Tucatinib's journey from clinical development to clinical practice: New horizons for HER2-positive metastatic disease and promising prospects for brain metastatic spread.

Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice.

Magnetic resonance imaging characteristics of pediatric pilocytic astrocytoma.

PURPOSE: MRI has an important role in diagnosing pilocytic astrocytoma and post-surgical follow-up since the surgical approach has a leading role in its treatment. The purpose of our study is to provide an overview of the typical and atypical MRI findings in a series of pediatric patients with isolated-not NF1-related-pilocytic astrocytomas and to correlate specific MRI patterns with clinical variables. METHODS: This is a cross-sectional retrospective study providing the analysis of several clinical and neuroradiological findings from a cohort of pediatric pilocytic astrocytoma, starting from the data collected in the Fondazione IRCCS Istituto Neurologico Carlo Besta (FINCB) internal Cancer Registry during an 11-year time period (January 2008-January 2019). RESULTS: Fifty-six patients were included in the study. Median age at diagnosis was 9.4 years; a slight female prevalence was noticed (m/f ratio 44.6%/55.4%). The majority of pPAs had well-defined contours: 51 (91.1%), 47 (88.7%) were hypointense on T1-wi, all of them were hyperintense on T2-wi, 46 (90.2%) were hyperintense on FLAIR, and 48 (85.7%) were heterogeneous on T1-wi and T2-wi sequences. We found positive correlation between pPAs location and age (r = 0.017), and small degree of connection between pPAs location and gender (Cramer's V = 0.268). CONCLUSIONS: We presented typical and atypical pPAs MRI findings. Age and tumor location were positevely correlated, while degree of connection between gender and pPAs location was small. All of this may aid clinicians, most of all neuroradiologists, neurosurgeons, and neurologists in proper diagnoses and follow-up of these specific patient population.

Surgical management of Glioma Grade 4: technical update from the neuro-oncology section of the Italian Society of Neurosurgery (SINch®): a systematic review.

PURPOSE: The extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal. METHODS: A systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients. RESULTS: A total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early postoperative MRI, with CE II and SR B. The EOR was defined the strongest independent risk factor for both OS and tumor recurrence with CE II and SR B. For intraoperative imaging only the use of 5-ALA reached a CE II and SR B. The estimation of EOR was established to be fundamental in planning postoperative adjuvant treatments with CE II and SR B and the stereotactic image-guided brain biopsy to be the procedure of choice when an extensive surgical resection is not feasible (CE II and SR B). CONCLUSIONS: A growing number of evidences evidence support the role of maximal safe resection as primary OS predictor in GG4 patients. The ongoing development of intraoperative techniques for a precise real-time identification of peritumoral functional pathways enables surgeons to maximize EOR minimizing the post-operative morbidity.

The "STARS" study: advanced preoperative rehearsal and intraoperative navigation in neurosurgical oncology.

BACKGROUND: Neurosurgical 3D visualizers and simulators are innovative devices capable of defining a surgical strategy in advance and possibly making neurosurgery safer by rehearsing the phases of the operation beforehand. The aim of this study is to evaluate Surgical Theater™ (Surgical Theater LLC, Mayfield, OH, USA), a new 3D neurosurgical planning, simulation, and navigation system, and qualitatively assess its use in the operating room. METHODS: Clinical data were collected from 30 patients harboring various types of brain tumors; Surgical Theater™ was used for the preoperative planning and intraoperative 3D navigation. Preoperative and postoperative questionnaires were completed by first and second operators to get qualitative feedback on the system's functionality. Furthermore, we measured and compared the impact of this technology on surgery duration. RESULTS: Neurosurgeons were overall satisfied when using this rehearsal and navigation tool and found it efficient and easy to use; interestingly, residents considered this device more useful as compared to their more senior colleagues (with significantly higher scores, P<0.05), possibly because of their limited anatomical experience and spatial/surgical rehearsal ability. The length of the surgical procedure was not affected by this technology (P>0.05). CONCLUSIONS: Surgical Theater™ system was found to be clinically useful in improving anatomical understanding, surgical planning, and intraoperative navigation, especially for younger and less experienced neurosurgeons.

A new study protocol for in-vivo assessment of tumor diagnosis and microscopic tumor infiltration at the resection cavity in central nervous system tumors by a new miniature confocal endomicroscope (CONVIVO system).

BACKGROUND: Confocal laser technology has been recently suggested as a promising method to obtain near real-time intraoperative histological data. We recently demonstrated the accuracy of a newly designed confocal endomiscroscope (CONVIVO) in offering an intraoperative diagnosis during high-grade gliomas (HGGs) removal in an ex vivo study. With this work we aim to perform a standardized, prospective and blinded-to-histological section study for evaluating the potentiality of CONVIVO in offering in-vivo data regarding histological diagnosis and presence of tumor at margins during resection of central nervous system (CNS) tumors. METHODS: This prospective, observational, standardized, blinded-to-histological section, clinical trial was approved by the institutional review board in Carlo Besta Neurologic Institute IRCCS Foundation in Milan and is expected to last 24 months. 75 patients will be included, with at least 53 of them being HGGs based on the statistical sample size calculation. Main objectives will be the assessing of the concordance of tumor diagnoses between CONVIVO images and frozen section at the center of all tumor subtypes and the evaluation of the accuracy of CONVIVO in the identification of tumor tissue at the margins, compared to standard histology. For this purpose, "virtual biopsies" and physical biopsies will be performed directly on patient tumor tissue and surrounding brain parenchima during tumor resection, comparing the results of CONVIVO analysis and frozen and histological sections. RESULTS: Despite promising preliminary data on ex vivo usefulness of CLE machines are emerging in literature, still few studies are available when looking at in vivo potentiality of CONVIVO. At this regard, this study will be the first work where a standardized, prospective, and blinded-to-histological section CONVIVO analysis will be performed in an in-vivo setting in neuro-oncological surgery. CONCLUSIONS: We hypothesize that this new technique may have a role in offering data regarding presence of tumor tissue, eventually giving an intraoperative diagnosis in neuro-oncological surgery, rendering more fluid the decision-making process in the operating room. Furthermore, the result of this study will provide a solid base for further expanding the clinical applications of confocal machines in neurosurgery.

Diagnostic and surgical management of primary central nervous system angioleiomyoma: A case report and literature review.

Angioleiomyoma (ALM) is a benign smooth muscle neoplasm that mainly occurs in lower extremities subcutaneous tissue and generally affects middle-aged adults. This tumor histotype may rarely localize intracranially, although only a few cases have been described in the literature. We report a case of intracranial ALM, whose differential diagnosis has been particularly challenging, and firstly provide a comprehensive radiological and intra-operative evaluation of a such rare entity. This represents also the first report of the use of intraoperative confocal microscopy in ALM and the first documented short-term recurrence. At this regard, a scoping literature review has been conducted with the aim of presenting the major clinical and diagnostic features along with the proposed therapeutic strategies.

Intracranial Sonodynamic Therapy With 5-Aminolevulinic Acid and Sodium Fluorescein: Safety Study in a Porcine Model.

BACKGROUND: Sonodynamic therapy (SDT) is an emerging ultrasound-based treatment modality for malignant gliomas which combines ultrasound with sonosensitizers to produce a localized cytotoxic and modulatory effect. Tumor-specificity of the treatment is achieved by the selective extravasation and accumulation of sonosensitizers in the tumor-bearing regions. The aim of this study is to demonstrate the safety of low-intensity ultrasonic irradiation of healthy brain tissue after the administration of FDA-approved sonosensitizers used for SDT in experimental studies in an in vivo large animal model. METHODS: In vivo safety of fluorescein (Na-Fl)- and 5 aminolevulinic acid (5-ALA)-mediated low-intensity ultrasound irradiation of healthy brain parenchyma was assessed in two sets of four healthy swine brains, using the magnetic resonance imaging (MRI)-guided Insightec ExAblate 4000 220 kHz system. After administration of the sonosensitizers, a wide fronto-parietal craniotomy was performed in pig skulls to allow transmission of ultrasonic beams. Sonication was performed on different spots within the thalamus and periventricular white matter with continuous thermal monitoring. Sonication-related effects were investigated with MRI and histological analysis. RESULTS: Post-treatment MRI images acquired within one hour following the last sonication, on day one, and day seven did not visualize any sign of brain damage. On histopathology, no signs of necrosis or apoptosis attributable to the ultrasonic treatments were shown in target areas. CONCLUSIONS: The results of the present study suggest that either Na-FL or 5-ALA-mediated sonodynamic therapies under MRI-guidance with the current acoustic parameters are safe towards healthy brain tissue in a large in vivo model. These results further support growing interest in clinical translation of sonodynamic therapy for intracranial gliomas and other brain tumors.

Sonodynamic Therapy for the Treatment of Intracranial Gliomas.

High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas.

Resection of primary central nervous system lymphoma: impact of patient selection on overall survival.

OBJECTIVE: Primary central nervous system lymphoma (PCNSL) is a rare CNS tumor with a poor prognosis. It is usually diagnosed by needle biopsy and treated mainly with high-dose chemotherapy. Resection is currently not considered a standard treatment option. A possible prolonged survival after resection of PCNSL lesions in selected patients has been suggested, but selection criteria for surgery, especially for solitary lesions, have never been established. METHODS: The authors retrospectively searched their patient database for records of adult patients (≥ 18 years) who were diagnosed and treated for a solitary PCNSL between 2005 and 2019. Patients were divided into groups according to whether they underwent resection or needle biopsy. Statistical analyses were performed in an attempt to identify variables affecting outcome and possible survival advantage and to characterize subgroups of patients who would benefit from resection of their tumor compared with undergoing biopsy only. RESULTS: A total of 113 patients with a solitary lesion of PCNSL were identified; 36 patients underwent resection, and 77 had a diagnostic stereotactic biopsy only. The statically significant preoperative risk factors included age ≥ 70 years (adjusted HR 9.61, 95% CI 2.42-38.11; p = 0.001), deep-seated lesions (adjusted HR 3.33, 95% CI 1.13-9.84; p = 0.030), and occipital location (adjusted HR 4.26, 95% CI 1.08-16.78; p = 0.039). Having a postoperative Karnofsky Performance Scale (KPS) score < 80 (adjusted HR 3.21, 95% CI 1.05-9.77; p = 0.040) and surgical site infection (adjusted HR 4.27, 95% CI 1.18-15.47; p = 0.027) were significant postoperative risk factors after the adjustment and selection by means of other possible risk factors. In a subgroup analysis, patients younger than 70 years who underwent resection had a nonsignificant trend toward longer survival than those who underwent needle biopsy (median survival 35.0 months vs 15.2 months, p = 0.149). However, patients with a superficial tumor who underwent resection had significantly longer survival times than those who underwent needle biopsy (median survival 34.3 months vs 8.9 months, p = 0.014). Patients younger than 70 years who had a superficial tumor and underwent resection had significantly prolonged survival, with a median survival of 35.0 months compared with 8.9 months in patients from the same group who underwent needle biopsy (p = 0.007). CONCLUSIONS: Specific subgroups of patients with a solitary PCNSL lesion might gain a survival benefit from resection compared with undergoing only a diagnostic biopsy.

Incidence and risk factors of neurosurgical site infections: results of a prospective multicenter cohort study on 6359 surgeries.

BACKGROUND: Neurosurgical surgical site infections (SSI) are life-threatening complications, requiring medical treatment and additional surgeries and remain a substantial cause of morbidity. In order to identify the incidence and the main risk factors for SSI, we developed the Prophylaxis with Antibiotic Protocol for Neurosurgical Site Infections Study (PASSIS), a prospective observational multicenter cohort study for examining a large number of neurosurgical procedures. METHODS: The study PASSIS involved four Italian departments of neurosurgery applying the same antibiotic prophylaxis (ABP) protocol on 6359 consecutive neurosurgical procedures. In high-risk conditions (intra-operative contamination and/or postoperative cerebro-spinal fluid [CSF], and/or subcutaneous drainage and/or postoperative hyperpyrexia) and in presence of wound complication (CSF leak and/or CSF collection and/or wound diastasis), a prolongation protocol was prescribed. RESULTS: The crude rate of SSI in the whole series was and 1.7% for patient and 1.5% for procedure. Patient related SSI risk factors: Younger patients (≤14 years) had a significantly higher SSI risk compared with older patients (RR: 2.17; 95% CI: 1.13-4.14). Patients underwent two surgeries were at increased SSI risk (RR: 3.80; 95% CI: 2.33-6.18), and the risk increased with the number of surgeries. Surgeries lasting longer than 3 hours (RR: 2.27; 95% CI: 1.15-4.50), undergoing two or more surgeries and the presence of prosthetic implants (RR: 2.40; 95% CI: 1.53-3.77) were procedure related SSI risk factors positively associated with SSI. In high-risk conditions and in wound complication as defined previously, ABP prolongation showed limited efficacy (RR:1.97; 95% CI: 1.21-3.22 and 9.31; 95% CI: 5.90-14.68 respectively). CONCLUSIONS: The subjects submitted to complicated, repeated, long lasting craniotomies, especially if experiencing postoperative deterioration, display the higher risk of SSIs, as a final life-threatening complication. In order to reduce the SSI rate, further studies should address to design tailored prophylaxis protocols for each high risk situation as hereby defined; the wound complications deserve an increased microbiological surveillance, focusing the attention on the timing and source of infections.

Characteristics of Patients Returning to Work After Brain Tumor Surgery.

Objective: To investigate the differences between patients returning to work and those who did not after brain tumor surgery. Methods: Patients were evaluated before surgery and after 3 months. The Montreal Cognitive Assessment test, Trail-Making Test (parts A and B), 15-word Rey-Osterrieth Word List (immediate and delayed recall), F-A-S tests, and Karnosfky Performance Status were used to assess cognitive status, attention, executive functions, memory, word fluency, and functional status. Patient-reported outcome measures (PROMs) used to evaluate emotional distress and disability were the Hospital Anxiety and Depression Scale and World Health Organization Disability Assessment Schedule. Clinical and work-related variables, PROMs, and cognitive tests were compared using chi-squared, t-test or Mann-Whitney U test. Results: Sixty patients were included. Patients returning to work were 61.3 and 31.0% among people with meningioma and glioma, respectively. They reported lower postoperative disability and lesser home-to-work travel time. Patients with meningioma also showed better preoperative and postoperative attention and executive functions, better postoperative functional and cognitive status, and lower frequency of treatments. Conclusions: These variables should be considered in a clinical context to plan interventions for people who need support during return to work and in future research to investigate preoperative and postoperative predictive factors of going back to work.

In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents.

Real-time intraoperative imaging for brain tumor surgery is crucial for achieving complete resection. We are developing novel lipid-based microbubbles (MBs), engineered with specific ligands, which are able to interact with the integrins overexpressed in the endothelium of the brain tumor vasculature. These MBs are designed to visualize the tumor and to carry therapeutic molecules into the tumor tissue, preserving the ultrasound acoustic properties of the starting plain lipid MBs. The potential toxicity of this novel technology was assessed in rats by intravenous injections of two doses of plain MBs and MBs engineered for targeting and near-infrared fluorescence visualization at two time-points, 10 min and 7 days, for potential acute and chronic responses in rats [(1) MB, (2) MB-ICG, (3) MB-RGD, and (4) MB-ICG-RGD]. No mortality occurred during the 7-day study period in any of the dosing groups. All animals demonstrated a body weight gain during the study period. Minor, mostly reversible changes in hematological and biochemical analysis were observed in some of the treated animals. All changes were reversible by the 7-day time-point. Histopathology examination in the high-dose animals showed development of foreign body granulomatous inflammation. We concluded that the low-dose tested items appear to be safe. The results allow for proceeding to clinical testing of the product.

In Vivo Biodistribution of Engineered Lipid Microbubbles in Rodents.

Maximal resection of intrinsic brain tumors is a major prognostic factor for survival. Real-time intraoperative imaging tools, including ultrasound (US), are crucial for maximal resection of such tumors. Microbubbles (MBs) are clinically used in daily practice as a contrast agent for ultrasound and can be further developed to serve combined therapeutic and diagnostic purposes. To achieve this goal, we have developed novel MBs conjugated to specific ligands to receptors which are overexpressed in brain tumors. These MBs are designed to target a tumor tissue, visualize it, and deliver therapeutic molecules into it. The objective of this study was to assess the biodistribution of the test items: We used MBs labeled with indocyanine green (MB-ICG) for visualization and MBs conjugated to a cyclic molecule containing the tripeptide Arg-Gly-Asp (RGD) labeled with ICG (MB-RGD-ICG) to target brain tumor integrins as the therapeutic tools. Male Sprague Dawley rats received a single dose of each MB preparation. The identification of the MB in various organs was monitored by fluorescence microscopy in anesthetized animals as well as real-time US for brain imaging. Equally sized control groups under identical conditions were used in this study. One control group was used to establish fluorescence background conditions (ICG), and two control groups were used to test autofluorescence from the test items (MBs and MB-RGD). ICG with or without MBs (naked or RGD-modified) was detected in the brain vasculature and also in other organs. The pattern, duration, and intensity of the fluorescence signal could not be differentiated between animals treated with ICG alone and animals treated with microbubbles MBs-ICG or MBs-RGD-ICG. Following MB injection, either naked or combined with RGD, there was a sharp rise in the Doppler signal within seconds of injection in the brain. The signal was mainly located at the choroid plexus, septum pellucidum, and the meninges of the brain. The signal subsided within a few minutes. Injection of saline or ICG alone to respective animals did not result in a similar raised signal. Following a single intravenous administration of MB-ICG and MB-RGD-ICG to rats, the MBs were found to be effectively present in the brain.

Ultrasound guided mini-invasive tailored approach and intraoperative neurophysiological monitoring: a synergistic strategy for the removal of tumors near the motor cortex. A preliminary experience.

BACKGROUND: The aim of this paper was to evaluate the synergic strategy comprising intraoperative neurophysiological monitoring and ultrasound sonography in terms of clinical motor scores and extent of resection. METHODS: Patients harboring tumors in close relationship with the motor cortex were operated on with image-guided mini-invasive approach and multimodal neurophysiological monitoring. The peculiarity is the partial exposure of the motor cortex and the limited electrophysiological mapping used to search for negative spots. Multimodal neurophysiological monitoring comprised the electrocortical stimulation, somatosensory evoked potentials, motor evoked potentials and subcortical stimulation. Ultrasound sonography guided the tumor removal. The post-op clinical motor scores and the extent of resection were assessed. RESULTS: Twelve patients were operated on with the combined approach and were further analyzed. Six had high grade gliomas, 1 anaplastic astrocytoma, 1 oligodendroglioma, 1 pilocytic astrocytoma and three had metastasis. One out of 12 had a worsening of the motor scores at the last follow-up. The mean extent of resection was 90% ranging from 60% to 100%, but in 9 out of 12 patients, it reached or exceeded 90%. CONCLUSIONS: The synergic strategy comprising intraoperative multimodal neurophysiological monitoring and the ultrasound sonography is feasible in all surgeries. Data are promising in terms of both clinical motor scores and extent of resection. This strategy represents an alternative approach to the treatment of supratentorial tumors, although further studies are necessary to confirm the long-term efficacy of this procedure.

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 α = .046). The secondary end point was overall survival (tested hierarchically at α = .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.

Pattern of care and outcome in elderly patients with glioblastoma: Data in 151 patients from 3 Lombardia Hospitals.

The appropriate treatment approach for elderly patients with glioblastoma multiforme (GBM) is unclear, although different studies suggest survival benefit in fit patients treated with radiotherapy and chemiotherapy after surgery. We performed a retrospective analysis of 151 patients older than 65years with GBM treated in 3 Lombardia Hospitals. In univariate regression analysis higher KPS (p=0.02), macroscopical total resection (p<0.003), radiotherapy (p<0.0001), chemotherapy (p<0.0001) and second line chemotheraphy (p=0.02) were of positive prognostic value. On the contrary older age (>70years), presence of seizure at onset and additional resection after tumor recurrence did not influence OS. Multivariate analysis revealed radiotherapy (HR 0.2 p<0.0001) and extent of surgery (HR 0.3, p=0,0063) as positive independent prognostic factors. Patients receiving radio-chemiotherapy displayed more treatment-related toxicities with a slightly prolonged OS versus those receiving hypofractionated radiotherapy. With the limits of a retrospective study, our data suggest that in elderly fit patients extensive surgery should be considered, moreover adjuvant treatments led to an increase in OS. Randomized controlled study are needed to develop treatment guidelines for elderly GBM patients and to assess whether the combination of post-surgical radio and chemiotherapy may be superior to hypofractionated radiotherapy and chemiotherapy in fit patients.

Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells.

Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996-1007. ©2016 AACR.