Usefulness of a clinicopathological classification in predicting treatment-related outcomes and multimodal therapeutic approaches in pituitary adenoma patients: retrospective analysis on a Portuguese cohort of 129 patients from a tertiary pituitary center.

PURPOSE: A clinicopathological classification has been designed to predict recurrence/progression in patients with pituitary adenomas (PAs). We aimed to study its usefulness in predicting PAs that will have a challenging disease course and may require more often complex multimodal and multiple therapeutic approaches. METHODS: Retrospective analysis of 129 patients with PAs operated in our institution between 2001 and 2020 (84 non-clinically functioning PAs, 32 acromegaly, 9 Cushing's disease, 2 prolactinomas and 2 thyrotropinomas). Grading was based on invasion and proliferation: 1a (non-invasive, non-proliferative; n = 59), 1b (non-invasive, proliferative; n = 17), 2a (invasive, non-proliferative; n = 38), and 2b (invasive, proliferative; n = 15). RESULTS: Of the 129 patients, 68 (52.7%) were females, and the mean age at diagnosis was 53.7 ± 15.4 years. The mean follow-up duration was 93.1 ± 61.8 months. Grade 2b PAs when compared to other grades (2b-2a-1b-1a) had significantly higher rates of persistent tumor remnant within 1-year after operation (93-78-18-30%; p < 0.001), active disease at last follow-up (40-27-12-10%; p = 0.004), re-operation (27-16-0-5%; p = 0.023), irradiation (53-38-12-7%; p < 0.001), multimodal treatment (67-49-18-25%; p = 0.003), multiple treatment (33-27-6-9%; p = 0.017). Patients with grade 2b PAs also required a higher mean number of treatments (2.6-2.1-1.2-1.4; p < 0.001). CONCLUSIONS: This clinicopathological classification appears to be a useful grading system to identify PAs that may be more refractory and more often require complex multimodal and multiple therapeutic approaches. Invasive PAs, especially grade 2b tumors, may be more likely to need complex treatment approach, including radiotherapy, and may display higher rates of active disease at last follow-up, despite receiving higher number of treatments.

BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions - Markers in the clinical stratification of pediatric gliomas.

BACKGROUND: Genetic alterations in pediatric primary brain tumors can be used as diagnostic and prognostic markers and are the basis for the development of new target therapies that, ideally, would be associated with lower mortality and morbidity. This study evaluates the incidence and interplay of the presence of BRAF V600E mutation and chromosomal 9p21 deletions in a series of 100 pediatric gliomas, aiming to determine the role of these alterations in recurrence and malignant transformation, and to verify if they could be used in the clinical set for stratifying patients for tailored therapies and surveillance. METHODS: Sanger sequencing was used for the assessment of BRAF mutations at exon 15 and Fluorescent In Situ Hybridization (FISH) with BAC: RP11-14192 for the detection of 9p21 alterations. Expression levels of the CDKN2A and MTAP by real-time PCR were evaluated in cases with 9p21 deletions. Statistical analysis of genetic and clinical data was performed using Graph Pad Prism 5 and SPSS Statistics 24 software. RESULTS: In our cohort it was observed that 7 /78 (8,9%) of the low-grade tumors recurred and 2 (2,6%) showed malignant transformation. BRAF V600E mutations were detected in 15 cases. No statistically significant correlations were found between the presence of BRAF V600E mutation and patient's morphologic or clinical features. Deletions at 9p21 abrogating the CDKN2A/B and MTAP loci were rare in grade I gliomas (12.2%, p = 0.0178) but frequent in grade IV gliomas (62.5%, p = 0.0087). Moreover it was found that deletions at these loci were correlated with a shorter overall survival (p = 0.011) and a shorter progression-free survival (p = 0.016). CONCLUSIONS: It was demonstrated that in these tumors BRAF V600E mutated and that CDKN2A/B MTAP co-deletions may be used for stratifying patients for a stricter surveillance. The Investigating and defining if glial tumors with CDKN2A/B and MTAP homozygous loss may be vulnerable to new forms of therapy, namely those affecting the methionine salvage pathway, was proven to be of importance.

Pediatric central nervous system tumors: review of a single Portuguese institution.

INTRODUCTION: Despite being the second most frequent tumor in children, pediatric central nervous system (CNS) tumors are rare, and the published European epidemiological data is limited. Our goal is to present the first surgical series of pediatric CNS tumors in Portugal and to review other similar worldwide series. METHODS: Retrospective review of all patients younger than 19 years old, operated to a CNS tumor in the Neurosurgery Department at Hospital de Santa Maria (Lisbon, Portugal) between January 2004 and December 2014. Demographic data, tumor location, clinical data, histopathology, and surgical treatment were analyzed and compared to surgical series of pediatric CNS tumors published in PubMed indexed journals over the last 20 years. RESULTS: We performed 253 surgeries in 215 patients, with a male:female ratio of 1.2:1 and a mean age of 9.2 years old. Primary brain tumors accounted for 95 % of all tumors and had more often a supratentorial location. Tumors of neuroepithelial tissue, particularly astrocytic tumors, embryonal tumors, neuronal and mixed neuronal-glial tumors, and oligodendrogliomas accounted for 81 % of cases. A gross-total resection was achieved in most cases. There was no mortality, and the overall morbidity was low. CONCLUSIONS: The demography, topography, and clinical presentation of the tumors and the surgical results of this series are comparable to other European ones. We found a higher incidence of neuronal and mixed neuronal-glial tumors and oligodendrogliomas and a slight lower incidence of ependymomas. Our results should encourage further national multi-institutional studies to better characterize these tumors in the pediatric population.

Tranexamic acid decreases transfusion requirements during the modified pi-plasty procedure for sagittal craniosynostosis.

The aim of our study was to evaluate the effectiveness of intraoperative tranexamic acid (TXA) administration in decreasing transfusion needs in patients undergoing modified pi-plasty. A retrospective study was performed using a population of 59 patients who underwent modified pi-plasty, wherein patients who received TXA during surgery (study group, n = 26) were compared with patients who did not receive TXA (control group, n = 33). The primary study endpoints were intraoperative red blood cell substitution (%), postoperative red blood cell substitution (%), total red blood cell substitution (%), and hematocrit variation. Perioperative administration of TXA significantly decreased the total red blood cell substitution (62.90% vs 86.70%; p = 0.002) and resulted in a higher postoperative hematocrit (29.47% vs 27.53%; p = 0.060). In conclusion, perioperative administration of TXA significantly decreased blood transfusion requirements in patients with sagittal craniosynostosis undergoing modified pi-plasty.

Metopic craniosynostosis: Dynamic cranioplasty for trigonocephaly versus fronto-orbital remodeling and advancement - A retrospective study.

The aim of this study was to compare a traditional fronto-orbital remodeling and advancement (FORA) with the dynamic cranioplasty for trigonocephaly (DCT). The authors analyzed patients who underwent surgery for trigonocephaly. Perioperative data were compared. Parents were asked to use a visual analog scale to evaluate the pre- and postoperative distance between the eyes, the forehead shape, and the global appearance of the face. A panel of observers was asked to grade pre- and postoperative photographs using a similar visual analog scale. Pre- and postoperative anthropometric data were collected and analyzed in a subset of the study population aged 9 years or older. The total sample size was 51 patients (DCT n = 39; FORA n = 12). Durations of surgery and anesthesia were shorter in the DCT group (115 vs 194 min, p = 0.001; 226 vs 289 min, p = 0.001). Patients in the DCT group received similar preoperative ratings to those in the FORA group, but significantly higher postoperative ratings by parents for all three questions. There were no significant differences in postoperative ratings by the panel or postoperative anthropometric data. DCT is safe and effective. It is preferred over FORA because it is associated with shorter durations of surgery and anesthesia, while providing higher degrees of parental satisfaction and similar aesthetic and anthropometric outcomes.

UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease.

Background: Despite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies. Methods: Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of UBE2C, a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins. Results: Tissue microarray analysis of an independent BM patient cohort revealed that high expression of UBE2C was associated with decreased survival. UBE2C-driven orthotopic mouse models developed extensive leptomeningeal dissemination, likely due to increased migration and invasion. Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Conclusions: Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.

Patient-derived models of brain metastases recapitulate human disseminated disease.

Dissemination of cancer cells from primary tumors to the brain occurs in many cancer patients, increasing morbidity and death. There is an unmet medical need to develop translational platforms to evaluate therapeutic responses. Toward this goal, we established a library of 23 patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumors. In vivo tumor formation correlates with patients' poor survival. Mouse subcutaneous xenografts develop spontaneous metastases and intracardiac PDXs increase dissemination to the CNS, both models mimicking the dissemination pattern of the donor patient. We test the FDA-approved drugs buparlisib (pan-PI3K inhibitor) and everolimus (mTOR inhibitor) and show their efficacy in treating our models. Finally, we show by RNA sequencing that human BMs and their matched PDXs have similar transcriptional profiles. Overall, these models of BMs recapitulate the biology of human metastatic disease and can be valuable translational platforms for precision medicine.

Rupture of middle fossa arachnoid cyst simulating new-onset migraine with aura.

Arachnoid cysts represent a common, innocent, finding in routine neuroimaging of headache patients. We present the first report of symptomatic migraine with aura caused by the spontaneous rupture of a middle fossa arachnoid cyst into the subdural space. Brain imaging enabled an accurate diagnosis and, subsequently, adequate surgical management.

Pituitary Apoplexy: Should Endoscopic Surgery Be the Gold Standard?

BACKGROUND: Pituitary apoplexy is an uncommon, potentially fatal condition due to spontaneous ischemia or hemorrhage in a pituitary adenoma. The treatment of this disorder has long been a matter of debate. METHODS: Retrospective cohort study including all patients admitted with pituitary apoplexy in our department between 2005 and 2015 was undertaken. Clinical symptoms and signs on admission, treatment (conservative vs. surgical), neurologic deficit on discharge and at 6 months' follow-up, and endocrinologic evaluation at 6 months' follow-up were analyzed. The statistical analysis was performed with STATA 13.0. Endocrinologic and visual outcomes at 6 months in the different groups according to treatment were compared by applying an independent multinomial probit regression test. Outcomes between the conservative and the surgical (endoscopic and microscopic considered together) groups also were compared and the differences between surgical treated groups were analyzed with logistic regression analysis. P values <0.05 were considered significant. RESULTS: Twenty-three patients were included in this study; 60.9% (n = 14) were treated surgically (5 microsurgically; 9 endoscopically) and 39.1% (n = 9) conservatively. Statistical analysis revealed no significant differences in the visual function between the 3 treatment groups in both univariate and multivariate analysis (P > 0.05). The endocrinologic outcome was better in the surgical group (P = 0.017; adjusted P = 0.027), with a significant difference between the conservative group and the endoscopic group (P = 0.004; adjusted P = 0.005). When we compared both surgical groups, the endoscopic group has a better endocrinologic outcome (P = 0.020; adjusted P = 0.012). CONCLUSIONS: Our results support endoscopic intranasal transsphenoidal surgery as a treatment of pituitary apoplexy patients, as it probably decreases the need for long-term hormonal replacement.

Lumbar pseudo-tail associated with dermal sinus - A case report.

BACKGROUND: Lumbosacral and coccygeal skin covered appendages are a rare malformation, considered human-tails. CASE REPORT: The authors describe the case of a full term newborn girl with lumbar skin appendage and a normal neurologic examination. The magnetic resonance of the spine revealed a dermal sinus continuous with the skin appendage and with extension into to the spinal canal. Due to the infection risk, a surgery was performed on the third day of life, with dermal sinus ligation and appendage removal. At 12 months of follow-up the girl has a normal neurologic examination. CONCLUSIONS: With the description of this case the authors aim to emphasize that although rare, lumbar skin appendages can be associated with spinal dysraphism and other lesions, requiring extensive work-up and long-term surveillance.

Are mothers always right? When acute meningitis is something more.

A 22-month-old girl with a history of a congenital occipital cutaneous cyst was brought to the paediatric emergency department for lethargy and occipital headache. She had been discharged 5 days before for acute meningitis without bacterial isolates. At physical observation, she presented with irritability and neck hyperextension, with negative meningeal signs. CT scan revealed a vermian cyst and hydrocephalus. She was submitted to neurosurgery with removal of an infected midline dermoid cyst with a fistulous track to the skin. Surgery was successful and without complications. During follow-up, the child was asymptomatic with normal psychomotor development.

Whole-Brain Radiation to Treat a Recurrent Malignant Subdural Effusion.

We report the first case of a recurrent malignant subdural effusion that was treated with whole-brain radiation therapy. A 72-year-old man presented with headaches and de novo left central facial palsy and right upper extremity weakness. His past medical history was remarkable for a prostatic adenocarcinoma diagnosed in 1999 (T4N0M0) with no metastatic disease diagnosed to date. Brain magnetic resonance imaging with gadolinium showed carcinomatous meningitis and a 1.5-cm thick left hemisphere subdural collection causing a mass effect. Left-side frontal and parietal burr holes were created and a clear effusion was successfully drained under high pressure. A biopsy od the dura mater was also taken. Analysis of the effusion showed a protein concentration of 1233 mg/dL. Histopathological examination of the dura matter showed adenocarcinomatous cells. Despite the clinical improvement, serial postoperative computed tomography scans of the head showed massive recurrence of the subdural effusion. The patient was offered radiation therapy as a palliative treatment for effusion control. Whole-brain radiation therapy was performed from day 10 to 17 after surgery at a palliative dose of 20 Gy in 5 fractions. No treatment-associated complications were reported. Thirty days after radiotherapy, the computed tomography scan of the head showed total resolution of the malignant effusion.

Pediatric brain tumors: genetics and clinical outcome.

OBJECT: In this paper the authors' goal was to investigate the genetic characteristics of primary brain tumors in children and determine their influence on clinical outcome. METHODS: The authors performed high-resolution comparative genomic hybridization studies in 14 low-grade and 12 high-grade brain neoplasms in 26 children who underwent surgery between 2005 and 2007. RESULTS: Complex comparative genomic hybridization alterations were observed in 2 (14.3%) of the 14 lowgrade lesions and in 8 (66.6%) of the 12 high-grade lesions. High-level amplifications of DNA were detected in 3 cases, namely in a desmoplastic medulloblastoma where a c-Myc amplification was found. Gains of 1q were detected in 2 low-grade and 6 high-grade lesions that were classified as ependymomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, and gangliogliomas. When the authors correlated genetics with outcome, they noted that among the low-grade neoplasms only the 2 patients who presented with complex comparative genomic hybridization alterations had to undergo reoperation because of recurrent disease. The patient with c-Myc amplification died of progressive disease. Gains of 1q were only observed in tumor cases with progressive disease. CONCLUSIONS: Complex genetic alterations are indicative of a less favorable outcome in low-grade tumors. In these cases, closer follow-up should be pursued. The authors corroborate that c-Myc amplification is a marker of poor prognosis in medulloblastomas. In this study, they were able to verify that a 1q gain correlates with a poor clinical outcome, independent of tumor grade and histological type. The authors propose that it may be considered a common marker of poor prognosis in these neoplasms.

Genetic alterations in a papillary glioneuronal tumor.

Papillary glioneuronal tumors (PGNTs) are rare lesions of the central nervous system, and no information exists on the genetic alterations in these neoplasms. The authors report on such a case in a child. Genetic studies revealed that the tumor was characterized by gains and structural alterations involving only chromosome 7 with breakpoints at 7p22. By using comparative genomic hybridization, the authors observed a high-level amplification region at 7p14~q12. Fluorescence in situ hybridization with a probe for EGFR revealed that this gene was not amplified. Similar to other patients with PGNTs, the patient in the present case fared well. From a genetic point of view the data in the present case are in accordance with previous findings of EGFR amplifications as uncommon in low-grade gliomas and gangliogliomas. Recurrent rearrangements of chromosome 7 have been noted in other mixed glioneuronal tumors. The data in this case suggest that genes located at chromosome 7 can also be involved in the pathogenesis of PGNT. In clinical terms it will be especially important to corroborate, through the analysis of further cases, the involvement of the chromosome 7p22 locus, a region where glial and neuronal linked genes (RAC1 and NXPH1) are known to be located.

Lumbar pseudo-tail associated with dermal sinus - A case report / Pseudocola lumbar asociada a seno dérmico - Caso clínico

Background: Lumbosacral and coccygeal skin covered appendages are a rare malformation, considered human-tails. Case report: The authors describe the case of a full term newborn girl with lumbar skin appendage and a normal neurologic examination. The magnetic resonance of the spine revealed a dermal sinus continuous with the skin appendage and with extension into to the spinal canal. Due to the infection risk, a surgery was performed on the third day of life, with dermal sinus ligation and appendage removal. At 12 months of follow-up the girl has a normal neurologic examination. Conclusions: With the description of this case the authors aim to emphasize that although rare, lumbar skin appendages can be associated with spinal dysraphism and other lesions, requiring extensive work-up and long-term surveillance

Antecedentes: Los apéndices humanos lumbosacros y coccígeos recubiertos de piel son malformaciones raras, consideradas colas humanas. Caso clínico: Describimos el caso de una niña recién nacida a término, con un apéndice cutáneo lumbar y con una exploración neurológica normal. La resonancia magnética lumbosacra demostró un seno dérmico contiguo al apéndice cutáneo con extensión al canal vertebral. Dado el riesgo de infección, fue operada al tercer día de vida realizándose ligación del seno dérmico y resección del apéndice cutáneo. Pasados 12 meses la niña continúa presentando un examen neurológico normal. Conclusiones: Con la descripción de este caso los autores pretenden realzar que, aunque raros, los apéndices cutáneos lumbares suelen asociarse a disrafismos espinales. Precisan, por ello, un estudio exhaustivo y seguimiento a largo plazo