Publications by authors named "Hani M Babiker"

71 Publications

Exceptional response to cyclophosphamide and dexamethasone in a patient with metastatic castrate-resistant prostate cancer and RB1 mutation.

Anticancer Drugs 2021 Mar;32(3):337-343

Hematology and Oncology, University of Arizona College of Medicine, Tucson, Arizona, USA.

Rates of prostate cancer relapsing from anti-androgen therapies are increasing in the United States and worldwide. It has been suggested that this is caused by variant and altered lineage marker expression within the tumor, allowing for lineage plasticity that then facilitates therapeutic resistance. The genomic landscape of castrate-resistant prostate cancer has been well-defined with the advent of next-generation sequencing, but the clinical applications of these findings as measured by patient outcomes remains poorly understood. Here, we report on a patient with recurrent, metastatic castrate-resistant prostate cancer and identified RB1 mutation with progressive symptomatology, who was treated with cyclophosphamide and dexamethasone after other standard treatment regimens failed. After completing 2 years of treatment, he experienced complete resolution of his symptoms. Disease remission was confirmed on multiple imaging modalities and through serial measurements of prostate-specific antigen levels that showed a reduction of 99%. Our patient's case supports ongoing research that genetic profiling can help elucidate key biological and molecular tumor components, which can then inform targeted, individualized treatment approaches in the management of recurrent, castrate-resistant prostate cancer.
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http://dx.doi.org/10.1097/CAD.0000000000001025DOI Listing
March 2021

Quantitative metric for assessment of pancreatic ductal adenocarcinoma treatment response in T1-weighted gadolinium-enhanced magnetic resonance imaging.

Ann Pancreat Cancer 2020 Nov 25;3. Epub 2020 Nov 25.

Department of Radiology and the Translational Imaging Institute, Houston Methodist Hospital, Houston, TX, USA.

Background: We theoretically derived a new quantitative metric reflecting the product of T1 signal intensity and contrast media concentration () using first principles for the signal provided by the gradient echo sequence. This metric can be used with conventional gadolinium contrast-enhanced magnetic resonance imaging (CE-MRI) exams. We used this metric to test our hypothesis that gadolinium enhancement changes with pancreatic ductal adenocarcinoma (PDA) treatment response, and that this metric may differentiate responders from non-responders.

Methods: Out of 264 initially identified patients, a final total of 35 patients with PDA were included in a retrospective study of responders (n=24) and non-responders (n=11), which used changes in cancer antigen 19-9 (CA 19-9) and tumor size as reference standards. was computed for the pancreatic mass in the arterial, portal venous, and delayed phases in pre-treatment and post-treatment MRIs. Changes in measurements and correlations with treatment response were assessed by repeated measures analysis of variance and paired -tests.

Results: In the treatment responder group, significantly increased in the arterial, portal venous, and delayed phases (P=7.57e-5, P=3.25e-4, P=1.75e-4). In the non-responder group, did not significantly change in any phase (P>0.58). Post-treatment significantly differed between responders and non-responders (P=0.044) by repeated measures analysis of variance.

Conclusions: significantly increases in all phases of CE-MRI in responders to treatment, but does not change in non-responders. correlates with treatment response, can be computed from clinical MRI exams, and may be useful as an additional metric to stratify patients undergoing treatment.
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http://dx.doi.org/10.21037/apc-20-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755136PMC
November 2020

Contemporary Management of Pancreatic Cancer from an Internist Perspective.

Am J Med 2020 Dec 11. Epub 2020 Dec 11.

Mayo Clinic, Phoenix, Ariz.

Primary care physicians are in a favorable position to curb the growing burden of pancreatic ductal adenocarcinoma. This review aims to provide an overview of pancreatic ductal adenocarcinoma from a primary care perspective, with a specific focus on risk factors, selection of high-risk individuals for screening, patient presentation at the primary-care clinic, and the role of the internist in supportive care. Overall, the internist is an essential member of the multidisciplinary care team with respect to optimizing patients' quality of life across various stages of the pancreatic cancer.
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http://dx.doi.org/10.1016/j.amjmed.2020.11.009DOI Listing
December 2020

Clinical complexity of utilizing FGFR inhibitors in cancer therapeutics.

Expert Opin Investig Drugs 2020 Dec 6;29(12):1413-1429. Epub 2020 Nov 6.

Early Phase Clinical Trials Program, University of Arizona Cancer Center , Tucson, AZ, USA.

Introduction: Fibroblast growth factor receptors (FGFR 1-4) are a highly conserved family of receptor tyrosine kinases, involved in several physiological processes. Genetic aberrations of FGFRs and their ligands, fibroblast growth factors (FGFs) are involved in several pathological processes including cancer. The FGF-FGFR axis has emerged as a treatment target in oncology. Because these aberrations drive cancer progression, the development of FGFR targeted therapies have been accelerated.

Areas Covered: In this comprehensive review, we evaluate molecular pathology and targeted therapies to FGFRs. We reviewed the evidence for safety and efficacy from preclinical and clinical studies (phase I-III) of FGFR targeted therapies. We also discuss potential challenges in bringing these targeted therapies from bench to bedside and the potential opportunities.

Expert Opinion: Despite the challenges of the clinical development of FGFR targeted therapies, two FGFR small-molecule inhibitors, namely Erdafitinib and Pemigatinib, are FDA approved for urothelial cancer and cholangiocarcinoma, respectively. Understanding and detection of FGFR genomic aberrations, protein overexpression and the development of isoform-specific inhibitors are factors in the clinical success of these therapies. An enhanced understanding of patient selection based on a gene signatures or biomarkers is key to success of FGFR targeted therapies.
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http://dx.doi.org/10.1080/13543784.2020.1838484DOI Listing
December 2020

Evaluation of Potential Drug-Drug Interaction Risk of Pexidartinib With Substrates of Cytochrome P450 and P-Glycoprotein.

J Clin Pharmacol 2021 Mar 12;61(3):298-306. Epub 2020 Sep 12.

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Herein, 2 open-label, single-sequence, crossover studies evaluated the drug-drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P-gp. Thirty-two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P-gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates' pharmacokinetics. No drug-drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration-time curve from time zero to the last measurable time point (AUC ) of midazolam, whereas AUC values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite-to-parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19-mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUC . These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19-mediated metabolism or P-gp transport.
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http://dx.doi.org/10.1002/jcph.1734DOI Listing
March 2021

Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations.

Cancers (Basel) 2020 Jun 18;12(6). Epub 2020 Jun 18.

Department of Medicine-Hematology/Oncology, University of Texas Health San Antonio, Mays Cancer Center, San Antonio, TX 78229, USA.

Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants-1670 in oncogenes and 1673 in tumor suppressor genes-generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.
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http://dx.doi.org/10.3390/cancers12061618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352311PMC
June 2020

Analyzing outcomes of neoadjuvant and adjuvant treatment for borderline-resectable pancreatic adenocarcinoma in the perioperative period at an academic institution.

Ann Pancreat Cancer 2020 Mar 9;3. Epub 2020 Mar 9.

Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.

Background: Only 15-20% of pancreatic ductal adenocarcinoma (PDAC) patients are upfront surgical candidates at presentation, and for this cohort of patients, the 5-year survival is a mere 20% despite adjuvant therapy. Previous data indicate that in clinical practice most of these cases are "borderline-resectable," and there is currently no mature data on perioperative treatment.

Methods: We performed a retrospective electronic chart review of patients with "borderline-resectable"PDAC treated at an academic comprehensive cancer center, dividing them into groups based on surgery alone, surgery plus neoadjuvant, adjuvant, or neoadjuvant plus adjuvant perioperative treatment groups. The objectives were to determine the median overall survival (mOS), progression-free survival (PFS) and disease-free survival (DFS). Statistical analysis was performed to assess the association of demographic, tumor traits, and interventions with OS, PFS and DFS.

Results: Only surgery followed by adjuvant therapy showed an increase in mOS [hazard ratio (HR) 0.22; 95% CI, 0.09-0.51; P<0.001), after adjustment for radiation (yes no), resection margins (R0 R1 or R2), and tumor location (head body or tail). Patients who received adjuvant therapy after surgery had 2.1 times greater odds to be alive at 24 months after diagnosis than those who had surgery alone (P=0.015). PFS and DFS were not statistically significantly different among treatment groups after adjustment. Those whose disease was located in the head of the pancreas had a significantly improved OS (HR =0.27; 95% CI, 0.11-0.64; P=0.003), PFS (HR =0.40; 95% CI, 0.17-0.94; P=0.035), and DFS (HR =0.30; 95% CI, 0.13-0.67; P=0.004). Negative margins led to a significant improvement in PFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001) and DFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001). Those who received radiation had a non-significantly improved OS, PFS, and DFS (P>0.05).

Conclusions: Our study corroborated that patients treated with adjuvant therapy after surgical resection had an mOS benefit as reported on prior phase III clinical trials. Patients with "borderline-resectable" pancreatic cancer are encouraged to participate in a clinical trial or clinically be treated with adjuvant therapy until more mature results from the ongoing perioperative prospective study are available.
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http://dx.doi.org/10.21037/apc.2020.02.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170377PMC
March 2020

Correction to: Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer.

Cancer Chemother Pharmacol 2020 May;85(5):1009-1010

Mayo Clinic, Phoenix, AZ, USA.

In the original publication of the article the author has found few incorrect values in the Table 1.
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http://dx.doi.org/10.1007/s00280-020-04056-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645457PMC
May 2020

A Comparative Analysis of Tumors and Plasma Circulating Tumor DNA in 145 Advanced Cancer Patients Annotated by 3 Core Cellular Processes.

Cancers (Basel) 2020 Mar 16;12(3). Epub 2020 Mar 16.

Early Phase Clinical Trials Program, University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA.

Matched-targeted and immune checkpoint therapies have improved survival in cancer patients, but tumor heterogeneity contributes to drug resistance. Our study categorized gene mutations from next generation sequencing (NGS) into three core processes. This annotation helps decipher complex biologic interactions to guide therapy. We collected NGS data on 145 patients who have failed standard therapy (2016 to 2018). One hundred and forty two patients had data for tissue (Caris MI/X) and plasma cell-free circulating tumor DNA (Guardant360) platforms. The mutated genes were categorized into cell fate (CF), cell survival (CS), and genome maintenance (GM). Comparative analysis was performed for concordance and discordance, unclassified mutations, trends in alterations, and PD-L1 expression. Two gene mutation maps were generated to compare each NGS platform. Mutated genes predominantly matched to CS with concordance between Guardant360 (64.4%) and Caris (51.5%). alterations comprised a significant proportion of the mutation pool in Caris and Guardant360, 14.7% and 13.1%, respectively. Twenty-six potentially actionable gene alterations were detected from matching ctDNA to Caris unclassified alterations. The CS core cellular process was the most prevalent in our study population. Clinical trials are warranted to investigate biomarkers for the three core cellular processes in advanced cancer patients to define the next best therapies.
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http://dx.doi.org/10.3390/cancers12030701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140098PMC
March 2020

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer.

Cancer Chemother Pharmacol 2020 03 8;85(3):621-626. Epub 2020 Feb 8.

Mayo Clinic, Phoenix, AZ, USA.

Purpose: CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize clinical activity. CC-486 300 mg daily, administered for 14 or 21 days of 28-day treatment cycles, is currently under investigation in two ongoing phase III trials. The 300-mg daily dose in these studies is administered as two 150-mg tablets (Formulation A).

Methods: We evaluated the bioequivalence of one 300-mg CC-486 tablet (Formulation B) with Formulation A and food effect on Formulation B, in adult patients with cancer in a 2-stage crossover design study.

Results: The ratios of the geometric means of the maximum azacitidine plasma concentration (C) and of the area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC) were 101.5% and 105.7%, demonstrating the bioequivalence of Formulations A and B. Formulation B was rapidly absorbed under fasted and fed conditions. The geometric mean of C was significantly decreased by ~ 21% in the fed state. Median T was reached at 2 h and 1 h post-dose in fed and fasted states, respectively (P < 0.001). Nevertheless, systemic drug exposure (AUC) in fed and fasted states was within the 80-125% boundaries of bioequivalence and differences in C and T are not expected to have a clinical impact.

Conclusion: The single 300-mg CC-486 tablet was bioequivalent to two 150-mg tablets, which have shown to be efficacious and generally well-tolerated in clinical trials, and can be taken with or without food.
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http://dx.doi.org/10.1007/s00280-020-04037-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036073PMC
March 2020

Exposure to proton pump inhibitors and risk of pancreatic cancer: a meta-analysis.

Expert Opin Drug Saf 2020 Mar 21;19(3):327-334. Epub 2020 Jan 21.

Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.

: To estimate the pancreatic cancer risk among subjects exposed versus not exposed to proton pump inhibitors.: The authors searched PubMed, EMBASE, Scopus, Cochrane Library, and clinicaltrials.gov to identify relevant studies. The authors quantified pancreatic cancer risk among subjects exposed versus not exposed to PPIs, expressed as the pooled (adjusted) odds ratio (OR/aOR) and 95% confidence interval (95%CI) in overall and sensitivity analyses.: One randomized trial, two cohort, four case-control, and five nested case-control studies with 700,178 subjects (73,985 cases; 626,193 controls) were retained. PPI exposure was associated with pancreatic cancer risk (OR = 1.75, 95%CI = 1.12-2.72, I = 99%); confirmed in sensitivity analyses for high-quality studies, observational studies, case-control studies, studies with pancreatic cancer as the primary outcome, and in sensitivity analyses for diabetes and obesity but not for pancreatitis and smoking. This association was independent of the duration and Defined Daily Dose of PPI exposure. Rabeprazole had a singular significant association with pancreatic cancer (OR = 5.40, 95%CI = 1.98-14.703, I = 87.9%).: The class of PPIs is associated with a 1.75-fold increase in pancreatic cancer risk, confirmed in sensitivity analyses.
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http://dx.doi.org/10.1080/14740338.2020.1715939DOI Listing
March 2020

Evaluation of the safety and effectiveness of direct oral anticoagulants and low molecular weight heparin in gastrointestinal cancer-associated venous thromboembolism.

World J Gastrointest Oncol 2019 Oct;11(10):866-876

University of Arizona College of Pharmacy, Tucson, AZ 85725, United States.

Background: Gastrointestinal cancer (GICA) is associated with a higher incidence of venous thromboembolism (VTE) compared to other solid tumors, moreover, recurrent VTE and major bleeding (MB) complications during anticoagulation treatment have an associated increase rate. GICA-VTE remains a challenging clinical scenario with MB concerns for utilization of direct oral anticoagulants (DOAC), especially with active cancer therapies.

Aim: To evaluate patient risk factors, effectiveness (VTE) and safety (MB) of DOACs and low molecular weight heparin (LMWH) in patients with active GICA-VTE.

Methods: A retrospective chart review of patients receiving DOACs and LMWH with GICA and symptomatic or incidental VTE treated at comprehensive cancer center from November 2013 to February 2017 was performed. Inclusion criteria included active GI cancer diagnosed at any stage or treatment +/- 6 mo of VTE diagnosis, whom were prescribed 6 mo or more of DOACs or LMWH. The Chi-squared test was used for overall and the Fisher exact test for pairwise comparisons of the proportions of patients experiencing recurrent VTE and MB events. Odds ratios were used to compare the relative odds of the occurrence of the outcome given exposure to the risk factor.

Results: A total of 144 patients were prescribed anticoagulation, in which 106 fulfilled inclusion criteria apixaban (27.3%), rivaroxaban (34.9%) and enoxaparin (37.7%), and 38 were excluded. Patients median age was 66.5 years at GICA diagnosis and 67 years at CAVTE event, with 62% males, 80% Caucasian, 70% stage IV, pancreatic cancer (40.5%), 30% Khorana Score (≥ 3 points), and 43.5% on active chemotherapy. Sixty-four percent of patients completed anticoagulation therapy (range 1 to 43 mo). Recurrent VTE at 6 mo was noted in 7.5% ( = 3), 6.8% ( = 2) and 2.7% ( = 1) of patients on enoxaparin, apixaban and rivaroxaban, respectively (all = NS). MB at 6 mo were 5% ( = 2) for enoxaparin, 6.8% ( = 2) for apixaban and 21.6% ( = 8) for rivaroxaban (overall = 0.048; LMWH = 0.0423; all other = NS). Significant predictors of a primary or secondary outcome for all anticoagulation therapies included: Active systemic treatment (OR = 5.1, 95%CI: 1.3-19.3), high Khorana Score [≥ 3 points] (OR = 5.5, 95%CI: 1.7-17.1), active smoker (OR = 6.7, 95%CI: 2.1-21.0), pancreatic cancer (OR = 6.8, 95%CI: 1.9-23.2), and stage IV disease (OR = 9.9, 95%CI: 1.2-79.1).

Conclusion: Rivaroxaban compared to apixaban and enoxaparin had a significantly higher risk of MB on GICA-VTE patients with equivocal efficacy.
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http://dx.doi.org/10.4251/wjgo.v11.i10.866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815918PMC
October 2019

Response Rate Following Albumin-Bound Paclitaxel Plus Gemcitabine Plus Cisplatin Treatment Among Patients With Advanced Pancreatic Cancer: A Phase 1b/2 Pilot Clinical Trial.

JAMA Oncol 2019 Oct 3. Epub 2019 Oct 3.

HonorHealth Research Institute, Scottsdale, Arizona.

Importance: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations, indicating a DNA repair deficiency associated with sensitivity to DNA damaging agents, such as platinum.

Objective: To determine response rate following treatment with nab-paclitaxel plus gemcitabine plus platinum-based cisplatin for patients with metastatic pancreatic ductal adenocarcinoma (PDA).

Design, Setting, And Participants: This was a single-arm, open-label, phase 1b/2 clinical trial of nab-paclitaxel plus gemcitabine plus cisplatin treatment in which 25 patients with previously untreated metastatic PDA were enrolled. The trial was conducted from December 2013 to July 2016 at 3 US sites, with the last patient receiving study treatment at the end of October 2016, and the study closing January 2018.

Interventions: Patients were treated with nab-paclitaxel plus gemcitabine plus various doses of cisplatin, 25 mg/m2, 37.5 mg/m2, and 50 mg/m2, on days 1 and 8 of a 21-day cycle.

Main Outcomes And Measures: Primary end point was complete response rate as assessed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and levels of carbohydrate antigen 19-9 (or in nonexpressers, carbohydrate antigen 125 or carcinoembryonic antigen). Efficacy analysis included evaluable patients (those who received at least 1 dose of study treatment and had at least 1 postbaseline tumor assessment).

Results: Of 25 patients enrolled in the study, the median (range) age was 65.0 (47.0-79.0) years, 14 (56%) were men, and most (24) were white (96%). The maximum tolerable dose of cisplatin was 25 mg/m2. The most common treatment-related adverse events grade 3 or higher were thrombocytopenia (17 patients [68%]), anemia (8 patients [32%]), and neutropenia (6 patients [24%]). Fatal events occurred for 3 patients (12%); 2 were related to study participation. A median (range) of 8 (1-15) cycles was completed. The RECIST responses in 24 evaluable patients included 2 complete responses (8%), which was below the primary end point of 25%, 15 partial responses (62%), 4 stable disease (17%), and 3 progressive disease (12%), with median overall survival of 16.4 (95% CI, 10.2-25.3) months; 16 patients (64%) were alive at 1 year, 10 (40%) at 2 years, 4 (16%) at 3 years, and 1 (4%) at 4 plus years. Overall survival ranged from 36 to 59 months. Median progression-free survival was 10.1 (95% CI, 6.0-12.5) months. Thus, the overall response rate was 71%, and the disease control rate was 88%.

Conclusions And Relevance: This triple drug regimen showed substantial clinical activity in this small study. Although the primary end point was not reached, the high overall response rate, disease control rate, and median survival time among patients with advanced PDA treated with this combination are encouraging. The regimen is being studied in patients with PDA in the neoadjuvant setting and in patients with advanced biliary cancers.

Trial Registration: ClinicalTrials.gov identifier: NCT01893801.
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http://dx.doi.org/10.1001/jamaoncol.2019.3394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777241PMC
October 2019

PD-1 Inhibition Achieves a Complete Metabolic Response in a Patient with Malignant Peripheral Nerve Sheath Tumor.

Cancer Immunol Res 2019 Sep 5;7(9):1396-1400. Epub 2019 Aug 5.

The University of Arizona Cancer Center, Tucson, Arizona.

High-grade malignant peripheral nerve sheath tumors (MPNST) have a poor prognosis with limited responsiveness to systemic therapy. We document a case of a complete metabolic response to pembrolizumab monotherapy in metastatic disease. Tumor molecular profiling identified programmed-death ligand-1 (PD-L1) positivity. This characteristic provided a rationale for immune-checkpoint therapy. Treatment with pembrolizumab resulted in a complete metabolic response after four cycles of therapy. Patients with PD-L1-positive, metastatic MPNST may be candidates for immune-checkpoint therapy, which may produce a durable complete remission. Future study of anti-PD-1/PD-L1 therapy is warranted.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0072DOI Listing
September 2019

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios inversely correlate to clinical and pathologic stage in patients with resectable pancreatic ductal adenocarcinoma.

Ann Pancreat Cancer 2019 Jun 11;2. Epub 2019 Jun 11.

University of Arizona Cancer Center, Tucson, AZ, USA.

Background: Post-surgical pathology (SP) staging correlates with long-term survival. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been shown to predict prognosis and extent of tumor in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to correlate NLR and PLR to radiological clinical staging (CS), carbohydrate antigen (CA) 19-9 tumor marker and SP staging in patients with resectable-PDAC (R-PDAC); and to investigate NLR and PLR as potential markers to guide neoadjuvant therapy.

Methods: Data were collected retrospectively from R-PDAC patients who received upfront surgery from November 2011 to December 2016. NLR and PLR values on the day of diagnosis and surgery were collected. SP, tumor size, location, resected margins (RM), lymphovascular/perineural invasion (LVI/PNI), lymph node involvement, and AJCC/TNM 8th Edition staging were obtained. Associations were assessed using linear, ordinal logistic, and poison regressions or Kruskal Willis Rank Sum Test per the nature of outcome variables, with statistical significance at p-value <0.05.

Results: Fifty-five patients were identified with resectable stage I (61%) and II (38%). They had a mean age of 66 years (48-87 years) and were 47.2% male, 83.6% white, 90.9% non-Hispanic and 89% with ECOG 0-1. NLR/PLR at diagnosis for R0, R1 and R2 were 6.7/241, 4.8/224, and 2.9/147 (P=0.01/0.002), respectively. NLR/PLR for N0 and N1 were 5.1/212 and 2.7/138.3 (P=0.03/0.009) at diagnosis. No other significant association was detected.

Conclusions: These findings suggest that NLR/PLR inversely correlates with RM and lymph node status in patients with R-PDAC, but require prospective evaluation in clinically defined scenarios.
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http://dx.doi.org/10.21037/apc.2019.06.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663083PMC
June 2019

A Multidisciplinary Evaluation of Barriers to Enrolling Cancer Patients into Early Phase Clinical Trials: Challenges and Patient-centric Recommendations.

Expert Opin Investig Drugs 2019 Aug 29;28(8):675-686. Epub 2019 Jul 29.

a Department of Medicine, Division of Hematology-Oncology, University of Arizona Cancer Center, Early Phase Clinical Trials Program , Tucson , AZ , USA.

: Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug's safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic. : This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management. : We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.
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http://dx.doi.org/10.1080/13543784.2019.1646726DOI Listing
August 2019

Comparative efficacy and safety of immunotherapies targeting the PD-1/PD-L1 pathway for previously treated advanced non-small cell lung cancer: A Bayesian network meta-analysis.

Crit Rev Oncol Hematol 2019 Oct 10;142:16-25. Epub 2019 Jul 10.

Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA; Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ, USA; University of Arizona Cancer Center, Tucson, AZ, USA; Department of Family and Community Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address:

Background: Two PD-1 (pembrolizumab, nivolumab) and one PD-L1(atezolizumab) inhibitors are approved for previously treated advanced non-small cell lung cancer but have not been compared in head-to-head trials.

Method: A network meta-analysis was conducted to compare efficacy/safety of PD-1/PD-L1 inhibitors.

Results: In five-trials (including long-term updates) with docetaxel as common comparator there were no differences in OS and PFS between PD-1/PD-L1 inhibitors. Pembrolizumab (odds ratio(OR) = 2.22, 95%CrI = 1.28-3.70) and nivolumab (OR = 1.92, 95%CrI = 1.15-3.23) had higher ORRs than atezolizumab and at PD-L1 expression ≥50% and ≥1%. Probabilistically, pembrolizumab ranked first in OS and ORR, and in OS sub-analyses for adenocarcinoma, EGFR-mutant, ECOG-score-1, male, and age <65 years. Nivolumab ranked first in PFS, and in OS sub-analyses for squamous-cell disease, EGFR-wild-type, and ECOG-score-0. Pembrolizumab and nivolumab ranked the best option for most of adverse events.

Conclusion: While pembrolizumab and nivolumab prevailed in rank in OS and ORR benefit, patient characteristics, safety and tolerance should be considered in treatment decision-making.
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http://dx.doi.org/10.1016/j.critrevonc.2019.07.004DOI Listing
October 2019

Everolimus for the treatment of advanced pancreatic ductal adenocarcinoma (PDAC).

Expert Opin Investig Drugs 2019 Jul 21;28(7):583-592. Epub 2019 Jun 21.

a Early Phase Clinical Trials Program , University of Arizona Cancer Center , Tucson , AZ , USA.

: PDAC is a lethal malignancy with a clear unmet need; almost all patients fail 1, 2, and 3 line multi-agent cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) has been identified as a key signaling node enhancing tumor survival and drug resistance in PDAC; hence, it is considered a promising therapeutic target. : We comprehensively reviewed the evidence from preclinical and phase I and II clinical trials, based on the authors'clinical experience and a PubMed, Cochrane library, Embase, and Google Scholar search everolimus + pancreatic cancer. : Everolimus has not demonstrated efficacy in PDAC; however, an mTOR inhibitor in combination with stroma-targeted therapies may be a promising area to explore in clinical trials.
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http://dx.doi.org/10.1080/13543784.2019.1632289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681663PMC
July 2019

Implementation of a Low-Cost Quality Improvement Intervention Increases Adherence to Cancer Screening Guidelines and Reduces Healthcare Costs at a University Medical Center.

J Cancer Educ 2020 10;35(5):930-936

University of Arizona Cancer Center, Department of Medicine, The University of Arizona, Tucson, AZ, USA.

Adherence to US Preventative Services Task Force (USPSTF) cancer screening guidelines remains considerably lower than the recommendation of the Healthy People 2020 initiative. Patient populations recommended for screening are not screened at an appropriate rate, and populations not recommended for screening are inappropriately screened. Closer adherence to guidelines should improve outcomes and reduce costs, estimated to reach $158 billion/year by 2020. We evaluated whether a use of low-cost educational health maintenance (HM) card by medical residents at a university hospital could impact education and adherence to updated cancer screening guidelines. We also analyzed savings to the healthcare system. Adherence to cervical, breast, and colorectal cancer screening guidelines, defined as percentage that was screened (or not screened) in accordance with the USPSTF guidelines, in clinic visits from December 2012 (n = 336) was compared to those from December 2013 (n = 306) after a quality improvement intervention. Post-intervention, adherence to screening guidelines increased by 40.8% (p < 0.01) for cervical, 33.2% (p < 0.01) for breast, and 20.5% (p < 0.01) for colorectal cancer in average-risk patients. Inappropriate screening was reduced by 26.8% (p < 0.01) for cervical and 32.8% (p < 0.01) for breast cancer. A non-significant 1.1% decrease (p = 0.829) was observed for colorectal cancer. The annual potential savings from avoiding inappropriate screenings were $998,316 (95% CI; $644,484-$1,352,148). We showed a significant absolute increase in USPSTF knowledge of 28.3% irrespective of the house staff level that remained high at 2 years from the educational intervention. The low-cost HM card increased appropriate knowledgeable cancer screening adherence while reducing unnecessary testing and producing substantial savings to the healthcare system.
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http://dx.doi.org/10.1007/s13187-019-01544-zDOI Listing
October 2020

Locally Advanced Rectal Cancer Evaluation by Magnetic Resonance Imaging after Neoadjuvant Therapy on Decision Making: Cancer Center Experience and Literature Review.

J Gastrointest Cancer 2020 Mar;51(1):254-259

Hematology and Medical Oncology, University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ, 85724, USA.

Purpose: An accurate clinical and radiological staging is the pyramid of treatment decisions in locally advanced rectal cancer (LARC). Guidelines recommended neoadjuvant chemoradiation therapy (CRT) followed by surgical resection for fit patients with LARC. Determining the aggressiveness of intervention while avoiding needless morbidity according to patient risk remains an unmet pre-operative decision-making need. With newer magnetic resonance imaging (MRI) techniques and image acquisition available at our Cancer Center, we seek to retrospectively review the correlation between pre- and post-CRT MRI response to the surgical pathological stage in order to aide multidisciplinary team decision making.

Methods: Our Cancer Center Rectal Cancer Registry between 2011 and 2015 included 57 patients with LARC, 20 completed standard CRT with surgery, and of those 10 had repeated MRI after CRT.

Results: Our retrospective case series revealed that 90% of the patients had a downstage tumor response on surgical specimen compared to radiological evaluation after CRT, and furthermore, all patients who were re-staged with MRI prior to surgery correlated with the gold standard pathological stage (p = 0.02).

Conclusions: Post-CRT MRI could potentially aide decision making to further avoid 20% of patients with a complete pathological response from a morbid surgery, whereas 10% of patients with an upstaged disease state may require a more aggressive neoadjuvant or planned surgical intervention. We concluded that future multidisciplinary oncology care treatment decision making would benefit from a repeat MRI after neoadjuvant CRT of LARC.
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http://dx.doi.org/10.1007/s12029-019-00246-5DOI Listing
March 2020

A Rare Cause of Thrombotic Thrombocytopenia Purpura- (TTP-) Like Syndrome, Vitamin B12 Deficiency: Interpretation of Significant Pathological Findings.

Case Rep Hematol 2019 18;2019:1529306. Epub 2019 Mar 18.

Department of Hematology-Oncology, University of Arizona Cancer Center, Tucson, AZ, USA.

Thrombotic thrombocytopenia purpura (TTP) is a hematological emergency that requires rapid assessment followed by prompt initiation of therapy due to high mortality associated with delayed treatment. TTP has many causes including heritable syndromes, ADAMTS13 deficiency, and drugs-related etiologies. Profound vitamin B12 deficiency can, in rare cases, mimic TTP in presentation, and since plasmapheresis can be of limited benefit, prompt diagnosis is necessary for accurate treatment with B12. Therefore, careful analysis of all clinical signs, symptoms, and labs must be assessed. We report a patient who presented with a diagnosis of TTP, and repeat assessment confirmed a diagnosis of sever vitamin B12 (B12) deficiency with pancytopenia who was appropriately treated with B12.
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http://dx.doi.org/10.1155/2019/1529306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442445PMC
March 2019

The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis.

Prostate 2019 06 22;79(8):880-895. Epub 2019 Mar 22.

Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, Arizona.

Background: A prior meta-analysis found no association between BRCA1 mutation and prostate cancer (PCa). Subsequent BRCA2 mutation studies have shown an association with PCa risk and mortality. We conducted a meta-analysis of overall BRCA mutation carriers and in subgroups to (1) estimate PCa risk in BRCA mutation carriers, (2) evaluate the frequency of BRCA mutation carriers in patients with PCa, and (3) compare cancer-specific survival (CSS) and overall survival (OS) among BRCA mutation carriers and noncarriers.

Methods: We searched the PubMed/MEDLINE, Embase, and Cochrane databases. Unadjusted odds ratio (OR), percentage (%), and hazard ratio (HR) were used to calculate pooled estimates for PCa risk, frequency, and survival, respectively. Subgroup analyses by mutation type ( BRCA1 or BRCA2) were conducted for the three objectives. Further subgroup analyses by study design (age-sex-adjusted or crude), ascertainment method (ascertained or inferred genotyping), population (Ashkenazi Jewish or general population), and survival outcomes (CSS or OS) were conducted. The associations were evaluated using random-effects models, in two-sided statistical tests.

Results: A total of 8 cohort, 7 case-control, 4 case-series, 28 frequency, and 11 survival studies were included. Being a BRCA mutation carrier ( BRCA1 and/or BRCA2) was associated with a significant increase in PCa risk (OR = 1.90, 95% CI = 1.58-2.29), with BRCA2 mutation being associated with a greater risk of PCa (OR = 2.64, 95% CI = 2.03-3.47) than BRCA1 (OR = 1.35, 95% CI = 1.03-1.76). The frequency of BRCA1 and BRCA2 carriers in patients with PCa was 0.9% and 2.2%, respectively. OS (HR = 2.21, 95% CI = 1.64-2.30) and CSS (HR = 2.63, 95% CI = 2.00-3.45) were significantly worse among BRCA2 carriers compared to noncarriers, whereas OS (HR = 0.47, 95% CI = 0.11-1.99) and CSS (HR = 1.07, 95% CI = 0.38-2.96) were statistically not significant when comparing BRCA1 carriers and noncarriers.

Conclusions: There is a 1.90-fold greater risk of PCa in overall BRCA mutation carriers. This elevated PCa risk is attributable mainly to a 2.64-fold greater risk of PCa in BRCA2 carriers compared to a moderate 1.35-fold greater risk in BRCA1 carriers. The frequency of BRCA2 mutations was higher than BRCA1 mutations among patients with PCa. BRCA2 but not BRCA1 mutations were associated with higher PCa mortality. The BRCA mutation may be a clinical factor to stratify high-risk patients and guide clinical strategies for more effective treatments for patients with PCa.
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http://dx.doi.org/10.1002/pros.23795DOI Listing
June 2019

Comprehensive Lifestyle Improvement Program for Prostate Cancer (CLIPP): Protocol for a Feasibility and Exploratory Efficacy Study in Men on Androgen Deprivation Therapy.

JMIR Res Protoc 2019 Feb 5;8(2):e12579. Epub 2019 Feb 5.

University of Arizona, Tucson, AZ, United States.

Background: Androgen deprivation therapy (ADT) for prostate cancer is associated with adverse cardiometabolic effects such as reduced libido, hot flashes, metabolic syndrome, diabetes, myocardial infarction, and stroke. This reduces quality of life and potentially increases mortality. Several large clinical trials have demonstrated improvements in cardiometabolic risk with comprehensive multimodality lifestyle modification. However, there is a lack of data for such interventions in men on ADT for prostate cancer, and existing studies have used non-standardized interventions or lacked data on metabolic risk factors.

Objective: The Comprehensive Lifestyle Improvement Project for Prostate Cancer (CLIPP) is designed to address these gaps by using an intervention modeled on the Diabetes Prevention Program, a standardized multicomponent intervention with demonstrated effectiveness in reducing cardiometabolic risk factors that has been successfully adapted for multiple disease types including breast cancer.

Methods: A single-arm unblinded clinical trial will be conducted to determine the feasibility of conducting a 24-week comprehensive lifestyle modification intervention that targets weight loss and increased physical activity modeled on the Diabetes Prevention Program in 30 men on ADT for prostate cancer. Secondary aims are to determine the effect of the intervention on cardiometabolic markers and quality of life. The tertiary aim is to determine the effect of the intervention on markers of inflammation and angiogenesis, important mechanisms for prostate cancer progression. Participants will be recruited from the University of Arizona Cancer Center and the surrounding community. The intervention will be delivered weekly in person and over the phone for 16 weeks. For Weeks 16-24, participants receive weekly phone calls from the study health coach to motivate them to continue their lifestyle modification. Questionnaire and biological data are collected at baseline, 12 weeks, and 24 weeks. Body composition using dual-energy x-ray absorptiometry scans will be performed at baseline and end of study.

Results: Based on a sample size of 30, the two-sided 95% confidence interval will not be wider than 0.373 standard deviations for the adherence rate and will not be wider than 0.374 for the retention rate. In addition, the study will have a power of 80% to detect a change of 0.47 standard deviations from baseline for each of the markers investigated in the secondary and tertiary aims assuming a within-subject correlation of 0.20 at a significance level of 5%. The recruitment period is from October 2018 to April 2019.

Conclusions: The aim of CLIPP is to determine the feasibility of conducting a Diabetes Prevention Program-style comprehensive lifestyle modification intervention in men with ADT for prostate cancer and its effects on cardiometabolic adverse effects, quality of life, as well as markers of inflammation and angiogenesis. Results will inform the development of future clinical trials in this population.

International Registered Report Identifier (irrid): DERR1-10.2196/12579.
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http://dx.doi.org/10.2196/12579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379812PMC
February 2019

Erratum: Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma [Corrigendum].

Oncolytic Virother 2019 4;8. Epub 2019 Jan 4.

Division of Hematology-Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ

[This corrects the article on p. 11 in vol. 6, PMID: 28224120.].
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http://dx.doi.org/10.2147/OV.S196145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324917PMC
January 2019

Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC).

Expert Opin Investig Drugs 2019 02 16;28(2):161-177. Epub 2018 Dec 16.

d Early Phase Therapeutics Program , University of Arizona Cancer Center , Tucson , AZ , USA.

Introduction: Prognosis remains dismal for pancreatic ductal adenocarcinoma (PDAC). Genomics and proteomics have depicted heterogeneity in PDAC. Collectively, this information could be useful in improving diagnosis, prognosis, modalities of therapy, treatment responses, deciphering drug resistance and new drug development.

Areas Covered: We describe major advances in the cellular and molecular subtypes based on next-generation sequencing and their predictive and prognostic value in PDAC patients. We review aberrant genes involving in defined cellular processes in PDAC. Finally, the current state of drug development with novel investigational agents targeting cell fate, cell survival, genomic instability, tumor-stroma, and immune checkpoints are discussed.

Expert Opinion: Molecular techniques have revealed distinct driver mutations in PDAC. Common genes and cellular processes are dysregulated in the pathogenesis of PDAC. These cellular processes categorized by aberrant pathways include control cell fate, genome maintenance, and cell survival. Dysregulation of the tumor microenvironment promotes an intense fibrosis and immune suppression that play a major role in drug resistance. New information on tumor biology has led to the development of targeted/stromal therapies, immunotherapies or combinations with current chemotherapy in PDAC. New drug development targeting multiple hallmarks of PDAC we hope will positively impact the quality and survival of PDAC patients.
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http://dx.doi.org/10.1080/13543784.2019.1557145DOI Listing
February 2019