Rohan Ramakrishna

Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival.

Background: A paucity of data exists concerning the prognostic usefulness of preoperative and postoperative imaging after resection of glioblastoma multiforme (GBM). This study aimed to connect outcome with imaging features of GBM. Methods: Retrospective computer-assisted volumetric calculations quantified central necrotic (T0), gadolinium-enhanced (T1) and increased T2-weighted signal volumes (T2) in 70 patients with untreated GBM. Clinical and treatment data, including extent of resection (EOR), were obtained through chart review. T1 volume was used as a measure of solid tumor burden; and T2 volume, as an indicator of invasive isolated tumor cell (ITC) burden. Indicators of invasiveness included T2:T1 ratios as a propensity for ITC infiltration compared to solid tumor volumes and qualitative analysis of subependymal growth and infiltration of the basal ganglia, corpus callosum or brainstem. Cox multivariate analysis (CMVA) was used to identify significant associations between imaging features and survival. Results: In the 70 patients studied, significant associations with reduced survival existed for gadolinium-enhancing tumor crossing the corpus callosum (odds ratio, 3.14) and with increased survival with gross total resection (GTR) (GTR median survival, 62 weeks versus 37 and 34 weeks for sub-total resection and biopsy, respectively). For a selected “GTR-eligible” subgroup of 52 patients, prolonged survival was associated with smaller preoperative gadolinium-enhancing volume (T1) and actual GTR. Conclusion: Some magnetic resonance (MR) imaging indicators of tumor invasiveness (gadolinium-enhancing tumor crossing the corpus callosum) and tumor burden (GTR and preoperative T1 volume in GTR-eligible subgroup) correlate with survival. However, ITC-infiltrative tumor burden (T2 volume) and “propensity” for ITC invasiveness (T2:T1 ratio) did not impact survival. These results indicate that while the ITC component is the ultimate barrier to cure for GBM, the pattern of spread and volumes of gadolinium-enhancing solid tumor are more robust indicators of prognosis.

Seed, soil, and beyond: The basic biology of brain metastasis

First invoked by Paget, the seed and soil hypothesis suggests that the successful growth of metastatic cells depends on the interactions and properties of cancer cells (seeds) and their potential target organs (soil). In the context of the seed and soil hypothesis this review examines recent advances in the understanding of molecular and cellular features that permit transformed epithelial cells to gain access to the blood stream (intravasation), survive their journey through the blood stream, and ultimately traverse through the microvasculature of target organs (extravsation) to deposit, survive, and grow in a foreign tissue environment. In addition to a review of the clinical and experimental evidence supporting the seed and soil theory to cancer metastasis, additional concepts highlighted include: (i) The role of cancer stem-like cells as putative cells of metastatic origin (the “seeds”); (ii) the mechanism of epithelial to mesenchymal transition (EMT) in driving epithelial cell conthose molecules do no blood stream to avoid anoikis, or anchorage independent cell death; and (iv) the reverse process of EMT, or mesenchymal to epithelial transition (MET), which promotes conversion back to the parent cell morphology and growth of macrometastsis in the target organ. The unique biology of metastases once established in the brain, and in particular the “sanctuary” role that the brain microenvironment plays in promoting metastatic growth and treatment resistance, will also be examined. These issues are of more than academic interest since as systemic therapies gradually improve local tumor control, the relative impact of brain metastasis will inexorably play a proportionally greater role in determining patient morbidity and mortality.

Lateral Transorbital Neuroendoscopic Approach to the Lateral Cavernous Sinus

Objective To design and assess the quality of a novel lateral retrocanthal endoscopic approach to the lateral cavernous sinus. Design Computer modeling software was used to optimize the geometry of the surgical pathway, which was confirmed on cadaver specimens. We calculated trajectories and surgically accessible areas to the middle fossa while applying a constraint on the amount of soft tissue retraction. Setting Virtual computer model to simulate the surgical approach and cadaver laboratory. Participants The authors. Main Outcome Measures Adequate surgical access to the lateral cavernous sinus and adjacent regions as determined by operations on the cadaver specimens. Additionally, geometric limitations were imposed as determined by the model so that retraction on soft tissue structures was maintained at a clinically safe distance. Results Our calculations revealed adequate access to the lateral cavernous sinus, Meckel cave, orbital apex, and middle fossa floor. Cadaveric testing revealed sufficient access to these areas using <10 mm of orbital retraction. Conclusions Our study validates not only the use of computer simulation to plan operative approaches but the feasibility of the lateral retrocanthal approach to the lateral cavernous sinus.

Hemangiopericytoma: Radical resection remains the cornerstone of therapy

Hemangiopericytomas (HPC) are mesenchymal tumors with a propensity towards chronicity and metastasis. This study aimed to reflect a single institution experience with both World Health Organization (WHO) grade II and III HPC. Pathology records from the years 1990-2013 at the University of Washington were searched to identify tumors unequivocally classified as HPC. Electronic chart review was then utilized to collect pertinent patient data. Of the WHO grade II HPC, there were four men and two women (average age 52 years) while the grade III HPC group had eight men and two women (average age 51 years). Sixty-six percent of WHO grade II tumors were located in the middle or posterior fossa as compared to none of the grade III tumors. Survival analysis revealed a significant survival benefit for patients who underwent complete resection (223 months) versus those with subtotal resection (138 months, p<0.05). Factors such as age, sex, the use of up-front radiation, and whether the patient had a recurrence did not show statistical significance related to overall survival or progression free survival. Radiation in the form of external beam radiotherapy given at the time of the first recurrence did trend towards improved progression free survival (56 months) compared to those patients who were not radiated (22 months, p=0.09) All patients with radical resection went on to never have a recurrence. Our results indicate that HPC are tumors with limited response to radiation and best treated with aggressive resection. Future studies will determine whether molecular-based therapies may provide added adjuvant benefit.

Outcomes in Reoperated Low-Grade Gliomas.

BACKGROUND Low-grade gliomas (LGGs) comprise a diverse set of intrinsic brain tumors that correlate strongly with survival. Data on the effect of reoperation are sparse. OBJECTIVE To evaluate the effect of reoperation on patients with LGG. METHODS Fifty-two consecutive patients with reoperated LGGs treated at the University of Washington between 1986 and 2004 were identified and evaluated in a retrospective analysis. RESULTS The average overall survival (OS) for this cohort was 12.95 ± 0.96 years. The overall 10-year survival rate was 57%. The absence of any residual tumor at either the first or second operation was associated with significantly increased OS. Negative prognostic variables for OS included the use of upfront radiation and pathology at recurrence. The average overall progression-free survival to the first recurrence (PFS1) was 6.23 ± 0.51 years. Positive prognostic factors for improved PFS1 included the use of upfront radiation therapy. Variables not associated with differences in PFS1 included the use of upfront chemotherapy, enhancement, pathology, extent of resection, the presence of residual tumor, and Karnofsky Performance Scale score <80. The average overall progression-free survival to the second recurrence was 2.73 ± 0.39 years. Pathology at recurrence was associated with significant differences in progression-free survival to the second recurrence, as was extent of resection at time of first recurrence, and Karnofsky Performance Scale score <80. CONCLUSION This is among the largest studies to assess variables associated with outcome in patients with reoperated LGG. Reresection appears to provide significant benefit, and extent of resection remains the strongest predictor of OS.

Transorbital neuroendoscopic surgery for the treatment of skull base lesions

Transorbital neuroendoscopic surgery (TONES) is a relatively new technique that not only allows access to the contents of the orbit but also the intracranial compartment, including the anterior cranial fossa, middle fossa and lateral cavernous sinus. In this study, we aimed to retrospectively review the largest experience to our knowledge with regards to surgical outcomes of skull base pathologies treated with a TONES procedure. Forty patients (aged 3-89 years) underwent 45 TONES procedures between the years of 2006-2013. Pathologies were cerebrospinal fluid leak repair (n=16), traumatic fracture (n=8), tumor (n=11), meningoencephalocele (n=5), hematoma (n=1), and infection (n=4). Three patients had a persistent complication at 3 months, including a case each of enophthalmos (unnoticed by patient), epiphora (delayed presentation at 2 months requiring dacryocystorhinostomy), and ptosis (improved at 1 year). Surgical success was achieved in all patients. Of special import, there were no cases of visual decline, diplopia, or stroke. There was no mortality. To our knowledge this is the first study and largest experience of TONES (level 4 evidence) to detail outcomes with respect to skull base pathologies. Our results indicate that TONES procedures can be performed with minimal morbidity. Further studies are needed to assess equivalency with craniotomy based approaches though this initial report is encouraging.

Low-dose head computed tomography in children: a single institutional experience in pediatric radiation risk reduction: clinical article.

OBJECT In this study, the authors describe their experience with a low-dose head CT protocol for a preselected neurosurgical population at a dedicated pediatric hospital (Seattle Childrens Hospital), the largest number of patients with this protocol reported to date. METHODS All low-dose head CT scans between October 2011 and November 2012 were reviewed. Two different low-dose radiation dosages were used, at one-half or one-quarter the dose of a standard head CT scan, based on patient characteristics agreed upon by the neurosurgery and radiology departments. Patient information was also recorded, including diagnosis and indication for CT scan. RESULTS Six hundred twenty-four low-dose head CT procedures were performed within the 12-month study period. Although indications for the CT scans varied, the most common reason was to evaluate the ventricles and catheter placement in hydrocephalic patients with shunts (70%), followed by postoperative craniosynostosis imaging (12%). These scans provided adequate diagnostic imaging, and no patient required a follow-up full-dose CT scan as a result of poor image quality on a low-dose CT scan. Overall physician comfort and satisfaction with interpretation of the images was high. An additional 2150 full-dose head CT scans were performed during the same 12-month time period, making the total number of CT scans 2774. This value compares to 3730 full-dose head CT scans obtained during the year prior to the study when low-dose CT and rapid-sequence MRI was not a reliable option at Seattle Childrens Hospital. Thus, over a 1-year period, 22% of the total CT scans were able to be converted to low-dose scans, and full-dose CT scans were able to be reduced by 42%. CONCLUSIONS The implementation of a low-dose head CT protocol substantially reduced the amount of ionizing radiation exposure in a preselected population of pediatric neurosurgical patients. Image quality and diagnostic utility were not significantly compromised.

Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy

Increasing age is the most robust predictor of greater malignancy and treatment resistance in human gliomas. However, the adverse association of clinical course with aging is rarely considered in animal glioma models, impeding delineation of the relative importance of organismal versus progenitor cell aging in the genesis of glioma malignancy. To address this limitation, we implanted transformed neural stem/progenitor cells (NSPCs), the presumed cells of glioma origin, from 3‐ and 18‐month‐old mice into 3‐ and 20‐month host animals. Transplantation with progenitors from older animals resulted in significantly shorter (P ≤ 0.0001) median survival in both 3‐month (37.5 vs. 83 days) and 20‐month (38 vs. 67 days) hosts, indicating that age‐dependent changes intrinsic to NSPCs rather than host animal age accounted for greater malignancy. Subsequent analyses revealed that increased invasiveness, genomic instability, resistance to therapeutic agents, and tolerance to hypoxic stress accompanied aging in transformed NSPCs. Greater tolerance to hypoxia in older progenitor cells, as evidenced by elevated HIF‐1 promoter reporter activity and hypoxia response gene (HRG) expression, mirrors the upregulation of HRGs in cohorts of older vs. younger glioma patients revealed by analysis of gene expression databases, suggesting that differential response to hypoxic stress may underlie age‐dependent differences in invasion, genomic instability, and treatment resistance. Our study provides strong evidence that progenitor cell aging is responsible for promoting the hallmarks of age‐dependent glioma malignancy and that consideration of progenitor aging will facilitate development of physiologically and clinically relevant animal models of human gliomas.

Left iliac artery injury during anterior lumbar spine surgery diagnosed by intraoperative neurophysiological monitoring

Serious vascular injury is a rare, but potentially devastating complication during anterior lumbar spinal surgery. The authors describe the first reported case where vascular injury was detected by multimodality neurophysiological monitoring during an L3–S1 anterior lumbar interbody fusion. The case demonstrates the need for multi-modality monitoring and the combined use of somatosensory-evoked potentials and motor-evoked potentials.

Innovative Hypofractionated Stereotactic Regimen Achieves Excellent Local Control with No Radiation Necrosis: Promising Results in the Management of Patients with Small Recurrent Inoperable GBM

Management of recurrent glioblastoma multiforme (GBM) remains a challenge. Several institutions reported that a single fraction of ≥ 20 Gy for small tumor burden results in excellent local control; however, this is at the expense of a high incidence of radiation necrosis (RN). Therefore, we developed a hypofractionation pattern of 33 Gy/3 fractions, which is a radiobiological equivalent of 20 Gy, with the aim to lower the incidence of RN. We reviewed records of 21 patients with recurrent GBM treated with hypofractionated stereotactic radiation therapy (HFSRT) to their 22 respective lesions. Sixty Gy fractioned external beam radiotherapy was performed as first-line treatment. Median time from primary irradiation to HFSRT was 9.6 months (range: 3.1 – 68.1 months). In HFSRT, a median dose of 33 Gy in 11 Gy fractions was delivered to the 80% isodose line that encompassed the target volume. The median tumor volume was 1.07 cm3 (range: 0.11 – 16.64 cm3). The median follow-up time after HFSRT was 9.3 months (range: 1.7 – 33.6 months). Twenty-one of 23 lesions treated (91.3%) achieved local control while 2/23 (8.7%) progressed. Median time to progression outside of the treated site was 5.2 months (range: 2.2 – 9.6 months). Progression was treated with salvage chemotherapy. Five of 21 patients (23.8%) were alive at the end of this follow-up; two patients remain disease-free. The remaining 16/21 patients (76.2%) died of disease. Treatment was well tolerated by all patients with no acute CTC/RTOG > Grade 2. There was 0% incidence of RN. A prospective trial will be underway to validate these promising results.