Guidelines for Neuroprognostication in Critically Ill Adults with Intracerebral Hemorrhage.

BACKGROUND: The objective of this document is to provide recommendations on the formal reliability of major clinical predictors often associated with intracerebral hemorrhage (ICH) neuroprognostication. METHODS: A narrative systematic review was completed using the Grading of Recommendations Assessment, Development, and Evaluation methodology and the Population, Intervention, Comparator, Outcome, Timing, Setting questions. Predictors, which included both individual clinical variables and prediction models, were selected based on clinical relevance and attention in the literature. Following construction of the evidence profile and summary of findings, recommendations were based on Grading of Recommendations Assessment, Development, and Evaluation criteria. Good practice statements addressed essential principles of neuroprognostication that could not be framed in the Population, Intervention, Comparator, Outcome, Timing, Setting format. RESULTS: Six candidate clinical variables and two clinical grading scales (the original ICH score and maximally treated ICH score) were selected for recommendation creation. A total of 347 articles out of 10,751 articles screened met our eligibility criteria. Consensus statements of good practice included deferring neuroprognostication-aside from the most clinically devastated patients-for at least the first 48-72 h of intensive care unit admission; understanding what outcomes would have been most valued by the patient; and counseling of patients and surrogates whose ultimate neurological recovery may occur over a variable period of time. Although many clinical variables and grading scales are associated with ICH poor outcome, no clinical variable alone or sole clinical grading scale was suggested by the panel as currently being reliable by itself for use in counseling patients with ICH and their surrogates, regarding functional outcome at 3 months and beyond or 30-day mortality. CONCLUSIONS: These guidelines provide recommendations on the formal reliability of predictors of poor outcome in the context of counseling patients with ICH and surrogates and suggest broad principles of neuroprognostication. Clinicians formulating their judgments of prognosis for patients with ICH should avoid anchoring bias based solely on any one clinical variable or published clinical grading scale.

Perioperative external ventricular drainage vs. no-EVD strategy in pediatric posterior fossa tumors-pilot study results.

INTRODUCTION: Pediatric brain tumors of the posterior fossa often present with occlusive hydrocephalus. Endoscopic third ventriculostomy (ETV) or ventriculoperitoneal shunting (VPS) has been established for definite hydrocephalus treatment. The aim of the study was to analyze the impact and safety of perioperative temporary external ventricular CSF drainage (EVD) placement on postoperative hydrocephalus outcome compared to a no-EVD strategy. PATIENTS AND METHODS: In a prospective database, 36 posterior fossa tumor patients of 2-18 years were included with a follow-up of 1 year. Fifty-eight percent presented with preoperative hydrocephalus. Patients were assigned to non-hydrocephalus group: group I (n = 15) and to preoperative hydrocephalus, group IIa with EVD placement (n = 9), and group IIb without EVD (n = 12). RESULTS: Median age of patients was 8.1 years (range 3.17 to 16.58 years). One-third of 21 hydrocephalus patients required ETV or VPS (n = 7). Occurrence of de novo hydrocephalus in group I after surgery was not observed in our cohort. Age and histology were no confounding factor for EVD placement between group IIa and IIb (p = 0.34). The use of EVD did not result in better control of hydrocephalus compared to no-EVD patients considering pre- and postoperative MRI ventricular indices (p = 0.4). Perioperative placement of an EVD resulted in a threefold risk for subsequent VPS or ETV (group IIa 55.5% vs group IIb 16.6%): relative risk for EVD patients compared to no-EVD patients with hydrocephalus was 3.3 (CI = 1.06-13.43, p = 0.09). CONCLUSION: Perioperative EVD placement appears to harbor a threefold relative risk of requiring subsequent permanent CSF diversion in children above 2 years. EVD was not more effective to control ventricular enlargement compared to tumor removal alone. The no-EVD strategy was safe and did not result in postoperative complications. Thus, to evaluate potential adverse effects on hydrocephalus outcome by EVD placement, a prospective study is warranted to falsify the results.

Trimethylamine N-oxide (TMAO) in patients with subarachnoid hemorrhage: a prospective observational study.

BACKGROUND: It is suspected that microbiome-derived trimethylamine N-oxide (TMAO) may enhance platelet responsiveness and accordingly be thrombophilic. The purpose of this prospective observational study is to evaluate TMAO in patients with subarachnoid hemorrhage (SAH) and compare it with a control group. A secondary aim was to investigate TMAO in the cerebrospinal fluid (CSF) from SAH patients. This should provide a better understanding of the role of TMAO in the pathogenesis of SAH and its thrombotic complications. METHODS: The study included patients with diagnosed spontaneous SAH recruited after initial treatment on admission and patients with nerve, nerve root, or plexus disorders serving as controls. Blood samples were gathered from all patients at recruitment. Additionally, sampling of SAH patients in the intensive care unit continued daily for 14 days. The CSF was collected out of existing external ventricular drains whenever possible. RESULTS: Thirty-four patients diagnosed with SAH, and 108 control patients participated in this study. Plasma TMAO levels at baseline were significantly lower in the SAH group (1.7 µmol/L) compared to the control group (2.9 µmol/L). TMAO was detectable in the CSF (0.4 µmol/L) and significantly lower than in plasma samples of the SAH group at baseline. Plasma and CSF TMAO levels correlated positively. The TMAO levels did not differ significantly during the observation period of 15 days. CONCLUSIONS: Although we assumed that patients with higher TMAO levels were at higher risk for SAH a priori, plasma TMAO levels were lower in patients with SAH compared with control subjects with nerve, nerve root, or plexus disorders on admission to the hospital. A characteristic pattern of plasma TMAO levels in patients with SAH was not found.

The impact of neurological performance and volumetrics on overall survival in brain metastasis in colorectal cancer: a retrospective single-center case series.

BACKGROUND: Brain metastasis (BM) of colorectal cancer is a disease with a poor prognosis of only a few months survival. However, it is difficult to estimate the individual prognosis of each patient due to the lack of definitive prognosis parameters. The number of metastases and the Karnofsky performance score are known predictors for survival. We investigated whether or not the neurological performance score and the tumor volumetrics are equally suitable predictors for survival. DESIGN: All patients with histologically diagnosed BM linked to colorectal cancer between 2012 and March 2020 were reviewed. The Medical Research Council Neurological Performance Score was used to quantify neurological performance. Univariate analysis with Kaplan-Meier estimate and log-rank test was performed. Survival prediction and multivariate analysis were performed employing Cox proportional hazard regression. RESULTS: Twenty-five patients were included in our analysis with an overall survival of 4.9 months after surgery of the BM. Survival decreased in the univariate analysis with increasing postoperative neurological performance score, low Karnofsky performance score, absence of radiation therapy and radiation therapy modality. The neurological performance score is a reliable scoring parameter for estimating the prognostic course analogous to the Karnofsky performance score. Neither preoperative nor post resection residual tumor volume had any impact on overall survival in our small cohort. CONCLUSION: Our data suggest that the postoperative neurological performance is a valuable prognostic factor for colorectal cancer patients with BM. Tumor volumetrics show no correlation to survival. Further investigations with a larger number of cases are mandatory.

Predictors of psychiatric comorbidity in cancer patients at the time of their discharge from the hospital.

PURPOSE: A cancer diagnosis can have a substantial impact on one's mental health. The present study investigated the prevalence and predictors of psychiatric comorbidities in cancer patients at the time of their discharge from the hospital. METHODS: Psychiatric comorbidities were assessed shortly before hospital discharge and half a year after hospitalization using a structured clinical interview (SCID), based on the diagnostic and statistical manual of mental disorders (DSM-IV). Frequencies at both time points were estimated using percentages and corresponding 95% confidence intervals. Predictors of mental disorders were identified using binary logistic regression models. RESULTS: At time of hospital discharge, 39 out of 334 patients (12%) were diagnosed with a psychiatric comorbidity, and 15 (7%) were diagnosed half a year later. Among the diagnoses, adjustment disorders (3%) were most frequent at the time of hospital release, while major depression (3%) was the most frequent 6 months later. Having a mental disorder was associated with unemployment (odds ratio (OR) 3.4, confidence interval (CI) 1.1-10.9, p = 0.04). There was no evidence that school education (OR 2.0, CI 0.4-9.0, p = 0.38), higher education (OR 0.7, CI 0.2-2.4, p = 0.60), income (OR 1.0, CI 1.0-1.0, p = 0.06), tumor stage (OR 1.1, CI 0.4-3.2, p = 0.85), type of disease (OR 0.6, CI 0.2-2.1, p = 0.47), pain (OR 1.0, CI 1.0-1.0, p = 0.15), fatigue (OR 1.0, CI 1.0-1.0, p = 0.77), or physical functioning (OR 1.0, CI 1.0-1.0, p = 0.54) were related to the presence of a psychiatric comorbidity. CONCLUSIONS: Unemployment was associated with at least a threefold increased risk of mental disorder, which highlights the need for special attention to be given to this subgroup of cancer patients.

White Matter Integrity of the Corticospinal Tract for Estimation of Individual Patient Risk for Postoperative Neurological Deterioration after Glioma Surgery.

BACKGROUND: Tractography has become a standard tool for planning neurosurgical operations and has been proven to be useful for risk stratification. In various conditions, tractography-derived white matter integrity has been shown to be associated with neurological outcome. Postoperative performance has been shown to be a prognostic marker in glioma. We aimed to assess the relation of preoperative corticospinal tract (CST) integrity with postoperative neurological deterioration in patients with malignant glioma. METHODS: We retrospectively analyzed a cohort of 24 right-handed patients (41.7% female) for perioperative neurological performance score (NPS) and applied our anatomical tractography workflow to extract the median fractional anisotropy (FA) of the CST in preoperative magnetic resonance imaging (MRI). RESULTS: Median FA of the CST ipsilateral to the tumor correlated significantly with preoperative NPS (p = 0.025). After rank order correlation and multivariate linear regression, we found that the preoperative median FA of the right CST correlates with preoperative NPS, independently from epidemiological data (p = 0.019). In patients with lesions of the right hemisphere, median FA of the right CST was associated with a declining NPS in multivariate linear regression (p = 0.024). Receiver operating characteristic (ROC) analysis revealed an optimal FA cutoff at 0.3946 in this subgroup (area under the curve 0.83). Patients below that cutoff suffered from a decline in neurological performance significantly more often (p = 0.020). CONCLUSIONS: Assessment of preoperative white matter integrity may be a promising biomarker for risk estimation of patients undergoing craniotomy for resection of malignant glioma.

[Need for and predictability of magnetic resonance imaging examinations in patients with implanted neurostimulators]. / Bedarf und Vorhersagbarkeit von Magnetresonanztomographieuntersuchungen bei Patienten mit implantiertem Neurostimulator.

BACKGROUND: With an increasing number of magnetic resonance imaging (MRI) examinations in the general population, there are no data available regarding the requirements of patients with implanted neurostimulators in Germany. Published data from the United States of America suggest a high need. The limited approval for MRI scans of implants are a common problem. OBJECTIVE: The focus is on the MRI needs of these pain patients and the predictability at the time of implantation. MATERIAL AND METHOD: We carried out a retrospective evaluation of the database of our hospital information system. We searched for all MRI requests for patients with an implanted neurostimulator between November 2011 and March 2019. In addition, we compared these data with the implantation of neurostimulators in the same period. RESULTS: We identified 171 MRI examinations and 22 requests without a subsequent examination. Out of 294 (28%) patients implanted in our center 83 had at least 1 MRI scan in our hospital. We observed a steadily increasing demand. In 111 of 171 (65%) performed examinations, there was no association between the indications leading to neurostimulator implantation and to MRI. A predictability could only be assumed for 43 of 193 (22%) MRI requests. CONCLUSION: In Germany, patients with an implanted neurostimulator have a high need for MRI diagnostics which cannot be predicted at the time of implantation. Therefore, only MRI-conditional systems should be implanted. The manufacturers need to adapt the implants and their approval to requirements.

Viability of Glioblastoma Cells and Fibroblasts in the Presence of Imidazole-Containing Compounds.

The naturally occurring dipeptide carnosine (ß-alanyl-L-histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L-alanyl-L-histidine (LA-LH), ß-alanyl-L-alanine, L-histidine, histamine, imidazole, ß-alanine, and L-alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L-histidine and formation of histamine was investigated by high-performance liquid chromatography coupled to mass spectrometry. Carnosine and LA-LH inhibited tumor cell growth with minor effects on fibroblasts, and L-histidine, histamine, and imidazole affected viability in both cell types. Compounds without the imidazole moiety did not diminish viability. In the presence of LA-LH but not in the presence of carnosine, a significant rise in intracellular amounts of histidine was detected in all cells. The formation of histamine was not detectable in the presence of carnosine, LA-LH, or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA-LH. Despite the fact that histamine has a strong effect on cell viability, the formation of histamine is not responsible for the effects on the cell viability of carnosine, LA-LH, and histidine.

Erythrocytes Prevent Degradation of Carnosine by Human Serum Carnosinase.

The naturally occurring dipeptide carnosine (ß-alanyl-l-histidine) has beneficial effects in different diseases. It is also frequently used as a food supplement to improve exercise performance and because of its anti-aging effects. Nevertheless, after oral ingestion, the dipeptide is not detectable in human serum because of rapid degradation by serum carnosinase. At the same time, intact carnosine is excreted in urine up to five hours after intake. Therefore, an unknown compartment protecting the dipeptide from degradation has long been hypothesized. Considering that erythrocytes may constitute this compartment, we investigated the uptake and intracellular amounts of carnosine in human erythrocytes cultivated in the presence of the dipeptide and human serum using liquid chromatography-mass spectrometry. In addition, we studied carnosine's effect on ATP production in red blood cells and on their response to oxidative stress. Our experiments revealed uptake of carnosine into erythrocytes and protection from carnosinase degradation. In addition, no negative effect on ATP production or defense against oxidative stress was observed. In conclusion, our results for the first time demonstrate that erythrocytes can take up carnosine, and, most importantly, thereby prevent its degradation by human serum carnosinase.

Choroid plexus coagulation in trisomy 9 mosaic-related hydrocephalus-a case report.

In trisomy 9 mosaicism, plexus hypertrophy has been described as a phenotypical feature and cause of hydrocephalus. We report on a 15-month-old child with hydrocephalus and trisomy 9 mosaicism primarily diagnosed in amniocentesis. After implantation of a ventriculoperitoneal shunt and subsequent revision, he presented with an exhaustion of peritoneal absorption leading to massive ascites. The implantation of a peritoneal drainage offered the unique opportunity to monitor cerebrospinal fluid (CSF) production indirectly via abdominal CSF drainage. In an individual trial, we performed endoscopic choroid plexus cauterization to reduce cerebrospinal fluid production, which failed to reduce excessive CSF production. In a second procedure, a ventriculoatrial shunt was implanted and succeeded to treat persistent hydrocephalus.

The prognostic value of peri-operative neurological performance in glioblastoma patients.

BACKGROUND: IDH-wild-type glioblastoma (GBM) is a disease with devastating prognosis. First-line therapy consists of gross total resection and adjuvant radiotherapy with concomitant temozolomide. Several clinical parameters have been identified to provide prognostic value. We investigated whether peri-operative overall neurological performance could also be used to evaluate patients' prognosis. METHODS: All patients with histologically diagnosed GBM between 2014 and 2017 over 18 years and MRI within 72 h after surgery were reviewed. To quantify neurological performance, the medical research council neurological performance score (MRC-NPS) was used. Univariate analysis with Kaplan-Meier estimate and log-rank test was performed. Survival prediction and multivariate analysis were performed employing Cox proportional hazard regression. RESULTS: One hundred thirty-nine patients were included. In univariate analysis, survival decreased with increasing post-operative MRC-NPS scale. Moreover, post-operative MRC-NPS of 4 was statistically significant associated with reduced overall survival when analyzed for complete (p = 0.027) and partial resection (p = 0.002) as well as unilobar (p = 0.003) and multilobar tumor location (p < 0.0005). In multivariate analysis, extent of resection (hazard ratio (HR) 3.142), adjuvant therapy regimen (HR 3.001), tumor location (HR 2.005), and post-operative MRC-NPS (HR 2.310) had significant influence on overall survival. CONCLUSION: We propose the post-operative neurological performance as an independent prognostic factor for GBM patients.

Early unplanned readmission of neurosurgical patients after treatment of intracranial lesions: a comparison between surgical and non-surgical intervention group.

BACKGROUND: Recent health care policy making has highlighted the necessity for understanding factors that influence readmission. To elucidate the rate, reason, and predictors of readmissions in neurosurgical patients, we analyzed unscheduled readmissions to our neurosurgical department after treatment for cranial or cerebral lesions. METHODS: From 2015 to 2017, all adult patients who had been discharged from our Department of Neurosurgery and were readmitted within 30 days were included into the study cohort. The patients were divided into a surgical and a non-surgical group. The main outcome measure was unplanned inpatient admission within 30 days of discharge. RESULTS: During the observation period, 183 (7.4%) of 2486 patients had to be readmitted unexpectedly within 30 days after discharge. The main readmission causes were surgical site infection (34.4 %) and seizure (16.4%) in the surgical group, compared to natural progression of the original diagnosis (38.2%) in the non-surgical group. Most important predictors for an unplanned readmission were younger age, presence of malignoma (OR: 2.44), and presence of cardiovascular side diagnoses in the surgical group. In the non-surgical group, predictors were length of stay (OR: 1.07) and the need for intensive care (OR: 5.79). CONCLUSIONS: We demonstrated that reasons for readmission vary between operated and non-operated patients and are preventable in large numbers. In addition, we identified treatment-related partly modifiable factors as predictors of unplanned readmission in the non-surgical group, while unmodifiable patient-related factors predominated in the surgical group. Further patient-related risk adjustment models are needed to establish an individualized preventive strategy in order to reduce unplanned readmissions.

Carnosine influences transcription via epigenetic regulation as demonstrated by enhanced histone acetylation of the pyruvate dehydrogenase kinase 4 promoter in glioblastoma cells.

Carnosine (ß-alanyl-L-histidine) affects a plethora of signaling pathways and genes in different biological systems. Although known as a radical scavenger, not all of these effects can simply be ascribed to its chemical nature. As previous experiments pointed towards the possibility that carnosine affects epigenetic regulation via histone acetylation, we investigated this hypothesis using the glioblastoma cell lines U87 and T98G in which carnosine's anti-neoplastic effect is accompanied by increased expression of pyruvate dehydrogenase kinase 4. Viability and expression of PDK4 was analyzed after incubation in carnosine and different histone deacetylase inhibitors (HDACi) using cell-based assays and qRT-PCR. In addition, chromatin immunoprecipitation (ChIP) experiments were performed and the global influence of carnosine on histone H3 acetylation was analyzed by Western blot. Carnosine as well as the HDACi used increased expression of PDK4. In addition, all compounds reduced cell viability, although differences were observed with regard to magnitude and required concentrations. ChIP analysis revealed increased acetylation of histone H3 in the PDK4 promoter of U87 and T98G cells (~ 1.3- and ~ 1.7-fold, respectively) 6 h after the addition of carnosine (50 mM) followed by increased expression of PDK4 mRNA. Western blots did not detect a general increase of H3 acetylation at a genome-wide scale under the influence of carnosine. Our experiments for the first time demonstrate that carnosine influences epigenetic regulation via increased histone acetylation.

The proton-coupled oligopeptide transporters PEPT2, PHT1 and PHT2 mediate the uptake of carnosine in glioblastoma cells.

The previous studies demonstrated that carnosine (ß-alanyl-L-histidine) inhibits the growth of tumor cells in vitro and in vivo. Considering carnosine for the treatment of glioblastoma, we investigated which proton-coupled oligopeptide transporters (POTs) are present in glioblastoma cells and how they contribute to the uptake of carnosine. Therefore, mRNA expression of the four known POTs (PEPT1, PEPT2, PHT1, and PHT2) was examined in three glioblastoma cell lines, ten primary tumor cell cultures, in freshly isolated tumor tissue and in healthy brain. Using high-performance liquid chromatography coupled to mass spectrometry, the uptake of carnosine was investigated in the presence of competitive inhibitors and after siRNA-mediated knockdown of POTs. Whereas PEPT1 mRNA was not detected in any sample, expression of the three other transporters was significantly increased in tumor tissue compared to healthy brain. In cell culture, PHT1 expression was comparable to expression in tumor tissue, PHT2 exhibited a slightly reduced expression, and PEPT2 expression was reduced to normal brain tissue levels. In the cell line LN405, the competitive inhibitors ß-alanyl-L-alanine (inhibits all transporters) and L-histidine (inhibitor of PHT1/2) both inhibited the uptake of carnosine. SiRNA-mediated knockdown of PHT1 and PHT2 revealed a significantly reduced uptake of carnosine. Interestingly, despite its low expression at the level of mRNA, knockdown of PEPT2 also resulted in decreased uptake. In conclusion, our results demonstrate that the transporters PEPT2, PHT1, and PHT2 are responsible for the uptake of carnosine into glioblastoma cells and full function of all three transporters is required for maximum uptake.

Carnosine's inhibitory effect on glioblastoma cell growth is independent of its cleavage.

The naturally occurring dipeptide carnosine (ß-alanyl-L-histidine) inhibits the growth of tumor cells. As its component L-histidine mimics the effect, we investigated whether cleavage of carnosine is required for its antineoplastic effect. Using ten glioblastoma cell lines and cell cultures derived from 21 patients suffering from this malignant brain tumor, we determined cell viability under the influence of carnosine and L-histidine. Moreover, we determined expression of carnosinases, the intracellular release of L-histidine from carnosine, and whether inhibition of carnosine cleavage attenuates carnosine's antineoplastic effect. We observed a significantly higher response of the cells to L-histidine than to carnosine with regard to cell viability in all cultures. In addition, we detected protein and mRNA expression of carnosinases and a low but significant release of L-histidine in cells incubated in the presence of 50 mM carnosine (p < 0.05), which did not correlate with carnosine's effect on viability. Furthermore, the carnosinase 2 inhibitor bestatin did not attenuate carnosine's effect on viability. Interestingly, we measured a ~ 40-fold higher intracellular abundance of L-histidine in the presence of 25 mM extracellular L-histidine compared to the amount of L-histidine in the presence of 50 mM carnosine, both resulting in a comparable decrease in viability. In addition, we also examined the expression of pyruvate dehydrogenase kinase 4 mRNA, which was comparably influenced by L-histidine and carnosine, but did not correlate with effects on viability. In conclusion, we demonstrate that the antineoplastic effect of carnosine is independent of its cleavage.

Carnosine increases efficiency of temozolomide and irradiation treatment of isocitrate dehydrogenase-wildtype glioblastoma cells in culture.

Aim: The naturally occurring dipeptide carnosine (CAR) has been considered for glioblastoma therapy. As CAR also protects against ionizing irradiation (IR), we investigated whether it may counteract standard therapy consisting of postsurgery IR and treatment with temozolomide (TMZ). Materials & methods: Four isocitrate dehydrogenase-wildtype primary cell cultures were exposed to different doses of IR and different concentrations of TMZ and CAR. After exposure, viability under the different conditions and combinations of them was determined. Results: All cultures responded to treatment with TMZ and IR with reduced viability. CAR further decreased viability when TMZ and IR were combined. Conclusion: Treatment with CAR does not counteract glioblastoma standard therapy. As the dipeptide also protects nontumor cells from IR, it may reduce deleterious side effects of treatment.

The association of socioeconomic status with quality of life in cancer patients over a 6-month period using individual growth models.

PURPOSE: Studies examining longitudinal associations between socioeconomic factors and quality of life (QoL) in cancer patients are rare. This study investigates changes in QoL over a 6-month period. METHODS: Four hundred forty-two cancer patients (mean age 64, SD = 11, 70% male) completed standardized questionnaires at the beginning (t1) and end (t2) of their hospital stay and 3 (t3) and 6 months (t4) thereafter. QoL was assessed with the EORTC QLQ-C30 core questionnaire. Mixed effect models were employed to analyze individual changes in QoL in relation to socioeconomic status (education, income, job status) over the four timepoints. Age, sex, cohabitation, disease and treatment factors, and comorbidity were included as covariates in the models. RESULTS: Income was a predictive factor for QoL. Patients with a low income had 8.8 percentage points (PP) lower physical, 4.9 PP lower emotional, and 11.4 PP lower role functioning. They also had 6.6 PP lower global QoL. Lower social functioning (6.2 PP) was found in patients with higher education or university degrees compared with those who were less educated or had not undergone an apprenticeship. Income also influenced trajectories of role functioning. There was no evidence that primary or secondary education and job type were related to QoL. CONCLUSIONS: The fact that income is negatively associated with many aspects of quality of life should be considered during and after treatment with a focus on patients with special needs.

Neurophysiological examination combined with functional intraoperative navigation using TMS in patients with brain tumor near the central region-a pilot study.

OBJECTIVE: Feasibility and value of non-invasive transcranial magnetic brain stimulation (TMS MAGVENTURE® MagPro R30 Denmark) for preoperative diagnosis and surgical planning of brain tumor operations in everyday clinical practice. METHODS: A prospective monocentric study was conducted, which included preoperative neurological and electrophysiological examination, TMS, and display of functional data in the navigation system (LOCALITE® TMS Navigator Germany). During surgery, the TMS data were correlated with the intraoperative monitoring (IOM). Twenty-four hours to 96 h and after at least 3 months, follow-ups with neurological, electrophysiological examinations and TMS stimulation were performed. RESULTS: Twenty-five patients with tumors in or near by the primary motor cortex region were included in the study. Twenty-one patients completed preoperative and first postoperative TMS and the neurological examination. Eight of 21 patients showed slight worsening of primary motor cortex function, 8 patients had an unchanged state, and 4 patients showed an improvement early after surgery. The changes of the electrophysiological examination like significant delay of the latency and/or reduced amplitudes matched well with the postoperative neurological outcome: if patients showed a worsening of the SEP's and MEP's, the postoperative results revealed deterioration. CONCLUSION: A preoperatively performed TMS using the MAGVENTURE® MagPro R30 and the LOCALITE® TMS Navigator could be established in our clinical daily practice and allowed a safe and reliable mapping of the primary motor cortex in order to minimize the risk of postoperative neurological deficits and improve the neurological outcome of the patients.

Carnosine selectively inhibits migration of IDH-wildtype glioblastoma cells in a co-culture model with fibroblasts.

BACKGROUND: Glioblastoma (GBM) is a tumor of the central nervous system. After surgical removal and standard therapy, recurrence of tumors is observed within 6-9 months because of the high migratory behavior and the infiltrative growth of cells. Here, we investigated whether carnosine (ß-alanine-l-histidine), which has an inhibitory effect on glioblastoma proliferation, may on the opposite promote invasion as proposed by the so-called "go-or-grow concept". METHODS: Cell viability of nine patient derived primary (isocitrate dehydrogenase wildtype; IDH1R132H non mutant) glioblastoma cell cultures and of eleven patient derived fibroblast cultures was determined by measuring ATP in cell lysates and dehydrogenase activity after incubation with 0, 50 or 75 mM carnosine for 48 h. Using the glioblastoma cell line T98G, patient derived glioblastoma cells and fibroblasts, a co-culture model was developed using 12 well plates and cloning rings, placing glioblastoma cells inside and fibroblasts outside the ring. After cultivation in the presence of carnosine, the number of colonies and the size of the tumor cell occupied area were determined. RESULTS: In 48 h single cultures of fibroblasts and tumor cells, 50 and 75 mM carnosine reduced ATP in cell lysates and dehydrogenase activity when compared to the corresponding untreated control cells. Co-culture experiments revealed that after 4 week exposure to carnosine the number of T98G tumor cell colonies within the fibroblast layer and the area occupied by tumor cells was reduced with increasing concentrations of carnosine. Although primary cultured tumor cells did not form colonies in the absence of carnosine, they were eliminated from the co-culture by cell death and did not build colonies under the influence of carnosine, whereas fibroblasts survived and were healthy. CONCLUSIONS: Our results demonstrate that the anti-proliferative effect of carnosine is not accompanied by an induction of cell migration. Instead, the dipeptide is able to prevent colony formation and selectively eliminates tumor cells in a co-culture with fibroblasts.

Interaction of quality of life, mood and depression of patients and their informal caregivers after surgical treatment of high-grade glioma: a prospective study.

INTRODUCTION: Patients who are diagnosed with high-grade gliomas (HGG) have poor prognoses and often experience rapid declines in functional and cognitive status, which makes caring for them particularly stressful. We conducted a prospective study to investigate the factors influencing the quality of life of HGG patients and their informal caregivers and analyzed their reciprocal impacts. Based on our results, we elaborated a screening model to identify patients and caregivers in need of psychooncological support. METHODS: A total of 45 matched HGG patient-caregiver dyads completed the Multidimensional Mood State Questionnaire, the 12-Item Short Form Medical Outcome Questionnaire and the Center for Epidemiology Studies Depression Scale. A subsequent semi-structured interview was performed with each individual. RESULTS: We found a significant relationship between the mood and depression scores of patients and caregivers, with a third of them displaying symptoms of a major depressive episode. Our screening model showed that 73% of the dyads exhibited signs of severe emotional strain with the need of psychooncological support. Beneficial factors that helped patients and caregivers cope with the illness included mutual respect, good communication, caregiver mastery and resilience. CONCLUSIONS: For a more comprehensive understanding of patient-caregiver interactions, we recommend using a combination of standardized psychometric tests and a semi-structured interview. The high percentage of emotional strain and depression found in patients and their caregivers facing HGG highlights the necessity of methodical screening for warning signs and consequent initiation of psycho-oncological interventions.