DDRE-31. MITOCHONDRIAL TRAFFICKING AS A TARGET FOR GBM THERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi81-vi81
Author(s):  
Javier Lepe ◽  
Christopher Douglas ◽  
Naomi Lomeli ◽  
Kaijun Di ◽  
Bhaskar Das ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Radiation Treatment ◽  
Standard Of Care ◽  
Chemotherapy Response ◽  
Mitochondrial Matrix ◽  
Tumor Initiating Cells ◽  
Current Standard ◽  
Human Pituitary ◽  
Who Grade ◽  
Standard Of Care Treatment

Abstract Glioblastoma (WHO Grade IV glioma) is the most aggressive brain cancer. The current standard of care treatment includes surgery, radiation, and chemotherapy. Tumor recurrence is almost inevitable as less than 50% of patients survive more than two years. The low survival rate poses a dire need to develop an effective therapy for GBM patients. GBM cells are resistant to treatment, as they activate their DNA damage response mechanisms to overcome the effects of radiation and temozolomide (TMZ) treatments. Recurrent tumors can arise from slow cycling and self-renewing stem/tumor-initiating cells resistant to radiation and TMZ. No second-line therapy was proven to prolong survival after TMZ failure. Magmas (Mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a subunit of the TIM23 complex regulating precursor protein trafficking into the mitochondrial matrix. Magmas is encoded by pam16, known to be upregulated in human pituitary adenomas, prostate cancer and GBM. Previous studies have demonstrated that Magmas negatively regulates the stimulatory activity of Pam18, which in turn stimulates the ATPase activity of mitochondrial heat shock protein 70 (mtHsp70). No small molecules targeting Magmas are in clinical use. We developed a novel small molecule inhibitor (BT9) that has been specifically designed to inhibit Magmas binding to Pam18. BT9 induces apoptosis through cleavage of caspase-3, reduced mitochondrial respiration and glycolysis. Our recent findings also demonstrate that BT9 treatment reduced protein trafficking of Lon protease into the mitochondrial matrix. Pretreatment of glioma cells with BT9 sensitizes cells to radiation treatment and enhances the TMZ activity. BT9 can cross the blood-brain-barrier and improve survival in intracranial glioma PDX models. BT9 has potential therapeutic value by directly dysregulating mitochondrial function in GBM, enhancing radiation and chemotherapy response, and improving survival in a relevant animal model.

P14.90 Survival outcomes and prognostic factors in glioblastoma patients treated with radiotherapy plus concomitant and adjuvant temozolomide - real-world study

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii55-ii55
Author(s):  
M J Sousa ◽  
J Magalhães ◽  
R Basto ◽  
C Costa ◽  
A Pego ◽  
...  
Keyword(s):  
Survival Rate ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Rank Test ◽  
Survival Outcomes ◽  
Hematologic Toxicity ◽  
Current Standard ◽  
Adjuvant Temozolomide ◽  
Standard Of Care Treatment ◽  
Ecog Ps

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour in adults. The current standard of care for newly diagnosed GBM is maximal surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ). This study aimed to evaluate the survival outcomes and identify predictors of survival among these patients. MATERIAL AND METHODS We performed a single-centre retrospective analysis of GBM patients treated with radiotherapy plus concomitant and adjuvant TMZ from 2013 to 2020. The analyses of progression-free survival (PFS) and overall survival (OS), each one evaluated starting from initial diagnosis, were performed. Survival curves were estimated with the Kaplan- Meier method and compared using the log-rank test. RESULTS Fifty-eight patients were identified. The median age was 61 years (range 18- 80), 51 (88%) patients were in ECOG-PS 0–1, 6 (10%) patients had isocitrate dehydrogenase (IDH) mutation and 53 (91%) of patients had undergone debulking surgery. At a median follow-up of 21 months, median OS was 12.8 months (95% confidence interval [CI] 9.7–15.9), whereas median PFS was 9.5 months (95% CI 8.5–10.5). The 1-year survival rate was 42% and the 2-year survival rate was 10%. Grade 3 or 4 hematologic toxicity occurred in 11 (19%) patients. Twenty-five (42%) patients completed at least 6 cycles of TMZ monotherapy with statistically significant differences between this sub-group and those who weren’t able to continue TMZ monotherapy [median OS 19.3 months (95% CI 14.4–24.2) vs 10.6 months (95% CI 7.8–13.4) p<0.001]. ECOG-PS = 0 [median OS 16.7 months (95% CI 13.4–20.0, p=0.001)] and patients under 65 years of age [median OS 15.6 months (95% CI 12.3–18.9, p=0.02) were associated with significantly better median OS. CONCLUSION The current standard of care treatment for GBM remains poor. An important factor predictor of survival is the completion of the 6 maintenance cycles of TMZ. At baseline, ECOG PS and the patient’s age could be used to define patient prognosis.

Limited-Stage Disease: Optimal Use of Chemotherapy and Radiation Treatment

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 321-325 ◽  
Author(s):  
John Radford
Keyword(s):  
Hodgkin Lymphoma ◽  
Radiation Treatment ◽  
Late Toxicity ◽  
Standard Of Care ◽  
Early Years ◽  
Wide Field ◽  
Current Standard ◽  
Limited Stage ◽  
Stage Disease ◽  
Involved Field

AbstractIn the early years of treatment for limited-stage Hodgkin lymphoma there was an understandable focus on disease elimination. This has been replaced by concerns about the amount and balance of different therapies and eventually, as cure rates improve, a desire to individualize management based on risk factors at presentation and response to initial treatment. In limited stage Hodgkin lymphoma, early success was obtained with wide field radiotherapy but later combined modality approaches were employed to overcome the problem of out of field radiotherapy relapses. The acute and delayed toxicity of alkylating agent based therapies led to their replacement with ABVD and concerns about the late toxicity of radiotherapy resulted in smaller field sizes being first assessed in clinical trial and later introduced into clinical practice. The current standard of care of 3 or 4 cycles of ABVD followed by involved-field radiotherapy in clinically staged patients is the culmination of years of work involving many thousands of patients taking part in clinical trials.Our current focus is on the role of PET imaging and whether a response-adapted approach guided by PET can individualize therapy such that radiotherapy and its attendant late toxicity that impacts on future quality of life and survival can be avoided altogether in a subset of patients.

scholarly journals HGG-41. CHARACTERIZATION OF THE IMMUNE RESPONSE FOLLOWING VARIOUS RADIOTHERAPY TREATMENTS IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i26-i26
Author(s):  
Carolina Cocito ◽  
Mylene Branchtein ◽  
Tatyana Gongora ◽  
Nadia Dahmane ◽  
Jeffrey Greenfield
Keyword(s):  
Immune Response ◽  
Radiation Treatment ◽  
Malignant Gliomas ◽  
Tumor Infiltrating Lymphocytes ◽  
Standard Of Care ◽  
Current Standard ◽  
Syngeneic Mouse Model ◽  
Infiltrating Lymphocytes ◽  
The Brain

Abstract Malignant gliomas represent 6.5% of all childhood brain neoplasms with a 5-years survival rate of less than 20%. Current standard of care for these tumors include radiotherapy; recent data in solid tumors indicate that adequate radiation protocols may synergize with immunotherapy strategies for better outcomes. Nonetheless, a great discrepancy between preclinical studies and clinical trials outcomes persists, the basis of which is not fully understood. One hypothesis may be due to different radiation protocols used. We used the GL261 syngeneic mouse model of glioma to test this hypothesis and characterize the immune response to radiotherapy, with either a single dose of 10Gy, a dose often used in preclinical models, or a fractionated treatment of 2Gy for five consecutive days (2Gyx5), as fractioned radiotherapy is most often used in patients. The immune content of the brain and the blood was assessed by flow cytometry in un-irradiated (control), 10Gyx1 and 2Gyx5 treated mice for three weeks after radiation. In the brain, both radiation regimens drastically reduced the number of CD45+ cells for the first two weeks after treatment. When compared to controls, 10Gyx1 but not 2Gyx5 treated mice showed a significant increase in tumor infiltrating lymphocytes (CD3+) starting from the second week following treatment. This effect persisted until three weeks post treatment. The 10Gyx1 dose was better tolerated by the resident microglia (CD45lowCD11b+) when compared to the 2Gyx5 treatment. Our data describe the dynamics through which the immune microenvironment responds to two radiation regimens over time. Our results show that 10Gyx1 is the most effective regimen to impede tumor growth and to induce lymphocyte infiltration once the system recovers from the treatment. Our work suggests that, in the GL261 model, the fractionated radiation treatment we tested may be less optimal in priming glioma cells to the immune system.

scholarly journals RARE-09. CYSTIC GLIOBLASTOMA PRESENTATION AS A BENEFICIAL PROGNOSTIC INDICATOR FOR OVERALL SURVIVAL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi223-vi223
Author(s):  
Lee Curtin ◽  
Paula Whitmire ◽  
Cassandra Rickertsen ◽  
Peter D Canoll ◽  
Maciej Mrugala ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Benefit ◽  
Standard Of Care ◽  
Prognostic Impact ◽  
Current Standard ◽  
Significant Survival Benefit ◽  
Care Treatment ◽  
Significant Survival ◽  
Cystic Component ◽  
Standard Of Care Treatment

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median overall survival of 15 months with standard-of-care treatment. GBM patients sometimes present with a cystic component, which can be identified through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7–22% of GBM patients and have reported mixed results regarding whether cystic GBM have a survival benefit compared to noncystic GBM. Using our large retrospective cohort of 493 first-diagnosis GBM patients, we aim to elucidate this link between cystic GBM and survival. Within this cohort, 88 patients had a significant cystic component at presentation as identified on MRI. Compared to noncystic GBM (n=405), cystic GBM patients had significantly better overall survival (15 vs 22 months median, log-rank, p=0.001) and were significantly younger at the time of presentation (t-test, p=0.002). However, within patients that received current standard-of-care treatment (n=184), cystic GBM (n=40) was not as beneficial for outcome (22 vs 25 months, log-rank, p=0.3). We also did not observe a significant survival benefit when comparing this standard-of-care cystic cohort to cystic GBM patients diagnosed before the standard was established (n=19, 25 vs 23 months, log-rank, p=0.3), but the analogous result for noncystic GBM patients gives a sizeable benefit, as expected (n=144, n=111, respectively, 22 vs 12 months, log-rank p < 0.0001). Together, these results on current standard-of-care may explain later studies that note no significant survival benefit for cystic GBM patients receiving current standard-of-care. We also report differences in the absolute and relative sizes of imaging abnormalities on MRI and in prognostic impact of cysts based on sex. We discuss current hypotheses for these observed differences, including the possibility that the presence of a cyst could be indicative of a less aggressive tumor.

Abstract WP32: Introducing STAR: A Multicenter International Collaborative Registry of Real-World Outcomes After Mechanical Thrombectomy for Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ali M Alawieh ◽  
Shakeel Chowdhry ◽  
Italo Linfante ◽  
Jonathan Grossberg ◽  
Benjamin Gory ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Real World ◽  
Mechanical Thrombectomy ◽  
Standard Of Care ◽  
Outcome Data ◽  
Treatment Level ◽  
Current Standard ◽  
Anterior Circulation ◽  
Standard Of Care Treatment

Introduction: Mechanical thrombectomy (MT) for acute stroke is the current standard of care treatment. Level 1 evidence for efficacy of thrombectomy has been established in multiple randomized controlled trials on selective patient populations; however, the high effect size of MT had led multiple centers in the US and globally to expand their patient selection to include populations that were not studied in major trials. To provide ongoing data on MT outcomes in different patient populations from the real-world, we have initiated an international multicenter initiative, STAR (Stroke Thrombectomy and Aneurysm Registry). Methods: STAR is a multicenter and international platform to curate patient outcome data after MT for acute ischemic stroke at comprehensive stroke centers. STAR includes all patients who underwent MT for acute ischemic stroke irrespective of age, time from onset, ASPECT score, and NIHSS. Patients were curated from 01/2015 to date and is prospectively maintained. Patient charts are reviewed for demographics, baseline functioning, and admission deficits. Procedure notes are reviewed for technical variables and technical outcomes. Clinical outcomes were collected at 90-day follow-up by stroke neurologist. Results: A total of 24 centers globally have enrolled in STAR. By December 2018, the total number of enrolled and verified patients in STAR was 3,850 (mean age 69±14, 51% females). Anterior circulation strokes were treated in 89% of cases, average NIHSS on admission was 15.5±7, and 73% had pre-stroke mRS below 2. Around 51% of patients received IV-tPA. Mechanical thrombectomy was performed using aspiration (45%), stent retriever (28%), primary combined approach (24%) or intracranial stenting (3%). Successful recanalization was achieved in 84% of cases, the rate of favorable outcome (mRS 0-2) was 41%, and mortality was 25%. Complication rate was 6% and rate of symptomatic post-procedural hemorrhage was 6%. Conclusions: STAR represent a large real-world international registry for outcomes after MT, and constitutes a statistically robust platform to study real-world practice outcome in patient sub-populations that are under-represented in randomized trials. Link: https://medicine.musc.edu/departments/neurosurgery/star

scholarly journals Updates on clinical trials evaluating the regenerative potential of allogenic mesenchymal stem cells in COVID-19

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Dhavan Sharma ◽  
Feng Zhao
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Adaptive Immune Response ◽  
Standard Of Care ◽  
Multiple Organ ◽  
Current Standard ◽  
Number Of Patients ◽  
Standard Of Care Treatment

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected nearly 118 million people and caused ~2.6 million deaths worldwide by early 2021, during the coronavirus disease 2019 (COVID-19) pandemic. Although the majority of infected patients show mild-to-moderate symptoms, a small fraction of patients develops severe symptoms. Uncontrolled cytokine production and the lack of substantive adaptive immune response result in hypoxia, acute respiratory distress syndrome (ARDS), or multiple organ failure in severe COVID-19 patients. Since the current standard of care treatment is insufficient to alleviate severe COVID-19 symptoms, many clinics have been prompted to perform clinical trials involving the infusion of mesenchymal stem cells (MSCs) due to their immunomodulatory and therapeutic properties. Several phases I/II clinical trials involving the infusion of allogenic MSCs have been performed last year. The focus of this review is to critically evaluate the safety and efficacy outcomes of the most recent, placebo-controlled phase I/II clinical studies that enrolled a larger number of patients, in order to provide a statistically relevant and comprehensive understanding of MSC’s therapeutic potential in severe COVID-19 patients. Clinical outcomes obtained from these studies clearly indicate that: (i) allogenic MSC infusion in COVID-19 patients with ARDS is safe and effective enough to decreases a set of inflammatory cytokines that may drive COVID-19 associated cytokine storm, and (ii) MSC infusion efficiently improves COVID-19 patient survival and reduces recovery time. These findings strongly support further investigation into MSC-infusion in larger clinical trials for COVID-19 patients with ARDS, who currently have a nearly 50% of mortality rate.

scholarly journals SYST-08. A phase II trial of concurrent Sunitinib, Temozolomide and Radiation Therapy followed by adjuvant Temozolomide for newly diagnosed Glioblastoma patients with an unmethylated MGMT gene promoter (A01-M121-11A, McG1132)

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv10-iv10
Author(s):  
Mame Daro Faye ◽  
Siham Sabri ◽  
Paula De Robles ◽  
Raman Agnihotram ◽  
Alexander Torres-Vasquez ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Standard Of Care ◽  
Treatment Modalities ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Who Grade ◽  
Adjuvant Temozolomide ◽  
Mgmt Promoter ◽  
Grade 3

Abstract INTRODUCTION Despite advances in treatment modalities, the overall prognosis of GBM remains dismal, particularly for patients with unmethylated MGMT promoter. Thus, alternative treatment strategies are warranted. Our group has previously shown that addition of Sunitinib (SU11248) to standard therapy significantly improved the response of unmethylated MGMT cells through decreased angiogenicity and tumorigenicity. In this phase II trial, we tested for the first time the combination of Sunitinib with RT and Temozolomide in newly diagnosed MGMT unmethylated GBM patients. METHODS Patients with histologically confirmed WHO Grade IV GBM and MS-PCR confirmed unmethylated MGMT promoter, age 18-70, KPS ≥70, life expectancy ≥6 months were eligible. 41 patients treated between 2012 and 2017 were screened, 37 of which were eligible. Patients received 12.5 mg of daily Sunitinib for 7 days, followed by concurrent RT, Temozolomide and 12.5 mg Sunitinib for 6 weeks, then adjuvant Temozolomide x6 cycles. RT and Temozolomide doses were as per standard of care. Primary objective was PFS as assessed by RANO criteria, secondary objectives were OS and safety. RESULTS Median follow-up time was 15 months. Median PFS was 7 months (95%CI, 6.7-7.2) and 6-month PFS was 59.3%. Median OS was 13 months (95%CI, 12.62-13.37) and 2-year OS was 17.8%. Two patients had OS &gt;50 months, with one surviving 71 months. Having received &gt;3 cycles of adjuvant Temozolomide, surgery at progression or age ≤65 significantly predicted for better OS, with hazard ratios of 0.184 (p=0.001), 0.402 (p=0.026) and 10.017 (for age &gt;65, p=0.002) respectively. Grade ≥3 thrombocytopenia occurred in 18.9% of patients, grade ≥3 neutropenia in 10.8% and grade ≥3 thromboembolic events in 13.5%. There were no grade 5 evens. CONCLUSION Addition of Sunitinib to RT and Temozolomide was well tolerated and survival outcomes compared favorably to the current standard of care for GBM patients with unmethylated MGMT promoter status.

scholarly journals Homologous recombination proficiency in ovarian and breast cancer patients

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Justin Fortune Creeden ◽  
Nisha S. Nanavaty ◽  
Katelyn R. Einloth ◽  
Cassidy E. Gillman ◽  
Laura Stanbery ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Standard Of Care ◽  
Breast Cancer Patients ◽  
Genome Maintenance ◽  
Testing Methods ◽  
Breast And Ovarian Cancer ◽  
Current Standard ◽  
Standard Testing ◽  
Standard Of Care Treatment

AbstractHomologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi’s. Finally, standard of care treatment and synthetic lethality will be reviewed.

CTNI-19. CONCURRENT CHEMORADIATION AND TUMOR TREATING FIELDS (TTFields, 200 kHz) FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA MAY INCREASE THE RATE OF DISTANT RECURRENCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi63-vi63
Author(s):  
Ayesha S Ali ◽  
Muneeb Niazi ◽  
Voichita Bar-Ad ◽  
Maria Werner-Wasik ◽  
David Andrews ◽  
...  
Keyword(s):  
Radiation Treatment ◽  
Synergistic Effects ◽  
Secondary Analysis ◽  
Standard Of Care ◽  
Distant Recurrence ◽  
Concurrent Chemoradiation ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Tumor Treating Fields ◽  
Newly Diagnosed Glioblastoma

Abstract INTRODUCTION: Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) along with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. Secondary analysis of EF14 trial demonstrated TTFields treatment may increase the rate of distant recurrence. We report our experience evaluating areas of progression in our pilot clinical trial of concurrent chemoradiation with TTFields. METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from primary enhancing lesion. RESULTS: A total of 30 patients were enrolled on the trial. Twenty were male, and ten were female, with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 11.6 months (1.7-22.1 months). Twenty (66.7%) patients had an unmethylated MGMT promotor status and ten (33.3%) patients had a methylated promoter status. Twenty patients (66.7%) had progression, with median PFS of 9.1 months (range 1.6 to 12.9 months). Five patients (26%) of patient presented with distant recurrence, with median distance from primary lesion of 5.1 cm (2.26-9.12 cm). One infratentorial progression was noted. Another patient transferred care and location of progression is unknown. CONCLUSIONS: Concurrent chemoradiation with TTFields for patients with newly diagnosed glioblastoma may have increased incidence of distant recurrence. This finding is suggestive of improved local control of primary site. Further data are needed to validate this finding.

scholarly journals A Primer on the Current State-of-the-Science Neoadjuvant and Adjuvant Therapy for Patients with Locally Advanced Rectal Adenocarcinomas

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jeffrey T. Yorio ◽  
Nishin A. Bhadkamkar ◽  
Bryan K. Kee ◽  
Christopher R. Garrett
Keyword(s):  
Adjuvant Therapy ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Current Standard ◽  
Colon Cancers ◽  
Standard Of Care Treatment ◽  
Rectal Cancers ◽  
State Of The Science

Patients with rectal cancers, due to the unique location of the tumor, have a recurrence pattern distinct from colon cancers. Advances in adjuvant therapy over the last three decades have played an important role in improving patient outcomes. This article serves to review the clinical studies that lay the basis for our current standard-of-care treatment of patients with locally advanced rectal cancer, as well as touch upon future ongoing experimental clinical trials of adjuvant chemoradiation therapy.

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