MGMT promoter methylation in gliomas-assessment by pyrosequencing and quantitative methylation-specific PCR

Background Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is a favorable prognostic factor in glioblastoma patients. However, reported methylation frequencies vary significantly partly due to lack of consensus in the choice of analytical method. Method We examined 35 low- and 99 high-grade gliomas using quantitative methylation specific PCR (qMSP) and pyrosequencing. Gene expression level of MGMT was analyzed by RT-PCR. Results When examined by qMSP, 26% of low-grade and 37% of high-grade gliomas were found to be methylated, whereas 97% of low-grade and 55% of high-grade gliomas were found methylated by pyrosequencing. The average MGMT gene expression level was significantly lower in the group of patients with a methylated promoter independent of method used for methylation detection. Primary glioblastoma patients with a methylated MGMT promoter (as evaluated by both methylation detection methods) had approximately 5 months longer median survival compared to patients with an unmethylated promoter (log-rank test; pyrosequencing P = .02, qMSP P = .06). One third of the analyzed samples had conflicting methylation results when comparing the data from the qMSP and pyrosequencing. The overall survival analysis shows that these patients have an intermediate prognosis between the groups with concordant MGMT promoter methylation results when comparing the two methods. Conclusion In our opinion, MGMT promoter methylation analysis gives sufficient prognostic information to merit its inclusion in the standard management of patients with high-grade gliomas, and in this study pyrosequencing came across as the better analytical method

Filling the gap between the OR and virtual simulation : a European study on a basic neurosurgical procedure

Aki Laakso tutkimusryhmän jäsenenä.Currently available simulators are supposed to allow young neurosurgeons to hone their technical skills in a safe environment, without causing any unnecessary harm to their patients caused by their inexperience. For this training method to be largely accepted in neurosurgery, it is necessary to prove simulation efficacy by means of large-scale clinical validation studies. We correlated and analysed the performance at a simulator and the actual operative skills of different neurosurgeons (construct validity). We conducted a study involving 92 residents and attending neurosurgeons from different European Centres; each participant had to perform a virtual task, namely the placement of an external ventricular drain (EVD) at a neurosurgical simulator (ImmersiveTouch). The number of attempts needed to reach the ventricles and the accuracy in positioning the catheter were assessed. Data suggests a positive correlation between subjects who placed more EVDs in the previous year and those who get better scores at the simulator (p = .008) (fewer attempts and better surgical accuracy). The number of attempts to reach the ventricle was also analysed; senior residents needed fewer attempts (mean = 2.26; SD = 1.11) than junior residents (mean = 3.12; SD = 1.05) (p = .007) and staff neurosurgeons (mean = 2.89, SD = 1.23). Scoring results were compared by using the Fisher's test, for the analysis of the variances, and the Student's T test. Surprisingly, having a wider surgical experience overall does not correlate with the best performance at the simulator. The performance of an EVD placement on a simulator correlates with the density of the neurosurgical experience for that specific task performed in the OR, suggesting that simulators are able to differentiate neurosurgeons according to their surgical ability. Namely this suggests that the simulation performance reflects the surgeons' consistency in placing EVDs in the last year.Peer reviewe

The impact of surgical simulation on patient outcomes: a systematic review and meta-analysis

The use of simulation in surgical training is ever growing. Evidence suggests such training may have beneficial clinically relevant effects. The objective of this research is to investigate the effects of surgical simulation training on clinically relevant patient outcomes by evaluating randomized controlled trials (RCT). PubMed was searched using PRISMA guidelines: “surgery” [All Fields] AND “simulation” [All Fields] AND “patient outcome” [All Fields]. Of 119 papers identified, 100 were excluded for various reasons. Meta-analyses were conducted using the inverse-variance random-effects method. Nineteen papers were reviewed using the CASP RCT Checklist. Sixteen studies looked at surgical training, two studies assessed patient-specific simulator practice, and one paper focused on warming-up on a simulator before performing surgery. Median study population size was 22 (range 3–73). Most articles reported outcome measures such as post-intervention Global Rating Scale (GRS) score and/or operative time. On average, the intervention group scored 0.42 (95% confidence interval 0.12 to 0.71, P = 0.005) points higher on a standardized GRS scale of 1–10. On average, the intervention group was 44% (1% to 87%, P = 0.04) faster than the control group. Four papers assessed the impact of simulation training on patient outcomes, with only one finding a significant effect. We found a significant effect of simulation training on operative performance as assessed by GRS, albeit a small one, as well as a significant reduction to operative time. However, there is to date scant evidence from RCTs to suggest a significant effect of surgical simulation training on patient outcomes

Predictors of survival in subtotally resected who grade i skull base meningiomas

Background: Although gross total resection (GTR) is the goal in meningioma surgery, this can sometimes be difficult to achieve in skull base meningiomas. We analyzed clinical outcomes and predictors of survival for subtotally resected benign meningiomas. Methods: A total of 212 consecutive patients who underwent subtotal resection (STR) for benign skull base meningioma between 1990–2010 were investigated. Results: Median age was 57.7 [IQR 18.8] years, median preoperative Karnofsky performance status (KPS) was 80.0 [IQR 20.0], 75 patients (35.4%) had posterior fossa meningioma. After a median follow-up of 6.2 [IQR 7.9] years, retreatment (either radiotherapy or repeated surgery) rate was 16% at 1-year, 27% at 3-years, 34% at 5-years, and 38% at 10-years. Ten patients (4.7%) died perioperatively, 9 (3.5%) had postoperative hematomas, and 2 (0.8%) had postoperative infections. Neurological outcome at final visit was improved/stable in 122 patients (70%). Multivariable analysis identified advanced age and preoperative KPS < 70 as negative predictors for overall survival (OS). Patients who underwent retreatment had no significant reduction of OS. Conclusions: Advanced age and preoperative KPS were independent predictors of OS. Retreatments did not prolong nor shorten the OS. Clinical outcomes in STR skull base meningiomas were generally worse compared to cohorts with high rates of GTR

Craniofacial resection of malignant tumors of the anterior skull base: a case series and a systematic review

Background: Craniofacial resection (CFR) is still considered as the gold standard for managing sinonasal malignancies of the anterior skull base (ASB), while endoscopic approaches are gaining credibility. The goal of this study was to evaluate outcomes of patients who underwent CFR at our institution and to compare our results to international literature. Method: Retrospective analysis of all patients undergoing CFR between 1995 and 2017, and systematic literature review according to the PRISMA statement. Results: 41 patients with sinonasal malignancy (81% with stage T4) of the ASB were included. There was no operative mortality. Complications were observed in 9 cases. We obtained 100% follow-up with mean observation 100 months. Disease-specific survival rates were 90%, 74% and 62% and recurrence-free survival was 85% at two, 72% at five and ten years follow-up, respectively. CFR as primary treatment, en bloc resection, and resection with negative margins correlated to better survival. Recursive partition analysis identified the latter as the most important prognostic factor, regardless surgical technique. The relative risk of non-radicality was significantly higher after piecemeal resection compared to en bloc resection. Compared to 15 original articles, totaling 2603 patients, eligible for review, the present study has the longest follow-up time, the second highest 5-year OS and the third highest 5-year DSS, despite having a higher proportion of patients with high-stage disease. Conclusion: CFR in true en bloc fashion can still be considered as the treatment of choice in cases of advanced-stage sinonasal malignancies invading the ASB

Efficacy of the Nordic and the MSKCC chemotherapy protocols on the overall and progression-free survival in intracranial PCNSL

Background: To compare the Nordic and the Memorial Sloan-Kettering Cancer Center (MSKCC) chemotherapy protocols for Overall Survival (OS) and Progression-Free Survival (PFS) for intracranial primary CNS lymphoma (PCNSL). Methods: A prospective database at Oslo University Hospital of PCNSL was reviewed over a 12-year period (2003–2014). Results: Overall, 79 patients with PCNSL were identified, of whom 57 received chemotherapy. MSKCC with Rituximab (RTX) was used in 18 patients (32%) who had median OS of 46.3 months [9.8–131.9] and median PFS of 34.6 months [6.4–131.9]. The Nordic protocol was used in 14 patients (25%) who had median OS of 30.9 months [2.7–106.3] and PFS of 14.3 months [0.0–106.3]. The MSKCC was used without RTX in 25 patients (44%) who had OS of 15.2 months [0.7–136.5] and PFS of 12.0 months [0.0–117.0]. MSKCC with RTX had a significantly longer median OS (p < 0.05) compared to the other regimens in univariate analysis. In multivariate analysis, the only prognostic factor for OS and PFS of significance was deep brain involvement (p < 0.005). Conclusions: In univariate analysis, the MSKCC with RTX achieved significantly longer median OS compared to the Nordic protocol. However, in multivariate analysis, the only prognostic factor for survival of statistical significance was deep brain involvement

Treatment of Sinonasal Adenocarcinoma: A Population-Based Prospective Cohort Study

Objectives Sinonasal adenocarcinoma (AC) is a potentially curable disease despite being an aggressive malignancy. Long-term survival can be achieved with early diagnosis and adequate multidisciplinary treatment. Our goal was to evaluate outcomes for patients with AC treated at our institution. Design In a population-based consecutive prospective cohort, we conducted an analysis of all patients treated for surface epithelial AC between 1995 and 2018. Results Twenty patients were included, and follow-up was 100%. The mean follow-up time was 89 months for the entire cohort (112 months for patients with no evidence of disease). Intestinal-type AC was found in 65%, whereas nonintestinal-type AC was found in 35% of all cases; 75% had stage T3/4 disease. Tumor grade was intermediate/high in 65%. Eighteen patients underwent treatment with curative intent (craniofacial resection [CFR] in 61%, transfacial approach in 39%, adjuvant radiotherapy in 89%), achieving negative margins in 56% of cases. Overall survival (OS) rates were 90, 68, and 54% after 2, 5, and 10 years of follow-up, respectively, and the corresponding disease-specific survival (DSS) rates were 90, 73, and 58%. Age over 60 years, tumor with a maxillary origin, and microscopic bone invasion were negative prognostic factors. Radical CFR was correlated with better OS and DSS. Conclusion The high probability of achieving radicality with CFR, the low complication rate, the acceptable toxicity of modern irradiation modalities, and the promising survival rates indicate that this strategy might be considered a safe and an effective option for treating patients with very advanced sinonasal AC

Evaluation of Memorial Sloan-Kettering Cancer Center and International Extranodal Lymphoma Study Group prognostic scoring systems to predict Overall Survival in intracranial Primary CNS lymphoma

Objectives: To evaluate the validity of Memorial Sloan‐Kettering Cancer Center (MSKCC) and International Extranodal Lymphoma Study Group (IELSG) prognostic scoring systems for Overall Survival (OS) in intracranial Primary CNS lymphoma (PCNSL) of all patients diagnosed at a single center. Material and Methods: Pretreatment clinical factors including tumor characteristics and histology, treatment, and survival of PCNSL patients with diagnostic biopsies over a 12‐year period (2003–2014) were retrieved from a prospective database at Oslo University Hospital. Results: Seventy-nine patients with intracranial PCNSL were identified. The female:male ratio was 1:1.63 and the median age was 65.3 years [range 18.9–80.7]. Involvement of deep brain structures was shown in 63 patients. Six patients were MSKCC risk group 1, 35 patients were in risk group 2, and 38 patients were in risk group 3. International Extranodal Lymphoma Study Group scores were <2 in 17 patients (22%). After a median follow‐up of 70.5 months, 55 patients were dead. Median OS was 16.4 months [range 0.2–157.7]. Age, sLDH by recursive partitioning analysis (RPA), Eastern Cooperative Oncology Group score (ECOG), lesion size, involvement of deep brain structures, IELSG score, and MSKCC score were significant factors for OS in univariate analysis. Multivariate analysis confirmed the significance of age (p < .05), sLDH by RPA (p < .005), ECOG (p < .05), and deep brain structure involvement (p < .05) for OS. The six‐tiered IELSG scores had to be dichotomized according to RPA analysis into <2 and ≥2 in order to have prognostic value. In contrast, when using the three‐tiered MSKCC, three distinct risk groups were identified. Conclusions: Our study failed to verify the IELSG, but validated the use of MSKCC for prognostication of OS in intracranial PCNSL

The effect of tumor removal via craniotomies on preoperative hydrocephalus in adult patients with intracranial tumors

The efficacy of tumor removal via craniotomies on preoperative hydrocephalus (HC) in adult patients with intracranial tumors is largely unknown. Therefore, we sought to evaluate the effect of tumor resection in patients with preoperative HC and identify the incidence and risk factors for postoperative VP shunt dependency. All craniotomies for intracranial tumors at Oslo University Hospital in patients ≥ 18 years old during a 10-year period (2004–2013) were reviewed. Patients with radiologically confirmed HC requiring surgery and subsequent development of shunt dependency were identified by cross-linking our prospectively collected tumor database to surgical procedure codes for hydrocephalus treatment (AAF). Patients with preexisting ventriculoperitoneal (VP) shunts (N = 41) were excluded. From 4774 craniotomies performed on 4204 patients, a total of 373 patients (7.8%) with HC preoperatively were identified. Median age was 54.4 years (range 18.1–83.9 years). None were lost to follow-up. Of these, 10.5% (39/373) required permanent CSF shunting due to persisting postoperative HC. The risk of becoming VP shunt dependent in patients with preexisting HC was 7.0% (26/373) within 30 days and 8.9% (33/373) within 90 days. Only secondary (repeat) surgery was a significant risk factor for VP shunt dependency. In this large, contemporary, single-institution consecutive series, 10.5% of intracranial tumor patients with preoperative HC became shunt-dependent post-craniotomy, yielding a surgical cure rate for HC of 89.5%. To the best of our knowledge, this is the first and largest study regarding postoperative shunt dependency after craniotomies for intracranial tumors, and can serve as benchmark for future studies

The role of adjuvant treatment in craniofacial malignancy: A critical review

Background: Tumors originating from the craniofacial region usually present in a locally advanced stage with frequent involvement of adjacent sites and have a strong tendency for local recurrence in the absence of adjuvant therapy, even when the original surgical resection was presumed to be radical. In the past decades, several advances in the radiological diagnosis and treatment of craniofacial malignancies have been introduced. There are, however, no randomized trials that define the optimal multimodal treatment of these tumors because of their rarity as well as heterogeneity in both histology and site of origin. The aim of this study was to conduct a critical review of the role of adjuvant therapy in the treatment of craniofacial malignancy. Method: We conducted a critical review of the past and contemporary literature available, focusing on adjuvant oncological treatments of the most common craniofacial malignancies. Results: Preoperative radiotherapy can have a documented role in the treatment of olfactory neuroblastoma and soft tissue sarcoma, while preoperative chemotherapy can be advocated in the treatment of sinonasal undifferentiated carcinoma, neuroendocrine carcinoma, olfactory neuroblastoma, and craniofacial sarcoma (both soft-tissue and high-grade osteosarcoma). Postoperative radiotherapy has a well-established role in the treatment of most craniofacial malignancies. The role of postoperative chemotherapy is unclear in most histologies, but is commonly used during the treatment of well-selected cases of paranasal sinus carcinoma, olfactory neuroblastoma, mucosal melanoma, soft tissue sarcoma and high-grade craniofacial osteosarcoma. Discussion: Alongside developments in surgery, there have also been improvements in diagnostics, radiotherapy, and chemotherapy. Implementation of novel radiation techniques allows delivery of higher radiation doses while minimizing irradiation-related morbidity. Better understanding of tumor biology allows the construction of more complex treatment strategies, incorporating adjuvant chemotherapy either pre- or postoperatively. In the era of personalized targeted therapy, rapid strides are being made to identify specific tumor-targets for use of novel biologic agents, with the potential to change current management paradigms