Steven A. Toms

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial

IMPORTANCE Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00916409.

Fiducial point placement and the accuracy of point-based, rigid body registration.

OBJECTIVETo demonstrate that the shape of the configuration of fiducial points is an important factor governing target registration error (TRE) in point-based, rigid registration. METHODSWe consider two clinical situations: cranial neurosurgery and pedicle screw placement. For cranial neurosurgery, we apply theoretical results concerning TRE prediction, which we have previously derived and validated, to three hypothetical fiducial marker configurations. We illustrate the profile of expected TRE for each configuration. For pedicle screw placement, we apply the same theory to a common anatomic landmark configuration (tips of spinous and transverse processes) used for pedicle screw placement, and we estimate the error rate expected in placement of the screw. RESULTSIn the cranial neurosurgery example, we demonstrate that relatively small values of TRE may be achieved by using widely spread fiducial markers and/or placing the centroid of the markers near the target. We also demonstrate that near-collinear marker configurations far from the target may result in large TRE values. In the pedicle screw placement example, we demonstrate that the screw must be approximately 4 mm narrower than the pedicle in which it is implanted to minimize the chance of pedicle violation during placement. CONCLUSIONThe placement of fiducial points is an important factor in minimizing the error rate for point-based, rigid registration. By using as many points as possible, avoiding near-collinear configurations, and ensuring that the centroid of the fiducial points is as near as possible to the target, TREs can be minimized.

Proteomic-Based Prognosis of Brain Tumor Patients Using Direct-Tissue Matrix-Assisted Laser Desorption Ionization Mass Spectrometry

Clinical diagnosis and treatment decisions for a subset of primary human brain tumors, gliomas, are based almost exclusively on tissue histology. Approaches for glioma diagnosis can be highly subjective due to the heterogeneity and infiltrative nature of these tumors and depend on the skill of the neuropathologist. There is therefore a critical need to develop more precise, non-subjective, and systematic methods to classify human gliomas. To this end, mass spectrometric analysis has been applied to these tumors to determine glioma-specific protein patterns. Protein profiles have been obtained from human gliomas of various grades through direct analysis of tissue samples using matrix-assisted laser desorption ionization mass spectrometry (MS). Statistical algorithms applied to the MS profiles from tissue sections identified protein patterns that correlated with tumor histology and patient survival. Using a data set of 108 glioma patients, two patient populations, a short-term and a long-term survival group, were identified based on the tissue protein profiles. In addition, a subset of 57 patients diagnosed with high-grade, grade IV, malignant gliomas were analyzed and a novel classification scheme that segregated short-term and long-term survival patients based on the proteomic profiles was developed. The protein patterns described served as an independent indicator of patient survival. These results show that this new molecular approach to monitoring gliomas can provide clinically relevant information on tumor malignancy and is suitable for high-throughput clinical screening.

Protein Profiling in Brain Tumors Using Mass Spectrometry Feasibility of a New Technique for the Analysis of Protein Expression

Purpose: The purpose of this research was to perform a preliminary assessment of protein patterns in primary brain tumors using a direct-tissue mass spectrometric technique to profile and map biomolecules. Experimental Design: We examined 20 prospectively collected, snap-frozen normal brain and brain tumor specimens using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS), and compared peptide and protein expression in primary brain tumor and nontumor brain tissues. Results: MS can be used to identify protein expression patterns in human brain tissue and tumor specimens. The mass spectral patterns can reliably identify glial neoplasms of similar histological grade and differentiate them from tumors of different histological grades as well as from nontumor brain tissues. Initial bioinformatics cluster analysis algorithms classified tumor and nontumor tissues into similar groups comparable with their histological grade. Conclusions: We describe a novel tool for the analysis of protein expression patterns in human glial neoplasms. Initial results demonstrate that MALDI-MS technology can significantly aid in the process of unraveling and understanding the molecular complexities of gliomas. MALDI-MS accurately and reliably identified normal and neoplastic tissues, and could be used to discriminate between tumors of increasing grades.

In Vivo Brain Tumor Demarcation Using Optical Spectroscopy

Abstract The applicability of optical spectroscopy for intraoperative detection of brain tumors/tumor margins was investigated in a pilot clinical trial consisting of 26 brain tumor patients. The results of this clinical trial suggest that brain tumors and infiltrating tumor margins (ITM) can be effectively separated from normal brain tissues in vivo using combined autofluorescence and diffuse-reflectance spectroscopy. A two-step empirical discrimination algorithm based on autofluorescence and diffuse reflectance at 460 and 625 nm was developed. This algorithm yields a sensitivity and specificity of 100 and 76%, respectively, in differentiating ITM from normal brain tissues. Blood contamination was found to be a major obstacle that attenuates the accuracy of brain tumor demarcation using optical spectroscopy. Overall, this study indicates that optical spectroscopy has the potential to guide brain tumor resection intraoperatively with high sensitivity.

Pathobiology of brain metastases

Brain metastasis is a major cause of systemic cancer morbidity and mortality. Many factors participate in the development and maintenance of brain metastases. The survival of the metastasis depends upon crucial interactions between tumour cells and the brain microenvironment during its development at the new site. This review focuses on the pathobiological mechanisms involved in the establishment and regulation of brain metastases. Developments in molecular biology have vastly expanded our knowledge about the mechanisms of invasion, proliferation, metastatic cell signalling, and angiogenesis in brain metastases. Advances in this understanding of the pathobiology of brain metastasis may lead to novel targeted treatment paradigms and a better prognosis for patients with brain metastatic disease.

Intraoperative optical spectroscopy identifies infiltrating glioma margins with high sensitivity.

OBJECTIVE Adult gliomas have indistinct borders. As the ratio of neoplastic cells to normal cells becomes lower, the ability to detect these cells diminishes. We describe a device designed to augment intraoperative identification of both solid tumor and infiltrating tumor margins. METHODS A novel, intraoperative, optical spectroscopic tool, using both white light reflectance and 337-nm excitation fluorescence spectroscopy, is described. Discrimination algorithms have been developed to segregate neoplastic tissues from normal glial and neuronal elements. The spectroscopy device was used to measure 5 to 10 locations during glioma resection. Beneath the tool, a biopsy sample was obtained and the pathological results were reviewed in a blinded fashion. Samples were classified as solid tumor, infiltrating tumor, or normal gray or white matter. Comparisons were made between the optical spectra and the histopathological results of sampled areas in evaluating the sensitivity and specificity of the tool for tissue discrimination. RESULTS Spectral data were obtained from 24 patients with glioma and from 11 patients with temporal lobe epilepsy. A sensitivity of 80% and a specificity of 89% in discriminating solid tumor from normal tissues were obtained. In addition, infiltrating tumor margins were distinguished from normal tissues with a sensitivity of 94% and a specificity of 93%. CONCLUSION We have developed a handheld, optical spectroscopic device that may be used rapidly and in near real time with high sensitivity and reproducibility as an optical tissue discrimination tool in glioma surgery.

Brain tumor demarcation using optical spectroscopy; an in vitro study

Optical spectroscopy for brain tumor demarcation was investigated in this study. Fluorescence and diffuse reflectance spectra were measured from normal and tumorous human brain tissues in vitro. A fluorescence peak was consistently observed around 460 nm (+/- 10 nm) emission from both normal and tumorous brain tissues using 337 nm excitation. Intensity of this fluorescence peak (F460) from normal brain tissues was greater than that from primary brain tumorous tissues. In addition, diffuse reflectance (Rd) between 650 and 800 nm from white matter was significantly stronger than that from primary and secondary brain tumors. A good separation between gray matter and brain tumors was found using the ratio of F460 and Rd at 460 nm (Rd460). Two empirical discrimination algorithms based on F460, Rd625, and F460/Rd460 were developed. These algorithms yielded an average sensitivity and specificity of 96% and 93%, respectively.

QUANTUM DOTS ARE PHAGOCYTIZED BY MACROPHAGES AND COLOCALIZE WITH EXPERIMENTAL GLIOMAS

OBJECTIVEThe identification of neoplastic tissue within normal brain during biopsy and tumor resection remains a problem in the operative management of gliomas. A variety of nanoparticles are phagocytized by macrophages in vivo. This feature may allow optical nanoparticles, such as quantum dots, to colocalize with brain tumors and serve as an optical aid in the surgical resection or biopsy of brain tumors. METHODSMale Fisher rats (Charles River Labs, Wilmington, MA) were implanted intracranially with C6 gliosarcoma cell lines to establish tumors. Two weeks after the implantation of tumors, 705-nm emission Qdot ITK Amino(PEG) Quantum Dots (Quantum Dot Corp., Hayward, CA) were injected via the tail vein at doses of 3 to 17 nmol. The animals were sacrificed 24 hours after the injection of quantum dots and their tissues were examined. RESULTSQuantum dots are avidly phagocytized by macrophages and are taken up by the liver, spleen, and lymph nodes. A dose-response relationship was noted. At low doses, the majority of the quantum dots are sequestered in the liver, spleen, and lymph nodes. At higher doses, increasing quantities of quantum dots are noted within the experimental brain tumors. Macrophages and microglia colocalize with glioma cells, carrying the quantum dot and thereby optically outlining the tumor. Excitation with blue or ultraviolet wavelengths stimulates the quantum dots, which give off a deep red fluorescence detectable with charge-coupled device cameras, optical spectroscopy units, and in dark-field fluorescence microscopy. CONCLUSIONQuantum dots are optical nanoparticles that, when delivered in nanomole doses, are phagocytized by the macrophages and microglia that infiltrate experimental gliomas. The optical signal may be detected, allowing for improved identification and visualization of tumors, potentially augmenting brain tumor biopsy and resection.

Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma a randomized clinical trial

Importance Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures Progression-free survival (tested at &agr; = .046). The secondary end point was overall survival (tested hierarchically at &agr; = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration clinicaltrials.gov Identifier: NCT00916409