Linda L Garland

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• Armin, J. S., Bedwell, R., Ali-Akbarian, L., Garland, L., Lockwood, B., & Muramoto, M. (2025). Practices and Perspectives of Clinicians Regarding Advance Care Planning With People Living With Cancer. The American journal of hospice & palliative care, 10499091251334741.
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  BackgroundWhile advance care planning (ACP) can facilitate a "good death" for people living with cancer, there remain gaps in understanding how to optimize ACP for better patient outcomes. This formative research aimed to explore experiences with advance care planning among oncology and primary care practitioners in primary/tertiary care settings.MethodsThe research team conducted structured and semi-structured in-depth interviews with family medicine practitioners (n = 12) and medical oncologists (n = 12) to understand their approaches to ACP.ResultsWhile oncologists and PCPs shared many of the same concerns about advance care planning, their unique contexts and specialties influenced their perspectives on the approach to ACP. Though oncologists and PCPs were both very likely to discuss ACP with their patients, oncologists more often discussed conducting ACP with other members of the health care team (e.g. social workers). Furthermore, disciplines differed in their emphasis on particular types of ACP documentation. Semi-structured interviews also revealed issues related to provider-patient communication as well as institutional challenges. Participants discussed their processes for timing the ACP conversation, addressing language-use challenges, assessing patient goals, and ensuring a good ACP workflow.ConclusionsParticipants recommended areas for institutional support and intervention to improve provider-patient ACP interactions.
• 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
• Bauman, J. E., Hsu, C. H., Centuori, S., Guillen-Rodriguez, J., Garland, L. L., Ho, E., Padi, M., Bageerathan, V., Bengtson, L., Wojtowicz, M., Szabo, E., & Sherry Chow, H. H. (2022). Randomized Crossover Trial Evaluating Detoxification of Tobacco Carcinogens by Broccoli Seed and Sprout Extract in Current Smokers. Cancers, 14(Issue 9). doi:10.3390/cancers14092129
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  Consumption of cruciferous vegetables, rich in the isothiocyanate glucoraphanin, is associated with reduced risk of tobacco-related cancers. Sulforaphane, released by hydrolysis of glucoraphanin, potently induces cytoprotective phase II enzymes. Sulforaphane decreased the incidence of oral cancer in the 4NQO carcinogenesis model. In residents of Qidong, China, broccoli seed and sprout extracts (BSSE) increased detoxification of air pollutants benzene and acrolein, also found in tobacco smoke. This randomized, crossover trial evaluated detoxification of tobacco carcinogens by the BSSE Avmacol® in otherwise healthy smokers. Participants were treated for 2 weeks with both low and higher-dose BSSE (148 µmol vs. 296 µmol of glucoraphanin daily), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxification of benzene, measured by urinary excretion of its mercapturic acid, SPMA. Secondary endpoints included bioavailability, detoxification of acrolein and crotonaldehyde, modulation by GST genotype, and toxicity. Forty-nine participants enrolled, including 26 (53%) females with median use of 20 cigarettes/day. Low and higher-dose BSSE showed a mean bioavailability of 11% and 10%, respectively. Higher-dose BSSE significantly upregulated urinary excretion of the mercapturic acids of benzene (p = 0.04), acrolein (p < 0.01), and crotonaldehyde (p = 0.02), independent of GST genotype. Retention and compliance were high resulting in early study completion. In conclusion, BSSE significantly upregulated detoxification of the tobacco carcinogens benzene, acrolein, and crotonaldehyde in current tobacco smokers.
• 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.
• Eshghi, N., Garland, L. L., Hamilton, R. J., Hsu, C. C., Kuo, P. H., Sawyer, T. W., & Sawyer, D. M. (2021). Pilot Study: Texture Analysis of PET Imaging Demonstrates Changes in 18F-FDG Uptake of the Brain After Prophylactic Cranial Irradiation.. Journal of nuclear medicine technology, 49(1), 34-38. doi:10.2967/jnmt.120.248393
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  Prophylactic cranial irradiation (PCI) is used to decrease the probability of developing brain metastases in patients with small cell lung cancer and has been linked to deleterious cognitive effects. Although no well-established imaging markers for these effects exist, previous studies have shown that structural and metabolic changes in the brain can be detected with MRI and PET. This study used an image processing technique called texture analysis to explore whether global changes in brain glucose metabolism could be characterized in PET images. Methods: 18F-FDG PET images of the brain from patients with small cell lung cancer, obtained before and after the administration of PCI, were processed using texture analysis. Texture features were compared between the pre- and post-PCI images. Results: Multiple texture features demonstrated statistically significant differences before and after PCI when texture analysis was applied to the brain parenchyma as a whole. Regional differences were also seen but were not statistically significant. Conclusion: Global changes in brain glucose metabolism occur after PCI and are detectable using advanced image processing techniques. These changes may reflect radiation-induced damage and thus may provide a novel method for studying radiation-induced cognitive impairment.
• 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.
• Argiris, A., Miao, J., Cristea, M. C., Chen, A. M., Sands, J., Decker, R. H., Gettinger, S. N., Daly, M. E., Faller, B. A., Albain, K. S., Yanagihara, R. H., Garland, L. L., Byers, L. A., Wang, D., Koczywas, M., Redman, M. W., Kelly, K., & Gandara, D. R. (2019). S1206: A dose-finding study followed by a phase II randomized placebo-controlled trial of chemoradiotherapy (CRT) with or without veliparib in stage III non-small cell lung cancer (NSCLC).. Journal of Clinical Oncology, 37(15_suppl), 8523-8523. doi:10.1200/jco.2019.37.15_suppl.8523
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  8523Background: Veliparib (V), a PARP inhibitor, may potentiate the antitumor effect of CRT in NSCLC. Methods: Eligibility included newly diagnosed unresectable stage III NSCLC. Patients were rando...
• 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.
• Garland, L. L., Hsu, C. C., Kim, S., Skrepnik, T., Suszko, J., & Yi, S. K. (2017). Poster(P083) Differential Complete Pathologic Response by Histology After High Dose Neoadjuvant Chemoradiation. International Journal of Radiation Oncology Biology Physics, 98(2), E37-E38. doi:10.1016/j.ijrobp.2017.02.179
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  Neoadjuvant chemoradiation(nADJ-CRT) with resection is acceptable for selected locally advanced non-small cell lung cancer(LA-NSCLC). Complete pathologic response (pCR) rates by histology are poorly defined in this setting. Similar to nADJ CRT for esophagus, we hypothesized greater pCR rates for squamous cell(SCC) compared to adenocarcinoma(AC). Patients(n=22) with stage II(9.1%) and IIIA(91.9%) NSCLC treated with nADJ-CRT and lobectomy(90.9%) or pneumonectomy(9.1%) and lymph node(LN) dissection(median 6 weeks from CRT) were retrospectively analyzed. Primary outcome was pCR defined as no malignant cells. Of N2 patients, mediastinal clearance was defined as negative N2 findings on resection. Outcomes were summarized using descriptive statistics and compared using analyses of variance or chi-square tests for continuous and categorical variables. Histology was 59.1% AC and 40.9% SCC, and 86.4% had N2 disease (94.7% biopsy proven). At median follow up of 11.4 months, progression free survival was 9.6 months, and 1-year overall survival was 83.0%. Patient characteristics were comparable by histology for age(66.5 vs 66.0years), smoking(23.5 vs 29pack-years), primary tumor size(5.7cm vs. 4.1cm), median RT dose(56Gy vs. 60Gy, range 45-66 Gy), and mean LNs removed(14.2 vs. 19.1) by SCC and AC, respectively. 82% achieved an R0 resection. Mediastinal clearance rates were 71.4% and 66.7% for SCC and AC, respectively(p=0.829). There was significantly higher pCR in the primary for SCC(62.5%) vs AC(7.7%, p=0.007). After nADJ-CRT, total pCR(primary and LN) was higher for SCC(44.0%) vs AC(7.7%, p=0.043). Patients treated with nADJ-CRT ≥60 Gy(63.4%) had a larger difference in total pCR for SCC(75.0%) and AC(10.0%, p=0.015). Patients with LA-NSCLC treated with nADJ-CRT had differential pCR rates based on histology in favor of SCC with improved pCR rates compared with AC, which persisted with definitive dose nADJ-CRT.
• 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.
• Cristea, M. C., Miao, J., Argiris, A., Chen, A. M., Daly, M. E., Decker, R. H., Garland, L. L., Wang, D., Koczywas, M., Kelly, K., Gandara, D. R., & Moon, J. C. (2016). SWOG S1206: A dose-finding study of veliparib (ABT-888) added to chemoradiotherapy (CRT) with carboplatin (C) and paclitaxel (P) for unresectable stage III non-small cell lung cancer (NSCLC).. Journal of Clinical Oncology, 34(15_suppl), 8537-8537. doi:10.1200/jco.2016.34.15_suppl.8537
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  8537Background: Preclinical studies of the PARP inhibitor velaparib (V) demonstrated synergistic effects when combined with various cytotoxic agents and radiation (RT). S1206 is a phase I trial of ...
• 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., Garland, L. L., Grewal, G. S., Holloway, D., Muchna, A., Mohler, J., & Najafi, B. (2015). Wearable sensor-based balance training in older adult cancer patients with chemotherapy-induced neuropathy: A randomized controlled trial.. Journal of Clinical Oncology, 33(29_suppl), 195-195. doi:10.1200/jco.2015.33.29_suppl.195
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  195 Background: Chemotherapy-induced peripheral neuropathy (CIPN) can affect lower extremity joint proprioception leading to balance deficits and increased fall risk. This study evaluated the effect of a sensor-based exercise program on improving postural control in cancer patients with CIPN. Methods: Twenty two cancer patients (Age 70.3±8.7 years) with objectively confirmed CIPN (vibration perception threshold test, VPT > 25 Volt) were randomized to twice weekly x 4 weeks sensor-based training including weight shifting and virtual obstacle crossing with real-time visual feedback of lower-extremities through wearable wireless sensors (intervention group, IG, n = 11) or no intervention (control group, CG, n = 11). Outcome measures included changes in sway of ankle, hip, and center of mass (CoM) in both medio-lateral (ML) and anterior-posterior (AP) directions during 30 second standing in feet closed position (both feet next to each other) with eyes open (EO) and eyes closed (EC), and semi-tandem position (...
• 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.
• Putnam, C. W., Garland, L. L., Centouri, S. M., Manziello, A. M., Martinez, J. D., Mount, D. W., & Pandey, R. (2014). Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma.. BMC medical genomics, 7(1), 33. doi:10.1186/1755-8794-7-33
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  Numerous microarray-based prognostic gene expression signatures of primary neoplasms have been published but often with little concurrence between studies, thus limiting their clinical utility. We describe a methodology using logistic regression, which circumvents limitations of conventional Kaplan Meier analysis. We applied this approach to a thrice-analyzed and published squamous cell carcinoma (SQCC) of the lung data set, with the objective of identifying gene expressions predictive of early death versus long survival in early-stage disease. A similar analysis was applied to a data set of triple negative breast carcinoma cases, which present similar clinical challenges..Important to our approach is the selection of homogenous patient groups for comparison. In the lung study, we selected two groups (including only stages I and II), equal in size, of earliest deaths and longest survivors. Genes varying at least four-fold were tested by logistic regression for accuracy of prediction (area under a ROC plot). The gene list was refined by applying two sliding-window analyses and by validations using a leave-one-out approach and model building with validation subsets. In the breast study, a similar logistic regression analysis was used after selecting appropriate cases for comparison..A total of 8594 variable genes were tested for accuracy in predicting earliest deaths versus longest survivors in SQCC. After applying the two sliding window and the leave-one-out analyses, 24 prognostic genes were identified; most of them were B-cell related. When the same data set of stage I and II cases was analyzed using a conventional Kaplan Meier (KM) approach, we identified fewer immune-related genes among the most statistically significant hits; when stage III cases were included, most of the prognostic genes were missed. Interestingly, logistic regression analysis of the breast cancer data set identified many immune-related genes predictive of clinical outcome..Stratification of cases based on clinical data, careful selection of two groups for comparison, and the application of logistic regression analysis substantially improved predictive accuracy in comparison to conventional KM approaches. B cell-related genes dominated the list of prognostic genes in early stage SQCC of the lung and triple negative breast cancer.
• 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
• Unger, W., Garland, L. L., Allen, P. K., Amini, A., Brown, P. D., Chang, J. Y., Chen, S. S., Heymach, J. V., Holt, J., Kim, E. S., Komaki, R., Liao, Z., Mcgovern, S. L., Munsell, M. F., Stea, B., Sulman, E. P., Wefel, J. S., & Welsh, J. W. (2013). Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 31(7), 895-902. doi:10.1200/jco.2011.40.1174
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  Brain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety..Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility..Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations..Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
• Welsh, J., Komaki, R., Amini, A., Munsell, M., Unger, W., Allen, P., Chang, J., Wefel, J., McGovern, S., Garland, L., Chen, S., Holt, J., Liao, Z., Brown, P., Sulman, E., Heymach, J., Kim, E., & Stea, B. (2013). Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. Journal of Clinical Oncology, 31(7). doi:10.1200/JCO.2011.40.1174
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  Purpose Brain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety. Patients and Methods Eligible patients hadBMfrom NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility. Results Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations. Conclusion Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination. © 2013 by American Society of Clinical Oncology.
• Garland, L. L., Gandara, D. R., Mack, P. C., Moon, J. C., Ou, S., Testa, J. R., Tsao, A. S., & Wozniak, A. J. (2012). SWOG 0722: A phase II study of mTOR inhibitor everolimus (RAD001) in malignant pleural mesothelioma (MPM).. Journal of Clinical Oncology, 30(15_suppl), 7083-7083. doi:10.1200/jco.2012.30.15_suppl.7083
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  7083 Background: MPM preclinical studies demonstrate activation of AKT pathway proteins, including mTOR, and provide the rationale to test everolimus, an mTOR inhibitor, in MPM. Methods: Unresectab...
• Tsao, A. S., Marom, E. M., Gandara, D. R., Garland, L. L., Kernstine, K. H., & Redman, M. W. (2011). Reply to the Letter to the Editor Entitled A Practical Guide to Measure “All” Malignant Pleural Mesothelioma Tumors by Modified RECIST Criteria?. Journal of Thoracic Oncology, 6(12), 2144-2145. doi:10.1097/jto.0b013e3182370e7e
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  We fully agree with Nackaerts et al. that there are significant radiographic challenges encountered when measuring thoracic mesothelioma tumors. As pointed out, mesothelioma is not always measurable by computed tomography (CT), magnetic resonance imaging, or positron emission tomography (PET) scans, and the classification of “nonmeasurable but evaluable” is a common conundrum. However, given our limitations with cost, technology availability, and consistency in radiographic measurements, the standard of care in cooperative group trials is to measure thoracic mesothelioma tumors with serial CT scans. Modified RECIST criteria by Byrne and Nowak1Byrne MJ Nowak AK Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.Ann Oncol. 2004; 15: 257-260Crossref PubMed Scopus (528) Google Scholar is the preferred method of evaluating pleural tumors on CT scans as pleural disease measurements, using the short-axis rather than the long-axis diameter, appear to correlate better with clinical outcome. Given the rare incidence of mesothelioma and occasional confusion on how to measure pleural rinds, the intent of our recent publication2Tsao AS, Garland L, Redman M, et al. A practical guide of the Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and modified RECIST criteria. J Thorac Oncol 6:598–601.Google Scholar was to serve as a practical guide (a step-by-step manual) to enhance consistency in disease measure-ments for the Southwest Oncology Group institutions. We concur with Nackaerts et al. that our current measurement practice is not optimal, and future studies of technology are vital to develop better and more consistent measurements. In our recent publication, we did not intend to write a review on the different imaging modalities of measuring mesothelioma, which was clearly summarized in the recent publication by Nowak et al.3Nowak AK Armato III, SG Ceresoli GL et al.Imaging in pleural mesothelioma: a review of imaging research presented at the 9th International Meeting of the International Mesothelioma Interest Group.Lung Cancer. 2010; 70: 1-6Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar The dilemma of measuring the “nonmeasurable but evaluable” mesothelioma tumors is that there is currently no technology that has been validated or consistently accurate. The labor-intensive strategy of area measurements rather than linear measurements would be impractical for a cooperative group to undertake, as not all investigators would have the resources, time, or expertise to conduct this study. While fluorodeoxyglucose PET and PET-CT scans are gaining popularity in imaging mesothelioma, and does show some promise, there are multiple factors that cause standardized uptake value measurements to vary from the initial baseline study to subsequent serial studies; and there is neither consensus nor validation of response criteria for mesothelioma. Some studies4Ceresoli GL Chiti A Zucali PA et al.Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose.J Clin Oncol. 2006; 24: 4587-4593Crossref PubMed Scopus (142) Google Scholar, 5Yildirim H Metintas M Entok E et al.Clinical value of fluorodeoxyglucose-positron emission tomography/computed tomography in differentiation of malignant mesothelioma from asbestos-related benign pleural disease: an observational pilot study.J Thorac Oncol. 2009; 4: 1480-1484Crossref PubMed Scopus (81) Google Scholar, 6Francis RJ Byrne MJ van der Schaaf AA et al.Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans.J Nucl Med. 2007; 48: 1449-1458Crossref PubMed Scopus (165) Google Scholar have previously reported a correlation to clinical outcome using either a metabolic response by measuring maximum standardized uptake values or total glycolytic volume; however, these trials are small in number and other studies7Schaefer NG, Veit-Haibach P, Soyka JD, et al. Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): Value of 18F-FDG-PET/CT. Eur J Radiol In press.Google Scholar, 8Veit-Haibach P Schaefer NG Steinert HC et al.Combined FDG-PET/CT in response evaluation of malignant pleural mesothelioma.Lung Cancer. 2010; 67: 311-317Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar have reported conflicting results. It is clear that additional prospective trials with radiographic correlates are needed to validate and develop new strategies based on our current technical capabilities; we hope that future research, perhaps new novel PET tracers, will overcome the complexity of measuring this nonspherical tumor.
• Tsao, A., Garland, L., Redman, M., Kernstine, K., Gandara, D., & Marom, E. (2011). Reply to the letter to the editor entitled a practical guide to measure "all" malignant pleural mesothelioma tumors by modified RECIST criteria?. Journal of Thoracic Oncology, 6(12). doi:10.1097/JTO.0b013e3182370e7e
• Garland, L. L., Miller, J. A., Alberts, D. S., Chew, W. M., Chow, H. S., Crowell, J. A., Hsu, C. H., Perloff, M., & Vining, D. R. (2010). Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study.. Cancer prevention research (Philadelphia, Pa.), 3(9), 1168-75. doi:10.1158/1940-6207.capr-09-0155
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  Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug- and carcinogen-metabolizing enzymes. Forty-two healthy volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-pi 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 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-pi level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions.
• 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.
• Blakely, L. J., Blumenschein, G., Cardenal, F., Eisenberg, P. D., Garland, L., Green, S., Gualberto, A., Haluska, P., Johnson, F. M., Karp, D. D., Langer, C. J., Novello, S., & Paz-ares, L. G. (2009). Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27(15), 2516-22. doi:10.1200/jco.2008.19.9331
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  We conducted a phase II study of combination of the anti-insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non-small-cell lung cancer (NSCLC)..Patients were randomly assigned (2:1) to paclitaxel 200 mg/m(2), carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI(10), PCI(20)) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI(10-20) patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI(20) was enrolled on completion of the randomized study..A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI(10) and 50 patients received PCI(20) in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI(20)/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship..These data suggest that PCI(20) is safe and effective in patients with NSCLC.
• Garland, L. L., Chansky, K., Gadgeel, S. M., Gandara, D. R., Gandara, D. R., Redman, M. W., Silva, M. D., Tsao, A., Vershraegen, C., & Wozniak, A. J. (2009). SWOG S0509: A phase II study of novel oral antiangiogenic agent AZD2171 (NSC-732208) in malignant pleural mesothelioma. Journal of Clinical Oncology, 27(15_suppl), 7511-7511. doi:10.1200/jco.2009.27.15_suppl.7511
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  7511 Background: Preclinical studies suggest the autocrine growth loop involving VEGF and its receptors is a relevant therapeutic target for malignant pleural mesothelioma (MPM). We evaluated AZD21...
• Karp, D. D., Pollak, M. N., Cohen, R. B., Eisenberg, P. D., Haluska, P., Yin, D., Lipton, A., Leitzel, K., Hixon, M. L., Terstappen, L. W., Paz-ares, L. G., Cardenal, F., Langer, C. J., Gualberto, A., Demers, L. M., & Garland, L. L. (2009). Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin.. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 4(11), 1397-403. doi:10.1097/jto.0b013e3181ba2f1d
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  This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors..Patients received paclitaxel 200 mg/m2, carboplatin (area under the curve of 6), and F (0.05-20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated..Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts..F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.
• Karp, D., Pollak, M., Cohen, R., Eisenberg, P., Haluska, P., Yin, D., Lipton, A., Demers, L., Leitzel, K., Hixon, M., Terstappen, L., Garland, L., Paz-Ares, L., Cardenal, F., Langer, C., & Gualberto, A. (2009). Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin. Journal of Thoracic Oncology, 4(11). doi:10.1097/JTO.0b013e3181ba2f1d
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  Introduction: This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods: Patients received paclitaxel 200 mg/m2, carboplatin (area under the curve of 6), and F (0.05-20 mg/kg) q3 weeks for up to six cycles. Patients with Objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression.Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated. Results: Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen Objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with Objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts. ConclusionS: F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation. © 2009 by the International Association for the Study of Lung Cancer.
• 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
• Garland, L. L., Gordon, M. S., Martell, R. E., Mendelson, D., Parker, K. E., Pegram, M., & Song, S. (2005). Phase I study of BMS-599626, an oral pan-HER tyrosine kinase inhibitor, in patients with advanced solid tumors. Journal of Clinical Oncology, 23(16_suppl), 3152-3152. doi:10.1200/jco.2005.23.16_suppl.3152
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  3152 Background: BMS-599626 is an orally bioavailable inhibitor of the HER1, HER2 and HER4 tyrosine kinases (IC50=22, 32 and 190 nM, respectively). Methods: Patients (pts) with advanced solid tumors were administered BMS-599626 orally once daily, 21-days on, 7-days off per cycle. Initial eligibility requirements included tumor expression of HER2 by immunohistochemistry; after 6 pts were enrolled, this criterion was modified to include all pts regardless of HER2 status. Seven pts have been treated on 3 dose levels of 100, 200 and 320 mg/day. Results: As of November 22, 2004, safety and PK data are available for pts treated in the 100 and 200mg cohorts (3 pts per dose level). No dose limiting toxicities have been observed during cycle 1. Grade 1 or 2 at least possibly drug-related adverse events have been reported and include: diarrhea (1), nausea (3), vomiting (1), rash (1), fatigue (3), musculoskeletal pain/cramp (3), cough (3). In cohort 1 (100 mg dose), BMS-599626 had Tmax ranging from 1 to 8h (median 2h). Following single dose, geomean Cmax =162 ng/ml, mean AUC0-∞=2920 ng/ml hr. A healthy volunteer study revealed similar results following a single 100 mg dose, with Tmax, Cmax and AUC of 2 h, 120 ng/ml and 2610 ng/ml hr respectively. Day 8 and day 21 PK revealed similar Cmax and AUC0-∞ with respective geomean values of Cmax =352, and 377 ng/ml, and AUC0-∞=9050 and 8300 ng/ml hr, suggesting no significant accumulation in exposure over time. Terminal half-life was about 20 hrs. Exposure increase was linear from 100 mg to 200 mg dose levels. Conclusion: To date, BMS-599626 has been well tolerated and has a favorable PK profile for daily dosing. Dose escalation is ongoing. HER2 positivity will be reinstated as an eligibility criterion once the MTD has been established for further study in a dose expansion cohort. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
• Garland, L., Gitlitz, B., Ebbinghaus, S., Pan, H., De Haan, H., Puri, R., Von Hoff, D., & Figlin, R. (2005). Phase I trial of intravenous IL-4 Pseudomonos exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor. Journal of Immunotherapy, 28(4). doi:10.1097/01.cji.0000162782.86008.mL
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  NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m2 daily × 5 days every 28 days. Neutralizing antibody (NAB) titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially. 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m 2. At 0.027 mg/m2, two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1:100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle 1 and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m2. NBI-3001 at 0.016 mg/m2 was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R. Copyright © 2005 by Lippincott Williams & Wilkins.
• Lush, R. M., Mccune, J. S., Tetteh, L., Thompson, J. A., Mahany, J. J., Suttle, A. B., Sullivan, D. M., & Garland, L. L. (2005). The absolute bioavailability of oral vinorelbine in patients with solid tumors.. Cancer chemotherapy and pharmacology, 56(6), 578-84. doi:10.1007/s00280-005-1025-0
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  Due to advances in the methods used to quantitate vinorelbine, this study was conducted to characterize fully the bioavailability of an oral dosage form of vinorelbine. Twenty-seven eligible patients with solid tumors were enrolled onto this study and were treated in a randomized crossover design to receive either 70 mg/m2 orally or 30 mg/m2 intravenously followed by the alternative treatment one week later. Vinorelbine was administered orally as a soft-gelatin capsule. Pharmacokinetic sampling was carried out for 7 days following each dose. Whole blood vinorelbine concentrations were measured using a sensitive LC/MS/MS method. The data from patients were excluded if they vomited within 3 h after the oral dose..Three subjects were removed from study following the first dose due to safety reasons. Of the remaining 24 subjects, five experienced vomiting within 3 h of oral dosing. Total body clearance calculated from the intravenous dose was 43.65 L/h (+/-10.9) and the terminal half-life was estimated to be 49 h. Using complete data from the remaining 19 subjects, the mean absolute bioavailability of the oral dosage formulation of vinorelbine was calculated to be 33% (+/-18%). In conclusion we have characterized the pharmacokinetics of both orally administered and intravenous vinorelbine over 7 days after administration and have determined the mean oral bioavailability of this oral formulation to be 33%.
• Pan, H., Puri, R. K., Ebbinghaus, S. W., Figlin, R. A., Garland, L. L., Gitlitz, B. J., Haan, H. D., & Hoff, D. V. (2005). Phase I trial of intravenous IL-4 pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor.. Journal of immunotherapy (Hagerstown, Md. : 1997), 28(4), 376-81. doi:10.1097/01.cji.0000162782.86008.ml
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  NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m2 daily x 5 days every 28 days. Neutralizing antibody (NAB) titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially. 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m2. At 0.027 mg/m2, two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1:100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle 1 and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m2. NBI-3001 at 0.016 mg/m2 was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R.
• Jacobsen, P. B., Garland, L. L., Booth-Jones, M., Donovan, K. A., Thors, C. L., Winters, E., & Grendys, E. (2004). Relationship of hemoglobin levels to fatigue and cognitive functioning among cancer patients receiving chemotherapy. Journal of Pain and Symptom Management, 28(Issue 1). doi:10.1016/j.jpainsymman.2003.11.002
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  The aim of this study was to examine the relationship of changes in hemoglobin levels to changes in fatigue and cognitive functioning in cancer patients undergoing chemotherapy treatment. Seventy-seven (77) patients completed a self-administered measure of fatigue and a battery of psychometrician-administered measures of cognitive performance before the start of chemotherapy and again before the start of the fourth treatment cycle. Hemoglobin levels were measured at corresponding timepoints. Findings partially supported the hypothesis that greater declines in hemoglobin over the course of repeated chemotherapy administrations would be accompanied by greater increases in fatigue and greater declines in cognitive performance over the same interval. Among the subset of 49 patients who demonstrated a decline in hemoglobin to a final value ≤12 g/dL, greater declines in hemoglobin were significantly (P
• 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...
• Reid, M., Duffield-Lillico, A., Garland, L., Turnbull, B., Clark, L., & Marshall, J. (2002). Selenium supplementation and lung cancer incidence: An update of the nutritional prevention of cancer trial. Cancer Epidemiology Biomarkers and Prevention, 11(11).
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  Interest in the chemopreventive effects of the trace element selenium has spanned the past three decades. Of >100 studies that have investigated the effects of selenium in carcinogen-exposed animals, two-thirds have observed a reduction in tumor incidence and/or preneoplastic endpoints (G. F. Combs and S. B. Combs, The Role of Selenium in Nutrition Chapter 10, pp. 413-462. San Diego, CA: Academic Press, 1986, and B. H. Patterson and O. A. Levander, Cancer Epidemiol. Biomark. Prev., 6: 63-69, 1997). The Nutritional Prevention of Cancer Trial, a randomized clinical trial reported by Clark et al. (L. C. Clark et al., JAMA, 276: 1957-1963, 1996), showed as a secondary end point, a statistically significant decrease in lung cancer incidence with selenium supplementation. The adjusted hazard ratio (HR) was 0.56 [95% confidence interval (CI), 0.31-1.01; P = 0.05]. These results were based on active follow-up of 1312 participants. This reanalysis used an extended Nutritional Prevention of Cancer Trial participant follow-up through the end of the blinded clinical trial on February 1, 1996. The additional 3 years added 8 cases to the selenium-treated group and 4 cases to the placebo group, and increased follow-up to 7.9 years. The relative risk of 0.70 (95% CI, 0.40-1.21; P = 0.18) is not statistically significant. Whereas the overall adjusted HR is not significant (HR = 0.74; 95% CI, 0.44-1.24; P = 0.26), and the HR for current and former smokers was not significant, the trend is toward a reduction in risk of incident lung cancer with selenium supplementation. In a subgroup analysis there was a nominally significant HR among subjects with baseline plasma selenium in the lowest tertile (HR = 0.42; 95% CI, 0.18-0.96; P = 0.04). The analysis for the middle and highest tertiles of baseline showed HRs of 0.91 and 1.25. The current reanalysis indicates that selenium supplementation did not significantly decrease lung cancer incidence in the full population, but a significant decrease among individuals with low baseline selenium concentrations was observed.
• Rabkin, C. S., Silverman, S., Tricot, G., Garland, L. L., Ballester, O., & Potter, M. (1996). The National Cancer Institute Silicone Implant/Multiple Myeloma Registry. Current Topics in Microbiology and Immunology. doi:10.1007/978-3-642-85226-8_41

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.
• Gimber, L. H., Taljanovic, M., 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., Taljanovic, M., & Gimber, L. H. (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.