Linda L Garland

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Scholarly Contributions

Journals/Publications

• 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.
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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.
• 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., Hsu, C., Yi, S. K., Yi, S. K., Stea, B., Stea, B., Khalpey, Z. I., Khalpey, Z. I., Garland, L. L., Garland, L. L., Bull, D. A., Bull, D. A., Kim, S. S., & 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., Najafi, B., Schwenk, M., Chadaz, T., Krupinski, E. A., Garland, L. L., & 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.
• 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
• 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.

Presentations

• 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. 40th Annual Meeting of the Society of Skeletal Radiology.
• 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.
• 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.
• 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. RSNA 2016.

Poster Presentations

• 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.
• 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.
• Crane, T. E., Thomson, C. A., O'Connor, P. A., Garland, L. L., Brady, B. R., Vidrine, J. L., Yuan, N. P., Yuan, N. P., Vidrine, J. L., Brady, B. R., O'Connor, P. A., Garland, L. L., Thomson, C. A., & Crane, T. E. (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., Crane, T. E., Thomson, C. A., O'Connor, P. A., O'Connor, P. A., Garland, L. L., Brady, B. R., Brady, B. R., Vidrine, J. L., Yuan, N. P., Yuan, N. P., Yuan, N. P., Vidrine, J. L., Brady, B. R., Vidrine, J. L., O'Connor, P. A., Garland, L. L., Garland, L. L., Thomson, C. A., , Thomson, C. A., et al. (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.