Publications by authors named "Roger Stupp"

247 Publications

Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.

Lancet Oncol 2021 Jun 29. Epub 2021 Jun 29.

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address:

Background: Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma.

Methods: This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 10 viral particles administered by 5·00 × 10 NSCs, the second cohort a dose of 1·25 × 10 viral particles administered by 1·00 × 10 NSCs, and the third cohort a dose of 1·875 × 10 viral particles administered by 1·50 × 10 NSCs. No further dose escalation was planned. Within 10-14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134.

Findings: Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14-22). One patient receiving 1·50 × 10 NSCs loading 1·875 × 10 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 10 NSCs loading 1·875 × 10 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5-not reached) and median overall survival was 18·4 months (15·7-not reached).

Interpretation: NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/S1470-2045(21)00245-XDOI Listing
June 2021

The impact of the molecular classification of glioblastoma on the interpretation of therapeutic clinical trial results.

Chin Clin Oncol 2021 Jun 2. Epub 2021 Jun 2.

Department of Neurological Surgery, Lurie Comprehensive Cancer Center, Chicago, IL, USA; Malnati Brain Tumor Institute and Lurie Comprehensive Cancer Center, Chicago, IL, USA; Department of Neurology, Lurie Comprehensive Cancer Center, Chicago, IL, USA; Department of Medicine (Section of Hematology & Oncology), Lurie Comprehensive Cancer Center, Chicago, IL, USA.

In 2016, the World Health Organization (WHO) released the most recent update to the classification of central nervous system tumors. This update has led to the reshaping of tumor identification and subsequently changed current understanding of treatment options for patients. Moreover, the restructuring of the classification of central nervous system tumors to include molecular markers has led to the need to re-evaluate how to interpret pivotal trials. These trials originally enrolled patients purely based upon histologic diagnoses without the use of adjunctive, and frequently diagnostic molecular testing. With this new paradigm also comes the need to assess how one should incorporate molecular markers into current trials as well as shape future trials. First, we will discuss updates on the molecular classification of glioblastoma (GBM) (and its histologic mimics). This will be followed by a review of key pivotal trials which have defined our standard of care for glioblastoma within the context of molecular classification of their study populations. This will be followed by preliminary results of ongoing phase 3 cooperative group trials for high-grade gliomas that were initiated prior to routine molecular classification of tumors and how one could interpret these results in light of advances in molecular classification. Finally, we will end with suggestions for future clinical trial design with a focus on enrollment based upon molecular diagnostics.
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http://dx.doi.org/10.21037/cco-21-33DOI Listing
June 2021

De novo purine biosynthesis is a major driver of chemoresistance in glioblastoma.

Brain 2021 May;144(4):1230-1246

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60616, USA.

Glioblastoma is a primary brain cancer with a near 100% recurrence rate. Upon recurrence, the tumour is resistant to all conventional therapies, and because of this, 5-year survival is dismal. One of the major drivers of this high recurrence rate is the ability of glioblastoma cells to adapt to complex changes within the tumour microenvironment. To elucidate this adaptation's molecular mechanisms, specifically during temozolomide chemotherapy, we used chromatin immunoprecipitation followed by sequencing and gene expression analysis. We identified a molecular circuit in which the expression of ciliary protein ADP-ribosylation factor-like protein 13B (ARL13B) is epigenetically regulated to promote adaptation to chemotherapy. Immuno-precipitation combined with liquid chromatography-mass spectrometry binding partner analysis revealed that that ARL13B interacts with the purine biosynthetic enzyme inosine-5'-monophosphate dehydrogenase 2 (IMPDH2). Further, radioisotope tracing revealed that this interaction functions as a negative regulator for purine salvaging. Inhibition of the ARL13B-IMPDH2 interaction enhances temozolomide-induced DNA damage by forcing glioblastoma cells to rely on the purine salvage pathway. Targeting the ARLI3B-IMPDH2 circuit can be achieved using the Food and Drug Administration-approved drug, mycophenolate mofetil, which can block IMPDH2 activity and enhance the therapeutic efficacy of temozolomide. Our results suggest and support clinical evaluation of MMF in combination with temozolomide treatment in glioma patients.
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http://dx.doi.org/10.1093/brain/awab020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105035PMC
May 2021

MGMT promoter methylation is associated with patient age and 1p/19q status in IDH-mutant gliomas.

Neuro Oncol 2021 05;23(5):858-860

Department of Neurological Surgery, Northwestern University, Chicago, Illinois, USA.

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http://dx.doi.org/10.1093/neuonc/noab039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099474PMC
May 2021

Establishing anchor-based minimally important differences for the EORTC QLQ-C30 in glioma patients.

Neuro Oncol 2021 Feb 18. Epub 2021 Feb 18.

European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.

Background: Minimally important differences (MIDs) allow interpretation of the clinical relevance of health-related quality of life (HRQOL) results. This study aimed to estimate MIDs for all EORTC QLQ-C30 scales for interpreting group-level results in brain tumor patients.

Methods: Clinical and HRQOL data from three glioma trials were used. Clinical anchors were selected for each EORTC QLQ-C30 scale, based on correlation (>0.30) and clinical plausibility of association. Changes in both HRQOL and the anchors were calculated, and for each scale and time period, patients were categorized into one of three clinical change groups: deteriorated by one anchor category, no change, or improved by one anchor category. Mean change method and linear regression were applied to estimate MIDs for interpreting within-group change and between-group differences in change over time, respectively. Distribution-based methods were applied to generate supportive evidence.

Results: A total of 1687 patients were enrolled in the three trials. The retained anchors were performance status and eight Common Terminology Criteria for Adverse Events (CTCAE) scales. MIDs for interpreting within-group change ranged from 4 to 12 points for improvement and -4 to -14 points for deterioration. MIDs for between-group difference in change ranged from 4 to 9 for improvement and -4 to -16 for deterioration. Most anchor-based MIDs were closest to the 0.3SD distribution-based estimates (range: 3-10).

Conclusions: MIDs for the EORTC QLQ-C30 scales generally ranged between 4-11 points for both within-group mean change and between-group mean difference in change. These results can be used to interpret QLQ-C30 results from glioma trials.
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http://dx.doi.org/10.1093/neuonc/noab037DOI Listing
February 2021

PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells.

Mol Cell 2021 03 3;81(6):1276-1291.e9. Epub 2021 Feb 3.

The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.
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http://dx.doi.org/10.1016/j.molcel.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979509PMC
March 2021

Calculating the net clinical benefit in neuro-oncology clinical trials using two methods: quality-adjusted survival effect sizes and joint modeling.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa147. Epub 2020 Oct 29.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Two methods combining survival and health-related quality of life (HRQoL) data in glioma trials to calculate the "net clinical benefit" were evaluated: Quality-adjusted effect sizes (QASES) and joint modeling (JM).

Methods: The net clinical benefit in two trials was calculated as proof of concept for other trials. With the QASES method, effect sizes for differences in progression-free survival (PFS) or overall survival (OS) and HRQoL between the experimental arm and standard treatment arm were calculated, while the relative emphasis placed on survival/HRQoL varied. JM allows simultaneous modeling of HRQoL and OS/PFS.

Results: In the EORTC 26951 trial, combined radiochemotherapy significantly prolonged OS (difference 11.7 months), but also resulted in more patients experiencing clinically relevant worsening (≥10 points) in appetite loss and nausea/vomiting shortly after treatment. Using QASES, the survival benefit of additional procarbazine, lomustine, and vincristine (PCV) decreased from 42.3 months to 29.5 and 28.2 months when accounting for appetite loss and nausea/vomiting, respectively. JM analyses resulted in a loss of the beneficial effect of additional PCV between 13% and 24% when adjusting for different HRQoL parameters. The EORTC 22033 trial showed no significant PFS difference between radiotherapy or temozolomide alone (46 vs 39 months), nor clinically relevant differences in HRQoL. JM analyses also showed no significant association between PFS and HRQoL scales/items, whereas QASES showed that temozolomide alone was more favorable when considering symptom burden (47-49 instead of 39 months).

Conclusions: Both methods resulted in different outcomes, but adjusting for the impact of treatment on HRQoL resulted in theoretically reduced survival benefits.
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http://dx.doi.org/10.1093/noajnl/vdaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772555PMC
October 2020

Efficacy of clobazam as add-on therapy in brain tumor-related epilepsy.

J Neurooncol 2021 Jan 4;151(2):287-293. Epub 2021 Jan 4.

Department of Neurology, Northwestern University, Chicago, IL, USA.

Purpose: Brain tumor-related epilepsy (TRE) is often resistant to currently available antiepileptic medications (AEDs). Clobazam was initially approved as adjunctive AED for patients with Lennox Gastaut syndrome but has been used in TRE, despite limited evidence in this context. This observational study aims to examine the effect of clobazam on seizure frequency on patients who have a primary CNS tumor and continued seizures despite their current AEDs.

Methods: A retrospective review of patients with histologically-confirmed primary brain tumors seen in the neuro-oncology interdisciplinary clinic from April 2016-2019 was completed, and patients on clobazam were identified. Response to clobazam was defined as a greater than 50% reduction in seizure frequency. Additional data including patient and tumor characteristics, treatment course, tolerability, AEDs used prior to addition of clobazam, and AEDs concomitantly used with clobazam were collected.

Results: A total of 35 patients with TRE on clobazam were identified, with 2 patients unable to tolerate the medication due to side effects. Of the 33 remaining patients, a total of 31 (93.9%) of patients were deemed responders. Ten patients (30.3%) were seizure free within 6 months of clobazam initiation and 21 (63.6%) reported a significant reduction in seizure frequency. This reduction also allowed several patients to modify concurrent AEDs.

Conclusions: Clobazam is an effective agent to use as add-on AED in TRE, with 94% of patients showing a significant response within 6 months. Furthermore, the addition of clobazam may yield a reduction in polypharmacy, as concomitant AEDs can be reduced and potentially withdrawn.
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http://dx.doi.org/10.1007/s11060-020-03664-9DOI Listing
January 2021

Measuring change in health-related quality of life: the impact of different analytical methods on the interpretation of treatment effects in glioma patients.

Neurooncol Pract 2020 Dec 7;7(6):668-675. Epub 2020 Jun 7.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Different analytical methods may lead to different conclusions about the impact of treatment on health-related quality of life (HRQoL). This study aimed to examine 3 different methods to evaluate change in HRQoL and to study whether these methods result in different conclusions.

Methods: HRQoL data from 15 randomized clinical trials were combined (CODAGLIO project). Change in HRQoL scores, measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and BN20 questionnaires, was analyzed in 3 ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms, (2) at the patient level per scale/item, calculating the percentage of patients that deteriorated, improved, or remained stable per scale/item, and (3) at the individual patient level, combining all scales/items.

Results: Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level, only the item "hair loss" showed a significant and clinically relevant change (ie, ≥10 points) over time, whereas change scores on the other scales/items were statistically significant only (all  < .001; range in change score, 0.1-6.2). Although a large proportion of patients had stable HRQoL over time (range, 27%-84%) on the patient level per scale/item, many patients deteriorated (range, 6%-43%) or improved (range, 8%-32%) on a specific scale/item. At the individual patient level, the majority of patients (86%) showed both deterioration and improvement, whereas only 1% remained stable on all scales.

Conclusions: Different analytical methods of changes in HRQoL result in distinct conclusions of treatment effects, all of which may be relevant for informing clinical decision making.
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http://dx.doi.org/10.1093/nop/npaa033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716184PMC
December 2020

Role of Resection in Glioblastoma Management.

Neurosurg Clin N Am 2021 Jan 5;32(1):9-22. Epub 2020 Nov 5.

Department of Neurological Surgery, Northwestern University, Northwestern Medicine, 676 North Saint Clair Street, Suite 2210, Chicago, IL 60611, USA; Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 North Saint Clair Street, Suite 2210, Chicago, IL 60611, USA. Electronic address:

Whenever possible, maximal safe resection is the first intervention for management of glioblastoma. Resection offers tissue for diagnosis, decompression of the brain, cytoreduction, and has been associated with prolonged survival in numerous retrospective studies. In this review, we provide a critical overview of the literature associating glioblastoma resection with survival. We discuss techniques that enhance extent of resection, and the role of clinical and surgeon-variables. At last, we analyze the covariates and confounders that might influence the relationship between extent of resection and survival for glioblastoma, as these might ultimately also influence outcomes and other therapeutic interventions tested in trials.
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http://dx.doi.org/10.1016/j.nec.2020.08.002DOI Listing
January 2021

Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033.

Neuro Oncol 2021 05;23(5):803-811

Department of Radiation Oncology (MAASTRO), GROW‒School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning.

Methods: Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time.

Results: Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes.

Conclusion: In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy.
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http://dx.doi.org/10.1093/neuonc/noaa252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099470PMC
May 2021

Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes.

Cancer Med 2020 11 29;9(22):8373-8385. Epub 2020 Sep 29.

Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to methylguanin-O6-methyltransferase promoter (MGMT) promoter hypermethylated tumors. Further resistance markers are largely unknown and would help for better stratification.

Methods: Clinical data and methylation profiles from the NOA-08 (104, elderly glioblastoma) and the EORTC 26101 (297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg Neuro-Oncology center have been analyzed focused on the predictive effect of DNA damage response (DDR) gene methylation. Candidate genes were validated in vitro.

Results: Twenty-eight glioblastoma 5'-cytosine-phosphat-guanine-3' (CpGs) from 17 DDR genes negatively correlated with expression and were used together with telomerase reverse transcriptase (TERT) promoter mutations in further analysis. CpG methylation of DDR genes shows highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) II glioblastoma subgroup. MES tumors have lower tumor purity compared to RTK I and II subgroup tumors. CpG hypomethylation of DDR genes TP73 and PRPF19 correlated with worse patient survival in particular in MGMT promoter unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival. Primary glioma cells show methylation patterns that resemble RTK I and II glioblastoma and long term established glioma cell lines do not match with glioblastoma subtypes. Silencing of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide in vitro.

Conclusion: Hypomethylation of DDR genes and TERT promoter mutations is associated with worse tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in IDH wild-type glioblastoma.
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http://dx.doi.org/10.1002/cam4.3447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666733PMC
November 2020

Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma.

J Exp Med 2021 Jan;218(1)

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation. BVax migrates to key secondary lymphoid organs and is proficient at antigen cross-presentation, which promotes both the survival and the functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunological memory that prevented the growth of new tumors upon subsequent reinjection in cured mice. GBM patient-derived BVax was successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.
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http://dx.doi.org/10.1084/jem.20200913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527974PMC
January 2021

Ribosomal protein S11 influences glioma response to TOP2 poisons.

Oncogene 2020 07 11;39(27):5068-5081. Epub 2020 Jun 11.

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States.

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We and others had shown that a subset of glioblastomas, the most malignant of all primary brain tumors in adults, is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, and 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 led to resistance to etoposide and doxorubicin and impaired the induction of proapoptotic gene APAF1 following treatment. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from gliomas and multiple other cancers.
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http://dx.doi.org/10.1038/s41388-020-1342-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646677PMC
July 2020

Experiences and views of different key stakeholders on the feasibility of treating cancer-related fatigue.

BMC Cancer 2020 May 24;20(1):458. Epub 2020 May 24.

Institute for Complementary and Integrative Medicine, University Hospital Zurich and University of Zurich, Sonneggstrasse 6, 8091, Zurich, Switzerland.

Background: Although cancer-related fatigue (CRF) has gained increased attention in the past decade, therapy remains a challenge. Treatment programs are more likely to be effective if the needs and interests of the persons involved are well represented. This can be achieved by stakeholder engagement. In this paper, different key stakeholders' experiences and views on the feasibility of treating CRF in the context of supportive care in hospital environments are analyzed.

Method: In a qualitative study with the aim of developing an integrative treatment program for CRF, a total of 22 stakeholders (6 medical oncologists, 5 nurses, 9 patients, 1 patient family member, 1 representative of the Swiss Cancer League) were interviewed either in a face-to-face (n = 12) or focus group setting (n = 2). For data analyses, the method of qualitative content analysis was used.

Results: The stakeholders referred to different contextual factors when talking about the feasibility of treating CRF in the context of supportive care in hospital environments. These included: assessment, reporting and information; treatability; attitude; infrastructure, time-management, costs and affordability; and integrative approach.

Conclusions: Key factors of a feasible treatment approach to CRF are a coherent, cost effective integrative treatment program facilitated by an interdisciplinary team of health care providers. Furthermore, the treatment approach should be patient orientated, adopting an individualized approach. The major challenges of making the integrative treatment program feasible for CRF are resources and interprofessional collaboration.
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http://dx.doi.org/10.1186/s12885-020-06858-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245792PMC
May 2020

Temporal activation of WNT/β-catenin signaling is sufficient to inhibit SOX10 expression and block melanoma growth.

Oncogene 2020 05 1;39(20):4132-4154. Epub 2020 Apr 1.

Department of Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Wagistrasse 14, 8952, Schlieren, UK.

Despite advances in the systemic treatment of patients with metastatic melanoma using immune checkpoint and tyrosine kinase inhibitors (TKI), the majority of stage IV melanoma patients eventually succumb to the disease. We have previously identified the transcription factor Sox10 as a crucial player in melanoma, yet the underlying molecular mechanisms mediating Sox10-dependent tumorigenesis remain largely uncharacterized. Here, we show that MEK and RAF inhibitors do not suppress levels of SOX10 protein in patient-derived cells in vitro, as well as in melanoma patients in vivo. In a search for pharmacological inhibitors of SOX10, we performed a mass spectrometry-based screen in human melanoma cells. Subsequent analysis revealed that SOX10 directly interacts with β-catenin, which is a key mediator of canonical Wnt/β-catenin signaling. We demonstrate that inhibitors of glycogen synthase kinase 3 alpha/beta (GSK3α/β) efficiently abrogate SOX10 protein in human melanoma cells in vitro and in melanoma mouse models in vivo. The mechanism of action of GSK3-mediated SOX10 suppression is transcription-independent and relies on the presence of a proteasome degradable form of β-catenin. Taken together, we provide evidence that activation of canonical Wnt signaling has a profound effect on melanoma growth and is able to counteract Sox10-dependent melanoma maintenance both in vitro and in vivo.
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http://dx.doi.org/10.1038/s41388-020-1267-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076051PMC
May 2020

Leptomeningeal metastasis from solid tumors.

J Neurol Sci 2020 Apr 23;411:116706. Epub 2020 Jan 23.

Northwestern University, Department of Neurology, United States of America; Lou & Jean Malnati Brain Tumor institute of the Robert H. Lurie Comprehensive Cancer Center, United States of America. Electronic address:

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges (pia, subarachnoid space and arachnoid mater), and dura. Leptomeningeal metastases (LM), also known by different terms including neoplastic meningitis and carcinomatous meningitis, occur in both solid tumors and hematologic malignancies. This review will focus exclusively on LM arising from solid tumors with a goal of providing the reader an understanding of the epidemiology, pathophysiology, clinical presentation, prognostication, current management and future directions.
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http://dx.doi.org/10.1016/j.jns.2020.116706DOI Listing
April 2020

Determining the Optimal Adjuvant Therapy for Improving Survival in Elderly Patients with Glioblastoma: A Systematic Review and Network Meta-analysis.

Clin Cancer Res 2020 06 17;26(11):2664-2672. Epub 2020 Jan 17.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada.

Purpose: Older patients with glioblastoma (GBM) are underrepresented in clinical trials. Several abbreviated and standard chemoradiotherapy regimens are advocated with no consensus on the optimal approach. Our objective was to quantitatively evaluate which of these regimens would provide the most favorable survival outcomes in older patients with GBM using a network meta-analysis.

Experimental Design: MEDLINE, Embase, Google Scholar, and the Cochrane Library were searched. Patients >60 years of age with histologically confirmed GBM were included. Primary outcome of interest was the pooled HR from randomized controlled trials (RCTs). Secondary outcomes of interest included pooled HR from studies controlling for MGMT promoter methylation status, and safety.

Results: Fourteen studies, including 5 RCTs, reporting 4,561 patients were included. Using highest quality data from RCTs, our network-based approach demonstrated that standard radiotherapy (SRT) and temozolomide (TMZ) provided similar survival benefit when compared with hypofractionated radiotherapy (HRT) and TMZ [HR = 0.90; 95% confidence interval (CI), 0.43-1.87], TMZ alone (HR 1.25; 95% CI, 0.69-2.26), HRT alone (HR = 1.34; 95% CI, 0.73-2.45), or SRT alone (HR = 1.43; 95% CI, 0.87-2.36). HRT-TMZ had the highest probability (85%) of improving survival in older patients with GBM followed by SRT-TMZ (72%). Pooled analysis of trials controlling for promoter methylation status demonstrated that TMZ monotherapy confers similar survival benefit to combined chemoradiotherapy.

Conclusions: Statistical comparisons using a network approach demonstrates that the common treatment regimens for older patients with GBM in previous RCTs confer similar survival benefits. Adjustments for MGMT promoter methylation status demonstrated that radiotherapy alone was inferior to TMZ-based approaches. Head-to-head comparison of TMZ monotherapy to combined TMZ and radiation is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3359DOI Listing
June 2020

Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations.

Clin Cancer Res 2020 01 12;26(2):477-486. Epub 2019 Dec 12.

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood-brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models.

Experimental Design: The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice.

Results: Despite similar antiglioma activity , ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated.

Conclusions: Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050644PMC
January 2020

Changing Paradigms in the Treatment of Brain Metastases.

Authors:
Roger Stupp

J Oncol Pract 2019 11;15(11):573-574

Northwestern University, Chicago, IL.

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http://dx.doi.org/10.1200/JOP.19.00602DOI Listing
November 2019

Extensive brainstem infiltration, not mass effect, is a common feature of end-stage cerebral glioblastomas.

Neuro Oncol 2020 04;22(4):470-479

Department of Neurological Surgery, Northwestern University, Chicago, Illinois.

Background: Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying.

Methods: The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide.

Results: In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P < 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P < 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003).

Conclusions: With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.
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http://dx.doi.org/10.1093/neuonc/noz216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158646PMC
April 2020

Symptom clusters in newly diagnosed glioma patients: which symptom clusters are independently associated with functioning and global health status?

Neuro Oncol 2019 11;21(11):1447-1457

Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.

Background: Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients' functioning.

Methods: Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders.

Results: Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5-10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (≥10 points difference) physical, role, and social functioning (betas ranged from -11.3 to -15.9, all P < 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of -12.3, P < 0.001), independent of other factors.

Conclusions: Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients' functioning as measured with a self-report questionnaire.
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http://dx.doi.org/10.1093/neuonc/noz118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827824PMC
November 2019

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

Cancers (Basel) 2019 Jul 12;11(7). Epub 2019 Jul 12.

Pathology Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, Per 17, CH-1700 Fribourg, Switzerland.

Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling preclinical results demonstrating that the inhibition of integrin αVβ3/αVβ5 and α5β1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients. Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, e.g., cancer-associated fibroblasts and immune/inflammatory cells. We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (e.g., together with immuno-oncology agents) are needed.
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http://dx.doi.org/10.3390/cancers11070978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678560PMC
July 2019

The medical necessity of advanced molecular testing in the diagnosis and treatment of brain tumor patients.

Neuro Oncol 2019 12;21(12):1498-1508

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Accurate pathologic diagnoses and molecularly informed treatment decisions for a wide variety of cancers depend on robust clinical molecular testing that uses genomic, epigenomic, and transcriptomic-based tools. Nowhere is this more essential than in the workup of brain tumors, as emphasized by the incorporation of molecular criteria into the 2016 World Health Organization classification of central nervous system tumors and the updated official guidelines of the National Comprehensive Cancer Network. Despite the medical necessity of molecular testing in brain tumors, access to and utilization of molecular diagnostics is still highly variable across institutions, and a lack of reimbursement for such testing remains a significant obstacle. The objectives of this review are (i) to identify barriers to adoption of molecular testing in brain tumors, (ii) to describe the current molecular tools recommended for the clinical evaluation of brain tumors, and (iii) to summarize how molecular data are interpreted to guide clinical care, so as to improve understanding and justification for their coverage in the routine workup of adult and pediatric brain tumor cases.
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http://dx.doi.org/10.1093/neuonc/noz119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917404PMC
December 2019

The added value of health-related quality of life as a prognostic indicator of overall survival and progression-free survival in glioma patients: a meta-analysis based on individual patient data from randomised controlled trials.

Eur J Cancer 2019 07 13;116:190-198. Epub 2019 Jun 13.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands; Department of Neurology, Haaglanden Medical Center, Den Haag, the Netherlands.

Objective: Prognostic value of health-related quality of life (HRQoL) data may be important to inform patients in clinical practice and to guide clinical decision-making. Our study investigated the added prognostic value of HRQoL for overall survival (OS) and progression-free survival (PFS) in a large heterogeneous sample of glioma patients, besides known prognostic factors.

Methods: We included individual baseline data from previously published randomised controlled trials (RCTs) in glioma patients in which HRQoL was assessed through the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BN20 questionnaires. Multivariable Cox regression models (stratified for newly diagnosed versus recurrent disease) were constructed, first with clinical variables (age, sex, tumour type, performance status, allocated treatment and extent of resection) only and subsequently with HRQoL variables added, separately for OS and PFS. The added prognostic value of HRQoL was calculated using C-indices.

Results: Baseline HRQoL and clinical data from 15 RCTs were included, comprising 5217 patients. In the model including both clinical and HRQoL variables, better cognitive and role functioning and less motor dysfunction were independently associated with longer OS, whereas better role and cognitive functioning, less nausea and vomiting and more appetite loss were independently associated with prolonged PFS. However, C-indices indicated only a small prognostic improvement of the models for OS and PFS when adding HRQoL to the clinical prognostic variables (+1.1% for OS and +.7% for PFS).

Conclusion: Our findings demonstrate that several baseline HRQoL variables are independently prognostic for OS and PFS, yet the added value of HRQoL to the known clinical prognostic variables was small.
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http://dx.doi.org/10.1016/j.ejca.2019.05.012DOI Listing
July 2019

Overcoming the Blood-Brain Barrier with an Implantable Ultrasound Device.

Clin Cancer Res 2019 07 10;25(13):3750-3752. Epub 2019 May 10.

Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center and Departments of Neurological Surgery and Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Ultrasound-based blood-brain barrier disruption enhances drug delivery. To bypass the human skull, an implantable ultrasound emitter was developed, and proven safe and feasible in a first-in-human trial. Next development steps aim for larger field of disruption, quantification of drug levels, use of various drugs, and ultimately a pivotal trial demonstrating improved outcome..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057332PMC
July 2019

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis.

Int J Cancer 2020 02 29;146(3):803-809. Epub 2019 Apr 29.

Department of Neurology and Wilhelm Sander-NeuroOncology Unit, Regensburg University Hospital, Regensburg, Germany.

Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.
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http://dx.doi.org/10.1002/ijc.32337DOI Listing
February 2020

Newly Diagnosed Glioblastoma: A Review on Clinical Management.

Oncology (Williston Park) 2019 Mar;33(3):91-100

Glioblastoma is an aggressive primary tumor of the central nervous system. This review will focus on clinical developments and management of newly diagnosed disease, including a discussion about the incorporation of molecular features into the classification of glioblastoma. Such advances will continue to shape our thinking about the disease and how to best manage it. With regards to treatment, the role of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields will be presented. Pivotal studies defining our current standard of care will be highlighted, as will key ongoing trials that may influence our management of glioblastoma in the near future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278092PMC
March 2019
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