Development and external validation of a clinical prediction model for predicting quality of recovery up to 1 week after surgery.

The Quality of Recovery Score-40 (QoR-40) has been increasingly used for assessing recovery after patients undergoing surgery. However, a prediction model estimating quality of recovery is lacking. The aim of the present study was to develop and externally validate a clinical prediction model that predicts quality of recovery up to one week after surgery. The modelling procedure consisted of two models of increasing complexity (basic and full model). To assess the internal validity of the developed model, bootstrapping (1000 times) was applied. At external validation, the model performance was evaluated according to measures for overall model performance (explained variance (R2)) and calibration (calibration plot and slope). The full model consisted of age, sex, previous surgery, BMI, ASA classification, duration of surgery, HADS and preoperative QoR-40 score. At model development, the R2 of the full model was 0.24. At external validation the R2 dropped as expected. The calibration analysis showed that the QoR-40 predictions provided by the developed prediction models are reliable. The presented models can be used as a starting point for future updating in prediction studies. When the predictive performance is improved it could be implemented clinically in the future.

Evolution of Making Clinical Predictions in Neurosurgery.

Prediction of clinical outcomes is an essential task for every physician. Physicians may base their clinical prediction of an individual patient on their intuition and on scientific material such as studies presenting population risks and studies reporting on risk factors (prognostic factors). A relatively new and more informative approach for making clinical predictions relies on the use of statistical models that simultaneously consider multiple predictors that provide an estimate of the patient's absolute risk of an outcome. There is a growing body of literature in the neurosurgical field reporting on clinical prediction models. These tools have high potential in supporting (not replacing) neurosurgeons with their prediction of a patient's outcome. If used sensibly, these tools pave the way for more informed decision-making with or for individual patients. Patients and their significant others want to know their risk of the anticipated outcome, how it is derived, and the uncertainty associated with it. Learning from these prediction models and communicating the output to others has become an increasingly important skill neurosurgeons have to master. This article describes the evolution of making clinical predictions in neurosurgery, synopsizes key phases for the generation of a useful clinical prediction model, and addresses some considerations when deploying and communicating the results of a prediction model. The paper is illustrated with multiple examples from the neurosurgical literature, including predicting arachnoid cyst rupture, predicting rebleeding in patients suffering from aneurysmal subarachnoid hemorrhage, and predicting survival in glioblastoma patients.

Structural damage burden and hypertrophic olivary degeneration in pediatric postoperative cerebellar mutism syndrome.

Cerebellar mutism syndrome (CMS) occurs in one out of four children after posterior fossa tumor surgery, with open questions regarding risk factors, pathophysiology, and prevention strategies. Because of similarities between several cerebellar syndromes, a common pathophysiology with damage to the dentato-thalamo-cortical and dentato-rubro-olivary pathways has been proposed. Hypertrophic olivary degeneration (HOD) is an imaging correlate of cerebellar injury observed for instance in stroke patients. Aim of this study was to investigate whether the occurrence and severity of CMS correlates with the extent of damage to the relevant anatomical structures and whether HOD is a time-dependent postoperative neuroimaging correlate of CMS. We performed a retrospective single center study of CMS patients compared with matched non-CMS controls. CMS occurred in 10 children (13% of the overall cohort) with a median age of 8 years. Dentate nucleus (DN) injury significantly correlated with CMS, and superior cerebellar peduncle (SCP) injury was associated by tendency. HOD was observed as a dynamic neuroimaging phenomenon in the postoperative course and its presence significantly correlated with CMS and DN injury. Children who later developed HOD had an earlier onset and tended to have longer persistence of CMS. These findings can guide surgical measures to protect the DN and SCP during posterior fossa tumor resections and to avoid a high damage burden (i.e., bilateral damage). Development of intraoperative neuromonitoring of the cerebellar efferent pathways as well as improved preoperative risk stratification could help to establish a patient-specific strategy with optimal balance between degree of resection and functional integrity.

Development and external validation of a clinical prediction model for survival in patients with IDH wild-type glioblastoma.

OBJECTIVE: Prognostication of glioblastoma survival has become more refined due to the molecular reclassification of these tumors into isocitrate dehydrogenase (IDH) wild-type and IDH mutant. Since this molecular stratification, however, robust clinical prediction models relevant to the entire IDH wild-type glioblastoma patient population are lacking. This study aimed to provide an updated model that predicts individual survival prognosis in patients with IDH wild-type glioblastoma. METHODS: Databases from Germany and the Netherlands provided data on 1036 newly diagnosed glioblastoma patients treated between 2012 and 2018. A clinical prediction model for all-cause mortality was developed with Cox proportional hazards regression. This model included recent glioblastoma-associated molecular markers in addition to well-known classic prognostic variables, which were updated and refined with additional categories. Model performance was evaluated according to calibration (using calibration plots and calibration slope) and discrimination (using a C-statistic) in a cross-validation procedure by country to assess external validity. RESULTS: The German and Dutch patient cohorts consisted of 710 and 326 patients, respectively, of whom 511 (72%) and 308 (95%) had died. Three models were developed, each with increasing complexity. The final model considering age, sex, preoperative Karnofsky Performance Status, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and adjuvant therapeutic regimen showed an optimism-corrected C-statistic of 0.73 (95% confidence interval 0.71-0.75). Cross-validation between the national cohorts yielded comparable results. CONCLUSIONS: This prediction model reliably predicts individual survival prognosis in patients with newly diagnosed IDH wild-type glioblastoma, although additional validation, especially for long-term survival, may be desired. The nomogram and web application of this model may support shared decision-making if used properly.

Is My Clinical Prediction Model Clinically Useful? A Primer on Decision Curve Analysis.

Decision curve analysis is an increasingly popular method to assess the impact of a prediction model on medical decision making. The analysis provides a graphical summary. A basic understanding of a decision curve is needed to interpret these graphics. This short introduction addresses the common features of a decision curve. Furthermore, using a glioblastoma patient set provided by the Machine Intelligence in Clinical Neuroscience Lab from the Department of Neurosurgery and Clinical Neuroscience Center, University Hospital Zurich a decision curve is plotted for two prediction models. The corresponding R code is provided.

Proposed definition of competencies for surgical neuro-oncology training.

OBJECTIVE: The aim of this work is to define competencies and entrustable professional activities (EPAs) to be imparted within the framework of surgical neuro-oncological residency and fellowship training as well as the education of medical students. Improved and specific training in surgical neuro-oncology promotes neuro-oncological expertise, quality of surgical neuro-oncological treatment and may also contribute to further development of neuro-oncological techniques and treatment protocols. Specific curricula for a surgical neuro-oncologic education have not yet been established. METHODS: We used a consensus-building approach to propose skills, competencies and EPAs to be imparted within the framework of surgical neuro-oncological training. We developed competencies and EPAs suitable for training in surgical neuro-oncology. RESULT: In total, 70 competencies and 8 EPAs for training in surgical neuro-oncology were proposed. EPAs were defined for the management of the deteriorating patient, the management of patients with the diagnosis of a brain tumour, tumour-based resections, function-based surgical resections of brain tumours, the postoperative management of patients, the collaboration as a member of an interdisciplinary and/or -professional team and finally for the care of palliative and dying patients and their families. CONCLUSIONS AND RELEVANCE: The present work should subsequently initiate a discussion about the proposed competencies and EPAs and, together with the following discussion, contribute to the creation of new training concepts in surgical neuro-oncology.

Age-stratified clinical performance and survival of patients with IDH-wildtype glioblastoma homogeneously treated by radiotherapy with concomitant and maintenance temozolomide.

OBJECTIVE: Isocitrate dehydrogenase (IDH)-wildtype glioblastomas are the most malignant glial tumours. Median survival is only 14-16 months after diagnosis, with patients aged ≥ 65 years reportedly showing worse outcome. This study aimed to further evaluate the prognostic role of age in a homogenously treated patient cohort. METHODS: The study includes 132 IDH-wildtype glioblastoma patients treated between 2013 and 2017 with open resection followed by radiotherapy with concomitant and maintenance temozolomide. Patients were dichotomized into a non-elderly (< 65 years) and an elderly (≥ 65 years) group. Extent of resection and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were determined for each tumour. Clinical and radiological follow-up data were obtained at 6 weeks after the end of radiation therapy and thereafter in 3-month intervals. Progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate cox regression analyses. RESULTS: The elderly group consisted of 58 patients (median age: 70.5 years) and the non-elderly group of 74 patients (median age: 55 years). Median pre- and postoperative operative Karnofsky Performance Scale (KPS), Eastern Cooperative Oncology Group (ECOG) score and National Institutes of Stroke Scale (NIHSS) were not significantly different between the groups, but KPS and ECOG scores became significantly worse in the elderly group at 6 weeks after termination of radiation therapy. Neither PFS nor OS differed significantly between the age groups. Patients with MGMT promoter-methylated tumours survived longer. CONCLUSION: Elderly patients in good pre- and postoperative clinical conditions may show similar outcome as younger patients when treated according to standard of care. However, elderly patients may suffer more frequently from clinical deterioration following chemoradiotherapy. In both age groups, MGMT promoter methylation was linked to longer PFS and OS.

Association between health insurance status and malignant glioma.

BACKGROUND: Prior studies have suggested an association between patient socioeconomic status and brain tumors. In the present study we attempt to indirectly validate the findings, using health insurance status as a proxy for socioeconomic status. METHODS: There are 2 types of health insurance in Germany: statutory and private. Owing to regulations, low- and middle-income residents are typically statutory insured, whereas high-income residents have the option of choosing a private insurance. We compared the frequencies of privately insured patients suffering from malignant neoplasms of the brain with the corresponding frequencies among other neurosurgical patients at our hospital and among the German population. To correct for age, sex, and distance from the hospital, we included these variables as predictors in logistic and binomial regression. RESULTS: A significant association (odds ratio [OR] = 1.59, CI = 1.45-1.74, P < .001) between health insurance status and brain tumors was found. The association is independent of patients' sex or age. Whereas privately insured patients generally tend to come from farther away, such a relationship was not observed for patients suffering from brain tumors. Comparing the out of house and in-house brain tumor patients showed no selection bias on our side. CONCLUSION: Previous studies have found that people with a higher income, level of education, or socioeconomic status are more likely to suffer from malignant brain tumors. Our findings are in line with these studies. Although the reason behind the association remains unclear, the probability that our results are due to some random effect in the data is extremely low.

The effect of midazolam as premedication on the quality of postoperative recovery after laparotomy: a randomized clinical trial.

PURPOSE: Despite the uncertain effects of anxiolytic premedication with benzodiazepines on the quality of postoperative recovery, perioperative benzodiazepine administration is still a common practice in many hospitals. We evaluated the effect of premedication with midazolam on the quality of recovery in hospitalized patients undergoing a laparotomy. METHODS: We conducted a single-centre randomized placebo-controlled, double-blinded clinical trial from July 2014 to September 2015. We included 192 patients aged > 18 yr scheduled for elective laparotomy with a planned postoperative stay of ≥ three days. Participants were randomized into two groups to receive either midazolam 3 mg or sodium chloride 0.9% intravenously as premedication prior to surgery. Patients were followed up for up to one week after surgery. The primary outcome was the Quality of Recovery-40 (QoR-40) score on postoperative day (POD) 3. The secondary outcomes included the QoR-40 score on POD 7, and the State-Trait Anxiety Inventory, State-Trait Anger Scale, Multidimensional Fatigue Inventory, and the Hospital Anxiety and Depression Scale scores. RESULTS: The mean (standard deviation) postoperative QoR-40 scores on POD 3 were not significantly different in the midazolam group compared with controls [166.4 (17.0) vs 163.9 (19.8), respectively; mean difference, 2.3; 95% confidence interval, - 2.9 to 8.4; P = 0.35]. There were no between-group differences in any of the secondary outcomes. CONCLUSIONS: Administration of midazolam as premedication for laparotomy patients did not improve the quality of recovery up to one week after surgery. General prescription of midazolam as premedication can be questioned and might only suit some patients. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01993459); registered 29 October, 2013.

Quantification of PpIX-fluorescence of cerebral metastases: a pilot study.

5-ALA fluorescence-guided surgery (FGS) is a major advance in neuro-oncological surgery. So far, Protoporphyrin IX (PpIX)-fluorescence has been observed in about half of cerebral metastases resected with routinely equipped microscopes during 5-ALA FGS. The aim of the present pilot study was to quantify PpIX-induced fluorescence of cerebral metastases with a spectrometer. We hypothesize that non-fluorescing metastases under the operating microscope may have spectrometrically measurable levels of fluorescence. A second aim was to analyze correlations between quantified 5-ALA fluorescence and histology or primary tumor type, respectively. Standard FGS was performed in all patients. The fluorescence intensity of the metastasis was semi-quantitatively determined in vivo by a senior surgeon using a special surgical microscope equipped for FGS. A systematic spectrometric ex vivo evaluation of tumor specimens and PpIX-induced fluorescence was performed using a spectrometer connected by optic fibers to a handheld probe. Quantification of 5-ALA-derived fluorescence was measured in a standardized manner with direct contact between mini-spectrometer and metastasis. The difference between the maximum PpIX-fluorescence at 635 nm and the baseline fluorescence was defined as the PpIX fluorescence intensity of the metastasis and given in arbitrary units (AU). Diagnosis of a cerebral metastasis was confirmed by histopathological analysis. A total of 29 patients with cerebral metastases were included. According to neuropathological analysis, 11 patients suffered from non-small cell lung cancer, 10 patients from breast cancer, 6 patients from cancer originating in the gastro-intestinal tract, 1 patient suffered from a malignant melanoma and one patient from renal cancer. The mean age was 63 years (37-81 years). 15 patients were female, 14 patients male. 13 cerebral metastases were considered as ALA-positive by the surgeon. In nine metastases, 5-ALA fluorescence was not visible to the naked eye and could only be detected using the spectrometer. The threshold for an ALA signal rated as "positive" by the surgeon was PpIX fluorescence above 1.1 × 106 AU. The mean PpIX fluorescence of all analyzed cerebral metastases was 1.29 × 106 ± 0.23 × 106 AU. After quantification, we observed a significant difference between the mean 5-ALA-derived fluorescence in NSCLC and breast cancer metastases (Mean Diff: - 1.2 × 106; 95% CI of difference: - 2.2 × 106 to - 0.15 × 106; Sidák-adjusted p = 0.026). In our present pilot series, about half of cerebral metastases showed a 5-ALA fluorescence invisible to the naked eye. Over 50% of these non-fluorescent metastases show a residual 5-ALA fluorescence which can be detected and quantified using a spectrometer. Moreover, the quantified 5-ALA signal significantly differed with respect to the primary tumor of the corresponding cerebral metastasis. Further studies should evaluate the predictive value of the 5-ALA signal and if a quantified 5-ALA signal enables a reliable intraoperative differentiation between residual tumor tissue and edematous brain-in particular in metastases with a residual fluorescence signal invisible to the naked eye.

Is the Intensity of 5-Aminolevulinic Acid-Derived Fluorescence Related to the Light Source?

OBJECTIVE: With the introduction of the 5-aminolevulinic acid (5-ALA) technique, surgical neuro-oncology has made a major advance. 5-ALA fluorescence-guided resection of malignant glioma results in more complete surgical resections and subsequently prolonged survival. However, it remains uncertain how light intensities of the blue light source and 5-ALA-derived fluorescence intensities of the illuminated tissue are connected. The aim of the present study was to compare light intensities of different blue light sources and protoporphyrin (PpIX) fluorescence intensities of PpIX solutions with defined concentrations after illumination with different light sources. MATERIAL AND METHODS: The light spectrum of 7 different blue light sources and the fluorescence intensity of 2 PpIX solutions (0.15 µg/mL and 5 µg/mL) were quantified after illumination. We compared the Zeiss OPMI Pentero microscope, the Zeiss OPMI Pentero 900 microscope, the Leica M530 OH6 microscope, an endoscope equipped with the 5-ALA technique, a mini-spectrometer equipped with a multi-channel light-emitting diode (LED) source emitting monochromatic light, a modified commercially available LED head lamp, and a commercially available unmodified UV-LED lamp. PpIX fluorescence was quantified in a standardized setup using a mini-spectrometer. RESULTS: Maximum light intensities of the evaluated light sources were reached at different wavelengths. All tested devices were able to detect PpIX-induced fluorescence. However, the intensity of PpIX fluorescence of the differently concentrated PpIX solutions (0.15 µg/mL and 5 µg/mL) was significantly dependent on the light source used. CONCLUSIONS: Intensity of the 5-ALA-derived fluorescence is related to the light source used.

Risk factors for in-brain local progression in elderly patients after resection of cerebral metastases.

Intracranial metastases are the most frequent brain tumor with recurrence rates after treatment of around 40-60%. Age is still considered a determinant of treatment and prognosis in this pathology. Recent studies analyzing the impact of metastasectomy in elderly patients focused on reporting perioperative mortality and morbidity rates but not on the evaluation of oncological outcome parameters. Aim of this study is to determine risk factors for in-brain local recurrence after brain surgery in this sub-population. From October 2009 until September 2016 all patients aged 65 years and above with histopathologically confirmed metastasis after surgical resection were retrospectively studied. Clinical, radiological and perioperative information was collected and statistically analysed. Follow-up consisted of clinical and radiological assessment every 3-months following surgery. 78 patients were included, of these 50% were female (39 patients). Median age was 71 years (66-83). Early postoperative-MRI verified a complete surgical resection in 41 patients (52.6%) and showed a tumor-remnant in 15 patients (19.2%). In 22 patients the MRI result was inconclusive (28.2%). None of the patients experienced severe complications due to surgery. The median postoperative NIHSS was adequate 1 ± 1.4 (0-6), nonetheless, insignificantly improved in comparison to the preoperative NIHSS (p = 0.16). A total of 20 patients (25.6%) presented local recurrence. The only statistically significant factor for development of local in-brain recurrence after resection of cerebral metastases in patients above 65 years of age was a tumor-remnant in the early postoperative MRI (p = 0.00005). Median overall survival was 13 months. Local in-brain recurrence after surgical resection of a cerebral metastasis in patients above 65 years of age was 25.6%. In our analysis, tumor-remnant in early postoperative MRI is the only risk factor for local in-brain recurrence. Oncological parameters in the present cohort do not seem to differ from recent phase III studies with non-geriatric patients. Nevertheless, controlled studies on the impact of metastasectomy in elderly patients delivering high quality reliable data are required.

Is 5-ALA fluorescence of cerebral metastases a prognostic factor for local recurrence and overall survival?

BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence-guided resection technique was first introduced for malignant glioma. However, the impact of the 5-ALA fluorescence behaviour of cerebral metastases is still unclear. Aim of this study was to determine the impact of PpIX-fluorescence on the local progression-free and overall survival. MATERIALS AND METHODS: A secondary analysis was performed and included an updated follow-up of 136 patients comprised in two previous studies. Additionally, 82 new patients were included. All patients underwent surgical resection of cerebral metastasis and intraoperative estimation of 5-ALA-induced fluorescence. The 5-ALA fluorescence behaviour of cerebral metastases was correlated with the rate of local recurrences, the local progression-free and overall survival. RESULTS: 218 patients suffering from cerebral metastatic spread fulfilled the inclusion criteria and were analysed: complete surgical resection could be achieved in 123/218 patients (56.4%). Dichotomised degree of surgical resection (complete vs. incomplete or questionable complete resection) was not related to dichotomized 5-ALA fluorescence of cerebral metastases (p = 0.66). 51 patients (23.4%) developed a local in-brain progression within or at the border of the resection cavity. Of these, 8 patients showed a PpIX-fluorescent metastasis. There was a trend towards a correlation between a higher local in-brain progression in PpIX-non-fluorescent metastases (p = 0.03). Median time to local in-brain progression was 4 ± 11 months. PpIX-fluorescent and PpIX-non-fluorescent metastases showed a significantly different progression-free survival (p = 0.01). PpIX-positive and -negative metastases showed a significantly different overall survival (20 and 14 months respectively; p = 0.006). CONCLUSION: The 5-ALA fluorescence behaviour was related to the local progression-free and the overall survival in the present retrospective series and might be considered a prognostic marker. Further studies are required to appreciate the oncological impact of the 5-ALA induced fluorescence behaviour of cerebral metastases.

Prognostic model for psychological outcomes in ambulatory surgery patients: A prospective study using a structural equation modeling framework.

INTRODUCTION: Surgical procedures are increasingly carried out in a day-case setting. Along with this increase, psychological outcomes have become prominent. The objective was to evaluate prospectively the prognostic effects of sociodemographic, medical, and psychological variables assessed before day-case surgery on psychological outcomes after surgery. METHODS: The study was carried out between October 2010 and September 2011. We analyzed 398 mixed patients, from a randomized controlled trial, undergoing day-case surgery at a university medical center. Structural equation modeling was used to jointly study presurgical prognostic variables relating to sociodemographics (age, sex, nationality, marital status, having children, religion, educational level, employment), medical status (BMI, heart rate), and psychological status associated with anxiety (State-Trait Anxiety Inventory (STAI), Hospital Anxiety and Depression Scale (HADS-A)), fatigue (Multidimensional Fatigue Inventory (MFI)), aggression (State-Trait Anger Scale (STAS)), depressive moods (HADS-D), self-esteem, and self-efficacy. We studied psychological outcomes on day 7 after surgery, including anxiety, fatigue, depressive moods, and aggression regulation. RESULTS: The final prognostic model comprised the following variables: anxiety (STAI, HADS-A), fatigue (MFI), depression (HADS-D), aggression (STAS), self-efficacy, sex, and having children. The corresponding psychological variables as assessed at baseline were prominent (i.e. standardized regression coefficients ≥ 0.20), with STAI-Trait score being the strongest predictor overall. STAI-State (adjusted R2 = 0.44), STAI-Trait (0.66), HADS-A (0.45) and STAS-Trait (0.54) were best predicted. CONCLUSION: We provide a prognostic model that adequately predicts multiple postoperative outcomes in day-case surgery. Consequently, this enables timely identification of vulnerable patients who may require additional medical or psychological preventive treatment or-in a worst-case scenario-could be unselected for day-case surgery.