the neuropsychological results of the tests administered.

Results: First, MIBIB proved to be suitable for patients with HGG tumors before and after surgery, and during long-term follow-up; it also showed a cluster structure representative of the principal cognitive domains. Second, we found a steep decline in the neuropsychological profile before death and/or tumor relapse for the 52% of the neuropsychological tests administered.

Conclusion: Complex neuropsychological batteries can be administered to HGG patients before and during follow-up after surgery. There is a correlation between neuropsychological deterioration and tumor relapse and/or death, which may reflect a progressive damage to cognitive functions due to tumor infiltration and progression.
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http://dx.doi.org/10.1007/s00701-020-04230-yDOI Listing
April 2020

Awake craniotomy for glioblastomas: is it worth it? Considerations about the article entitled "Impact of intraoperative stimulation mapping on high-grade glioma surgery outcome: a meta-analysis".

Acta Neurochir (Wien) 2020 02 18;162(2):427-428. Epub 2019 Dec 18.

Division of Neurosurgery, Azienda Socio Sanitaria Territoriale - Monza, Ospedale San Gerardo Via Pergolesi 33, 20900, Monza (MB), Italy.

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http://dx.doi.org/10.1007/s00701-019-04173-zDOI Listing
February 2020

Cerebrospinal Fluid Level of Aquaporin4: A New Window on Glymphatic System Involvement in Neurodegenerative Disease?

J Alzheimers Dis 2019 ;69(3):663-669

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UOSD Neurologia - Malattie Neurodegenerative, Milan, Italy.

Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.
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http://dx.doi.org/10.3233/JAD-190119DOI Listing
September 2020

Specific V-ATPase expression sub-classifies IDHwt lower-grade gliomas and impacts glioma growth in vivo.

EBioMedicine 2019 Mar 5;41:214-224. Epub 2019 Feb 5.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Fondazione Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy. Electronic address:

Background: Cancer cells use specific V-ATPase subunits to activate oncogenic pathways. Therefore, we investigated V-ATPase deregulation in aggressive gliomas and associated signaling.

Methods: V-ATPase genes expression and associated pathways were analyzed in different series of glioma available from public databases, as well as in patients' cohort. Activation of pathways was analyzed at gene and protein expression levels. A genetic model of glioma in Drosophila melanogaster and mice with GBM patients-derived orthotopic xenografts were used as in vivo models of disease.

Findings: GBM and recurrent gliomas display a specific V-ATPase signature. Such signature resolves the heterogeneous class of IDH-wild type lower-grade gliomas, identifying the patients with worse prognosis independently from clinical and molecular features (p = 0·03, by Cox proportional-hazards model). In vivo, V-ATPase subunits deregulation significantly impacts tumor growth and proliferation. At the molecular level, GBM-like V-ATPase expression correlates with upregulation of Homeobox genes.

Interpretation: Our data identify a V-ATPase signature that accompanies glioma aggressiveness and suggest new entry points for glioma stratification and follow-up. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV), Fondazione IRCCS Ca' Granda, and Fondazione INGM Grant in Molecular Medicine 2014 (to VV).
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http://dx.doi.org/10.1016/j.ebiom.2019.01.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441867PMC
March 2019

A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes.

EBioMedicine 2019 Mar 6;41:225-235. Epub 2019 Feb 6.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Fondazione Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy. Electronic address:

Background: The V-ATPase proton pump controls acidification of intra and extra-cellular milieu in both physiological and pathological conditions. We previously showed that some V-ATPase subunits are enriched in glioma stem cells and in patients with poor survival. In this study, we investigated how expression of a GBM-like V-ATPase pump influences the non-neoplastic brain microenvironment.

Methods: Large oncosome (LO) vesicles were isolated from primary glioblastoma (GBM) neurospheres, or from patient sera, and co-cultured with primary neoplastic or non-neoplastic brain cells. LO transcript and protein contents were analyzed by qPCR, immunoblotting and immunogold staining. Activation of pathways in recipient cells was determined at gene and protein expression levels. V-ATPase activity was impaired by Bafilomycin A1 or gene silencing.

Findings: GBM neurospheres influence their non-neoplastic microenvironment by delivering the V-ATPase subunit V1G1 and the homeobox genes HOXA7, HOXA10, and POU3F2 to recipient cells via LO. LOs reprogram recipient cells to proliferate, grow as spheres and to migrate. Moreover, LOs are particularly abundant in the circulation of GBM patients with short survival time. Finally, impairment of V-ATPase reduces LOs activity.

Interpretation: We identified a novel mechanism adopted by glioma stem cells to promote disease progression via LO-mediated reprogramming of their microenvironment. Our data provide preliminary evidence for future development of LO-based liquid biopsies and suggest a novel potential strategy to contrast glioma progression. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV) and by the Italian Minister of Health-Ricerca Corrente program 2017 (to SF).
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http://dx.doi.org/10.1016/j.ebiom.2019.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441844PMC
March 2019

Subacute posttraumatic ascending myelopathy (SPAM): A potential complication of subarachnoid shunt for syringomyelia?

J Spinal Cord Med 2020 09 29;43(5):714-718. Epub 2018 Aug 29.

Department of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

: Treatment of primary spinal syringomyelia is still controversial. Among others, shunting syrinx fluid to the subarachnoid, peritoneal or pleural space has been utilized with varying success. Shunt obstruction, migration, and infection represent the most common complications of these procedures. : The authors present the case of an 81-year-old woman who developed an unusual neurological deterioration resembling a subacute posttraumatic ascending myelopathy (SPAM) after the insertion of a syringosubarachnoid shunt for the treatment of slow-growing D10 syringomyelia. : To date, no cases of SPAM secondary to the insertion of a syringosubarachnoid shunt for the treatment of syringomyelia have been reported. The potential pathogenesis related to this phenomenon is discussed.
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http://dx.doi.org/10.1080/10790268.2018.1512735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534218PMC
September 2020

Optic Radiation Diffusion Tensor Imaging Tractography: An Alternative and Simple Technique for the Accurate Detection of Meyer's Loop.

World Neurosurg 2018 Sep 30;117:e42-e56. Epub 2018 May 30.

Unit of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The optic radiation (OR) is a white matter bundle with a very complex anatomy. Its anterior component bends sharply around the tip of the temporal horn, forming the Meyer's loop (ML), the sparing of which during surgery is crucial to preserve visual function. Defining its exact anatomy and accurately identifying its position remain challenging, even with diffusion tensor imaging (DTI) tractography and the most refined tracking procedure. We have developed an alternative tracking technique to detect the ML position.

Methods: We performed DTI studies in 26 patients undergoing resection of a temporo-parieto-occipital lesion. We then reconstructed the ORs of each patient using 2 techniques (the first developed by our team, the other taken from the literature), using the same tracking software and parameters. We evaluated the accuracy of each technique measuring 3 distances that define the ML position. We created 5 data groups and compared the 2 techniques. Finally, we compared our results with the results from 8 anatomic dissection studies and other tractographic studies.

Results: Our findings show that our technique allows a more accurate definition of the ML position. We found a statistically significant (P < 0.05) difference for all the distances between the 2 techniques; our results resemble those obtained in dissection studies. Our technique is also easy to perform and repeatable.

Conclusions: Our tracking technique may be of marked interest for the evaluation and anatomic definition of the ML position, particularly for neurosurgeons approaching the anterior temporal region.
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http://dx.doi.org/10.1016/j.wneu.2018.05.131DOI Listing
September 2018

Translaminar Approach for Treatment of Hidden Zone Foraminal Lumbar Disc Herniations: Surgical Technique and Preoperative Selection of Patients with Long-Term Follow-Up.

World Neurosurg 2018 Aug 19;116:182-187. Epub 2018 May 19.

Division of Neurosurgery, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy; Division of Neurosurgery, Azienda Socio Sanitaria Territoriale Monza-Ospedale San Gerardo, Monza, Italy. Electronic address:

Background: Lumbar disc herniation is a common degenerative disease of the lumbar spine with a prevalence of 1%-3% in some population studies. In 10% of patients, there is a fragment migrated cranially in Macnab's "hidden zone." In selected cases, this fragment can be removed with a translaminar approach that was described in 1998. We provide a detailed description of the technical advantages and pitfalls of the translaminar approach in a consecutive series of 32 patients treated at our institution.

Methods: Patients were divided preoperatively and postoperatively into 5 classes based on the Oswestry Disability Index (ODI): class 1, ODI 0%-20% (minimal disability); class 2, 20%-40% (moderate disability); class 3, 40%-60% (severe disability); 60%-80% (crippled); 80%-100% (bedridden or disabling symptoms).

Results: Four (12.5%) patients were upgraded 1 ODI class after the operation; 6 (18.7%) patients were upgraded 2 classes, 8 (25%) patients were upgraded 3 classes, and 11 (34.4%) patients were upgraded 4 classes. In 3 (9.4%) patients, ODI class did not change after the operation. After surgery, 7 (21.9%) patients developed mild low back pain. Mean follow-up was 25 months.

Conclusions: When performed by dedicated spinal neurosurgeons, the translaminar approach is safe and effective in patients with long-term follow-up. Most patients showed an improvement in ODI. Major pitfalls were related to surgical selection and the narrow working space.
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http://dx.doi.org/10.1016/j.wneu.2018.05.072DOI Listing
August 2018

Meningioma and Bone Hyperostosis: Expression of Bone Stimulating Factors and Review of the Literature.

World Neurosurg 2018 Jul 3;115:e774-e781. Epub 2018 May 3.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Several hypotheses have been proposed regarding the mechanisms underlying meningioma-related hyperostosis. In this study, we investigated the role of osteoprotegerin (OPG), insulin-like growth factor 1 (IGF-1), endothelin 1 (ET-1), and bone morphogenetic protein (BMP) 2 and 4.

Methods: A total of 149 patients (39 males and 110 females; mean age, 62 years) who underwent surgery were included. Depending on the relationship with the bone, meningiomas were classified as hyperostotic, osteolytic, infiltrative, or unrelated. Expression of OPG, and IGF-1, ET-1, BMP-2, and BMP-4 was evaluated by tissue microarray analysis of surgical samples.

Results: Our series comprised 132 cases of grade I, 14 cases of grade II, and 3 cases of grade III meningiomas, according to the World Health Organization classification. Based on preoperative computed tomography scan, the cases were classified as follows: hyperostotic, n = 11; osteolytic, n = 11; infiltrative, n = 15; unrelated to the bone, n = 108. Four cases were excluded from the statistical analysis. Using receiver operating characteristic curve analysis, we identified a 2% cutoff for the mean value of IGF-1 that discriminated between osteolytic and osteoblastic lesions; cases with a mean IGF-1 expression of <2% were classified as osteolytic (P = 0.0046), whereas those with a mean OPG expression of <10% were classified as osteolytic (P = 0.048). No other significant relationships were found.

Conclusions: Expression of OPG and expression of IGF-1 were found to be associated with the development of hyperostosis. Preliminary findings suggest that hyperostosis can be caused by an overexpression of osteogenic molecules that influence osteoblast/osteoclast activity. Based on our results, further studies on hyperostotic bony tissue in meningiomas are needed to better understand how meningiomas influence bone overproduction.
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http://dx.doi.org/10.1016/j.wneu.2018.04.176DOI Listing
July 2018

Constructional Apraxia in Older Patients with Brain Tumors: Considerations with an Up-To-Date Review of the Literature.

World Neurosurg 2018 Jun 31;114:e1130-e1137. Epub 2018 Mar 31.

Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. Electronic address:

Background: Constructional apraxia (CA) is a neuropsychological impairment of either basic perceptual and motor abilities or executive functions, in the absence of any kind of motor or perceptual deficit. Considering patients with focal brain tumors, CA is common in left or right parietal and parieto-occipital lesions. In neuropsychology, the Rey-Osterrieth Complex Figure Test (ROCFT; or parallel forms) is commonly used for the assessment of CA. This study stems from a clinical observation of a difficulty with CA tests for the majority of older neurosurgical patients without occipitoparietal lesions.

Methods: Patients were tested at 3 points: before surgery, 3 months after surgery, and 12 months after surgery. Thirty patients (15 meningiomas and 15 glioblastomas) were studied retrospectively.

Results: Older patients with focal brain lesions, regardless of the nature of the tumor, performed poorly at CA tests. More than 50% of patients obtained pathologic results at all 3 times considered.

Conclusions: Our findings suggest that as CA complex tests involve multiple domains, poor results in copy task may reflect a global cognitive deficit of older patients with tumors, without a specific constructional praxis deficit. CA complex tests (such as the ROCFT) do not give significant informations about visuo-constructional abilities.
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http://dx.doi.org/10.1016/j.wneu.2018.03.159DOI Listing
June 2018

Risk of post-operative venous thromboembolism in patients with meningioma.

J Neurooncol 2018 Jun 2;138(2):401-406. Epub 2018 Mar 2.

Neurosurgery, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via F. Sforza, 35, 20122, Milan, Italy.

The surgical resection of meningiomas can be complicated by venous thromboembolism (VTE) in the post-operative period, but the exact incidence of this event is not known. Aim of this study was to assess the occurrence of VTE in patients operated for meningioma who underwent a post-operative clinical and objective screening for VTE. Patients undergoing meningioma resection between 2000 and 2010 who accepted to be investigated for VTE in the post-operative period were included in the study. The screening included daily clinical assessment, pulmonary perfusion scintigraphy (Q-SCAN) on day 2 and venous compression ultrasonography (CUS) of the lower limbs within day 7. The univariate and multivariate statistical analysis of risk factors for VTE included sex, age, presence of comorbidities, pre- and post-operative Karnofsky Performance scale (KPS), post-operative neurological worsening and post-operative walking ability. Two-hundred and seventy-five patients were included in the study. VTE was diagnosed in 82 patients (29.8%). Univariate analysis revealed that age ≥ 65 years, cardiovascular comorbidities, pre- and post-operative KPS < 80/100, post-operative neurological worsening and impaired post-operative walking ability were significantly associated with VTE. Multivariate analysis confirmed only age ≥ 65 years (p = 0.011) and post-operative KPS < 80/100 (p = 0.002) as independent risk factors for VTE. Patients operated for meningioma have a 30% risk of VTE. Age ≥ 65 years and post-operative KPS < 80 were independent risk factors for VTE.
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http://dx.doi.org/10.1007/s11060-018-2810-zDOI Listing
June 2018

Is Neurosurgery Ready for Cisternostomy in Traumatic Brain Injuries?

World Neurosurg 2018 03;111:427

Division of Neurosurgery, University Hospital-Maggiore Hospital of Charity of Novara, Novara, Italy.

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http://dx.doi.org/10.1016/j.wneu.2017.11.139DOI Listing
March 2018

Surgery in elderly patients with intracranial meningioma: neuropsychological functioning during a long term follow-up.

J Neurooncol 2018 May 12;137(3):611-619. Epub 2018 Jan 12.

Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza, 35, 20122, Milan, Italy.

Surgical treatment of elderly patients with meningioma is has proved to be safe, especially when patients are selected using dedicated surgical scores. These scores take into account tumor size, edema, location and patient's co-morbidities. Neuropsychological functioning (NPF) of this kind of patients has been poorly studied in literature and it is not taken into account by these scores. Aim of our study was to describe the long-term outcome in terms of NPF of elderly patients undergoing surgery. Patients older than 70 years of age affected by intracranial meningioma and selected with the Clinical-Radiological Grading Score were included in our study. Neuropsychological testing was performed using a dedicated battery of tests before surgery, 3 and 12 months after surgery. Clinical, neurological and radiological outcomes were studied as well. Forty-one patients with a median age of 74 years were included in this study. Preoperatively only 1/41 patients showed a normal NPF with all tests scoring normally. Four out of 39 patients showed a complete neuropsychological recovery after 3 months; while 10/37 patients had a complete recovery after 12 months. NPF showed a trend of progressive improvement after surgery. Our study is the first experience reported in literature describing a long term follow-up in elderly patients after surgery for intracranial meningioma. In our series, surgery determined an improvement of NPF over time; especially with a low complication rate related to the selection of patients obtained through the CRGS. Further studies need to be performed in order to understand how brain edema, tumor size, volume and tumor location affect NPF in both short and long term.
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http://dx.doi.org/10.1007/s11060-018-2754-3DOI Listing
May 2018

IMP3 expression in NSCLC brain metastases demonstrates its role as a prognostic factor in non-neuroendocrine phenotypes.

Med Oncol 2017 Dec 1;35(1). Epub 2017 Dec 1.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.

Brain metastases from NSCLC are associated with a poor prognosis, and local radiotherapy is the most effective therapeutic strategy. The oncofetal protein IMP3 has been studied extensively, and evidence suggests that its expression is related to shorter overall survival and a more aggressive phenotype in solid malignancies. Here, the prognostic role of IMP3 was investigated in a cohort of patients with NSCLC brain metastases in correlation with survival and tumor histotype. A series of 42 NSCLC brain metastases samples was analyzed by tissue microarray and immunohistochemical staining for IMP3. IMP3 expression was associated with shorter overall survival in the whole series and in subgroups of metastases from non-neuroendocrine pulmonary malignancies and adenocarcinoma metastases. These results indicated that IMP3 is a strong prognostic factor in non-neuroendocrine brain metastases and in particular in patients with adenocarcinoma metastases.
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http://dx.doi.org/10.1007/s12032-017-1062-7DOI Listing
December 2017

Analysis of factors influencing the access to concomitant chemo-radiotherapy in elderly patients with high grade gliomas: role of MMSE, age and tumor volume.

J Neurooncol 2017 Sep 6;134(2):377-385. Epub 2017 Jul 6.

Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.

High grade gliomas (HGG) are tumors with a rapidly progressive course and the standard of care consists of surgery and chemo-radiotherapy. Elderly patients with HGG usually have a worse prognosis due to their comorbidities and difficulties in accessing or completing adjuvant treatments. The purpose of our study was to assess the influence of pre-operative factors (MMSE, age, sex, KPS, tumor volume) on the post-operative access to chemo-radiotherapy in the elderly population. In addition, the influence of the access to adjuvant therapies on overall survival (OS) was assessed. We retrospectively reviewed our consecutive case series of 117 elderly patients (≥65 years) with HGG treated in our Institution. All the clinical records regarding age, sex, tumor location, MMSE, KPS, access to adjuvant treatments and OS were analyzed. 72 males and 45 females with a median age of 71 years were analyzed. Adjuvant therapies were considered; concomitant chemo-radiotherapy with standard radiotherapy or hypofractionated radiation regimen. 84 patients had access to adjuvant therapies. Access to therapies was associated with a median age of 71(range 66-80) years, a median MMSE of 26(range 5-30), and a median tumor volume of 24 cm(range 1-140). The median OS was 13 months for patients who had access to adjuvant therapies and 5 months for patients who did not. In the elderly patients with HGG, the MMSE, age and tumor volume were predictive of post-surgery access to adjuvant treatments. OS was significantly longer in elderly patients with HGG who had access to post-surgery chemo-radiotherapy.
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http://dx.doi.org/10.1007/s11060-017-2537-2DOI Listing
September 2017

Supplementary Tests in Idiopathic Normal Pressure Hydrocephalus: A Single-Center Experience with a Combined Lumbar Infusion Test and Tap Test.

World Neurosurg 2017 Apr 9;100:567-574. Epub 2017 Jan 9.

Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy; Department of Neurosurgery, Ospedale Classificato "MoriggiaPelascini", Gravedona, Como, Italy.

Background: The lumbar infusion test (LIT) and tap test (TT) have previously been described for the diagnosis and selection of appropriate surgical candidates in idiopathic normal pressure hydrocephalus (iNPH).

Methods: We retrospectively reviewed 81 consecutive patients with a clinical diagnosis of iNPH selected for supplementary testing. Clinical evaluation was scored with the Japanese Grading Scale for Normal Pressure Hydrocephalus, the Global Deterioration Score, and the modified Rankin Scale (mRS). The test protocol included a cerebrospinal fluid pressure monitoring (PMi), an LIT, and a TT. Patients were selected for surgery if outflow resistance was ≥14 mm Hg/mL/minute or if a clinical improvement was recorded after TT.

Results: Sixty-eight patients were selected for ventriculoperitoneal shunting; 72.8% had a positive PMi or LIT, 74.1% had a positive TT, and 63.0% were positive to both tests. Complications were all transient. Clinical evaluation at 12 months after shunting showed a global improvement in 60 patients (88.2%). Overall, 75.0% of patients had no significant disability (mRS score, 1 and 2), 20.6% had an mRS score of 3 or 4, and 4.4% had severe disability after surgery. The positive predictive value of PMi/LIT, TT, or both combined was similar (89.8, 90.0, and 88.2%); however, 21.7% of patients who improved after surgery were selected with either a positive LIT or TT alone.

Conclusions: LIT and TT are complementary and they can easily be combined in sequence with a low complication rate and high probability of selecting patients with iNPH who may benefit from ventriculoperitoneal shunt surgery.
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http://dx.doi.org/10.1016/j.wneu.2017.01.003DOI Listing
April 2017

Is Complex Sphenoidal Sinus Anatomy a Contraindication to a Transsphenoidal Approach for Resection of Sellar Lesions? Case Series and Review of the Literature.

World Neurosurg 2017 Apr 5;100:173-179. Epub 2017 Jan 5.

Unit of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The transsphenoidal approach is considered the gold standard for resection of pituitary adenomas and other sellar region lesions. This approach is guided by a few fundamental anatomic landmarks that conduct the surgeon toward the sellar floor. Some anatomic structures may vary a lot (e.g., intrasphenoidal septa, intercarotid distance) and may be difficult to identify. Pneumatization and conformation of the sphenoidal sinus (SS) plays a key role in accessing the floor of the sella and other skull base structures. A poorly pneumatized SS may be a relative contraindication to the transsphenoidal approach. We analyzed outcome and complications in transsphenoidal surgery for sellar lesions with a difficult SS.

Methods: We analyzed 243 consecutive patients who underwent a transsphenoidal approach for sellar lesions. Patients with poor pneumatization of the SS were included. Neurosurgical and endocrinologic outcomes were reported.

Results: Successful treatment using a transsphenoidal approach with neuronavigation and Doppler ultrasound was achieved in 15 patients with a low degree of pneumatization of the SS. A pituitary adenoma was present in 13 of 15 patients. Endocrinologic and neurosurgical outcomes were similar to patients with normal pneumatization of the SS, showing a cure of disease in 6 of 9 patients with functioning adenomas and an improvement of symptoms in cases of nonfunctioning adenomas.

Conclusions: Patients with a poorly pneumatized SS can be treated safely with a transsphenoidal approach using image guidance techniques to avoid major neurovascular complications.
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http://dx.doi.org/10.1016/j.wneu.2016.12.123DOI Listing
April 2017

Role of Intraoperative Neurophysiologic Monitoring in the Resection of Thalamic Astrocytomas.

World Neurosurg 2016 Oct 23;94:50-56. Epub 2016 Jun 23.

Unit of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The thalamus is a deep-seated and crucial structure for the sensorimotor system. It has been long considered a surgically inaccessible area because of the morbidity associated with surgical resections. Astrocytomas of the thalamus are usually treated with bioptic procedures followed by adjuvant treatments. Intraoperative neurophysiologic monitoring (IONM) allows safe and satisfactory resections of lobar gliomas, but few data are available for thalamic lesions. The aim of this study was to review the outcome of a small series of patients with thalamic astrocytomas that were treated with surgical resection with the aid of IONM.

Methods: Surgical resection with IONM was performed in 5 patients with thalamic astrocytomas (1 grade I, 1 grade II, 2 grade III, 1 grade IV). Two astrocytomas were in the dominant hemisphere. Preoperative and postoperative neuropsychological assessments were performed in 3 patients. IONM was tailored to the individual patient and consisted of transcranial motor evoked potential monitoring, cortical motor evoked potential monitoring, somatosensory evoked potential monitoring, direct electrical stimulation, electroencephalography, and electrocorticography.

Results: None of the patients experienced permanent motor deficits; 2 patients had a transient hemiparesis requiring rehabilitation; 1 patient had a transient aphasia, and 1 patient had permanent aphasia. None of the patients had intraoperative seizures, but 1 patient experienced postoperative transient status epilepticus. The extent of resection on postoperative volumetric magnetic resonance imaging was >70% in all cases.

Conclusions: Surgical resection of thalamic astrocytomas appeared to be effective and relatively safe when guided by IONM. Larger series of patients are required to confirm these preliminary data.
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http://dx.doi.org/10.1016/j.wneu.2016.06.049DOI Listing
October 2016

Atypical Association of Ethmoidal Encephalocele and Hydrocephalus in an Adult Patient with Autosomal-Dominant Osteopetrosis Type I (ADO-I): A Case Report.

World Neurosurg 2016 May 4;89:731.e13-7. Epub 2016 Feb 4.

Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Osteopetroses are a heterogeneous group of heritable disorders characterized by increased bone density as the result of defective osteoclast-mediated bone resorption. The autosomal-dominant osteopetrosis type I (ADO-I) is defined by the presence of osteosclerosis involving mainly the skull bones, variably associated with compression of the foramina of cranial nerves and vascular structures, hypertelorism, exophthalmos, and less commonly with hydrocephalus, pseudotumor, and Chiari malformation type I.

Case Description: We describe an adult patient with ADO-I presenting with an atypical association of clinical manifestations that required a tailored management. On admission, the patient complained about chronic headache, recurrent sinusitis, and postnasal drip. Findings of the examination didn't show clear signs of increased intracranial pressure, whereas imaging studies revealed thickening of the skull bones and an unexpected fistula associated with anterior ethmoidal meningoencephalocele. Some days after endoscopic transnasal closure of the fistula, a severe hypertensive hydrocephalus developed, which required a prompt ventriculoperitoneal shunt placement, complicated by a diffuse subarachnoid hemorrhage. The 6-month follow-up showed complete recovery.

Conclusions: After reviewing the literature, we can confirm that ours was the second case of an adult ADO-I patient associated with anterior ethmoidal meningoencephalocele, the first one needing a combined treatment of the encephalocele and hydrocephalus. Because ADO-I is a rare disease with a wide spectrum of clinical manifestations, our case can represent a prototype for the future management of similar cases.
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http://dx.doi.org/10.1016/j.wneu.2016.01.070DOI Listing
May 2016

The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma.

Oncotarget 2015 Jul;6(19):17514-31

Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

The vacuolar H+ ATPase (V-ATPase) is a proton pump responsible for acidification of cellular microenvironments, an activity exploited by tumors to survive, proliferate and resist to therapy. Despite few observations, the role of V-ATPase in human tumorigenesis remains unclear.We investigated the expression of ATP6V0C, ATP6V0A2, encoding two subunits belonging to the V-ATPase V0 sector and ATP6V1C, ATP6V1G1, ATPT6V1G2, ATP6V1G3, which are part of the V1 sector, in series of adult gliomas and in cancer stem cell-enriched neurospheres isolated from glioblastoma (GBM) patients. ATP6V1G1 expression resulted significantly upregulated in tissues of patients with GBM and correlated with shorter patients' overall survival independent of clinical variables.ATP6V1G1 knockdown in GBM neurospheres hampered sphere-forming ability, induced cell death, and decreased matrix invasion, a phenotype not observed in GBM monolayer cultures. Treating GBM organotypic cultures or neurospheres with the selective V-ATPase inhibitor bafilomycin A1 reproduced the effects of ATP6V1G1 siRNA and strongly suppressed expression of the stem cell markers Nestin, CD133 and transcription factors SALL2 and POU3F2 in neurospheres.These data point to ATP6V1G1 as a novel marker of poor prognosis in GBM patients and identify V-ATPase inhibition as an innovative therapeutic strategy for GBM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627325PMC
http://dx.doi.org/10.18632/oncotarget.4239DOI Listing
July 2015

The oncofetal protein IMP3: a novel grading tool and predictor of poor clinical outcome in human gliomas.

Biomed Res Int 2015 28;2015:413897. Epub 2015 Jan 28.

Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, 20122 Milan, Italy ; Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy.

Morphologic criteria illustrated in WHO guidelines are the most significant prognostic factor in human gliomas, but novel biomarkers are needed to identify patients with a poorer outcome. The present study examined the expression of the oncofetal protein IMP3 in a series of 135 patients affected by high-grade (grade III and IV) gliomas, correlating the results with proliferative activity, molecular parameters, and clinical and follow-up data. Overall, IMP3 expression was higher in glioblastomas (68%) than in grade III tumors (20%, P < 0.0001), and IMP3-positive high-grade gliomas showed a shorter overall and disease-free survival than negative ones (P = 0.0002 and P = 0.006, resp.). IMP3 expression was significantly associated with the absence of mutations of IDH1 gene (P = 0.0001) and with the unmethylated phenotype of MGMT in high-grade gliomas (P = 0.004). High Ki67 levels were correlated with better prognosis in glioblastomas but IMP3 expression was not correlated with the proliferation index. These findings confirm the role of IMP3 as a marker of poor outcome, also in consideration of its association with IDH1 wild-type phenotype and MGMT unmethylated status. The data suggest that IMP3 staining could identify a subgroup of patients with poor prognosis and at risk of recurrence in high-grade gliomas.
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http://dx.doi.org/10.1155/2015/413897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324486PMC
November 2015

Third Ventriculostomy in Late-onset Idiopathic Aqueductal Stenosis Treatment: A Focus on Clinical Presentation and Radiological Diagnosis.

Neurol Med Chir (Tokyo) 2014 29;54(12):1014-21. Epub 2014 Nov 29.

Neurosurgery Unit, Fondazione I.R.C.C.S. "Ca' Granda" Ospedale Maggiore Policlinico.

Endoscopic third ventriculostomy (ETV) is considered the gold standard treatment for obstructive hydrocephalus due to partial or complete obstruction of cerebrospinal fluid (CSF) ventricular pathways caused by mass lesions. However long-term efficacy of this procedure remains controversial as treatment of chronic adult hydrocephalus due to stenosis of Sylvian acqueduct [late-onset idiopathic aqueductal stenosis (LIAS)]. The authors describe clinical presentation, diagnostic investigations in patients affected by LIAS, and define their clinical and radiological outcome after ETV. From January 2003 to December 2008, 13 consecutive LIAS patients treated by ETV were retrospectively reviewed. Pre- and post-operative clinical and radiological findings, including conventional and phase-contrast (PC) cine magnetic resonance imaging (MRI) were investigated. ETV was successfully performed in all patients. Patient's neurological condition improved. No one required a second ETV procedure or shunt implantation. Clinical and radiological results reveal a satisfactory outcome of LIAS patients treated by ETV. At follow-up a clinical improvement could be demonstrated in all cases. Selection criteria of LIAS patients seem to be crucial to obtain satisfactory and long-lasting results. Even in elderly patients with chronic hydrocephalus, ETV can be considered the treatment of choice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533356PMC
http://dx.doi.org/10.2176/nmc.oa.2013-0367DOI Listing
November 2016

Gene expression profile analysis of human mesenchymal stem cells from herniated and degenerated intervertebral discs reveals different expression of osteopontin.

Stem Cells Dev 2015 Feb 29;24(3):320-8. Epub 2014 Oct 29.

1 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .

Gene expression analysis provides an effective methodology to identify clinically relevant genes implicated in intervertebral disc (IVD) pathology. The analysis of gene profile in mesenchymal stem cells (MSCs) from human herniated IVD (H-IVD) and degenerated IVD (D-IVD) has not yet been investigated. We present in this study a characterization of MSCs isolated from clinically categorized H-IVD and D-IVD disc samples. H-IVD-MSCs and D-IVD-MSCs showed multipotent mesenchymal differentiation ability, expressing positivity for adipogenic, osteogenic, and chondrogenic markers with an immunophenotypical profile representative of MSCs. FACS analyses revealed a higher expression of CD44 in D-IVD-MSCs compared to H-IVD-MSCs. Gene expression profile revealed that most genes under investigation displayed large variations and were not significantly different in the two types of analyzed IVD-MSCs. Conversely, the gene expression of osteopontin (OPN), a protein involved in bone matrix mineralization and extracellular matrix destruction, was found markedly increased (more than 400-fold) in D-IVD-MSCs compared to H-IVD-MSCs. Moreover, the OPN protein expression was detectable only in D-IVD-MSCs, and its levels were directly related with D-IVD severity. These findings suggest that an abnormal expression of OPN in D-IVD-MSCs occurs and plays a pivotal role in the pathophysiological process of human disc degeneration. We speculate that the regulation of the OPN pathway might be a therapeutic target to counteract disc degeneration.
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http://dx.doi.org/10.1089/scd.2014.0282DOI Listing
February 2015

The importance of predicting factors in the surgical outcome of peripheral nerve sheath tumors.

J Neurol Surg A Cent Eur Neurosurg 2014 Mar 7;75(2):104-9. Epub 2013 Aug 7.

Division of Neurosurgery, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Objective: Peripheral nerve sheath tumors (PNSTs) are tumors arising from the neural sheath cells. Surgery plays a central role in the management of this disease, with the purpose of obtaining radical tumor's resection and at the same time providing the best outcome. We retrospectively analyzed 53 PNSTs in 42 patients in an attempt to identify some factors that may improve surgical outcome.

Material And Methods: Clinical, histologic, and imaging data of 42 patients with PNSTs treated at our Institute between 2001 and 2012 were collected and analyzed. We evaluated the outcome 1 month and 6 month after surgery using three clinical parameters (pain, motor deficits, and sensory deficits) in relation to different histotypes, the presence of neurofibromatosis type 1, tumor location, and duration of symptoms before treatment.

Results: The best functional results were observed in patients having neurofibromas; the worst outcomes were observed in patients with malignant PNSTs. The other factors were not associated with outcome.

Conclusion: The timing of surgery is the most important predictive factor of surgical outcome, being the only factor that allows to improve the outcome. With the current study, we want to stress the importance of treating PNSTs as soon as possible to provide the best outcome possible.
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http://dx.doi.org/10.1055/s-0033-1348351DOI Listing
March 2014

Continuous tamoxifen and dose-dense temozolomide in recurrent glioblastoma.

Anticancer Res 2013 Aug;33(8):3383-9

Neurosurgery, IRCCS Ca' Granda Foundation Ospedale Maggiore Policlinico - 22, F. Sforza street, Milan 20122, Italy.

Background: The current standard-of-care for glioblastoma (GBM) is represented by concomitant radiotherapy (RT) and temozolomide (TMZ), according to Stupp's protocol. Second-line treatments for GBM have not been yet defined. Tamoxifen is an anti-estrogen molecule with anti-neoplastic effects whose role is under investigation. tamoxifen is generally well tolerated but thromboembolic complications have been reported. In this study, we report our experience on the administration of tamoxifen plus dose-dense TMZ in patients with recurrent GBM.

Patients And Methods: All patients underwent surgical resection of GBM and completed concomitant RT and TMZ. Eligibility criteria also included evidence of GBM recurrence and good general conditions [Karnofsky Performance Score (KPS) >70] at recurrence. Patients with rapidly progressive disease, clearly unfavorable prognosis, or history of deep-venous thrombosis were excluded. The second-line treatment consisted of dose-dense TMZ (75-150 mg/m(2) one week on/ one week off) plus daily tamoxifen (80 mg/m(2)). Follow-up was performed with contrast-enhanced brain Magnetic Resonance Imaging (MRI) every three months.

Results: Thirty-two patients (18 males, 14 females; median age 57 years) with GBM relapse were included. Median overall survival time (OS) and time to tumor progression after recurrence (TTP-2) were 17.5 and 7 months, respectively. Interestingly, no differences in OS and TTP-2 were noted in GBM between those with methylated and unmethylated MGMT. None of the patients had complications related to TMZ plus tamoxifen administration.

Conclusion: The combinatorial administration of tamoxifen and TMZ appeared to be well-tolerated, and potentially effective in increasing the efficacy of dose-dense TMZ schedule as a second-line therapeutic strategy.
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August 2013

R583Q CACNA1A variant in SHM1 and ataxia: case report and literature update.

J Headache Pain 2012 Jul 19;13(5):419-23. Epub 2012 Apr 19.

Department of Neurosurgery, University of Milan, Milan, Italy.

Familial hemiplegic migraine (FHM) type 1 is a rare monogenic dominant autosomal disease due to CACNA1A gene mutations. Besides the classical phenotype, mutations on CACNA1A gene are associated with a broader spectrum of clinical features including cerebellar ataxia, making FHM1 a complex channelopathy. We report the case of a patient carrying the p.Arg583Gln mutation affected by hemiplegic migraine and late onset ataxia and we performed a literature review about the clinical features of p.Arg583Gln. Although p.Arg583Gln mutations are associated with a heterogeneous phenotype, carriers present cerebellar signs which consisted generally in ataxia and dysmetria, with intention tremor appearing mostly in advanced age, often progressive and permanent. The heterogeneous spectrum of CACNA1A gene mutations probably causes sporadic hemiplegic migraine (SHM) to be misdiagnosed. Given the therapeutic opportunities, SHM/FHM1 should be considered in differential diagnosis of patients with cerebellar ataxia and migraine with aura.
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http://dx.doi.org/10.1007/s10194-012-0444-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381060PMC
July 2012