The clinical and financial impact of a pediatric surgical neuro-oncology clinical trial.

Pediatric surgical trials are rare and the impact of such trials on the institutions in which they are conducted is unknown. The purpose of this study was to analyze the clinical and financial impact of The Re-MATCH trial, a Phase I clinical trial requiring the biopsy or resection of recurrent medulloblastoma or PNET for enrollment. Inpatient financial and clinical volume information was collected during the 3 years of trial enrollment and the years preceding and following it. The primary endpoints were the difference in direct contribution margin (DCM), or net gain, of study and non-study patients and the difference in surgical volume during the study and non-study periods. The trial enrolled 18 patients; 15 had surgery at the sponsor institution and three had surgery at their home institution, then transferred tumor material to the sponsor institution. There were no differences between the two groups for potentially confounding variables such as neurosurgical procedure work relative value units (P = 0.13) or insurance provider (P = 0.26). There was no difference between the inpatient DCM per case for the institution for non-study patients (mean ± SD, $9039 ± $28,549) and study patients ($14,332 ± $20,231) (P = 0.4819). During the non-study period, there were a mean of 2.78 ± 1.65 pediatric brain tumor resections per month compared to 3.34 ± 1.66 cases per month during the study period, a 17% increase. When the 15 study patients were excluded, there were 2.97 ± 1.64 cases per month, a 7% increase. However, this increase in total case volume including study and non-study patients was not significant (P = 0.121). Phase I investigator-initiated surgically-based clinical trials may increase institutional surgical volume without imposing a financial burden. Finances are unlikely to be a barrier for researchers negotiating for resources to conduct such trials.

Immunotherapy response assessment in neuro-oncology: a report of the RANO working group.

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate.

A novel, reproducible, and objective method for volumetric magnetic resonance imaging assessment of enhancing glioblastoma.

OBJECT: Robust methodology that allows objective, automated, and observer-independent measurements of brain tumor volume, especially after resection, is lacking. Thus, determination of tumor response and progression in neurooncology is unreliable. The objective of this study was to determine if a semi-automated volumetric method for quantifying enhancing tissue would perform with high reproducibility and low interobserver variability. METHODS: Fifty-seven MR images from 13 patients with glioblastoma were assessed using our method, by 2 neuroradiologists, 1 neurosurgeon, 1 neurosurgical resident, 1 nurse practitioner, and 1 medical student. The 2 neuroradiologists also performed traditional 1-dimensional (1D) and 2-dimensional (2D) measurements. Intraclass correlation coefficients (ICCs) assessed interobserver variability between measurements. Radiological response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and Macdonald criteria. Kappa statistics described interobserver variability of volumetric radiological response determinations. RESULTS: There was strong agreement for 1D (RECIST) and 2D (Macdonald) measurements between neuroradiologists (ICC = 0.42 and 0.61, respectively), but the agreement using the authors' novel automated approach was significantly stronger (ICC = 0.97). The volumetric method had the strongest agreement with regard to radiological response (κ = 0.96) when compared with 2D (κ = 0.54) or 1D (κ = 0.46) methods. Despite diverse levels of experience of the users of the volumetric method, measurements using the volumetric program remained remarkably consistent in all users (0.94). CONCLUSIONS: Interobserver variability using this new semi-automated method is less than the variability with traditional methods of tumor measurement. This new method is objective, quick, and highly reproducible among operators with varying levels of expertise. This approach should be further evaluated as a potential standard for response assessment based on contrast enhancement in brain tumors.

Worse outcomes for patients undergoing brain tumor and cerebrovascular procedures following the ACGME resident duty-hour restrictions.

OBJECT: On July 1, 2003, the Accreditation Council for Graduate Medical Education (ACGME) implemented duty-hour restrictions for resident physicians due to concerns for patient and resident safety. Though duty-hour restrictions have increased resident quality of life, studies have shown mixed results with respect to patient outcomes. In this study, the authors have evaluated the effect of duty-hour restrictions on morbidity, mortality, length of stay, and charges in patients who underwent brain tumor and cerebrovascular procedures. METHODS: The Nationwide Inpatient Sample was used to evaluate the effect of duty-hour restrictions on complications, mortality, length of stay, and charges by comparing the pre-reform (2000-2002) and post-reform (2005-2008) periods. Outcomes were compared between nonteaching and teaching hospitals using a difference-in-differences (DID) method. RESULTS: A total of 90,648 patients were included in the analysis. The overall complication rate was 11.7%, with the rates not significantly differing between the pre- and post-duty hour eras (p = 0.26). Examination of hospital teaching status revealed that complication rates decreased in nonteaching hospitals (12.1% vs 10.4%, p = 0.0004) and remained stable in teaching institutions (11.8% vs 11.9%, p = 0.73) in the post-reform era. Multivariate analysis demonstrated a significantly higher complication risk in teaching institutions (OR 1.33 [95% CI 1.11-1.59], p = 0.0022), with no significant change in nonteaching hospitals (OR 1.11 [95% CI 0.91-1.37], p = 0.31). A DID analysis to compare the magnitude in change between teaching and nonteaching institutions revealed that teaching hospitals had a significantly greater increase in complications during the post-reform era than nonteaching hospitals (p = 0.040). The overall mortality rate was 3.0%, with a significant decrease occurring in the post-reform era in both nonteaching (5.0% vs 3.2%, p < 0.0001) and teaching (3.2% vs 2.3%, p < 0.0001) hospitals. DID analysis to compare the changes in mortality between groups did not reveal a significant difference (p = 0.40). The mean length of stay for all patients was 8.7 days, with hospital stay decreasing from 9.2 days to 8.3 days in the post-reform era (p < 0.0001). The DID analysis revealed a greater length of stay decrease in nonteaching hospitals than teaching institutions, which approached significance (p = 0.055). Patient charges significantly increased in the post-reform era for all patients, increasing from $70,900 to $96,100 (p < 0.0001). The DID analysis did not reveal a significant difference between the changes in charges between teaching and nonteaching hospitals (p = 0.17). CONCLUSIONS: The implementation of duty-hour restrictions correlated with an increased risk of postoperative complications for patients undergoing brain tumor and cerebrovascular neurosurgical procedures. Duty-hour reform may therefore be associated with worse patient outcomes, contrary to its intended purpose. Due to the critical condition of many neurosurgical patients, this patient population is most sensitive and likely to be negatively affected by proposed future increased restrictions.

Impact of PhD training on scholarship in a neurosurgical career.

OBJECT: The purpose of this study was to report the prevalence of neurosurgeons with both medical degrees (MDs) and doctorates (PhDs) at top-ranked US academic institutions and to assess whether the additional doctorate education is associated with substantive career involvement in academia as well as greater success in procuring National Institutes of Health (NIH) research funding compared with an MD-only degree. METHODS: The authors reviewed the training of neurosurgeons across the top 10 neurosurgery departments chosen according to academic impact (h index) to examine whether MD-PhD training correlated significantly with career outcomes in academia. RESULTS: Six hundred thirteen neurosurgery graduates and residents between the years 1990 and 2012 were identified for inclusion in this analysis. Both MD and PhD degrees were held by 121 neurosurgeons (19.7%), and an MD alone was held by 492. Over the past 2 decades, MD-PhD trainees represented a gradually increasing percentage of neurosurgeons, from 10.2% to 25.7% (p < 0.01). Of the neurosurgeons with MD-PhD training, a greater proportion had appointments in academic medicine compared with their MD-only peers (73.7% vs 52.3%, p < 0.001). Academic neurosurgeons with both degrees were also more likely to have received NIH funding (51.9% vs 31.8%, p < 0.05) than their single-degree counterparts in academia. In a national analysis of all active NIH R01 grants awarded in neurosurgery, MD-PhD investigators held a disproportionate number, more than 4-fold greater than their representation in the field. CONCLUSIONS: Dual MD-PhD training is a significant factor that may predict active participation in and funding for research careers among neurological surgeons at top-ranked academic institutions. These findings and their implications are of increasing relevance as the population of neurosurgeons with dual-degree training continues to rise.

Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group.

BACKGROUND: The Response Assessment in Neuro-Oncology (RANO) Working Group is an international, multidisciplinary effort to develop new standardized response criteria for clinical trials in brain tumors. The RANO group identified knowledge gaps relating to the definitions of tumor response and progression after the use of surgical or surgically based treatments. OBJECTIVE: To outline a proposal for new response and progression criteria for the assessment of the effects of surgery and surgically delivered therapies for patients with gliomas. METHODS: The Surgery Working Group of RANO identified surgically related end-point evaluation problems that were not addressed in the original Macdonald criteria, performed an extensive literature review, and used a consensus-building process to develop recommendations for how to address these issues in the setting of clinical trials. RESULTS: Recommendations were formulated for surgically related issues, including imaging changes associated with surgical resection or surgically mediated adjuvant local therapies, the determination of progression in the setting where all enhancing tumor has been removed, and how new enhancement should be interpreted in the setting where local therapies that are known to produce nonspecific enhancement have been used. Additionally, the terminology used to describe the completeness of surgical resections has been recognized to be inconsistently applied to enhancing vs nonenhancing tumors, and a new set of descriptors is proposed. CONCLUSION: The RANO process is intended to produce end-point criteria for clinical trials that take into account the effects of prior and ongoing therapies. The RANO criteria will continue to evolve as new therapies and technologies are introduced into clinical trial and/or practice.

A novel method for volumetric MRI response assessment of enhancing brain tumors.

Current radiographic response criteria for brain tumors have difficulty describing changes surrounding postoperative resection cavities. Volumetric techniques may offer improved assessment, however usually are time-consuming, subjective and require expert opinion and specialized magnetic resonance imaging (MRI) sequences. We describe the application of a novel volumetric software algorithm that is nearly fully automated and uses standard T1 pre- and post-contrast MRI sequences. T1-weighted pre- and post-contrast images are automatically fused and normalized. The tumor region of interest is grossly outlined by the user. An atlas of the nasal mucosa is automatically detected and used to normalize levels of enhancement. The volume of enhancing tumor is then automatically calculated. We tested the ability of our method to calculate enhancing tumor volume with resection cavity collapse and when the enhancing tumor is obscured by subacute blood in a resection cavity. To determine variability in results, we compared narrowly-defined tumor regions with tumor regions that include adjacent meningeal enhancement and also compared different contrast enhancement threshold levels used for the automatic calculation of enhancing tumor volume. Our method quantified enhancing tumor volume despite resection cavity collapse. It detected tumor volume increase in the midst of blood products that incorrectly caused decreased measurements by other techniques. Similar trends in volume changes across scans were seen with inclusion or exclusion of meningeal enhancement and despite different automated thresholds for tissue enhancement. Our approach appears to overcome many of the challenges with response assessment of enhancing brain tumors and warrants further examination and validation.

Surgical management of petroclival meningiomas: defining resection goals based on risk of neurological morbidity and tumor recurrence rates in 137 patients.

OBJECTIVE: Meningiomas arising from the petroclival region remain a challenging surgical problem. Because of the substantial risk of neurological morbidity, uniformly pursuing a gross total resection (GTR) to minimize tumor recurrence rates may not be justified. We sought to define optimal resection goals based on risk factors for postoperative neurological morbidity and tumor recurrence rates. METHODS: This series represents our experience with 137 meningiomas arising from the petroclival region resected between June 1993 and October 2002. There were 38 male and 99 female patients with a mean age of 53 years. RESULTS: GTR was achieved in 40% of patients, and near total resection (NTR) was achieved in 40% of patients. One operative death occurred. Twenty-six percent of patients experienced new postoperative cranial nerve deficits, paresis, or ataxia when assessed at a mean follow-up of 8.3 months. The risk of cranial nerve deficits increased with prior resection (P < 0.001), preoperative cranial nerve deficit (P = 0.005), tumor adherence to neurovascular structures (P = 0.046), and fibrous tumor consistency (P = 0.005). The risk of paresis or ataxia increased with prior resection (P = 0.001) and tumor adherence (P = 0.045). Selective NTR rather than GTR in patients with adherent or fibrous tumors significantly reduced the rate of neurological deficits. Radiographic recurrence or progression occurred in 17.6% of patients at a mean follow-up of 29.8 months. Tumor recurrence rates after GTR and NTR did not differ significantly (P = 0.111). CONCLUSION: Intraoperatively defined tumor characteristics played a critical role in identifying the subset of patients with an increased risk of postoperative deficits. By selectively pursuing an NTR rather than a GTR, neurological morbidity was reduced significantly without significantly increasing the rate of tumor recurrence.