Martin Smrčka

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality

PURPOSE NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

Lateral supraorbital approach as an alternative to the classical pterional approach

OBJECTIVE The standard pterional approach has been used to approach aneurysms of the anterior circulation and the basilar tip, suprasellar tumors, cavernous lesions. The senior author (JH) established a lateral supraorbital approach as an alternative to the pterional approach after continuous trial and error. We describe the techniques of this approach based on clinical experiences. METHODS The lateral supraorbital approach is more subfrontal and anterior than the pterional approach. This approach has been regularly used by the senior author (JH) in the last decade in more than 2000 operations for mostly aneurysms of anterior circulation, but also for tumors of the anterior fossa and parasellar area as well as the sphenoid wing area. RESULTS This approach can be used to operate on most cases, in which the classical pterional approach would be used. There are almost no craniotomy-related complications with this approach. This approach is not suitable in certain lesions which need to be exposed from a more temporal perspective. CONCLUSION This approach is simpler, faster, safer and less invasive than the classical pterional approach.

MiR-195, miR-196b, miR-181c, miR-21 expression levels and O-6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients

Glioblastoma multiforme (GBM) is the most frequently occurring primary malignant brain tumor; patients with GBM often have a very poor prognosis and differing responses to treatment. Therefore, it is very important to find new biomarkers that can predict clinical outcomes and help in treatment decisions. MicroRNAs are small, non‐coding RNAs that function as post‐transcriptional regulators of gene expression and play a key role in the pathogenesis of GBM. In a group of 38 patients with primary GBM, we analyzed the expression of eight microRNAs (miR‐21, miR‐128a, miR‐181c, miR‐195, miR‐196a, miR‐196b, miR‐221, and miR‐222). In addition, we examined the methylation status of O‐6‐methylguanine‐DNA methyltransferase (MGMT) promoter by high‐resolution melting analysis, as this has been shown to be a predictive marker in GBM. MGMT methylation status correlated with progression‐free survival (P = 0.0201; log–rank test) as well as with overall survival (P = 0.0054; log–rank test). MiR‐195 (P = 0.0124; log–rank test) and miR‐196b (P = 0.0492; log–rank test) positively correlated with overall survival. Evaluation of miR‐181c in combination with miR‐21 predicted time to progression within 6 months of diagnosis with 92% sensitivity and 81% specificity (P < 0.0001). Our data confirmed that the methylation status of MGMT but also miR‐21, miR‐181c, miR‐195, and miR‐196b to be associated with survival of GBM patients. Above all, we suggest that the combination of miR‐181c and miR‐21 could be a very sensitive and specific test to identify patients at high risk of early progression after surgery. (Cancer Sci 2011; 102: 2186–2190)

Mild hypothermia therapy for patients with severe brain injury.

The authors present a group of patients with severe head injuries in which deliberate mild hypothermia was carried out together with the standard treatment protocol according to the European Brain Injury Consortium. Thirty patients with severe head injuries with Glasgow Coma Scale (GCS) score of 3-8 were enrolled into the study. The subjects were divided into two groups. The average age in the hypothermic group of 15 patients was 35 years. The average GCS was 4.5 at the site of accident. Eight patients (53%) sustained associated severe injuries of other organs. The average age of the 15 patients in the normothermic control group was 39 years with an average GCS of 4.3. All the patients in the normothermic group and 11 patients in the hypothermic group underwent neurosurgery, five of them also decompressive craniotomy. Artificial ventilation with continuous monitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP), arterial blood pressure, jugular bulb oximetry and urinary bladder temperature were instituted in the ICU. Cooling to a core temperature of 34 degrees C in the hypothermic group was achieved by forced air cooling in combination with circulating-water mattress cooling (Blanketrol II, Cincinnati Sub-Zero) and maintained for 72 h. The difference in the Glasgow Outcome Scale (GOS) between the hypothermic and normothermic groups of patients after 6 months was not statistically significant (P value 0.0843). In the hypothermic group, however, good neurological outcome (GOS 4 and 5) was reached in 13 patients (87%), which represents a 40% increase compared with the normothermic control group in which good neurological outcome was reached in 7 patients (47%). Mean normothermia ICP value of 18+/-2 mmHg was significantly (P value 0.0007) reduced during mild hypothermia therapy to 12+/-2 mmHg. Mean normothermia CPP value of 72+/-3 mmHg significantly increased (P value 0.0007) during this time to 80+/-4 mmHg with unchanged systolic arterial pressure (P value 0.9013). There were no cardiac or coagulopathy-related complications. Our results showed that mild therapeutic hypothermia could be useful in improving the outcome and neurological recovery in patients with severe head injuries.

Expression of immune-modulatory molecules HLA-G and HLA-E by tumor cells in glioblastomas: An unexpected prognostic significance?

The role of nonclassical human leukocyte antigens G and E (HLA‐G and HLA‐E) was originally thought to be restricted to the protection of the fetus from a maternal allorecognition. Now it is known that HLA‐G and HLA‐E exert multiple immunoregulatory functions. A prognostic significance of the expression of HLA‐G and HLA‐E by neoplastic cells in glioblastoma is not well characterized. In this study, we evaluated the expression of HLA‐G and HLA‐E by neoplastic cells in 39 cases of glioblastoma. We found the production of HLA‐G and HLA in a majority of cases. There was an unexpected positive correlation between the expression of HLA‐E and length of survival. We speculate that the expression of this molecule by neoplastic cells may represent a coincidental selective pro‐host advantage related to better response to subsequent therapeutic modalities. Mechanisms of glioblastoma cell pathophysiology and mechanisms of responses to therapeutic interventions in respect to the expression of these molecules deserves further study.

The influence of mild hypothermia on ICP, CPP and outcome in patients with primary and secondary brain injury

Aim of this study was to examine the hypothesis that only a subgroup of patients with lesser primary brain damage after severe head injury may benefit from therapeutic hypothermia. We prospectively analysed 72 patients with severe head injury, randomized into groups with (n = 37) and without (n = 35) hypothermia of 34 degrees C maintained for 72 hours. The influence of hypothermia on ICP, CPP and neurological outcome was analysed in the context of the extent of primary brain damage. Patients with normothermia and primary lesions (n = 17) values: GCS on admission 5 (median), ICP 18.9 (mean), CPP 73 (mean), GOS 4 (median). Patients with normothermia and extracerebral hematomas (n = 20): GCS 4, ICP 16, CPP 71, GOS 3. Patients with hypothermia and primary lesions (n = 21): GCS 4,62, ICP 10, 81, CPP 78,1, GOS 4. Patients with hypothermia and extracerebral hematomas (n = 14): GCS 5, ICP 13.2, CPP 78, GOS 5. Hypothermia decreased ICP and increased CPP regardless of the type of brain injury. Hypothermia was not able to improve outcome in patients with primary brain lesions but this pilot study suggests that it significantly improves outcome in patients with extracerebral hematomas.

Prevalence of Propionibacterium acnes in Intervertebral Discs of Patients Undergoing Lumbar Microdiscectomy: A Prospective Cross-Sectional Study

Background The relationship between intervertebral disc degeneration and chronic infection by Propionibacterium acnes is controversial with contradictory evidence available in the literature. Previous studies investigating these relationships were under-powered and fraught with methodical differences; moreover, they have not taken into consideration P. acnes’ ability to form biofilms or attempted to quantitate the bioburden with regard to determining bacterial counts/genome equivalents as criteria to differentiate true infection from contamination. The aim of this prospective cross-sectional study was to determine the prevalence of P. acnes in patients undergoing lumbar disc microdiscectomy. Methods and Findings The sample consisted of 290 adult patients undergoing lumbar microdiscectomy for symptomatic lumbar disc herniation. An intraoperative biopsy and pre-operative clinical data were taken in all cases. One biopsy fragment was homogenized and used for quantitative anaerobic culture and a second was frozen and used for real-time PCR-based quantification of P. acnes genomes. P. acnes was identified in 115 cases (40%), coagulase-negative staphylococci in 31 cases (11%) and alpha-hemolytic streptococci in 8 cases (3%). P. acnes counts ranged from 100 to 9000 CFU/ml with a median of 400 CFU/ml. The prevalence of intervertebral discs with abundant P. acnes (≥ 1x103 CFU/ml) was 11% (39 cases). There was significant correlation between the bacterial counts obtained by culture and the number of P. acnes genomes detected by real-time PCR (r = 0.4363, p<0.0001). Conclusions In a large series of patients, the prevalence of discs with abundant P. acnes was 11%. We believe, disc tissue homogenization releases P. acnes from the biofilm so that they can then potentially be cultured, reducing the rate of false-negative cultures. Further, quantification study revealing significant bioburden based on both culture and real-time PCR minimize the likelihood that observed findings are due to contamination and supports the hypothesis P. acnes acts as a pathogen in these cases of degenerative disc disease.

Lumbar Disc Surgery in Regional Anaesthesia – 40 years of Experience

Summary Lumbar disc operations have been performed in Brno since 1952 and from the very beginning they are performed under regional anaesthesia. Since 1965 until 1999 about 16000 operations for herniated discs have been performed here. The number of operations doubled with the foundation of the second neurosurgical department in Brno in 1992. Lumbar disc surgery represents 25% of the operation spectrum in our department. Epidural anaesthesia is advantageous for less risk of some complications compared with general anaesthesia and enables communication between the surgeon and the patient. Other advantages are: less visible bleeding in the operative field due to the lateral position and the fact that the surgeon can sit during the operation. On a long-term basis we found 4–5% had further surgery for reccurent problems. Objective neurological evaluation 6 weeks after the operation showed improvement in 92% of patients. The patients themselves consider their status as very good or satisfactory in 82% (median 3 years after the operation). Besides a correctly performed operation we emphesize also the role of correct diagnosis (good correlation between the patients problems and CT scan finding) for a good treatment result.

Risk Score based on microRNA expression signature is independent prognostic classifier of glioblastoma patients

Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. The prognosis of GBM patients varies considerably and the histopathological examination is not sufficient for individual risk estimation. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression and were repeatedly proved to play important roles in pathogenesis of GBM. In our study, we performed global miRNA expression profiling of 58 glioblastoma tissue samples obtained during surgical resections and 10 non-tumor brain tissues. The subsequent analysis revealed 28 significantly deregulated miRNAs in GBM tissue, which were able to precisely classify all examined samples. Correlation with clinical data led to identification of six-miRNA signature significantly associated with progression free survival [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.33-2.94, P < 0.001] and overa+ll survival (HR 2.86, 95% CI 1.91-4.29, P < 0.001). O(6)-methylguanine-DNA methyltransferase methylation status was evaluated as reference method and Risk Score based on six-miRNA signature indicated significant superiority in prediction of clinical outcome in GBM patients. Multivariate Cox analysis indicated that the Risk Score based on six-miRNA signature is an independent prognostic classifier of GBM patients. We suggest that the Risk Score presents promising prognostic algorithm with potential for individualized treatment decisions in clinical management of GBM patients.

Propionibacterium acnes biofilm is present in intervertebral discs of patients undergoing microdiscectomy.

Background In previous studies, Propionibacterium acnes was cultured from intervertebral disc tissue of ~25% of patients undergoing microdiscectomy, suggesting a possible link between chronic bacterial infection and disc degeneration. However, given the prominence of P. acnes as a skin commensal, such analyses often struggled to exclude the alternate possibility that these organisms represent perioperative microbiologic contamination. This investigation seeks to validate P. acnes prevalence in resected disc cultures, while providing microscopic evidence of P. acnes biofilm in the intervertebral discs. Methods Specimens from 368 patients undergoing microdiscectomy for disc herniation were divided into several fragments, one being homogenized, subjected to quantitative anaerobic culture, and assessed for bacterial growth, and a second fragment frozen for additional analyses. Colonies were identified by MALDI-TOF mass spectrometry and P. acnes phylotyping was conducted by multiplex PCR. For a sub-set of specimens, bacteria localization within the disc was assessed by microscopy using confocal laser scanning and FISH. Results Bacteria were cultured from 162 discs (44%), including 119 cases (32.3%) with P. acnes. In 89 cases, P. acnes was cultured exclusively; in 30 cases, it was isolated in combination with other bacteria (primarily coagulase-negative Staphylococcus spp.) Among positive specimens, the median P. acnes bacterial burden was 350 CFU/g (12 - ~20,000 CFU/g). Thirty-eight P. acnes isolates were subjected to molecular sub-typing, identifying 4 of 6 defined phylogroups: IA1, IB, IC, and II. Eight culture-positive specimens were evaluated by fluorescence microscopy and revealed P. acnes in situ. Notably, these bacteria demonstrated a biofilm distribution within the disc matrix. P. acnes bacteria were more prevalent in males than females (39% vs. 23%, p = 0.0013). Conclusions This study confirms that P. acnes is prevalent in herniated disc tissue. Moreover, it provides the first visual evidence of P. acnes biofilms within such specimens, consistent with infection rather than microbiologic contamination.