Paulo Linhares

Early pseudoprogression following chemoradiotherapy in glioblastoma patients: The value of RANO evaluation

Introduction. The aim of this study was to determine the frequency of pseudoprogression in a cohort of glioblastoma (GBM) patients following radiotherapy/temozolomide (RT/TMZ) by comparing Macdonald criterial to Response Assessment in Neuro-Oncology (RANO) criteria. The impact on prognosis and survival analysis was also studied. Materials and Methods. All patients receiving RT/TMZ for newly diagnosed GBM from January 2005 to December 2009 were retrospectively evaluated, and demographic, clinical, radiographic, treatment, and survival data were reviewed. Updated RANO criteria were used for the evaluation of the pre-RT and post-RT MRI and compared to classic Macdonald criteria. Survival data was evaluated using the Kaplan-Meier and log-rank analysis. Results and Discussion. 70 patients were available for full radiological response assessment. Early progression was confirmed in 42 patients (60%) according to Macdonald criteria and 15 patients (21%) according to RANO criteria. Pseudoprogression was identified in 10 (23.8%) or 2 (13.3%) patients in Macdonald and RANO groups, respectively. Cumulative survival of pseudoprogression group was higher than that of true progression group and not statistically different from the non-progressive disease group. Conclusion. In this cohort, the frequency of pseudoprogression varied between 13% and 24%, being overdiagnosed by older Macdonald criteria, which emphasizes the importance of RANO criteria and new radiological biomarkers for correct response evaluation.

Impact of EGFR Genetic Variants on Glioma Risk and Patient Outcome

Background: The epidermal growth factor receptor (EGFR) regulates important cellular processes and is frequently implicated in human tumors. Three EGFR polymorphisms have been described as having a transcriptional regulatory function: two single-nucleotide polymorphisms in the essential promoter region, −216G/T and −191C/A, and a polymorphic (CA)n microsatellite sequence in intron 1. We aimed to elucidate the roles of these EGFR polymorphisms in glioma susceptibility and prognosis. Methods: We conducted a case–control study with 196 patients with glioma and 168 cancer-free controls. Unconditional multivariate logistic regression models were used to calculate ORs and 95% confidence intervals. A Cox regression model was used to evaluate associations with patient survival. False-positive report probabilities were also assessed. Results: None of the EGFR −216G/T variants was significantly associated with glioma risk. The −191C/A genotype was associated with higher risk for glioma when the (CA)n alleles were classified as short for ≤16 or ≤17 repeats. Independently of the (CA)n repeat cutoff point used, shorter (CA)n repeat variants were significantly associated with increased risk for glioma, particularly glioblastoma and oligodendroglioma. In all tested models with different (CA)n cutoff points, only −191C/A genotype was consistently associated with improved survival of patients with glioblastoma. Conclusions: Our findings implicate EGFR −191C/A and the (CA)n repeat polymorphisms as risk factors for gliomas, and suggest −191C/A as a prognostic marker in glioblastoma. Impact: Our data support a role of these EGFR polymorphisms in determining glioma susceptibility, with potential relevance for molecularly based stratification of patients with glioblastoma for individualized therapies. Cancer Epidemiol Biomarkers Prev; 20(12); 2610–7. ©2011 AACR.

Suicide Attempts after Subthalamic Nucleus Stimulation for Parkinson’s Disease

A higher risk of suicidal attempt after subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) has been consistently reported. We retrospectively analyzed 3 PD patients with suicide attempts after STN-DBS. All patients had normal pre- and immediate postoperative psychopathological and cognitive evaluations, with STN-DBS yielding a good motor benefit. Levodopa medication was markedly reduced. Albeit there was a significant reduction in dopaminergic medication, there was also a considerable time lag to suicide attempt. Impulsive behavior could have played a higher role, going unnoticed in punctual psychopathological examinations. STN-DBS patients need a closer postoperative psychiatric and behavioral follow-up.

Transient disabling dyskinesias: a predictor of good outcome in subthalamic nucleus deep brain stimulation in Parkinson's disease.

We report 5 of 75 (6.6%) patients with Parkinson’s disease (PD) submitted to subthalamic nucleus deep brain stimulation (STN-DBS) who developed transient disabling dyskinesias immediately after surgery. Dyskinesias persisted despite levodopa withdrawal, cessation or reduction of stimulation, and resolved spontaneously in a maximum period of 12 weeks without the need to change stimulation active contact. Compared to the rest of our PD patients submitted to STN-DBS, the dyskinesia group needed a lower levodopa-equivalent daily dosage (LEDD) over the time of follow-up. A microlesion in the STN, probably concealed in cerebral MRI by the electrode-related artifact, could have been involved in the etiopathology of our patients’ symptoms. The presence of transient disabling dyskinesia in PD patients immediately after STN-DBS might be a predictor of good outcome as measured by a decrease in the LEDD needed.

Immunoglobulin genes implicated in glioma risk

Both genetic and environmental factors are thought to be causal in gliomagenesis. Several genes have been implicated in glioma development, but the putative role of a major immunity-related gene complex member, immunoglobulin heavy chain γ (IGHG) has not been evaluated. Prior observations that IGHG-encoded γ marker (GM) allotypes exhibit differential sensitivity to an immunoevasion strategy of cytomegalovirus, a pathogen implicated as a promoter of gliomagenesis, has lead us to hypothesize that these determinants are risk factors for glioma. To test this hypothesis, we genotyped the IGHG locus comprising the GM alleles, specifically GM alleles 3 and 17, of 120 glioma patients and 133 controls via TaqMan® genotyping assay. To assess the associations between GM genotypes and the risk of glioma, we applied an unconditional multivariate logistic regression analysis adjusted for potential confounding variables. In comparison to subjects who were homozygous for the GM 17 allele, the GM 3 homozygotes were over twice as likely, and the GM 3/17 heterozygotes were over three times as likely, to develop glioma. Similar results were achieved when analyzed by combining the data corresponding to alleles GM 3 and GM 3/17 in a dominant model. The GM 3/17 genotype and the combination of GM 3 and GM 3/17 were found to be further associated with over 3 times increased risk for high-grade astrocytoma (grades III-IV). Allele frequency analyses also showed an increased risk for gliomas and high-grade astrocytoma in association with GM 3. Our findings support the premise that the GM 3 allele may present risk for the development of glioma, possibly by modulating immunity to cytomegalovirus.

Juvenile psammomatoid ossifying fibroma of the orbit and paranasal sinuses. A case report

Juvenile psammomatoid ossifying fibroma (JPOF) is an uncommon benign fibro-osseous lesion predominantly arising in the paranasal sinuses and orbits of children and young adults. We report a case of JPOF involving the paranasal sinuses and orbit in a 15-year-old boy that presented due to progressive proptosis and downward displacement of the left eye. The lesion, first described as fibrous dysplasia (FD), was totally removed surgically, and then proved to be a JPOF, by histopathology. We discuss its differential diagnosis with other fibro-osseous lesions, histopathological features, and treatment options.

Early deep brain stimulation in patients with myoclonus-dystonia syndrome

Myoclonus-dystonia (MD) is a rare movement disorder which is disabling and frequently refractory to medical treatment. Deep brain stimulation (DBS) of the globus pallidus interna (GPi) has been used to treat some patients. Although there is significant motor improvement with DBS, the impact on disability and on quality of life has been infrequently reported. Also, the benefit of the procedure is not established in patients without ε-sarcoglycan gene (SGCE) mutations. We present two patients with severe MD treated with GPi-DBS, one of the patients without a SGCE mutation. Motor improvements (rest/action/total subscores of the Unified Myoclonus Rating Scale and movement subscore of the Burke-Fahn-Marsden Dystonia Rating Scale [BFMRS]) and disability (BFMRS disability subscore) were carefully evaluated preoperatively and at 6 and 12months after surgery. Quality of life (addressed using the Portuguese version of the Medical Outcomes Study 36-item Short-Form General Health Survey, version 2.0 [SF-36v2]) was tested preoperatively and 12months after DBS. At 12-month follow-up, myoclonus improved 78.6% in Patient 1 and 80.7% in Patient 2, while dystonia improved 37% and 86.7%, respectively. Improvements in disability ranged from 71.4% to 75%. With regard to quality of life, all parameters addressed by the SF-36v2 improved or stabilized in both patients. No major adverse effects were noticed. Improvements in motor symptoms are consistent with reports in the literature and were obtained regardless of the identification of a SGCE gene mutation. There were also significant benefits on disability and quality of life. DBS should be considered for MD.

Ossifying Fibromas of the Craniofacial Skeleton

Ossifying fibromas (OF) of the craniofacial skeleton, as described in WHO classification of odontogenic tumors (2005)(Barnes L 2005), are benign fibro-osseous neoplasms characterized by the replacement of normal bone by a fibrous cellular stroma containing foci of mineralized bone trabeculae and cementum-like material that vary in amount and appearance.(Brannon and Fowler 2001; El-Mofty 2002; Cruz, Alencar et al. 2008) The accurate nature and classification of OF has undergone considerable debate among pathologists, resulting in a confusing evolution of competing nomenclatures.(Brannon and Fowler 2001; Sarode, Sarode et al. 2011) Contemporary reviews have classified benign fibroosseous lesions of the craniofacial complex into neoplasms, developmental dysplastic lesions and inflammatory/reactive processes. [Table 1](Eversole, Su et al. 2008) In this reviews, subtypes vary with regard to behavior and propensity for recurrence after surgical excision. The definitive diagnosis can rarely be rendered on the basis of histopathological features alone and is usually dependent upon assessment of microscopic, clinical and imaging features together. This review will discuss the clinical, microscopic, radiological and therapeutic aspects of ossifying fibromas in this localization.

Twiddler (or Not) Syndrome: Questioning etiology for an uncommon form of hardware malfunction in deep brain stimulation.

Background: Hardware failure or malfunction after deep brain stimulation is an infrequent but costly occurrence with currently available systems. Case Description: The authors present the case of a 65-year-old female patient with predominantly tremoric Parkinsons disease who, 4 months after bilateral subthalamic nucleus stimulation with very good clinical results, began to display signs of recurrent disease and an increasingly smaller response to stimulation. Radiological studies, changes in electrode impedance and surgical findings and results established the diagnosis of Twiddler syndrome. Close patient follow-up, lack of a psychiatric history and physical examination findings were, however, contrary to the previously described causative mechanism. Conclusion: The clinical and radiological setup of Twiddler syndrome must be readily recognized. Its causative mechanism should remain under discussion, and intraoperative technical details may help to explain its occurrence.

Role of 99mTc-Sulesomab Immunoscintigraphy in the Management of Infection following Deep Brain Stimulation Surgery

Infection constitutes a serious adverse event in patients submitted to deep brain stimulation, often leading to removal of the device. We set to evaluate the potential role of immunoscintigraphy with 99mTc-labelled antigranulocyte antibody fragments (99mTc-sulesomab) in the management of infection following DBS. 99mTc-sulesomab immunoscintigraphy seems to correlate well with the presence and extent of infection, thus contributing to differentiate between patients who should remove the hardware entirely at presentation and those who could undergo a more conservative approach. Also, 99mTc-sulesomab immunoscintigraphy has a role in determining the most appropriate timing for reimplantation. Finally, we propose an algorithm for the management of infection following DBS surgery, based on the results of the 99mTc-sulesomab immunoscintigraphy.