Abstract
Intratumoral and interpatient heterogeneity are characteristics of glioblastoma and constitute important challenges in overcoming treatment resistance and developing new, more effective ...therapies. Using single-cell RNA sequencing, we characterized 60 933 cells from 4 developing fetal brains and 8 glioblastomas. By using fetal brain development as a road map, we show a tri-lineage (astrocytic, oligodendrocytic, and neuronal) hierarchical organization in all glioblastomas. In each patient, a population of progenitor cancer cells was found at the apex of this hierarchy. These cells were enriched in our patient-derived glioma stem cell samples, and, like progenitors in the developing brain, were the main dividing cell population within the cancer. Using expression signatures obtained from single-cell RNA-sequencing, we isolated progenitor cancer cells and compared them to other glioblastoma cell types. We showed the progenitors are the most resistant to chemotherapy and the most tumorigenic in mouse xenograft models. This newly found conserved developmental organization points to the cell of origin and suggests new therapeutic approaches.
Abstract
Background
The overall prognosis of glioblastoma (GBM) remains dismal, particularly for patients with unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In this phase II ...trial, we tested the combination of the antiangiogenic agent sunitinib with radiotherapy and temozolomide (TMZ) for newly diagnosed unmethylated MGMT GBM patients.
Methods
We enrolled 37 patients with unmethylated MGMT promoter GBM, age 18–70, and KPS ≥70. Patients received 12.5 mg of daily sunitinib for 7 days, followed by concurrent chemoradiation plus 12.5 mg sunitinib, then adjuvant TMZ. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), safety, and neutrophil-to-lymphocyte ratio (NLR) biomarker.
Results
At a median follow-up time of 15.3 months (range: 3.1–71.3 months), the median PFS was 7.15 months (95% CI: 5.4–10.5) and the 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8–19.4) and 2-year OS rate was 17.1%. Patients receiving >3 cycles of adjuvant TMZ, undergoing surgery at progression, and presenting a post-concurrent NLR ≤6 experienced a significant improved OS with hazard ratios of 0.197 (P = .001), 0.46 (P = .049), and 0.38 (P = .021), respectively, on multivariable analysis. Age >65 years predicted for worse OS with hazard ratio of 3.92 (P = .037). Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20%, and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events.
Conclusion
Our findings suggest a potential benefit of combining sunitinib with chemoradiation in newly diagnosed GBM patients with unmethylated MGMT status and provide a strong rationale to test this combination in future studies.
The Structural Genomics Consortium (SGC) and its clinical, industry and disease-foundation partners are launching open-source preclinical translational medicine studies.
The goal of this study was to find a registration technique to improve the alignment of ultrasound images taken before and after brain tumor resection. Validation was performed on 16 tumor cases in 2 ...ways: (1) manually selected tags on pre- and postresection ultrasounds were used to compute the mean Euclidean distance between corresponding points in the 2 volumes before and after registration; and (2) the surgeon was asked to rank and rate the quality of the alignment before and after registration. The mean distance was 2.7 mm after a rigid registration and 1.7 mm after a nonlinear registration. Of 16 cases, the surgeon determined that initially only 2 were satisfactorily aligned; after the rigid registration, 5 were satisfactory, and after the nonlinear registration, 13 were satisfactory. According to both the distance and the ranking metrics, the nonlinear registration approach significantly improved the alignment of the ultrasound images.
We present our work investigating the feasibility of combining intraoperative ultrasound for brain shift correction and augmented reality (AR) visualization for intraoperative interpretation of ...patient-specific models in image-guided neurosurgery (IGNS) of brain tumors. We combine two imaging technologies for image-guided brain tumor neurosurgery. Throughout surgical interventions, AR was used to assess different surgical strategies using three-dimensional (3-D) patient-specific models of the patient's cortex, vasculature, and lesion. Ultrasound imaging was acquired intraoperatively, and preoperative images and models were registered to the intraoperative data. The quality and reliability of the AR views were evaluated with both qualitative and quantitative metrics. A pilot study of eight patients demonstrates the feasible combination of these two technologies and their complementary features. In each case, the AR visualizations enabled the surgeon to accurately visualize the anatomy and pathology of interest for an extended period of the intervention. Inaccuracies associated with misregistration, brain shift, and AR were improved in all cases. These results demonstrate the potential of combining ultrasound-based registration with AR to become a useful tool for neurosurgeons to improve intraoperative patient-specific planning by improving the understanding of complex 3-D medical imaging data and prolonging the reliable use of IGNS.
Kv4.2 potassium channels play a critical role in postsynaptic excitability. Immunocytochemical studies reveal a somatodendritic Kv4.2 expression pattern, with the channels concentrated mainly at ...dendritic spines. The molecular mechanism that underlies the localization of Kv4.2 to this subcellular region is unknown. We used the yeast two-hybrid system to identify the Kv4.2-associated proteins that are involved in channel localization. Here we demonstrate a direct interaction between Kv4.2 and the actin-binding protein, filamin. We show that Kv4.2 and filamin can be coimmunoprecipitated both in vitro and in brain and that Kv4.2 and filamin share an overlapping expression pattern in the cerebellum and cultured hippocampal neurons. To examine the functional consequences of this interaction, we expressed Kv4.2 in filamin(+) and filamin(-) cells and performed immunocytochemical and electrophysiological analyses. Our results indicate that Kv4.2 colocalizes with filamin at filopodial roots in filamin(+) cells but shows a nonspecific expression pattern in filamin(-) cells, with no localization to filopodial roots. Furthermore, the magnitude of whole-cell Kv4.2 current density is approximately 2.7-fold larger in filamin(+) cells as compared with these currents in filamin(-) cells. We propose that filamin may function as a scaffold protein in the postsynaptic density, mediating a direct link between Kv4.2 and the actin cytoskeleton, and that this interaction is essential for the generation of appropriate Kv4.2 current densities.
Obtaining accurate quantitative information on the concentration and distribution of fluorescent markers lying at a depth below the surface of optically turbid media, such as tissue, is a significant ...challenge. Here, we introduce a fluorescence reconstruction technique based on a diffusion light transport model that can be used during surgery, including guiding resection of brain tumors, for depth-resolved quantitative imaging of near-infrared fluorescent markers. Hyperspectral fluorescence images are used to compute a topographic map of the fluorophore distribution, which yields structural and optical constraints for a three-dimensional subsequent hyperspectral diffuse fluorescence reconstruction algorithm. Using the model fluorophore Alexa Fluor 647 and brain-like tissue phantoms, the technique yielded estimates of fluorophore concentration within ±25% of the true value to depths of 5 to 9 mm, depending on the concentration. The approach is practical for integration into a neurosurgical fluorescence microscope and has potential to further extend fluorescence-guided resection using objective and quantified metrics of the presence of residual tumor tissue.
BACKGROUND Endoscopic third ventriculostomy (ETV) is a successful procedure for treating noncommunicating hydrocephalus as an alternative to initial ventriculoperitoneal (VP) shunt placement and as a ...salvage procedure when a VP shunt fails. Physiological changes of pregnancy can lead to VP shunt failure and complicate the management of shunt malfunction, particularly in the third trimester. OBSERVATIONS The authors present a case in which an ETV was successfully used in the third trimester (31 weeks of gestation) of pregnancy for acute hydrocephalus due to VP shunt malfunction, and the patient went on to deliver a healthy baby at term; the patient remained well in the long-term follow-up. An English-language PubMed literature review revealed four cases of VP shunt failure successfully treated with an ETV in the first or second trimester but no such reports in the third trimester of pregnancy. LESSONS ETV appears to be a safe and effective alternative to VP shunt replacement in the late prenatal period of pregnancy.
Subsets of breast tumors present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare histologies. Here, we developed 37 patient-derived xenografts (PDX) from ...these difficult-to-treat cancers to interrogate their molecular composition and functional biology. Whole-genome and transcriptome sequencing and reverse-phase protein arrays revealed that PDXs conserve the molecular landscape of their corresponding patient tumors. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases were most common, though a subset of models displayed high rates of dissemination in organotropic or diffuse patterns consistent with what was observed clinically. Chemosensitivity profiling was performed in vivo with standard-of-care agents, where multi-drug chemoresistance was retained upon xenotransplantation. Consolidating chemogenomic data identified actionable features in the majority of PDXs, and marked regressions were observed in a subset that was evaluated in vivo. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for preclinical studies on difficult-to-treat breast tumors.
Abstract
BACKGROUND
Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC ...(extended-release 5-fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Three Ph1 studies in patients with recurrent high grade glioma have demonstrated a tolerable safety profile and encouraging efficacy.
METHODS
Toca 5 is a multi-national, randomized, open-label Ph3 trial (NCT02414165) of Toca 511 & Toca FC versus standard of care (SOC) options that comprises Investigator’s choice of single agent chemotherapy (lomustine, temozolomide) or bevacizumab in patients who have undergone resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. 403 patients were randomized 1:1 to the Toca arm or the SOC arm and stratified by IDH1 status, KPS, and geographic region. Primary endpoint was overall survival (OS), and secondary endpoints were durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. The study used group sequential design including 2 interim analyses and 1 final analysis, and the stratified log-rank test are used for the analysis.
RESULTS
271 events were observed for this analysis. Median follow-up was 22.8 months, and the Toca arm missed the primary endpoint (OS) compared to the SOC arm (11.1 months median compared to 12.2 months, HR=1.06, p=0.6154). All secondary endpoints showed no meaningful difference between the arms of the trial. The safety, tolerability and adverse event profile of Toca 511 and Toca FC was as expected for this patient population, with low incidences of Grade 3–4 adverse events. Pre-planned subgroup analyses showed compelling OS improvement in patients with secondary recurrence, and favorable trends in IDH1 mutant and AA population. Detailed data will be presented at the time of the conference.
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