Linda L Garland

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• Bixby, B., Vrba, L., Lenka, J., Oshiro, M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2024).

  Cell-Free DNA Methylation Analysis as a Marker of Malignancy in Pleural Fluid. Sci Rep. 2024 Feb 5;14(1):2939. doi: 10.1038/s41598-024-53132-x. PMID: 38316884; PMCID: PMC10844328

  . Research Square, 10. doi:10.21203/rs.3.rs-3390107/v1
• Garland, L. L. (2022).  Ver Hoeve ES, Price SN, Torres TK,  Hamann HA, Garland LL. Coping with COVID-19 in Patients with Lung Cancer. . Oncol Issues (online publication), 37(5). doi:https://doi.org/10.1080/10463356.2022.2105597
• Garland, L. L. (2022). Garland LL, Guillen-Rodriguez J, Hsu, CH, Davis LE, Szabo E, Husted, CR, Liu H, LeClerc A, Alekseyev YO, Liu G, Bauman JE, Spira AE, Beane J, Wojtowicz M, Chow HS. Clinical Study of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers. . Cancers, 14(12).
• Garland, L. L. (2022).  Bauman JE, Hsu CH, Centuori S, Guillen-Rodriguez J, Garland LL, Ho E, Padi M, Bageerathan V, Bengtson L, Wojtowicz M, Szabo E, Chow HS. Randomized Crossover Trial Evaluating Detoxification of Tobacco Carcinogens by Broccoli Seed and Sprout Extract in Current Smokers.. Cancers, 14(9).
• Garland, L. L. (2022). Kaplan DM, Hamann HA, Price SN, Williamson TJ, Ver Hoeve ES, McConnell MH, Duchschere JE, Garland LL, Ostroff JS. Developing an ACT-based intervention to address lung cancer stigma: Stakeholder recommendations and feasibility testing in two NCI-designated cancer centers. . J Psychosoc Oncol, 1-7.
• Garland, L., Centuori, S., Hsu, C., Bauman, J. E., Guillen-Rodriguez, J., Ho, E., Bengtson, L., Wojtowicz, M., Szabo, E., & Chow, H. S. (2021). Abstract LB221: Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers. Cancer Research, 81(13_Supplement), LB221-LB221. doi:10.1158/1538-7445.am2021-lb221
• Yanagihara, R. H., Wang, D., Sands, J. M., Redman, M. W., Miao, J., Koczywas, M., Kelly, K., Gettinger, S. N., Garland, L. L., Gandara, D. R., Faller, B. A., Decker, R. H., Daly, M. E., Cristea, M. C., Chen, A. M., Byers, L. A., Argiris, A., Albain, K. S., Yanagihara, R. H., , Wang, D., et al. (2021). A Dose-finding Study Followed by a Phase II Randomized, Placebo-controlled Trial of Chemoradiotherapy With or Without Veliparib in Stage III Non-small-cell Lung Cancer: SWOG 1206 (8811).. Clinical lung cancer, 22(4), 313-323.e1. doi:10.1016/j.cllc.2021.02.009
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  We conducted a 2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non-small-cell lung cancer..In the phase I part, patients were treated successively at 3 dose levels of veliparib (40, 80, and 120 mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin and paclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care..Of 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P = .20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively..Veliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.
• Garland, L. L., Kuo, P., Sawyer, D. M., Sawyer, T. W., Hamilton, R. J., & Eshghi, N. (2020). Texture analysis of PET imaging demonstrates changes in 18F-FDG uptake of the brain after prophylactic cranial irradiation. J of Nuclear Medicine Technology.. doi:doi:10.2967/jnmt.120.248393
• Almutairi, A. R., Alkhatib, N., Martin, J., Babiker, H. M., Garland, L. L., McBride, A., & Abraham, I. (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. Critical reviews in oncology/hematology, 142, 16-25.
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  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.
• Garland, L. L., Guillen-Rodriguez, J., Hsu, C. H., Yozwiak, M., Zhang, H. H., Alberts, D. S., Davis, L. E., Szabo, E., Merenstein, C., Lel, J., Zhang, X., Liu, H., Liu, G., Spira, A. E., Beane, J. E., Wojtowicz, M., & Chow, H. S. (2019). Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial. Cancer prevention research (Philadelphia, Pa.), 12(11), 809-820.
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  A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blinded study in current heavy smokers to compare modulating effects of intermittent versus continuous low-dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-four participants were randomized to intermittent (ASA 81 mg daily for one week/placebo for one week) or continuous (ASA 81 mg daily) for 12 weeks. Low-dose ASA suppressed urinary prostaglandin E2 metabolite (PGEM; change of -4.55 ± 11.52 from baseline 15.44 ± 13.79 ng/mg creatinine for arms combined, = 0.02), a surrogate of COX-mediated ARA metabolism, but had minimal effects on nasal gene expression of nasal or bronchial gene-expression signatures associated with smoking, lung cancer, and chronic obstructive pulmonary disease. Suppression of urinary PGEM correlated with favorable changes in a smoking-associated gene signature ( < 0.01). Gene set enrichment analysis (GSEA) showed that ASA intervention led to 1,079 enriched gene sets from the Canonical Pathways within the Molecular Signatures Database. In conclusion, low-dose ASA had minimal effects on known carcinogenesis gene signatures in nasal epithelium of current smokers but results in wide-ranging genomic changes in the nasal epithelium, demonstrating utility of nasal brushings as a surrogate to measure gene-expression responses to chemoprevention. PGEM may serve as a marker for smoking-associated gene-expression changes and systemic inflammation. Future studies should focus on NSAIDs or agent combinations with broader inhibition of pro-inflammatory ARA metabolism to shift gene signatures in an anti-carcinogenic direction.
• Kim, S., Bull, D. A., Garland, L., Khalpey, Z., Stea, B., Yi, S., & Hsu, C. C. (2019). Is There a Role for Cancer-Directed Surgery in Early-Stage Sarcomatoid or Biphasic Mesothelioma?. The Annals of thoracic surgery, 107(1), 194-201.
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  Benefits of surgical resection for early-stage nonepithelioid malignant pleural mesothelioma (MPM) have not been clearly elucidated. This study investigated whether cancer-directed surgery affects overall survival compared with nonsurgical therapies for T1-T2 N0 M0 sarcomatoid or biphasic MPM patients.
• Vrba, L., Oshiro, M. M., Kim, S. S., Garland, L. L., Placencia, C., Mahadevan, D., Nelson, M. A., & Futscher, B. W. (2019). DNA methylation biomarkers discovered detect cancer in liquid biopsies from non-small cell lung cancer patients. Epigenetics, 1-12. doi:doi: 10.1080/15592294.2019.1695333.
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  Identification of cancer-specific methylation of DNA released by tumours can be used for non-invasive diagnostics and monitoring. We previously reported identification of DNA methylation loci specifically hypermethylated in common human cancers that could be used as epigenetic biomarkers. Using DNA methylation specific qPCR we now clinically tested a group of these cancer-specific loci on cell-free DNA (cfDNA) extracted from the plasma fraction of blood samples from healthy controls and non-small cell lung cancer (NSCLC) patients. These DNA methylation biomarkers distinguish lung cancer cases from controls with high sensitivity and specificity (AUC = 0.956), and furthermore, the signal from the markers correlates with tumour size and decreases after surgical resection of lung tumours. Presented observations suggest the clinical value of these DNA methylation biomarkers for NSCLC diagnostics and monitoring. Since we successfully validated the biomarkers using independent DNA methylation data from multiple additional common carcinoma cohorts (bladder, breast, colorectal, oesophageal, head and neck, pancreatic or prostate cancer) we predict that these DNA methylation biomarkers will detect additional carcinoma types from plasma samples as well.
• Weiss, S. A., Olszanski, A. J., Linette, G. P., Iannotti, N. O., Avsar, E., Srivastava, M. K., Trifan, O. C., Edelman, M. J., Schuchter, L. M., Kluger, H. M., Johnson, M. L., & Garland, L. L. (2019). Abstract CT089: Phase Ib/II of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC). Clinical Trials, 79(13_Supplement), CT089-CT089. doi:10.1158/1538-7445.am2019-ct089
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  Background: Despite recent success with checkpoint inhibitors, the majority of patients with M or NSCLC have a transient response or no response to checkpoint blockade. Preclinical data suggest that activation of CD40 can be combined with PD-1 blockade to trigger effective T cell immunity. We are conducting a multi-center, open label Phase Ib/II clinical trial to evaluate the combination of APX005M with nivo in subjects with M or NSCLC. We report safety and efficacy from the completed Phase Ib portion of the study and the 1st stage of the Phase II M cohort. Methods: Phase Ib followed a 3+3 design and enrolled adult subjects with M and disease progression (PD) while receiving anti-PD-1 therapy (anti-CTLA-4 more than 3 months prior to study entry was allowed) and subjects with immunotherapy naive NSCLC, in 3 dose levels of APX005M (0.03, 0.1 and 0.3 mg/kg) combined with a fixed dose of nivo (360mg) every 3 weeks. Primary objectives in Phase Ib were to evaluate safety and determine the Phase II dose (P2D) of APX005M. Phase II is enrolling subjects with M or NSCLC in two parallel Phase II cohorts, each following a Simon 2-stage design. Primary objective in Phase II is to evaluate the tumor response in each cohort. Phase Ib analyses were performed on dose limiting toxicity (DLT)-evaluable subjects. Phase II analyses were performed on all treated subjects. Results: Phase Ib: No DLTs were observed in the 9 subjects enrolled in Phase Ib and the P2D for APX005M is 0.3 mg/kg. Four subjects experienced Grade 3 AEs considered related to study drugs (non-DLTs, including transaminitis, hyperbilirubinemia, anemia, pneumonitis, 1 subject each) with no grade 4 AEs reported. Of the 5 subjects with M, 1 had a confirmed PR, 2 had prolonged SD (>8 months) and 2 had PD as best overall response. Of the 4 subjects with NSCLC, 1 had a robust confirmed PR, 2 had SD (on study lesion biopsies histology negative) and 1 had PD as best overall response. Phase II: The 1st stage of the M cohort enrolled 10 additional subjects. One subject experienced a Grade 3 AE considered related to study drugs with no grade 4 AEs reported. Of these 10 subjects, 2 had confirmed PR, 2 had SD, and 6 had PD as best overall response. The overall toxicity profile of the combination is consistent with the profiles of individual agents. NanoString analysis of paired tumor biopsies revealed high tumor-infiltrating lymphocytes, and increased expression of IFNγ inducible cytokines (CXCL9 and CXCL10) while on treatment. Increased tumor T cell infiltration was further confirmed by immunohistochemistry. Conclusions: APX005M + nivo demonstrated a good safety profile and promising antitumor activity in M subjects with PD while receiving anti-PD-1 therapy and potential activity in NSCLC. The study is currently enrolling subjects in the 2nd stage of the Phase II M cohort and the 1st stage of the Phase II NSCLC cohort. Clinical trial information: NCT03123783. Citation Format: Harriet Kluger, Sarah A. Weiss, Anthony J. Olszanski, Lynn Schuchter, Gerald P. Linette, Linda Garland, Nicholas O. Iannotti, Melissa Johnson, Emin Avsar, Minu K. Srivastava, Ovid C. Trifan, Martin J. Edelman. Phase Ib/II of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT089.
• Centuori, S. M., Gomes, C. J., Kim, S. S., Putnam, C. W., Larsen, B. T., Garland, L. L., Mount, D. W., & Martinez, J. D. (2018). Double-negative (CD27IgD) B cells are expanded in NSCLC and inversely correlate with affinity-matured B cell populations. Journal of translational medicine, 16(1), 30.
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  The presence of B cells in early stage non-small cell lung cancer (NSCLC) is associated with longer survival, however, the role these cells play in the generation and maintenance of anti-tumor immunity is unclear. B cells differentiate into a variety of subsets with differing characteristics and functions. To date, there is limited information on the specific B cell subsets found within NSCLC. To better understand the composition of the B cell populations found in NSCLC we have begun characterizing B cells in lung tumors and have detected a population of B cells that are CD79ACD27IgD. These CD27IgD (double-negative) B cells have previously been characterized as unconventional memory B cells and have been detected in some autoimmune diseases and in the elderly population but have not been detected previously in tumor tissue.
• Eshghi, N., Garland, L. L., Choudhary, G., Hsu, C. C., Eshghi, A., Han, J., Hamilton, R. J., Krupinski, E., & Kuo, P. H. (2018). Regional Changes in Brain F-FDG Uptake After Prophylactic Cranial Irradiation and Chemotherapy in Small Cell Lung Cancer May Reflect Functional Changes. Journal of nuclear medicine technology, 46(4), 355-358.
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  Chemotherapy followed by prophylactic cranial irradiation (PCI) is associated with increased survival in patients with small cell lung cancer but is associated with fatigue and cognitive impairment. This retrospective study evaluated regional differences in F-FDG uptake by the brain before and after PCI. The null hypothesis was that direct toxic effects on the brain from PCI and chemotherapy are symmetric; thus, asymmetric deviations may reflect functional changes due to therapy. Electronic medical records from 2013 to 2016 were reviewed for patients with small cell lung cancer, MRI of brain negative for metastasis, and F-FDG PET/CT scans before and after PCI. As the standard of care, patients received first-line chemotherapy or chemoradiation to the thorax followed by PCI. The F-FDG PET/CT scans nearest the PCI were selected. Sixteen patients met these initial criteria. Commercially available PET software was used to register and subtract the PET scans before and after PCI to obtain difference maps. Occipital and cerebellar regions were excluded from the final statistical analysis given the known high variability and misregistration. The χ test was used to analyze the data. Two patients had F-FDG uptake differences only in the occipital and cerebellar regions. The software registration failed on 1 patient's scans. Therefore, 13 patients were included in the final analysis. Nine of 13 patients demonstrated significant unilateral changes in only 1 region of the brain, and 3 of 13 showed significant changes unilaterally in 2 regions. The χ test revealed a significant unilateral regional difference on a patient level (χ = 6.24, = 0.025). The most commonly affected brain region was the frontal lobe. Significantly more patients had unilateral than bilateral regional differences (both increases and decreases) in F-FDG uptake in the brain before and after PCI. This finding suggests that differences in unilateral distribution are related to functional changes, since direct toxicity alone from PCI and chemotherapy would be symmetric. The frontal region was the most commonly affected, suggesting a potential contributing etiology for cognitive impairment and decreased executive function after therapy.
• Eshghi, N., Garland, L. L., Nia, E., Betancourt, R., Krupinski, E., & Kuo, P. H. (2018). F-FDG PET/CT Can Predict Development of Thyroiditis Due to Immunotherapy for Lung Cancer. Journal of nuclear medicine technology, 46(3), 260-264.
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  Our primary purpose was to determine whether increased F-FDG uptake in the thyroid gland predicts development of thyroiditis with subsequent hypothyroidism in patients undergoing immunotherapy with nivolumab for lung cancer. Secondarily, we determined whether F-FDG uptake in the thyroid gland correlates with number of administered cycles of nivolumab. Retrospective chart review over 2 y found 18 lung cancer patients treated with nivolumab who underwent F-FDG PET/CT before and during therapy. SUV, SUV, and total lesion glycolysis of the thyroid gland were measured. SUVs were also measured for the pituitary gland, liver, and spleen. Patients underwent monthly thyroid testing. PET/CT parameters were analyzed by unpaired testing for differences between 2 groups (patients who developed hypothyroidism and those who did not). Correlation between development of thyroiditis and number of cycles of nivolumab was also tested. Six of 18 patients developed hypothyroidism. The test comparing the 2 groups demonstrated significant differences in SUV ( = 0.04), SUV ( = 0.04), and total lesion glycolysis ( = 0.02) of the thyroid gland. Two of 4 patients who developed thyroiditis and had increased F-FDG uptake in the thyroid gland had a normal TSH level at the time of follow-up F-FDG PET/CT. Patients who developed thyroiditis with subsequent hypothyroidism stayed longer on therapy (10.6 cycles) than patients without thyroiditis (7.6 cycles), but the trend was not statistically significant. No significant difference in PET/CT parameters was observed for pituitary gland, liver, or spleen. F-FDG PET/CT can predict the development of thyroiditis with subsequent hypothyroidism before laboratory testing. Further study is required to confirm the positive trend between thyroiditis and duration of therapy.
• Gimber, L. H., Garland, L., Krupinski, E. A., Chadaz, T. S., Schwenk, M., Najafi, B., & Taljanovic, M. S. (2018). Diffusion Tensor Imaging of the Ankle as a Possible Predictor of Chemotherapy Induced Peripheral Neuropathy: Pilot Study. Current problems in diagnostic radiology.
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  Chemotherapy induced peripheral neuropathy (CIPN) is seen in up to 75% of treated cancer patients and can drastically limit their medical management and affect quality of life. Clinical and electrodiagnostic testing for CIPN have many pitfalls. Magnetic resonance neurography (MRN) is being increasingly used in the evaluation of peripheral nerves. Diffusion tensor imaging (DTI) shows promise in the workup of peripheral nerves. In this prospective pilot study, we investigated a possible relationship between DTI and peripheral neuropathy of the ankle and foot in cancer patients treated with chemotherapy.
• Hanke, N. T., Imler, E., Marron, M. T., Seligmann, B. E., Garland, L. L., & Baker, A. F. (2018). Characterization of carfilzomib-resistant non-small cell lung cancer cell lines. Journal of cancer research and clinical oncology.
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  We previously showed that carfilzomib (CFZ) has potent anti-proliferative and cytotoxic activity in a broad range of lung cancer cell lines. Here we investigate possible mechanisms of CFZ acquired resistance in lung cancer cell lines.
• Hsu, C., Yi, S. K., Stea, B., Khalpey, Z. I., Garland, L. L., Bull, D. A., Kim, S. S., Hsu, C., Yi, S. K., Stea, B., Khalpey, Z. I., Garland, L. L., Bull, D. A., & Kim, S. S. (2018). Is there a role for cancer directed surgery in early stage sarcomatoid or biphasic mesothelioma. Ann Thorac Surg. doi:10.1016/j.athoracsur.2018.07.081
• Taljanovic, M., Taljanovic, M., Najafi, B., Najafi, B., Schwenk, M., Schwenk, M., Chadaz, T., Chadaz, T., Krupinski, E. A., Krupinski, E. A., Garland, L. L., Garland, L. L., Gimber, L. H., & Gimber, L. H. (2018). Diffusion tensor imaging of the ankle as a possible predictor of chemotherapy induced peripheral neuropathy: pilot study. Current Problems in Diagnostic Radiology.
• Nia, E. S., Garland, L. L., Eshghi, N., Nia, B. B., Avery, R. J., & Kuo, P. H. (2017). Incidence of Brain Metastases on Follow-up F-FDG PET/CT Scans of Non-Small Cell Lung Cancer Patients: Should We Include the Brain?. Journal of nuclear medicine technology, 45(3), 193-197.
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  The brain is the most common site of distant metastasis from lung cancer. Thus, MRI of the brain at initial staging is routinely performed, but if this examination is negative a follow-up examination is often not performed. This study evaluates the incidence of asymptomatic brain metastases in non-small cell lung cancer patients detected on follow-up F-FDG PET/CT scans. In this Institutional Review Board-approved retrospective review, all vertex to thigh F-FDG PET/CT scans in patients with all subtypes of lung cancer from August 2014 to August 2016 were reviewed. A total of 1,175 F-FDG PET/CT examinations in 363 patients were reviewed. Exclusion criteria included brain metastases on initial staging, histologic subtype of small-cell lung cancer, and no follow-up F-FDG PET/CT examinations. After our exclusion criteria were applied, a total of 809 follow-up F-FDG PET/CT scans in 227 patients were included in the final analysis. The original report of each F-FDG PET/CT study was reviewed for the finding of brain metastasis. The finding of a new brain metastasis prompted a brain MRI, which was reviewed to determine the accuracy of the F-FDG PET/CT. Five of 227 patients with 809 follow-up F-FDG PET/CT scans reviewed were found to have incidental brain metastases. The mean age of the patients with incidental brain metastasis was 68 y (range, 60-77 y). The mean time from initial diagnosis to time of detection of incidental brain metastasis was 36 mo (range, 15-66 mo). When MRI was used as the gold standard, our false-positive rate was zero. By including the entire head during follow-up F-FDG PET/CT scans of patients with non-small cell lung cancer, brain metastases can be detected earlier while still asymptomatic. But, given the additional scan time, radiation, and low incidence of new brain metastases in asymptomatic patients, the cost-to-benefit ratio should be weighed by each institution.
• Centuori, S. M., Gomes, C. J., Putnam, C. W., Larsen, B. T., Garland, L. L., Putnam, C. W., Mount, D. B., Martinez, J. D., Larsen, B. T., Kim, S., Garland, L. L., & Centuori, S. M. (2016). Abstract 713: Determining the role of tumor-infiltrating B cells in NSCLC. Cancer Research, 76(14_Supplement), 713-713. doi:10.1158/1538-7445.am2016-713
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  Recent studies in human non-small cell lung cancer (NSCLC) have shown that upregulation of B cell-associated genes strongly correlate with early stage patient survival. After analyzing a gene expression database of lung tumors we showed that CD79A, a pan-B cell marker, had the strongest predictive value, suggesting that B cells are playing a crucial role in NSCLC immunity. In order to evaluate this we first examined where this genetic signature was originating from. We observed that patients with high levels of B cell-related genes also showed high numbers of CD79A+ B cells intimately associated with the tumor, but not being expressed by tumor cells themselves. A closer look at tumor-infiltrating B cells (TIL-B cells) by IHC and flow cytometry of fresh patient tumor samples has confirmed their presence and allowed us to begin elucidating their phenotype. Interestingly, we have found that not all early stage patients have detectable levels of TIL-B cells, but in those that do, TIL-B cells represent a marked proportion of the lymphocytic infiltration. Further evaluation of T cell populations in the same samples indicate that T cell numbers remain relatively consistent but that the numbers of B-cells, especially CD79A+ B-cells, does vary from patient to patient. These data indicate that CD79A+ TIL-B cells are contributing to the generation of an efficient immune response in some but not all patients, and are greatly influencing disease survivability. This information may allow us to stratify patients into low and high risk groups based on the presence or absence of TIL-B cells, respectively. Citation Format: Sara M. Centuori, Samuel Kim, Cecil Gomes, Charles Putnam, David Mount, Linda Garland, Brandon Larsen, Jesse D. Martinez. Determining the role of tumor-infiltrating B cells in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 713.
• Garland, L. L., Hanke, N., & Baker, A. (2016). Carfilzomib combined with suberanilohydroxamic acid (SAHA) synergistically promotes endoplasmic reticulum stress in non-small cell lung cancer cell lines.. Journal Cancer Research Clincal Oncology, 142(3), 549-60. doi:doi: 10.1007/s00432-015-2047-6
• Garland, L. L., Schwenk, . M., & Grewal, . G. (2016). Interactive Sensor-Based Balance Training in Older Cancer Patients with Chemotherapy-Induced Peripheral Neuropathy: A Randomized Controlled Trial. Gerontology, 62(5). doi:doi: 10.1159/000442253
• Gomes, C. J., Putnam, C. W., Garland, L. L., Centuori, S. M., Putnam, C. W., Mount, D. B., Martinez, J. D., Kim, S., Garland, L. L., & Centuori, S. M. (2015). Abstract 1299: Tumor-infiltrating B cells are predictive of human lung squamous cell survival. Immunology, 75(15_Supplement), 1299-1299. doi:10.1158/1538-7445.am2015-1299
• Hanke, N. T., Garland, L. L., & Baker, A. F. (2015). Carfilzomib combined with suberanilohydroxamic acid (SAHA) synergistically promotes endoplasmic reticulum stress in non-small cell lung cancer cell lines. Journal of cancer research and clinical oncology, 142(3), 549-60.
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  The endoplasmic reticulum (ER) stress response is a therapeutic target for pharmacologic intervention in cancer cells. We hypothesized that combining carfilzomib (CFZ), a proteasome inhibitor, and vorinostat (SAHA), a histone deacetylase (HDAC) inhibitor, would synergistically activate ER stress in non-small cell lung cancer (NSCLC) cell lines, resulting in enhanced anti-tumor activity.
• Ou, S. I., Moon, J., Garland, L. L., Mack, P. C., Testa, J. R., Tsao, A. S., Wozniak, A. J., & Gandara, D. R. (2015). SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 10(2), 387-91.
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  The PI3K/Akt/mammalian target of rapamycin pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mammalian target of rapamycin inhibitor, in patients with unresectable MPM.
• Schwenk, M., Grewal, G. S., Holloway, D., Muchna, A., Garland, L., & Najafi, B. (2015). Interactive Sensor-Based Balance Training in Older Cancer Patients with Chemotherapy-Induced Peripheral Neuropathy: A Randomized Controlled Trial. Gerontology.
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  Cancer patients with chemotherapy-induced peripheral neuropathy (CIPN) have deficits in sensory and motor skills leading to inappropriate proprioceptive feedback, impaired postural control, and fall risk. Balance training programs specifically developed for CIPN patients are lacking.
• Garland, L. L., Hsu, C. H., Chow, H. S., Hsu, C. H., Heckman-stoddard, B. M., Garland, L. L., Cornelison, T. L., Cordova, C. A., Chow, H. S., Chew, W. M., & Butler, V. D. (2013). Abstract 159: Modulating effects of resveratrol on systemic markers associated with breast cancer risk: a pilot clinical study in postmenopausal women with high adiposity.. Cancer Research, 73(8_Supplement), 159-159. doi:10.1158/1538-7445.am2013-159
• Miller, J. A., Hsu, C. H., Garland, L. L., Chow, H. S., Vining, D. R., Perloff, M., Miller, J. A., Hsu, C. H., Garland, L. L., Crowell, J. A., Chow, H. S., Chew, W., & Alberts, D. S. (2010). Abstract A57: High‐dose resveratrol modulates drug and carcinogen metabolizing enzymes in a healthy volunteer study. Cancer Prevention Research, 3(1_Supplement), A57-A57. doi:10.1158/1940-6207.prev-09-a57
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  Purpose: Resveratrol (RES) or 3, 4′, 5‐trihydroxystilbene has been shown to inhibit carcinogenesis by affecting various molecular events in the initiation, promotion and progression stages. The cancer chemopreventive activity of RES has been demonstrated in vivo in a wide variety of tumors including skin, mammary, gastrointestinal, and liver cancer models. Modulation of Phase I and Phase II enzymes has been suggested to be one of the mechanisms responsible for the cancer preventive effect of RES. We conducted a clinical study to determine the effect of pharmacological doses of RES on drug and carcinogen metabolizing enzymes. Methods: Forty‐two healthy volunteers underwent baseline assessment of Phase I and Phase II enzymes. A cocktail of cytochrome P450 (CYP) metabolic probe drugs, including caffeine, dextromethorphan, losartan, and buspirone, were administered to assess the activity of CYP1A2, 2D6, 2C9, and 3A4, respectively. Blood and urine samples were collected for 8 hours after probe drug administration to determine parent probe drug and metabolite concentrations for measurements of CYP enzyme activities. Blood lymphocyte glutathione S‐transferase (GST) activity and GST‐π level, and serum total and direct bilirubin, a surrogate for UDP‐glucuronosyl transferase (UGT) 1A1 activity, were measured to assess Phase II enzymes. After the baseline evaluation, study participants took 1 gm of RES once daily for 4 wks. Enzyme assessment was repeated upon intervention completion. Results: RES intervention was found to suppress the activity of CYP3A4, 2D6, and 2C9. The geometric mean change of the activity index of CPY3A4, 2D6, and 2C9 was 33% (p = 0.01), 70% (p = 0.01), and 171% (p Conclusion: We conclude that high doses of RES administration may modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which RES inhibits carcinogenesis. However, high doses of RES administration may lead to clinically relevant metabolic drug interactions. Further clinical studies are needed to determine whether lower doses of RES could be used to achieve cancer preventive activities. (Supported by N01CN35158 from the National Cancer Institute, Division of Cancer Prevention) Citation Information: Cancer Prev Res 2010;3(1 Suppl):A57.
• Garland, L. L., Hidalgo, M., Mendelson, D. S., Ryan, D. P., Arun, B. K., Lovalvo, J. L., Eiseman, I. A., Olson, S. C., Lenehan, P. F., & Eder, J. P. (2006). A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors.. Clinical cancer research : an official journal of the American Association for Cancer Research, 12(14 Pt 1), 4274-82. doi:10.1158/1078-0432.ccr-05-2507
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  CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose..Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing..CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics..It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.
• Garland, L. L., Pilkington, D. L., Cohen, J. L., Hoff, D. D., Hoff, D. D., & Taylor, C. W. (2006). A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors.. Clinical cancer research : an official journal of the American Association for Cancer Research, 12(17), 5182-9. doi:10.1158/1078-0432.ccr-06-0214
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  HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose..Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1..A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted..The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).
• Hakim, I. A., Garland, L. L., Rodney, S., Tobar, M., Cordova, C. A., Mikhael, D., Harris, R. B., Chow, H., & Goodman, L. (2006). Gender differences in smoking-induced DNA damage.. Cancer Epidemiol Biomarkers Prev.
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  Background: Oxidative reactions have been implicated as important modulators of human health and can play a role in both disease prevention and disease development. A large number of studies have demonstrated an increased oxidant burden and consequently increased markers of oxidative stress in the blood, and urine of patients with chronic obstructive pulmonary disease (COPD).The overall goal of this study is to explore the association between urinary markers of DNA damage as measured by 8-hydroxydeoxyguanosine ( 8-OhDG), antioxidant enzymes, and FEV1/FVC among smokers and former smokers with different levels of pulmonary obstruction. Methods : Cross-sectional analysis of data from baseline samples from participants in an ongoing chemoprevention trial. The study participants provided blood and urine samples which were used for the analysis of 8-OHdG, superoxide dismutase (SOD) and catalase (CAT) levels. All statistical analyses (descriptive & linear regressions) were performed using STATA. Results : The study protocol was approved by all parties in April 2004. A total of 119 COPD (mean FEV1/FVC = 65.7 ± 13.5) subjects (61 females and 58 males)were included in the study. Fifty nine percent were former smokers and 41% current smokers, with a mean pack year of 49.2±23.5. Urinary 8-OHdG levels were significantly associated with sex (p=0.0008), with females having higher levels of DNA damage regardless of theis smoking status or pack/years. Catalase levels were significantly associated with pack years (p=0.019) when sex was also considered (p=0.057). SOD levels were not associated with any of the studied variables. As expected FEV1/FVC was significantly associated with pack years in the study population (p=0.0058), however, this association was mainly significant among males (p=0.0489) compared to females(p=0.2023). Conclusions : Among older adult smokers and former smokers, females have higher levels of DNA damage than males as measured by urinary 8-OHdG even after controlling for smoking. Catalase activity has a negative association with pack years, and is lower among female subjects. FEV1/FVC was associated with pack years - as we expected more smoking is associated with lower lung function - but more significantly among males No significant relationship between FEV1/FVC and pack years was found among females. In summary, it seems that female smokers are much more prone to oxidative stress as compared to male smokers. More studies are needed to explore the role of gender in susceptibility to DNA damage among smokers
• Taylor, C. W., Walker, P., Tang-liu, D., Joshi, T., Gebremarian, C., Jordan, S., Yu, Z., Hoff, D. D., & Garland, L. L. (2004). A phase I and pharmacokinetic clinical trial of the orally administered retinoic acid receptor-{alpha} Agonist, AGN 195183. Journal of Clinical Oncology, 22(14_suppl), 2022-2022. doi:10.1200/jco.2004.22.90140.2022
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  2022 Background: AGN 195183 is a novel retinoid that trans-activates retinoic acid receptor-α (RAR-α). In preclinical models, AGN 195183 caused less skin toxicity compared to RAR interactive agents lacking RAR-α specificity and demonstrated anti-tumor activity in breast cancer and leukemia models. We initiated a clinical trial of AGN 195183 in advanced solid tumor patients (pts) in order to establish toxicity and pharmacokinetic profiles and to establish the maximum tolerated dose (MTD). Methods: Fifteen pts with advanced solid tumors meeting standard phase I entry criteria were enrolled on study; mean age was 60 years (range 45–79). Pts took AGN 195183 (5 and 50 mg soft gelatin capsules) by mouth with or without food on a continuous daily dosing schedule. Pharmacokinetic (PK) blood samples were collected on the days 1 and 14 prior to dosing and at 0.5, 1, 1.5, 2, 3, 5, 8, and 24 hours post-dose and prior to and 1 hour post-dose on days 7, 21, and 28. Results: Five pts were treated at the starting dose le...

Presentations

• Muramoto, M. L., Garland, L. L., Ali-Akbarian, L., Bedwell, R., & Armin, J. S. (2018, April). Discussing what to do if “things don’t go the way we want them to”: Insights from oncologists about advance care planning. Society for Applied Anthropology/Society for Medical Anthropology. Philadelphia, PA.
• Taljanovic, M., Najafi, B., Heidelberg, M. S., Johnson, K., Chadaz, T., Krupinski, E., Garland, L. L., & Gimber, L. H. (2017, March). MR Neurography and Diffusion Tensor Imaging as a Potential Biomarker of Chemotherapy Induced Peripheral Neuropathy. SSR 2017. Santa Barbara, CA: Society of Skeletal Radiology.
• Taljanovic, M., Taljanovic, M., Najafi, B., Najafi, B., Heidelberg, M. S., Heidelberg, M. S., Johnson, K., Johnson, K., Chadaz, T., Chadaz, T., Krupinski, E., Krupinski, E., Garland, L. L., Garland, L. L., Gimber, L. H., & Gimber, L. H. (2017, March). MR Neurography and Diffusion Tensor Imaging as a Potential Biomarker of Chemotherapy Induced Peripheral Neuropathy. 40th Annual Meeting of the Society of Skeletal Radiology.
• Gimber, L. H., Garland, L. L., Krupinski, E., Chadaz, T., Johnson, K., Heidelberg, M. S., Najafi, B., & Taljanovic, M. (2016, December). MR Neurography and Diffusion Tensor Imaging as a Potential Biomarker of Chemotherapy Induced Peripheral Neuropathy. Orthopedic MSK Research ConferenceUniversity of Arizona, Dept of Orthopedics.
• Taljanovic, M., Gimber, L. H., Najafi, B., Garland, L. L., Krupinski, E., Heidelberg, M. S., Johnson, K., Chadaz, T., Johnson, K., Chadaz, T., Heidelberg, M. S., Krupinski, E., Najafi, B., Garland, L. L., Gimber, L. H., & Taljanovic, M. (2016, December). MR Neurography and Diffusion Tensor Imaging as a Potential Biomarker of Chemotherapy Induced Peripheral Neuropathy. RSNA 2016.

Poster Presentations

• Baker, F. L., Garland, L. L., Curran, F., Ducey, I., Gibbons, O., Torres, E., Paine-Murrieta, G., & Chilton, F. S. (2024, November). Targeting T-Cell Migration Inhibition via Blocking Group X Secreted Phospholipase A2 (PLA2-X) Activity: A Novel Strategy to Overcome Immunotherapy Resistance in Non-Small Cell Lung Cancers.. University of Arizona Cancer Center Scientific Retreat Poster Presentation. UACC Cancer Center: UACC.
• Bauman, J. E., Hsu, C., Centuori, S. M., Jose, G., Garland, L. L., Ho, E., Bengtson, L., Wojtowicz, M., Szabo, E., & Chow, H. (2021, April). Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers. American Association for Cancer Research (AACR),. Virtual Interactive 2021: AACR.
• Armin, J. S., Ali-Akbarian, L., Garland, L. L., & Muramoto, M. L. (2017, April). Improving advance care planning for cancer patients through better care coordination. UACC Scientific Retreat. Tucson, AZ: UACC.
• Thomson, C. A., Garland, L. L., Vidrine, J. L., Yuan, N. P., Brady, B. R., O'Connor, P. A., Crane, T. E., Crane, T. E., O'Connor, P. A., Brady, B. R., Yuan, N. P., Vidrine, J. L., Garland, L. L., & Thomson, C. A. (2017, Spring). Abstract: Smoking bans in cancer patients enrolling for quitline cessation services: results from the Arizona Smokers’ Helpline (ASHLine). American Society of Preventive Oncology. Seattle, WA.
• Crane, T. E., O'Connor, P. A., Brady, B. R., Yuan, N. P., Vidrine, J. L., Garland, L. L., & Thomson, C. A. (2017, Spring). Abstract: Smoking bans in cancer patients enrolling for quitline cessation services: results from the Arizona Smokers’ Helpline (ASHLine). American Society of Preventive Oncology. Seattle, WA.