Publications by authors named "Tony Pourmohamad"

12 Publications

  • Page 1 of 1

The Utility of Novel Urinary Biomarkers in Mice for Drug Development Studies.

Int J Toxicol 2021 Jan-Feb;40(1):15-25. Epub 2020 Nov 9.

241854Janssen Research & Development, LLC, San Diego, CA, USA.

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there are few reports on the utility of these renal biomarkers in mice, another important and widely used preclinical animal species for drug development studies. The purpose of this study was to assess the value of these recently qualified biomarkers for the early detection of drug-induced kidney injury (DIKI) in different strains of mice using multiple assay panels. To this end, we evaluated biomarker response to kidney injury induced by several nephrotoxic agents including amphotericin B, compound X, and compound Y. Several of the biomarkers were shown to be sensitive to DIKI in mice. When measured, urinary albumin and neutrophil gelatinase-associated lipocalin were highly sensitive to renal tubular injury, regardless of the assay platforms, mouse strain, and nephrotoxic agents. Depending on the type of renal tubular injury, kidney injury molecule-1 was also highly sensitive, regardless of the assay platforms and mouse strain. Osteopontin and cystatin C were modestly to highly sensitive to renal tubular injury, but the assay type and/or the mouse strain should be considered before using these biomarkers. Calbindin D28 was highly sensitive to injury to the distal nephron in mice. To our knowledge, this is the first report that demonstrates the utility of novel urinary biomarkers evaluated across multiple assay platforms and nephrotoxicants in different mice strains with DIKI. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in mice for toxicology studies.
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http://dx.doi.org/10.1177/1091581820970498DOI Listing
November 2020

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors.

Clin Cancer Res 2019 06 15;25(11):3220-3228. Epub 2019 Feb 15.

University of Colorado Cancer Center, Aurora, Colorado.

Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.

Patients And Methods: The study consisted of a 3+3 dose-escalation stage ( = 66) and a tumor-specific expansion stage ( = 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day -1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.

Results: Patients ( = 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizumab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, non-small cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) dose-escalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.

Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980952PMC
June 2019

Investigating the Value of Urine Volume, Creatinine, and Cystatin C for Urinary Biomarkers Normalization for Drug Development Studies.

Int J Toxicol 2019 Jan/Feb;38(1):12-22. Epub 2019 Jan 23.

2 Janssen Research & Development, LLC, San Diego, CA, USA.

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there seems to be no standardized normalization method for analyzing these urinary biomarkers, as some users normalize with urinary creatinine (uCr), urine volume (uVol), or leave biomarker un-normalized. More recently, urinary cystatin C is also emerging as a urinary biomarker normalizer, given some of its characteristics as a glomerular filtration marker. The purpose of this study was to identify an optimal drug-induced kidney injury biomarker normalization method that can be adopted more uniformly in the field. To this end, we compared the variability of uVol, urinary cystatin C, and Cr in healthy rats; we evaluated the sensitivity of the renal biomarkers to renal injury after normalization with uVol, uCr, and cystatin C in rats with cisplatin-induced renal injury. We showed that, over time, uCr was less variable than urinary cystatin C and uVol. When the renal biomarkers were normalized with the 3 normalizing end points, the biomarkers showed (1) least variability following normalization with Cr in healthy animals and (2) poor sensitivity when normalized with urinary cystatin C in animals with renal injury. Overall, the results suggested that uCr is better than urinary cystatin C and uVol for normalizing renal biomarkers in rats under controlled preclinical conditions. To our knowledge, this is the first report that compared the variability of uVol, cystatin C, and Cr in the context of renal biomarkers' normalization.
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http://dx.doi.org/10.1177/1091581818819791DOI Listing
December 2019

Phase I study of the anti-α5β1 monoclonal antibody MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2018 08 15;82(2):339-351. Epub 2018 Jun 15.

California Cancer Associates for Research & Excellence, Encinitas, CA, USA.

Purpose: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Methods: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage.

Results: Twenty-four patients were enrolled in arm 1 (dose range 2-30 mg/kg) and 30 patients were enrolled in arm 2 (dose range 3-15 mg/kg). Monocyte α5β1 receptor occupancy was saturated at a dose of 15 mg/kg. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached in either arm. The most common adverse events, regardless of causality, included abdominal pain (25%), diarrhea (25%), nausea (21%), vomiting (21%), and fatigue (21%) in arm 1 and nausea (40%), fatigue (33%), vomiting (30%), dehydration (30%), headache (30%), and hypertension (30%) in arm 2. No grade ≥ 3 bleeding events were observed in either arm. No confirmed partial responses (PR) were observed in arm 1. In arm 2, one patient with thymic carcinoma experienced a confirmed PR and two patients with hepatocellular carcinoma (HCC) experienced durable minor radiographic responses.

Conclusions: MINT1526A, with or without bevacizumab, was well-tolerated. Preliminary evidence of combination efficacy, including in patients with HCC, was observed, but cannot be distinguished from bevacizumab monotherapy in this phase I study.
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http://dx.doi.org/10.1007/s00280-018-3622-8DOI Listing
August 2018

Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations.

Am J Med Genet A 2012 Nov 18;158A(11):2829-34. Epub 2012 Sep 18.

Yale HHT Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0-68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2-50) and 18 ± 21 (0-48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT.
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http://dx.doi.org/10.1002/ajmg.a.35622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610331PMC
November 2012

Cerebellar arteriovenous malformations: anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system.

Neurosurgery 2012 Dec;71(6):1111-24

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143-0112, USA.

Background: Anatomic diversity among cerebellar arteriovenous malformations (AVMs) calls for a classification that is intuitive and surgically informative. Selection tools like the Spetzler-Martin grading system are designed to work best with cerebral AVMs but have shortcomings with cerebellar AVMs.

Objective: To define subtypes of cerebellar AVMs that clarify anatomy and surgical management, to determine results according to subtypes, and to compare predictive accuracies of the Spetzler-Martin and supplementary systems.

Methods: From a consecutive surgical series of 500 patients, 60 had cerebellar AVMs, 39 had brainstem AVMs and were excluded, and 401 had cerebral AVMs.

Results: Cerebellar AVM subtypes were as follows: 18 vermian, 13 suboccipital, 12 tentorial, 12 petrosal, and 5 tonsillar. Patients with tonsillar and tentorial AVMs fared best. Cerebellar AVMs presented with hemorrhage more than cerebral AVMs (P < .001). Cerebellar AVMs were more likely to drain deep (P = .04) and less likely to be eloquent (P < .001). The predictive accuracy of the supplementary grade was better than that of the Spetzler-Martin grade with cerebellar AVMs (areas under the receiver-operating characteristic curve, 0.74 and 0.59, respectively). The predictive accuracy of the supplementary system was consistent for cerebral and cerebellar AVMs, whereas that of the Spetzler-Martin system was greater with cerebral AVMs.

Conclusion: Patients with cerebellar AVMs present with hemorrhage more often than patients with cerebral AVMs, justifying an aggressive treatment posture. The supplementary system is better than the Spetzler-Martin system at predicting outcomes after cerebellar AVM resection. Key components of the Spetzler-Martin system such as venous drainage and eloquence are distorted by cerebellar anatomy in ways that components of the supplementary system are not.
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http://dx.doi.org/10.1227/NEU.0b013e318271c081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923506PMC
December 2012

Evaluating performance of the spetzler-martin supplemented model in selecting patients with brain arteriovenous malformation for surgery.

Stroke 2012 Sep 19;43(9):2497-9. Epub 2012 Jul 19.

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA,

Background And Purpose: Our recently proposed point scoring model includes the widely-used Spetzler-Martin (SM)-5 variables, along with age, unruptured presentation, and diffuse border (SM-Supp). Here we evaluate the SM-Supp model performance compared with SM-5, SM-3, and Toronto prediction models using net reclassification index, which quantifies the correct movement in risk reclassification, and validate the model in an independent data set.

Methods: Bad outcome was defined as worsening between preoperative and final postoperative modified Rankin Scale score. Point scores for each model were used as predictors in logistic regression and predictions evaluated using net reclassification index at varying thresholds (10%-30%) and any threshold (continuous net reclassification index >0). Performance was validated in an independent data set (n=117).

Results: Net gain in risk reclassification was better using the SM-Supp model over a range of threshold values (net reclassification index=9%-25%) and significantly improved overall predictions for outcomes in the development data set, yielding a continuous net reclassification index of 64% versus SM-5, 67% versus SM-3, and 61% versus Toronto (all P<0.001). In the validation data set, the SM-Supp model again correctly reclassified a greater proportion of patients versus SM-5 (82%), SM-3 (85%), and Toronto models (69%).

Conclusions: The SM-Supp model demonstrated better discrimination and risk reclassification than several existing models and should be considered for clinical practice to estimate surgical risk in patients with brain arteriovenous malformation.
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http://dx.doi.org/10.1161/STROKEAHA.112.661942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431204PMC
September 2012

Perlecan domain V is upregulated in human brain arteriovenous malformation and could mediate the vascular endothelial growth factor effect in lesional tissue.

Neuroreport 2012 Jul;23(10):627-30

Department of Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, College Station, Texas 77843, USA.

Brain arteriovenous malformation (BAVM), a rare but important cause of intracranial hemorrhage, has increased angiogenesis and inflammation as key components of the nidus of abnormal vessels and stroma that form the resected surgical specimen. Accordingly, both vascular endothelial growth factor (VEGF) and transforming growth factor-β have been implicated in the pathology of BAVM for their proangiogenic and vascular-regulating roles. The C-terminal fragment of the extracellular matrix component perlecan (domain V, DV) has been shown to be increased and through the α5β1 integrin, to increase VEGF levels in and around areas of cerebral ischemic injury, another proangiogenic condition. We aimed to determine whether the concentrations of DV, DV's proangiogenic receptor α5β1 integrin, or DV's antiangiogenic receptor α2β1 integrin are elevated in human BAVM tissue. DV levels were increased in BAVM compared with control brain tissue from epileptic resection, as was α5β1 integrin. In addition, α5β1 integrin was preferentially increased and localized to endothelial cells compared with α2β1 integrin. VEGF and transforming growth factor-β levels were also increased in BAVM compared with control tissue. Furthermore, increases in all components were strongly correlated. Excessive generation of proangiogenic DV in BAVM suggests that DV may participate in its pathology and may represent a future therapeutic target.
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http://dx.doi.org/10.1097/WNR.0b013e3283554c5cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535489PMC
July 2012

An admission bioclinical score to predict 1-year outcomes in patients undergoing aneurysm coiling.

Stroke 2012 May 23;43(5):1253-9. Epub 2012 Feb 23.

Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94110, USA.

Background And Purpose: A number of scores were developed to predict outcomes after clipping for subarachnoid hemorrhages, yet there is no score for patients undergoing endovascular treatment. Our goal was to develop, compare, and validate a predictive score for 1-year outcomes in patients with coiled subarachnoid hemorrhage.

Methods: We studied 526 patients for 1 year after intensive care unit discharge. We developed an admission bioclinical score (ABC score), which integrated biomarkers such as troponin I and S100β, with the Glasgow Coma Scale. Using the receiver operating characteristic curve (95% CI), the ABC score was compared with the Glasgow Coma Scale, World Federation of Neurosurgical Societies score, and Fisher score in the derivation cohort and further validated in an independent cohort.

Results: In the derivation cohort (from 2003-2007, n=368), multivariate logistic regression analysis showed that only Glasgow Coma Scale (P<0.001), high S100β (P<0.001), and high troponin (P<0.02) were independently associated with 1-year mortality. Troponin, S100β, and Glasgow Coma Scale were thus integrated to derive the ABC score. In the derivation cohort, the ABC score reached an receiver operating characteristic curve of 0.82 (0.77-0.88, P<0.001) and was significantly greater than the receiver operating characteristic curves of the Glasgow Coma Scale, World Federation of Neurosurgical Societies, and Fisher scores for predicting 1-year mortality. In the validation cohort (from 2008-2009, n=158), the ABC score's receiver operating characteristic curve of 0.76 (0.67-0.86, P<0.001) remained superior to the 3 other scores for predicting 1-year mortality.

Conclusions: The ABC score improves 1-year outcome prediction at admission for patients with coiled subarachnoid hemorrhage. Our study provides large cohort-based evidence supporting integration of individual biomarkers and clinical characteristics to predict outcomes. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT01357057.
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http://dx.doi.org/10.1161/STROKEAHA.111.638197DOI Listing
May 2012

Silent intralesional microhemorrhage as a risk factor for brain arteriovenous malformation rupture.

Stroke 2012 May 2;43(5):1240-6. Epub 2012 Feb 2.

University of California, San Francisco, CA 94110, USA.

Background And Purpose: We investigated whether brain arteriovenous malformation silent intralesional microhemorrhage, that is, asymptomatic bleeding in the nidal compartment, might serve as a marker for increased risk of symptomatic intracranial hemorrhage (ICH). We evaluated 2 markers to assess the occurrence of silent intralesional microhemorrhage: neuroradiological assessment of evidence of old hemorrhage-imaging evidence of bleeding before the outcome events-and hemosiderin positivity in hematoxylin and eosin-stained paraffin block sections.

Methods: We identified cases from our brain arteriovenous malformation database with recorded neuroradiological data or available surgical paraffin blocks. Using 2 end points, index ICH or new ICH after diagnosis (censored at treatment, loss to follow-up, or death), we performed logistic or Cox regression to assess evidence of old hemorrhage and hemosiderin positivity adjusting for age, sex, deep-only venous drainage, maximal brain arteriovenous malformation size, deep location, and associated arterial aneurysms.

Results: Evidence of old hemorrhage was present in 6.5% (n=975) of patients and highly predictive of index ICH (P<0.001; OR, 3.97; 95% CI, 2.1-7.5) adjusting for other risk factors. In a multivariable model (n=643), evidence of old hemorrhage was an independent predictor of new ICH (hazard ratio, 3.53; 95% CI, 1.35-9.23; P=0.010). Hemosiderin positivity was found in 36.2% (29.6% in unruptured; 47.8% in ruptured; P=0.04) and associated with index ICH in univariate (OR, 2.18; 95% CI, 1.03-4.61; P=0.042; n=127) and multivariable models (OR, 3.64; 95% CI, 1.11-12.00; P=0.034; n=79).

Conclusions: The prevalence of silent intralesional microhemorrhage is high and there is evidence for an association with both index and subsequent ICH. Further development of means to detect silent intralesional microhemorrhage during brain arteriovenous malformation evaluation may present an opportunity to improve risk stratification, especially for unruptured brain arteriovenous malformations.
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http://dx.doi.org/10.1161/STROKEAHA.111.647263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335931PMC
May 2012

Brain arteriovenous malformation multiplicity predicts the diagnosis of hereditary hemorrhagic telangiectasia: quantitative assessment.

Stroke 2012 Jan 27;43(1):72-8. Epub 2011 Oct 27.

Division of Neuroradiology, Department of Medical Imaging, St Michael's Hospital, 30 Bond Street, Suite 6049, Toronto, Ontario, M4K-1W7, Canada.

Background And Purpose: The purpose of this study was to quantitatively estimate the relationship between multiplicity of brain arteriovenous malformations (bAVMs) and the diagnosis of hereditary hemorrhagic telangiectasia (HHT).

Methods: We combined databases from 2 large North American bAVM referral centers, including demographics, clinical presentation, and angiographic characteristics, and compared patients with HHT with non-HHT patients. Logistic regression analysis was performed to quantify the association between bAVM multiplicity and odds of HHT diagnosis. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated to determine accuracy of bAVM multiplicity for screening HHT.

Results: Prevalence of HHT was 2.8% in the combined group. bAVM multiplicity was present in 39% of patients with HHT and was highly associated with diagnosis of HHT in univariate (OR, 83; 95% CI, 40-173; P<0.0001) and multivariable (OR, 86; 95% CI, 38-195; P<0.001) models adjusting for age at presentation (P=0.013), symptomatic presentation (P=0.029), and cohort site (P=0.021). bAVM multiplicity alone was associated with high specificity (99.2%; 95% CI, 98.7%-99.6%) and negative predictive value (98.3%; 95% CI, 97.6%-98.8%) and low sensitivity (39.3%; 95% CI, 26.5%-53.2%) and positive predictive value (59.5%; 95% CI, 42.1%-75.2%). Positive and negative likelihood ratio was 51 and 0.61, respectively, for diagnosis of HHT. HHT bAVMs were also more often smaller in size (<3 cm), noneloquent in location, and associated with superficial venous drainage compared with non-HHT bAVMs.

Conclusions: Multiplicity of bAVMs is highly predictive of the diagnosis of HHT. The presence of multiple bAVMs should alert the clinician to the high probability of HHT and lead to comprehensive investigation for this diagnosis.
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http://dx.doi.org/10.1161/STROKEAHA.111.629865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727386PMC
January 2012