CTNI-20. FEASIBILITY OF SINGLE-PASS STEREOTACTIC NEEDLE BIOPSY IN RECURRENT GLIOBLASTOMA PATIENTS TO SUPPORT CLIA-CERTIFIED TUMOR PHARMACODYNAMICS FOR A PHASE 0/2 CLINICAL TRIAL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi63-vi63
Author(s):  
Yu-Wei Chang ◽  
Anita DeSantis ◽  
Chelsea Pennington-Krygier ◽  
Jennifer Molloy ◽  
Shwetal Mehta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Needle Biopsy ◽  
Stereotactic Biopsy ◽  
Recurrent Glioblastoma ◽  
Experimental Therapy ◽  
Time Interval ◽  
Single Pass ◽  
Phase 0 ◽  
Before And After ◽  
Pre Treatment

Abstract BACKGROUND In neuro-oncology clinical trials, pharmacodynamic (PD) analysis of tumor tissue before and after experimental therapy is challenging. Today, Phase 0 studies in brain tumor patients typically employ archival tissue from a prior resection as the baseline PD comparator. However, the time-interval between tissue acquisitions can be months to years and often includes confounding exposure to other therapies. Here, we demonstrate the feasibility of a pre-treatment, single-pass stereotactic needle biopsy to support CLIA-certified genetic screening and tumor PD analysis in a Phase 0/2 clinical trial. METHODS In support of an ongoing Phase 0/2 ‘trigger’ trial testing CDK4/6 plus ERK1/2 inhibition in recurrent glioblastoma (GBM), a single-pass stereotactic biopsy was completed in select patients prior to enrollment. Each biopsy yields six tissue cores for immunohistochemistry (IHC) and genetic characterization. Using CLIA-certified protocols, genomic DNA (gDNA) was extracted from two cores, followed by library preparation and next-generation sequencing of a customized panel of 37 genes (IvySeq). In the four remaining cores, IHC staining was performed for RB, pRB, pERK, pS6, CDKN2A, MIB-1, ClCas-3 and pH2AX. RESULTS Single-pass stereotactic needle biopsies were collected from five recurrent GBM patients. No intraoperative, perioperative, or radiographic evidence of morbidity was observed. 800-2400ng of gDNA was isolated from each stereotactic biopsy. IvySeq analysis detected CDKN2A deletion, ATRX loss, and mutations in IDH, PTEN and TP53 genes. Based on IHC and genetic analyses of the biopsied samples, three patients were enrolled into the Phase 0/2 clinical trial and baseline value were used for PD analysis. CONCLUSION Single-pass stereotactic needle biopsy is a feasible and safe strategy to collect pre-treatment tissue in support of a Phase 0 clinical trial, enabling CLIA-certified genetic analysis for trial screening and tumor PD analysis.

scholarly journals 347MO 5-Aminolevulinic acid sonodynamic therapy in recurrent glioblastoma: A first-in-human phase 0/1 clinical trial

2021 ◽  
Vol 32 ◽  
pp. S518-S519
Author(s):  
N. Sanai ◽  
A-C. Tien ◽  
A. Tovmasyan ◽  
Y-W. Chang ◽  
T. Margaryan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Aminolevulinic Acid ◽  
Recurrent Glioblastoma ◽  
Sonodynamic Therapy ◽  
Phase 0

CTNI-48. A PHASE 0 ‘TRIGGER’ TRIAL OF CDK4/6 PLUS ERK1/2 INHIBITORS IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi71
Author(s):  
Nader Sanai ◽  
Yu-Wei Chang ◽  
Tigran Margaryan ◽  
Anita DeSantis ◽  
Mackenna Elliott ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Drug Dose ◽  
Recurrent Glioblastoma ◽  
Optimal Time ◽  
Time Interval ◽  
Tumor Proliferation ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Recurrent Gbm ◽  
Dual Drug

Abstract BACKGROUND This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. METHODS Adult recurrent GBM patients (n=10) with intact RB expression, > 30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD) prior to a planned resection at 3-5 or 7-9 hour time interval after the final drug dose in a Time-Escalation Arm. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. RESULTS No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort) while median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. CONCLUSION Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.

A phase 0/II study for ribicoclib in patients with recurrent glioblastoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2083-TPS2083
Author(s):  
Nader Sanai ◽  
An-Chi Tien ◽  
Norissa Honea ◽  
Shwetal Mehta ◽  
Jing Li
Keyword(s):  
Clinical Trial ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Recurrent Glioblastoma ◽  
Free Survival ◽  
Therapeutic Regime ◽  
Phase 0 ◽  
Foxm1 Expression ◽  
Rb Phosphorylation ◽  
Cycle Regulation

TPS2083 Background: Disruption of CDK4/6-dependent G1-S cell cycle regulation is a hallmark of glioblastoma (GBM) progression in 78% of cases. Newly-developed CDK4/6 inhibitors have shown promise in non-CNS cancer trials and glioma animal models. To explore the utility of Ribociclib, a specific CDK4/6 inhibitor, in treating recurrent GBM patient, we designed a phase 0/II clinical trial to examine the pharmacokinetic (PK) and pharmacodynamics (PD) of Ribociclib. Methods: 24 adult patients are allocated to 3 time-escalation arms and receive 5 days of daily Ribociclib prior to planned GBM resection. Eligible patients are selected based on intact Rb expression and loss of Ink4a/Arf locus. Intensive PK sampling of blood, CSF, and tumor is performed intraoperatively and Ribociclib concentrations are determined by a validated LC-MS/MS method. PD endpoints, including RB phosphorylation and FoxM1 expression, are compared to matched archival tissue. Patients exhibiting positive PK and PD outcomes will graduate to a therapeutic regime of Ribociclib as part of the Phase II component of the study with a primary endpoint of progression-free survival, as determined by Response Assessment in Neuro-Oncology (RANO) criteria. Clinical trial information: NCT02933736.

Cytoprotective Effect of Tocotrienol-Rich Fraction and α-Tocopherol Vitamin E Isoforms Against Glutamate-Induced Cell Death in Neuronal Cells

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0140-0151 ◽  
Author(s):  
Thilaga Rati Selvaraju ◽  
Huzwah Khaza’ai ◽  
Sharmili Vidyadaran ◽  
Mohd Sokhini Abd Mutalib ◽  
Vasudevan Ramachandran ◽  
...  
Keyword(s):  
Vitamin E ◽  
Cell Viability ◽  
Neuronal Cells ◽  
Positive Control ◽  
Post Treatment ◽  
Mitochondrial Activity ◽  
Before And After ◽  
Pre Treatment ◽  
Tocotrienol Rich Fraction ◽  
Major Mediator

Glutamate is the major mediator of excitatory signals in the mammalian central nervous system. Extreme amounts of glutamate in the extracellular spaces can lead to numerous neurodegenerative diseases. We aimed to clarify the potential of the following vitamin E isomers, tocotrienol-rich fraction (TRF) and α-tocopherol (α-TCP), as potent neuroprotective agents against glutamate-induced injury in neuronal SK-N-SH cells. Cells were treated before and after glutamate injury (pre- and post-treatment, respectively) with 100 - 300 ng/ml TRF/α-TCP. Exposure to 120 mM glutamate significantly reduced cell viability to 76 % and 79 % in the pre- and post-treatment studies, respectively; however, pre- and post-treatment with TRF/α-TCP attenuated the cytotoxic effect of glutamate. Compared to the positive control (glutamate-injured cells not treated with TRF/α-TCP), pre-treatment with 100, 200, and 300 ng/ml TRF significantly improved cell viability following glutamate injury to 95.2 %, 95.0 %, and 95.6 %, respectively (p < 0.05).The isomers not only conferred neuroprotection by enhancing mitochondrial activity and depleting free radical production, but also increased cell viability and recovery upon glutamate insult. Our results suggest that vitamin E has potent antioxidant potential for protecting against glutamate injury and recovering glutamate-injured neuronal cells. Our findings also indicate that both TRF and α-TCP could play key roles as anti-apoptotic agents with neuroprotective properties.

Effect of new dietary supplement on sperm quality

2012 ◽  
Vol 153 (45) ◽  
pp. 1787-1792 ◽  
Author(s):  
Mária Horváth ◽  
Endre Czeizel
Keyword(s):  
Adverse Effect ◽  
Clinical Trial ◽  
Dietary Supplement ◽  
Male Fertility ◽  
Sperm Quality ◽  
Sperm Count ◽  
Before And After ◽  
The Usa ◽  
New Treatments

Introduction: There is a decline in male fertility thus new treatments are needed. Aims: To test the efficacy of a new dietary supplement developed in the USA and registered as a curing drug in Hungary (OGYI). Methods: In a clinical trial 100 men with low sperm quality (spermium count 5–20 M/ml, good motility 10–40%, and adverse shape 30–50%) were examined. Results: Sperm parameters were measured before and after a 3-month treatment and after another 3-month without treatment. This dietary supplement statistically and clinically significantly improved sperm count and motility. In 74 cases this dietary supplement demonstrated a beneficial effect on sperm quality (more than 10% increase in sperm count, or quality of motility, or shape); in 16 cases the improvement exceeded 30%. No adverse effect could be accounted for this treatment. Conclusions: This new dietary supplement may contribute to the treatment of male infertility. Orv. Hetil., 2012, 153, 1787–1792.

Window-of-Opportunity Clinical Trial of Pembrolizumab in Recurrent Glioblastoma (GBM) Patients

2018 ◽  
Author(s):  
John de Groot ◽  
Marta Penas-Prado ◽  
Kristin D. Alfaro-Munoz ◽  
Kathy Hunter ◽  
Barbara O’Brien ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Recurrent Glioblastoma ◽  
Window Of Opportunity

scholarly journals Time-to-Treatment in Oral Cancer: Causes and Implications for Survival

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1321
Author(s):  
Constanza Saka-Herrán ◽  
Enric Jané-Salas ◽  
Antoni Mari-Roig ◽  
Albert Estrugo-Devesa ◽  
José López-López
Keyword(s):  
Oral Cancer ◽  
Previous Treatment ◽  
Diagnostic Procedures ◽  
Original Data ◽  
Primary Treatment ◽  
Medical Attention ◽  
Time Interval ◽  
Pre Treatment ◽  
The Impact ◽  
Lack Of Knowledge

The purpose of this review was to identify and describe the causes that influence the time-intervals in the pathway of diagnosis and treatment of oral cancer and to assess its impact on prognosis and survival. The review was structured according to the recommendations of the Aarhus statement, considering original data from individual studies and systematic reviews that reported outcomes related to the patient, diagnostic and pre-treatment intervals. The patient interval is the major contributor to the total time-interval. Unawareness of signs and/or symptoms, denial and lack of knowledge about oral cancer are the major contributors to the process of seeking medical attention. The diagnostic interval is influenced by tumor factors, delays in referral due to higher number of consultations and previous treatment with different medicines or dental procedures and by professional factors such as experience and lack of knowledge related to the disease and diagnostic procedures. Patients with advanced stage disease, primary treatment with radiotherapy, treatment at an academic facility and transitions in care are associated with prolonged pre-treatment intervals. An emerging body of evidence supports the impact of prolonged pre-treatment and treatment intervals with poorer survival from oral cancer.

scholarly journals A prospective, observational clinical trial on the impact of COVID-19-related national lockdown on thyroid hormone in young males

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giulia Brigante ◽  
Giorgia Spaggiari ◽  
Barbara Rossi ◽  
Antonio Granata ◽  
Manuela Simoni ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Serum Levels ◽  
Stressful Event ◽  
Italian Population ◽  
Reference Ranges ◽  
Endocrine Regulation ◽  
Before And After ◽  
Hpt Axis ◽  
The Impact

AbstractTrying to manage the dramatic coronavirus disease 2019 (COVID-19) infection spread, many countries imposed national lockdown, radically changing the routinely life of humans worldwide. We hypothesized that both the pandemic per se and the consequent socio-psychological sequelae could constitute stressors for Italian population, potentially affecting the endocrine system. This study was designed to describe the effect of lockdown-related stress on the hypothalamic-pituitary-thyroid (HPT) axis in a cohort of young men. A prospective, observational clinical trial was carried out, including patients attending the male infertility outpatient clinic before and after the national lockdown for COVID-19 pandemic. The study provided a baseline visit performed before and a follow-up visit after the lockdown in 2020. During the follow-up visit, hormonal measurements, lifestyle habits and work management were recorded. Thirty-one male subjects were enrolled (mean age: 31.6 ± 6.0 years). TSH significantly decreased after lockdown (p = 0.015), whereas no significant changes were observed in the testosterone, luteinising hormone, follicle-stimulating hormone, estradiol and prolactin serum levels. No patient showed TSH serum levels above or below reference ranges, neither before nor after lockdown. Interestingly, TSH variation after lockdown was dependent on the working habit change during lockdown (p = 0.042). We described for the first time a TSH reduction after a stressful event in a prospective way, evaluating the HPT axis in the same population, before and after the national lockdown. This result reinforces the possible interconnection between psychological consequences of a stressful event and the endocrine regulation.

scholarly journals FRI0612-HPR EFFECT OF THERMOFORMABLE ORTHOSES ON FOOT FUNCTION IN RHEUMATOID ARTHRITIS PATIENTS: PRELIMINARY RESULTS FROM AN OPEN CLINICAL TRIAL.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 911.2-912
Author(s):  
I. Aachari ◽  
H. Rkain ◽  
F. Safaa ◽  
L. Benzakour ◽  
T. Latifa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Trial ◽  
Small Sample ◽  
Activity Limitation ◽  
Foot Orthoses ◽  
Functional Impact ◽  
Pain Disability ◽  
Before And After ◽  
Foot Function ◽  
The Impact

Background:Orthoses and footwear can play an important role in managing foot pathology in patients whose systemic disease is controlled. Foot orthoses are frequently prescribed in clinical practice as an intervention for people with rheumatoid arthritis (RA).Objectives:The aim of our study is to evaluate the impact of thermoformable orthoses on the functional index of the foot (FFI) in patients with rheumatoid arthritis.Methods:We conducted an open clinical trial, having consecutively included 14 patients (85.7% female, average age 54.8 ± 10 years) suffering from rheumatoid arthritis (median progression time of 9 years [5 - 12]). The average DAS28 was 2.7 ± 1.2 and the functional impact objectified by the Health Assessment Questionnaire (HAQ) was on average 0.9 ± 0.7.The median deadline from the start of RA and the onset of the foot problem was 3 years [0 – 7,75]. The foot problem was bilateral in 100% of the cases and inaugural in 85.7% of the cases.We evaluated the functional impact of foot injury for all our patients at baseline and 8 weeks after the use of thermoformable orthoses, based on the FFI (Foot function Index) measuring the impact of foot pathology on function in terms of pain, disability and activity limitation.The comparison of the FFI domains before and after the use of orthoses was carried out using parametric or nonparametric paired tests using The SPSS statistical software.Results:With the use of foot orthoses, FFI values decreased in all subscales (p=0,024) (pain, disability and activity limitation). This reduction was significant for disability (0,011) but not for pain and activity limitation.There were no significant correlations between the global FFI and the progression of RA, the duration of foot damage and the functional impact measured by the HAQ.Table 1. The comparison of the FFI domains before and after the use of orthoses.psignificatif if< 0,05; Test used: Non-parametric test for two linked samples.Conclusion:Foot orthoses were effective as an adjuvant in the management of rheumatoid foot. They significantly reduced disability as measured by the FFI. The absence of factors associated with pain and limitation of activity could possibly be related to the small sample size.Disclosure of Interests:None declared

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