Gamal Akabani | Texas A&M University (original) (raw)

Papers by Gamal Akabani

Journal of Clinical Oncology, Mar 1, 2002

To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin m... more To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma. In this phase II trial, 120 mCi of (131)I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis. Median survival achieved with (131)I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with (131)I-labeled 81C6 compares favorably with either (125)I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of (131)I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.

The Journal of Nuclear Medicine, Dec 12, 2007

a-Particle-emitting radionuclides, such as 211 At, with a 7.2-h half-life, may be optimally suite... more a-Particle-emitting radionuclides, such as 211 At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of a-particles than of b-particles, 211 At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. Methods: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of 211 At by use of N-succinimidyl 3-[ 211 At]astatobenzoate. Eighteen patients were treated with 211 At-labeled ch81C6 (211 At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial g-camera imaging and blood sampling over 24 h were performed. Results: A total of 96.7% 6 3.6% (mean 6 SD) of 211 At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was #0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of 211 At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. Conclusion: This study provides proof of concept for regional targeted radiotherapy with 211 At-labeled molecules in oncology. Specifically, the regional administration of 211 At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Journal of Clinical Oncology, Jul 15, 2004

1569 Background: In a prior phase I study we established the dose of 100mCi as the maximum tolera... more 1569 Background: In a prior phase I study we established the dose of 100mCi as the maximum tolerated dose of iodine 131-labeled murine anti-tenascin antibody 81C6 (131I-81C6) injected into a surgically created resection cavity (SCRC) for the treatment of recurrent malignant glioma in adult patients. METHODS In the current phase II study we have treated 42 patients with recurrent brain tumors (GBM=32, AA=6, AO=2, infiltrating glioma = 1, metastatic =1). Patients were included into study if they had: 1) gross total resection, 2) KPS > 60%, 3) normal bone marrow and normal hepatic and renal function. All patients had received standard external beam radiation and 14 (33%) patients had received prior chemotherapy. RESULTS The median age was 54.5 years and 27 patients (64%) were males. All patients received 100mCi except for two patients that received 67mCi and 75mCi respectively due to the limited size of the SCRC. Toxicities were divided into acute (< 4 weeks), subacute (4-16 weeks) and delayed (>16 weeks) periods. Acute and sub-acute reversible, grade 4 hematologic toxicity was seen in 2 patients (4%) and 3 (7%) patients, respectively. Delayed grade 3 or 4 neurotoxicity was seen in 2 patients (4%). The median survival of all patients and GBM patients was 59 weeks for both groups, respectively. For patients with GBM the probability of 1-year survival is 0.56 (CI-95%; 0.41-0.78). As of December 16, 2003, 15 patients remain alive with a median follow up of 81.9 weeks for GBMs and 78.9 weeks for all patients. CONCLUSIONS I131- labeled murine anti-tenascin antibody 81C6 is associated with minimal hematologic toxicity and provides an improvement in survival in patients with recurrent malignant glioma that have failed conventional therapy. No significant financial relationships to disclose.

PubMed, Jun 1, 2005

The objective was to perform dosimetry and evaluate dose-response relationships in newly diagnose... more The objective was to perform dosimetry and evaluate dose-response relationships in newly diagnosed patients with malignant brain tumors treated with direct injections of (131)I-labeled anti-tenascin murine 81C6 monoclonal antibody (mAb) into surgically created resection cavities (SCRCs) followed by conventional external-beam radiotherapy and chemotherapy. Methods: Absorbed doses to the 2-cm-thick shell, measured from the margins of the resection cavity interface, were estimated for 33 patients with primary brain tumors. MRI/SPECT registrations were used to assess the distribution of the radiolabeled mAb in brain parenchyma. Results from biopsies obtained from 15 patients were classified as tumor, radionecrosis, or tumor and radionecrosis, and these were correlated with absorbed dose and dose rate. Also, MRI/PET registrations were used to assess radiographic progression among patients. Results: This therapeutic strategy yielded a median survival of 86 and 79 wk for all patients and glioblastoma multiforme (GBM) patients, respectively. The average SCRC residence time of (131)I-mu81C6 mAb was 76 h (range, 34-169 h). The average absorbed dose to the 2-cm cavity margins was 48 Gy (range, 25-116 Gy) for all patients and 51 Gy (range, 27-116 Gy) for GBM patients. In MRI/SPECT registrations, we observed a preferential distribution of (131)I-mu81C6 mAb through regions of vasogenic edema. An analysis of the relationship between the absorbed dose and dose rate and the first biopsy results yielded a most favorable absorbed dose of 44 Gy. A correlation between decreased survival and irreversible neurotoxicity was noted. A comparative analysis, in terms of median survival, was performed with previous brachytherapy clinical studies, which showed a proportional relationship between the average boost absorbed dose and the median survival. Conclusion: This study shows that (131)I-mu81C6 mAb increases the median survival of GBM patients. An optimal absorbed dose of 44 Gy to the 2-cm cavity margins is suggested to reduce the incidence of neurologic toxicity. Further clinical studies are warranted to determine the effectiveness of (131)I-mu81C6 mAb based on a target dose of 44 Gy rather than a fixed administered activity.

OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information), 1999

The objective of this study was to validate the use of a 3-D discrete Fourier Transform (3D-DFT) ... more The objective of this study was to validate the use of a 3-D discrete Fourier Transform (3D-DFT) convolution method to carry out the dosimetry for I-131 for soft tissues in radioimmunotherapy procedures. To validate this convolution method, mathematical and physical phantoms were used as a basis of comparison with Monte Carlo transport (MCT) calculations which were carried out using the EGS4 system code. The mathematical phantom consisted of a sphere containing uniform and nonuniform activity distributions. The physical phantom consisted of a cylinder containing uniform and nonuniform activity distributions. Quantitative SPECT reconstruction was carried out using the Circular Harmonic Transform (CHT) algorithm.

The Journal of Nuclear Medicine, Nov 1, 2003

The sodium/iodide symporter (NIS) has been identified as an attractive target for cancer therapy.... more The sodium/iodide symporter (NIS) has been identified as an attractive target for cancer therapy. The efficacy of 131 I-iodide for NIS-expressing tumor therapy may be limited by a combination of poor cellular retention and unfavorable physical characteristics (long physical half-life and low linear-energy-transfer [LET] radiative emissions). On the other hand, 211 At-astatide is also transported by NIS and offers several therapeutic advantages over 131 I-iodide due to its physical characteristics (short half-life, high LET ␣-particle emissions). The objective of this study was to directly compare the radiotoxicity of both radionuclides using a NIS-transfected cultured cell model. Methods: Cytotoxicity was determined by colony-forming assays. Also, a first-order pharmacokinetic model was used to simulate the closed compartmental system between the medium and cells. Experimental data were then fitted to this model and used to estimate the transfer coefficients between medium and cells, k m c , and between cells and medium, k c m. Using the pharmacokinetic model, the cumulated activity concentrations in the medium and cells were calculated. Monte Carlo transport methods were then used to assess absorbed doses from 131 I and 211 At. Results: 211 At-Astatide was significantly more cytotoxic than 131 I-iodide in this closed compartmental system. For 211 At-astatide, absorbed doses per unit administered activity were 54to 65-fold higher than for 131 I-iodide. Both NIS-expressing and control cells showed increased sensitivity to 211 At over 131 I, with significantly lower D 0 (absorbed dose required to reduce the survival fraction to e Ϫ1) and SF 2 (2-Gy survival fraction) values, highlighting the higher intrinsic cytotoxicity of ␣-particles. However, NIS-independent (nonspecific) binding of 211 At-astatide was higher than that of 131 I-iodide, therefore, yielding a lower absorbed dose ratio between NIS-transfected and-nontransfected cells. Conclusion: Treatment of NIS-expressing cells with 211 At-astatide resulted in higher absorbed doses and increased cytotoxicity per unit administered activity than that observed with 131 I-iodide. These results suggest that 211 At-astatide may be a promising treatment strategy for the therapy of NIS-expressing tumors.

Cancer Research, 2004

5238 Adequate quality and quantity of genomic DNA is a bottleneck in genetic analysis of clinical... more 5238 Adequate quality and quantity of genomic DNA is a bottleneck in genetic analysis of clinical tumor samples. In brain tumor patients, most often only tiny amounts of tissue are available from stereotactic needle biopsies. The yield of genomic template from these specimens by common methods of DNA isolation does frequently not allow high-throughput genetic analysis in these patients, which however may be important for treatment stratification in targeted therapy. Much effort has been invested in developing methods for whole genome amplification (WGA). Substantial variation in the extent of amplification occurring between different markers, incomplete coverage, and inadequate average DNA size has limited the use of existing WGA methods, making them particularly unsuitable for diagnostic testing. Most recently, a novel technique for WGA has been described, termed multiple displacement amplification (MDA), which provides a highly uniform representation across the human genome. MDA e...

Journal of Nuclear Medicine, 2020

In 2018, the National Cancer Institute (NCI) and the NRG Oncology partnered for the first time to... more In 2018, the National Cancer Institute (NCI) and the NRG Oncology partnered for the first time to host a joint Workshop on Systemic Radiopharmaceutical Therapy (RPT) to specifically address issues and strategies of dosimetry for future clinical trials. The workshop focused on (1) current dosimetric approaches for clinical trials, (2) strategies under development that would provide optimal dose reporting, and (3) future desired/optimized approaches for the new and novel emerging radionuclides and carriers in development. In this proceedings, we review the main approaches that are applied clinically to calculate the absorbed dose: These include absorbed doses calculated over a variety of spatial scales including "whole body", organ, sub-organ, and voxel, the latter three all achievable within the Medical Internal Radiation Dose (MIRD) schema (S-value) can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This proceeding will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biological effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation-when merited by evidence collected during earlyphase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

Radiation Protection Dosimetry, 2018

One of the most important issues in the nuclear power industry is the implementation of the 2007 ... more One of the most important issues in the nuclear power industry is the implementation of the 2007 Recommendations of the International Commission on Radiological Protection (ICRP) published in ICRP Publication 103. These recommendations include the implementation of the concept of dose constraints for occupationally exposed workers at nuclear power plants (NPPs). When considering these changes from a cost–benefit standpoint, the implementation of dose constraints is still highly controversial. This study analysed annual occupational dose distributions to determine whether a dose constraint is needed for occupationally exposed workers at the US NPPs. Results of the analysis showed that the use of dose constraints had no positive impact on radiation safety of workers at NPPs in the USA. In fact, it appears that the implementation of dose constraints will impose an unnecessary regulatory burden on licensees. Based on these results, implementation of dose constraints is not recommended.

Nuclear Technology, 2018

The 2007 Recommendation of the International Commission on Radiological Protection [ICRP Publicat... more The 2007 Recommendation of the International Commission on Radiological Protection [ICRP Publication 103, Elsevier (2007)] requires implementation of the concept of a dose constraint for members of the public living around nuclear facilities. Under the paradigm of regulatory science, the use of dose constraints is still highly debatable. This study determines whether a dose constraint is necessary for members of the public living near U.S. nuclear power plants (NPPs) using data from the years 2007 to 2009, which were provided by the Nuclear Regulatory Commission. As a result of analysis of exposure data, it is concluded that a dose constraint is not necessary for members of the public living around U.S. NPPs and that such a constraint may place an unnecessary regulatory burden on the licensees.

Journal of Clinical Oncology, 2005

Medical Physics, 2000

Hematologic toxicity limits the radioactivity that may be administered for radiolabeled antibody ... more Hematologic toxicity limits the radioactivity that may be administered for radiolabeled antibody therapy. This work examines approaches for obtaining biodistribution data and performing dosimetry when the administered antibody is known to bind to a cellular component of blood, bone, or marrow. Marrow dosimetry in this case is more difficult because the kinetics of antibody clearance from the blood cannot be related to the marrow. Several approaches for obtaining antibody kinetics in the marrow are examined and evaluated. The absorbed fractions and S factors that should be used in performing marrow dosimetry are also examined and the effect of including greater anatomical detail is considered. The radiobiology of the red marrow is briefly reviewed. Recommendations for performing marrow dosimetry when the antibody binds to the marrow are provided.

International Journal of Radiation Oncology*Biology*Physics

Radiation research, Jun 1, 2018

Epidemiological investigation is an important approach to assessing the risk of late effects afte... more Epidemiological investigation is an important approach to assessing the risk of late effects after radiotherapy, and organ dosimetry is a crucial part of such analysis. Computed tomography (CT) images, if available, can be a valuable resource for individualizing the dosimetry, because they describe the specific anatomy of the patient. However, CT images acquired for radiation treatment planning purposes cover only a portion of the body near the target volume, whereas for epidemiology, the interest lies in the more distant normal tissues, which may be located outside the scan range. To address this challenge, we developed a novel method, called the Anatomically Predictive Extension (APE), to extend a partial-body CT image stack using images of a computational human phantom matched to the patient based on their height and weight. To test our method, we created five APE phantoms from chest and abdominal images extracted from the chest-abdomen-pelvis (CAP) CT scans of five patients. Org...

Journal of the American Chemical Society, Jan 31, 2018

Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies tha... more Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies that seek to optimize both the drug and drug carrier together in a concerted effort remain uncommon yet may be powerful. In this work, two block polymers and one dimeric prodrug molecule were designed to be coassembled into degradable, functional nanocarriers, where the chemistry of each component was defined to accomplish important tasks. The result is a poly(ethylene glycol) (PEG)-protected redox-responsive dimeric paclitaxel (diPTX)-loaded cationic poly(d-glucose carbonate) micelle (diPTX@CPGC). These nanostructures showed tunable sizes and surface charges and displayed controlled PTX drug release profiles in the presence of reducing agents, such as glutathione (GSH) and dithiothreitol (DTT), thereby resulting in significant selectivity for killing cancer cells over healthy cells. Compared to free PTX and diPTX, diPTX@CPGC exhibited improved tumor penetration and significant inhibition o...

Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine, 2018

The selective delivery of radionuclides to tissues of interest remains a problematic task during ... more The selective delivery of radionuclides to tissues of interest remains a problematic task during treatment. The lack of tissue specificity for many therapeutics limit their efficacy by putting healthy organs and tissues at risk (e.g., side effects). Therefore, high specificity therapeutic strategies are needed to overcome these risks. The objective of this study was to use a modified citrate reduction technique to synthesize gold nanoparticles (AuNPs) containing 125I in order to combine their unique therapeutic and diagnostic properties. This task was accomplished by varying the insertion time of 125I, which will cause complete aggregation if added too early in the AuNP synthesis process. Even though 125I was utilized in this experiment, studies are underway to see if this approach can be extrapolated to shorter-lived isotopes (e.g., 211At). Characterization of the 125I-AuNPs was carried out using UV-Vis spectrometry and Transmission Electron Microscopy (TEM). The appropriate additi...

Amino Acids, 2016

Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by... more Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by seizures, which can be caused by a diverse array of afflictions. As such, drug interventions that target a single biological pathway will only help the specific individuals where that drug&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s mechanism of action is relevant to their disorder. Most likely, this will not alleviate all forms of epilepsy nor the potential biological pathways causing the seizures, such as glucose/amino acid transport, mitochondrial dysfunction, or neuronal myelination. Considering our current inability to test every individual effectively for the true causes of their epilepsy and the alarming number of misdiagnoses observed, we propose the use of the ketogenic diet (KD) as an effective and efficient preliminary/long-term treatment. The KD mimics fasting by altering substrate metabolism from carbohydrates to fatty acids and ketone bodies (KBs). Here, we underscore the need to understand the underlying cellular mechanisms governing the KD&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s modulation of various forms of epilepsy and how a diverse array of metabolites including soluble fibers, specific fatty acids, and functional amino acids (e.g., leucine, D-serine, glycine, arginine metabolites, and N-acetyl-cysteine) may potentially enhance the KD&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s ability to treat and reverse, not mask, these neurological disorders that lead to epilepsy.