Amanda Kirane, MD, PhD-c, FACS, FSSO

All Publications

• Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative JOURNAL OF SURGICAL ONCOLOGY Makris, E. A., Tran, T. B., Delitto, D. J., Lee, B., Ethun, C. G., Grignol, V., Howard, J., Bedi, M., Gamblin, T., Tseng, J., Roggin, K. K., Chouliaras, K., Votanopoulos, K., Cullinan, D., Fields, R. C., Cardona, K., Poultsides, G., Kirane, A. 2024

  Abstract

  Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS.From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed.Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation.For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

  View details for DOI 10.1002/jso.27620

  View details for Web of Science ID 001194891800001

  View details for PubMedID 38562002

• Clinical and Translational Opportunities of Nanocarriers Containing RNAi for the Management of Triple-Negative Breast Cancer ADVANCED THERAPEUTICS Sharma, S., Pradhan, R., Lee, D., Sharma, M., Nasab, S., Hejmady, S., Chander, S., Mohaghegh, N., Maity, S., Khan, S., Khademhosseini, A., Kirane, A. 2024

  View details for DOI 10.1002/adtp.202300388

  View details for Web of Science ID 001190306300001

• Toward the Development of Functional Biomarker Assays: Analysis of Neoadjuvant Intralesional Oncolytic Virus Response in High-Risk Stage II Melanoma Kirane, A., Lee, D., Ahmad, M., Sharma, S., Serasanambati, M., Lowe, M., Applebee, C., Safrygina, E., Swetter, S., Reddy, S., Warner, A., Funchain, P., Wang, J., Levy, R., Larijani, B., Maverakis, E. SPRINGER. 2024: S33-S34

  View details for Web of Science ID 001185577500066

• Macrophage function over phenotype determines sensitization to immunotherapy Lee, D., Sharma, S., Serasanambati, M., Ahmad, M., Larijani, B., Kirane, A. SPRINGER. 2024: S214

  View details for Web of Science ID 001185577500478

• Single cell pharmacogenic pipeline identifies novel opportunities in uterine leiomyosarcoma Daniel, S. K., Foster, D., Nosrati, F., Korah, M., Fallah, M., Sun, B. J., Loftus, T., Hu, D., Dua, M., Visser, B., Poultsides, G., Kirane, A., Longaker, M., Ganjoo, K., Lee, B., Delitto, D. SPRINGER. 2024: S42

  View details for Web of Science ID 001185577500085

• Phenylthiazolidin-4-one piperazine Conjugates: Design, Synthesis, anticancer and antimicrobial studies RESULTS IN CHEMISTRY Singh, D., Patel, R., Aggarwal, A., Das, A., Sharma, S., Behera, B., Panigrahy, R., Kirane, A. R., Kharkwal, H., Kumar, P., Bokolia, N., Sankaranarayanan, M., Chander, S. 2024; 7

  View details for DOI 10.1016/j.rechem.2023.101237

  View details for Web of Science ID 001135230300001

• Design, Synthesis, Anticancer and Antimicrobial Studies of 2-Phenylthiazolidin-4-one Glycinamide Conjugates CHEMISTRYSELECT Singh, D., Aggarwal, A., Patel, R., Das, A., Sharma, S., Behera, B., Panigrahy, R., Maity, S., Kirane, A. R., Kharkwal, H., Sankaranarayanan, M., Wadhwa, P., Khan, A., Alshehri, J. M., Chander, S. 2023; 8 (42)

  View details for DOI 10.1002/slct.202301806

  View details for Web of Science ID 001096924100001

• Detection of Circulating Tumor DNA Predicts Recurrence in Soft Tissue Sarcomas Sun, B. J., Li, A., Alobuia, W., Hur, D., Daniel, S. K., Kirane, A. R., Poultsides, G., Lee, B. SPRINGER. 2023: S16

  View details for Web of Science ID 001046841200028

• The Impact of Mesenchymal Transition and Macrophage Phenotype in Immunotherapy-Resistant Melanoma Ahmad, M., Han, B., Ju, A., Sun, B. J., Maverakis, E., Kirane, A. R. SPRINGER. 2023: S236

  View details for Web of Science ID 001046841200519

• Multiregional Sequencing Analysis Reveals Extensive Genetic Heterogeneity in Gastric Tumors from Latinos. Cancer Research Communications Toal, T., Polanco-Echeverry, M. M., Sahasrabudhe, R., Lott, P., Suarez-Olaya, J. J., Guevara-Tique, A. A., et al 2022; 2 (11): 1496

  Abstract

  Gastric cancer is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multiregional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with The Cancer Genome Atlas (TCGA) and on mutation clonality, druggability, and signatures. We found that only approximately 30% of all mutations were clonal and that only 61% of the known TCGA gastric cancer drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate gastric cancer drivers such as EYS, FAT4, PCDHA1, RAD50, EXO1, RECQL4, and FSIP2. The genomically stable (GS) molecular subtype, which has the worse prognosis, was identified in 48% of our Latino patients, a fraction that was >2.3-fold higher than in TCGA Asian and White patients. Only a third of all tumors harbored clonal pathogenic mutations in druggable genes, with most (93%) GS tumors lacking actionable clonal mutations. Mutation signature analyses revealed that, in microsatellite-stable (MSS) tumors, DNA repair mutations were common for both tumor initiation and progression, while tobacco, POLE, and inflammation signatures likely initiate carcinogenesis. MSS tumor progression was likely driven by aging- and aflatoxin-associated mutations, as these latter changes were usually nonclonal. In microsatellite-unstable tumors, nonclonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing gastric cancer molecular diagnostics and suggests clonal status is important to understanding gastric tumorigenesis. Our findings of a higher frequency of a poor prognosis associated molecular subtype in Latinos and a possible new aflatoxin gastric cancer etiology also advance cancer disparities research.Our study contributes to advancing our knowledge of gastric carcinogenesis, diagnostics, and cancer health disparities.

  View details for DOI 10.1158/2767-9764.CRC-22-0149

  View details for PubMedCentralID PMC10035402

• Intralesional Interleukin-2 Augmentation Therapy in Treatment-Refractory Melanoma. Dermatologic therapy Le, S. T., Ji-Xu, A., Liakos, W., Toussi, A. M., Cheng, M. Y., Ma, C., Wang, E. A., Wilken, R., Boddu, S., Downing, L., Kao, J., Davis, J. R., Monjazeb, A. M., Fung, M. A., Konia, T. H., Maverakis, E., Kirane, A. R. 2022: e15853

  View details for DOI 10.1111/dth.15853

  View details for PubMedID 36151592

• Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G. JCI insight Merleev, A., Ji-Xu, A., Toussi, A., Tsoi, L. C., Le, S. T., Luxardi, G., Xing, X., Wasikowski, R., Liakos, W., Brüggen, M. C., Elder, J. T., Adamopoulos, I. E., Izumiya, Y., Leal, A. R., Li, Q., Kuzminykh, N. Y., Kirane, A., Marusina, A. I., Gudjonsson, J. E., Maverakis, E. 2022; 7 (16)

  Abstract

  Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq-based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.3, located within PCSK9 (rs662145 C > T). This finding was verified in independently acquired genomic and RNA-Seq data sets. Single-cell RNA-Seq (scRNA-Seq) identified keratinocytes as the primary source of PCSK9 in human skin. PCSK9 expression, however, was not uniform across keratinocyte subpopulations. scRNA-Seq and IHC demonstrated an epidermal gradient of PCSK9, with expression being highest in basal and early spinous layer keratinocytes and lowest in granular layer keratinocytes. IL36G expression followed the opposite pattern, with expression highest in granular layer keratinocytes. PCSK9 siRNA knockdown experiments confirmed this inverse relationship between PCSK9 and IL36G expression. Other immune genes were also linked to PCSK9 expression, including IL27RA, IL1RL1, ISG20, and STX3. In both cultured keratinocytes and nonlesional human skin, homozygosity for PCSK9 SNP rs662145 C > T was associated with lower PCSK9 expression and higher IL36G expression, when compared with heterozygous skin or cell lines. Together, these results support PCSK9 as a psoriasis-susceptibility locus and establish a putative link between PCSK9 and inflammatory cytokine expression.

  View details for DOI 10.1172/jci.insight.141193

  View details for PubMedID 35862195

  View details for PubMedCentralID PMC9462487

• Biogeographic and disease-specific alterations in epidermal lipid composition and single cell analysis of acral keratinocytes. JCI insight Merleev, A. A., Le, S. T., Alexanian, C., Toussi, A., Xie, Y., Marusina, A. I., Watkins, S. M., Patel, F., Billi, A. C., Wiedemann, J., Izumiya, Y., Kumar, A., Uppala, R., Kahlenberg, J. M., Liu, F., Adamopoulos, I. E., Wang, E. A., Ma, C., Cheng, M. Y., Xiong, H., Kirane, A., Luxardi, G., Andersen, B., Tsoi, L. C., Lebrilla, C. B., Gudjonsson, J. E., Maverakis, E. 2022

  Abstract

  The epidermis is the outermost layer of skin. Here, we use targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and use single-cell RNA sequencing to compare keratinocyte gene expression at acral and non-acral surfaces. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there is a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a two-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene co-expression analysis revealed a strong connection between lipid and immune gene expression. This work highlights mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces, and how inflammation-associated alterations in gene expression affect the epidermal lipidome.

  View details for DOI 10.1172/jci.insight.159762

  View details for PubMedID 35900871

• PDXNet portal: patient-derived Xenograft model, data, workflow and tool discovery. NAR cancer Koc, S., Lloyd, M. W., Grover, J. W., Xiao, N., Seepo, S., Subramanian, S. L., Ray, M., Frech, C., DiGiovanna, J., Webster, P., Neuhauser, S., Srivastava, A., Woo, X. Y., Sanderson, B. J., White, B., Lott, P., Dobrolecki, L. E., Dowst, H., Evrard, Y. A., Wallace, T. A., Moscow, J. A., Doroshow, J. H., Mitsiades, N., Kaochar, S., Pan, C. X., Chen, M. S., Carvajal-Carmona, L., Welm, A. L., Welm, B. E., Lewis, M. T., Govindan, R., Ding, L., Li, S., Herlyn, M., Davies, M. A., Roth, J., Meric-Bernstam, F., Robinson, P. N., Bult, C. J., Davis-Dusenbery, B., Dean, D. A., Chuang, J. H. 2022; 4 (2): zcac014

  Abstract

  We created the PDX Network (PDXNet) portal (https://portal.pdxnetwork.org/) to centralize access to the National Cancer Institute-funded PDXNet consortium resources, to facilitate collaboration among researchers and to make these data easily available for research. The portal includes sections for resources, analysis results, metrics for PDXNet activities, data processing protocols and training materials for processing PDX data. Currently, the portal contains PDXNet model information and data resources from 334 new models across 33 cancer types. Tissue samples of these models were deposited in the NCI's Patient-Derived Model Repository (PDMR) for public access. These models have 2134 associated sequencing files from 873 samples across 308 patients, which are hosted on the Cancer Genomics Cloud powered by Seven Bridges and the NCI Cancer Data Service for long-term storage and access with dbGaP permissions. The portal includes results from freely available, robust, validated and standardized analysis workflows on PDXNet sequencing files and PDMR data (3857 samples from 629 patients across 85 disease types). The PDXNet portal is continuously updated with new data and is of significant utility to the cancer research community as it provides a centralized location for PDXNet resources, which support multi-agent treatment studies, determination of sensitivity and resistance mechanisms, and preclinical trials.

  View details for DOI 10.1093/narcan/zcac014

  View details for PubMedID 35475145

  View details for PubMedCentralID PMC9026194

• The Role of AXL Tyrosine Kinase in the Melanoma Immune Microenvironment Sun, B., Ahmad, M., Gingrich, A. A., Walsh, A., Nielsen, R., Maverakis, E., Kirane, A. R. SPRINGER. 2022: 465

  View details for Web of Science ID 000789811800310

• Neoadjuvant Intralesional Therapy for High Risk Stage II Melanoma Lowe, M. C., Ahmad, M., Sun, B., Gholami, S., Maverakis, E., Kirane, A. R. SPRINGER. 2022: 534

  View details for Web of Science ID 000789811800468

• Author Correction: Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidates for targeted treatment. Nature communications Sun, H., Cao, S., Mashl, R. J., Mo, C. K., Zaccaria, S., Wendl, M. C., Davies, S. R., Bailey, M. H., Primeau, T. M., Hoog, J., Mudd, J. L., Dean, D. A., Patidar, R., Chen, L., Wyczalkowski, M. A., Jayasinghe, R. G., Rodrigues, F. M., Terekhanova, N. V., Li, Y., Lim, K. H., Wang-Gillam, A., Van Tine, B. A., Ma, C. X., Aft, R., Fuh, K. C., Schwarz, J. K., Zevallos, J. P., Puram, S. V., Dipersio, J. F., Davis-Dusenbery, B., Ellis, M. J., Lewis, M. T., Davies, M. A., Herlyn, M., Fang, B., Roth, J. A., Welm, A. L., Welm, B. E., Meric-Bernstam, F., Chen, F., Fields, R. C., Li, S., Govindan, R., Doroshow, J. H., Moscow, J. A., Evrard, Y. A., Chuang, J. H., Raphael, B. J., Ding, L. 2022; 13 (1): 294

  View details for DOI 10.1038/s41467-021-27678-7

  View details for PubMedID 34996889

  View details for PubMedCentralID PMC8742097

• Chemotherapy After Diagnosis of Malignant Bowel Obstruction is Associated with Superior Survival for Medicare Patients with Advanced Malignancy. Annals of surgical oncology Bateni, S. B., Gingrich, A. A., Kirane, A. R., Sauder, C. A., Gholami, S., Bold, R. J., Meyers, F. J., Canter, R. J. 2021; 28 (12): 7555-7563

  Abstract

  Although malignant bowel obstruction (MBO) often is a terminal event, systemic therapies are advocated for select patients to extend survival. This study aimed to evaluate factors associated with receipt of chemotherapy after MBO and to determine whether chemotherapy after MBO is associated with survival.This retrospective cohort study investigated patients 65 years of age or older with metastatic gastrointestinal, gynecologic, or genitourinary cancers who were hospitalized with MBO from 2008 to 2012 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Fine and Gray models were used to identify factors associated with receipt of chemotherapy accounting for the competing risk of death. Cox models identified factors associated with overall survival.Of the 2983 MBO patients, 39% (n = 1169) were treated with chemotherapy after MBO. No differences in receipt of chemotherapy between the surgical and medical patients were found in the univariable analysis (subdistribution hazard ratio [SHR], 0.96; 95% confidence interval [CI], 0.86-1.07; p = 0.47) or multivariable analysis (SHR, 1.12; 95% CI, 1.00-1.26; p = 0.06). Older age, African American race, medical comorbidities, non-colorectal and non-ovarian cancer diagnoses, sepsis, ascites, and intensive care unit stays were inversely associated with receipt of chemotherapy after MBO (p < 0.05). Chemotherapy with surgery was associated with longer survival than surgery (adjusted hazard ratio [aHR], 2.97; 95% CI, 2.65-3.34; p < 0.01) or medical management without chemotherapy (aHR, 4.56; 95% CI, 4.04-5.14; p < 0.01). Subgroup analyses of biologically diverse cancers (colorectal, pancreatic, and ovarian) showed similar results, with greater survival related to chemotherapy (p < 0.05).Chemotherapy plays an integral role in maximizing oncologic outcome for select patients with MBO. The data from this study are critical to optimizing multimodality care for these complex patients.

  View details for DOI 10.1245/s10434-021-09831-0

  View details for PubMedID 33829359

  View details for PubMedCentralID PMC8519893

• Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment. Nature communications Sun, H., Cao, S., Mashl, R. J., Mo, C. K., Zaccaria, S., Wendl, M. C., Davies, S. R., Bailey, M. H., Primeau, T. M., Hoog, J., Mudd, J. L., Dean, D. A., Patidar, R., Chen, L., Wyczalkowski, M. A., Jayasinghe, R. G., Rodrigues, F. M., Terekhanova, N. V., Li, Y., Lim, K. H., Wang-Gillam, A., Van Tine, B. A., Ma, C. X., Aft, R., Fuh, K. C., Schwarz, J. K., Zevallos, J. P., Puram, S. V., Dipersio, J. F., Davis-Dusenbery, B., Ellis, M. J., Lewis, M. T., Davies, M. A., Herlyn, M., Fang, B., Roth, J. A., Welm, A. L., Welm, B. E., Meric-Bernstam, F., Chen, F., Fields, R. C., Li, S., Govindan, R., Doroshow, J. H., Moscow, J. A., Evrard, Y. A., Chuang, J. H., Raphael, B. J., Ding, L. 2021; 12 (1): 5086

  Abstract

  Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs' recapitulation of human tumors.

  View details for DOI 10.1038/s41467-021-25177-3

  View details for PubMedID 34429404

  View details for PubMedCentralID PMC8384880

• Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nature genetics Woo, X. Y., Giordano, J., Srivastava, A., Zhao, Z. M., Lloyd, M. W., de Bruijn, R., Suh, Y. S., Patidar, R., Chen, L., Scherer, S., Bailey, M. H., Yang, C. H., Cortes-Sanchez, E., Xi, Y., Wang, J., Wickramasinghe, J., Kossenkov, A. V., Rebecca, V. W., Sun, H., Mashl, R. J., Davies, S. R., Jeon, R., Frech, C., Randjelovic, J., Rosains, J., Galimi, F., Bertotti, A., Lafferty, A., O'Farrell, A. C., Modave, E., Lambrechts, D., Ter Brugge, P., Serra, V., Marangoni, E., El Botty, R., Kim, H., Kim, J. I., Yang, H. K., Lee, C., Dean, D. A., Davis-Dusenbery, B., Evrard, Y. A., Doroshow, J. H., Welm, A. L., Welm, B. E., Lewis, M. T., Fang, B., Roth, J. A., Meric-Bernstam, F., Herlyn, M., Davies, M. A., Ding, L., Li, S., Govindan, R., Isella, C., Moscow, J. A., Trusolino, L., Byrne, A. T., Jonkers, J., Bult, C. J., Medico, E., Chuang, J. H. 2021; 53 (1): 86-99

  Abstract

  Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

  View details for DOI 10.1038/s41588-020-00750-6

  View details for PubMedID 33414553

  View details for PubMedCentralID PMC7808565

• Novel Targets in Melanoma: Intralesional and Combination Therapy to Manipulate the Immune Response. Surgical oncology clinics of North America Gingrich, A. A., Kirane, A. R. 2020; 29 (3): 467-483

  Abstract

  Clinical outcomes for metastatic melanoma have been dramatically altered by recent developments in immunotherapy and targeted strategies, but response to these therapies is not uniform, the majority of patients do not respond, and clinical response can be self-limited. Current directions in melanoma treatment aim to leverage a combination of therapies for tumors refractory to monoimmunotherapy, to include tumor-directed strategies, such as intralesional therapy and inhibitors designed for novel targets, which may augment current systemic agents when used in combination. Here, we summarize new classes of agents and emerging multimodal combination strategies that demonstrate significant promise in future melanoma management.

  View details for DOI 10.1016/j.soc.2020.02.012

  View details for PubMedID 32482321

• Elderly Age Is Associated With More Conservative Treatment of Invasive Melanoma. Anticancer research Bateni, S. B., Johns, A. J., Gingrich, A. A., Gholami, S., Bold, R. J., Canter, R. J., Kirane, A. R. 2020; 40 (5): 2895-2903

  Abstract

  Competing mortality risks complicate treatment of elderly melanoma patients potentially leading to conservative management, including no sentinel lymph node biopsy. As systemic immunotherapy offers justification for nodal evaluation, we examined treatment trends among elderly melanoma patients.We performed a National Cancer Database analysis of melanoma patients from 2004-2015. Patients were categorized by age (elderly ≥80-years-old). Multivariable logistic regression analyses were performed comparing characteristics and treatment by age.Of 187,814 patients, 2.7% were 1-25, 11.6% were 26-40, 46.6% were 41-64, 28.8% were 65-79, and 10.3% were ≥80-years-old with clinicopathologic and treatment differences between age cohorts. Nodal surgery was least common among elderly patients (43.1% vs. 60.7-69.8%, p<0.0001). For stage III, immunotherapy was least common among the elderly (p<0.0001), but associated with greater survival (HR=0.52, 95%CI=0.32-0.84, p=0.008).Elderly melanoma patients were often treated conservatively, including no nodal evaluation, concerning for the potential undertreatment of this population.

  View details for DOI 10.21873/anticanres.14266

  View details for PubMedID 32366440

• The Role of Palliative Surgery for Malignant Bowel Obstruction and Perforation in Advanced Microsatellite Instability-High Colorectal Carcinoma in the Era of Immunotherapy: Case Report. Frontiers in oncology Judge, S. J., Ji, J., Liu, J., Kaur, M., Kim, E., Gong, J., Tam, K. W., Kirane, A. R., Gholami, S., Canter, R. J., Bold, R. J., Gangi, A., Fakih, M., Cho, M. 2020; 10: 581

  Abstract

  The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors.

  View details for DOI 10.3389/fonc.2020.00581

  View details for PubMedID 32373540

  View details for PubMedCentralID PMC7186327

• Association of MRI T2 Signal Intensity With Desmoid Tumor Progression During Active Observation: A Retrospective Cohort Study. Annals of surgery Cassidy, M. R., Lefkowitz, R. A., Long, N., Qin, L. X., Kirane, A., Sbaity, E., Hameed, M., Coit, D. G., Brennan, M. F., Singer, S., Crago, A. M. 2020; 271 (4): 748-755

  Abstract

  The aim of this study was to identify predictors of desmoid progression during observation.Untreated desmoids can grow, remain stable, or regress, but reliable predictors of behavior have not been identified.Primary or recurrent desmoid patients were identified retrospectively from an institutional database. In those managed with active observation who underwent serial magnetic resonance imaging (MRIs) with T2-weighted sequences, baseline tumor size was recorded, and 2 radiologists independently estimated the percentage of tumor volume showing hyperintense T2 signal at baseline. Associations of clinical or radiographic characteristics with progression-free survival (PFS; by RECIST) were evaluated by Cox regression and Kaplan-Meier statistics.Among 160 patients with desmoids, 72 were managed with observation, and 37 of these had serial MRI available for review. Among these 37 patients, median age was 35 years and median tumor size was 4.7 cm; all tumors were extra-abdominal (41% in abdominal wall). Although PFS was not associated with size, site, or age, it was strongly associated with hyperintense T2 signal in ≥90% versus <90% of baseline tumor volume (as defined by the "test" radiologist; hazard ratio = 11.3, P = 0.003). For patients in the ≥90% group (n = 20), 1-year PFS was 55%, compared with 94% in the <90% group (n = 17). The percentage of baseline tumor volume with hyperintense T2 signal defined by a validation radiologist correlated with results of the test radiologist (ρ = 0.75).The percent tumor volume characterized by hyperintense T2 signal is associated with desmoid progression during observation and may help distinguish patients who would benefit from early intervention from those who may be reliably observed.

  View details for DOI 10.1097/SLA.0000000000003073

  View details for PubMedID 30418203

  View details for PubMedCentralID PMC6736761

• Advances in Modeling the Immune Microenvironment of Colorectal Cancer. Frontiers in immunology Yoon, P. S., Del Piccolo, N., Shirure, V. S., Peng, Y., Kirane, A., Canter, R. J., Fields, R. C., George, S. C., Gholami, S. 2020; 11: 614300

  Abstract

  Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment-including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature-are crucial for studies of immunity in the CRC TME and the utility of immunotherapies for CRC patients. We briefly review the discoveries, advantages, and disadvantages of current in vitro and in vivo model systems, including 2D cell culture models, 3D culture systems, murine models, and organ-on-a-chip technologies.

  View details for DOI 10.3389/fimmu.2020.614300

  View details for PubMedID 33643296

  View details for PubMedCentralID PMC7902698

• Morbidity, mortality and temporal trends in the surgical management of retroperitoneal sarcoma: An ACS-NSQIP follow up analysis. Journal of surgical oncology Judge, S. J., Lata-Arias, K., Yanagisawa, M., Darrow, M. A., Monjazeb, A. M., Kirane, A. R., Bold, R. J., Canter, R. J., Canter, D. J. 2019; 120 (4): 753-760

  Abstract

  Calls for multivisceral resection (MVR) of retroperitoneal sarcoma (RPS) are increasing, although the risks and benefits remain controversial. We sought to analyze current 30-day morbidity and mortality rates, and trends in utilization of MVR in a national database.Overall morbidity, severe morbidity, mortality rates, and temporal trends were analyzed utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP).From 2012 to 2015, a total of 564 patients underwent RPS resection with 233 patients (41%) undergoing MVR. The MVR group had a higher rate of preoperative weight loss and larger tumors overall. When comparing MVR to non-MVR, there was no significant difference in overall morbidity (22% vs 17%, P = .13), severe morbidity (11% vs 8%, P = .18), or mortality (<1% vs 2%, P = .25). On multivariate analysis, MVR was not associated with increased overall morbidity or severe morbidity. Mortality rates were too low for meaningful statistical analysis. Annual rates of MVR ranged from 37% to 46% with no significant change over time (P = .47).Short-term morbidity and mortality rates after MVR for RPS remain acceptable, but rates of MVR show little change over time in NSQIP hospitals. Concerns about increased morbidity and mortality should not be viewed as a contraindication to wider implementation of MVR for RPS.

  View details for DOI 10.1002/jso.25649

  View details for PubMedID 31355444

• Clinical Outcomes and Costs Following Unplanned Excisions of Soft Tissue Sarcomas in the Elderly. The Journal of surgical research Bateni, S. B., Gingrich, A. A., Jeon, S. Y., Hoch, J. S., Thorpe, S. W., Kirane, A. R., Bold, R. J., Canter, R. J. 2019; 239: 125-135

  Abstract

  Surgical guidelines for soft tissue sarcoma (STS) emphasize pretreatment evaluation and reports of the perils of unplanned excision exist. Given the paucity of population-based data on this topic, our objective was to analyze clinical outcomes and costs of planned versus unplanned STS excisions in the Medicare population.We analyzed 3913 surgical patients with STS ≥66 y old from 1992 to 2011 using the Surveillance, Epidemiology, and End Results-Medicare datafiles. Planned excisions were classified based on preoperative MRI and/or biopsy, whereas unplanned excisions were classified by excision as the first procedure. Inverse probability of treatment weighting with propensity scores was used to adjust for clinicopathologic differences. Re-excisions, complications, and Medicare payments were compared with multivariate models. Overall survival and disease-specific survival were analyzed using Cox proportional hazards and competing risk models.Before the first excision, 24.3% had an MRI and biopsy, 27.3% had an MRI, 11.4% had a biopsy, and 36.9% were unplanned. Re-excision rates were highest for unplanned excisions: 46.3% compared to 18.1%, 36.4%, and 29.7% for other groups (P < 0.0001). There was no difference in disease-specific survival or overall survival between groups (P > 0.05). Planned excisions were associated with increased Medicare costs (P < 0.05), with the first resection contributing to the majority of costs. Subgroup analyses by histologic grade and tumor size revealed similar results.Survival was comparable with greater health care costs in elderly patients undergoing planned STS excision. Although unplanned excisions remain a quality of care issue with high re-excision rates, these data have important implications for the surgical management of STS in the elderly.

  View details for DOI 10.1016/j.jss.2019.01.055

  View details for PubMedID 30825757

  View details for PubMedCentralID PMC6488355

• Extremity soft tissue sarcoma in the elderly: Are we overtreating or undertreating this potentially vulnerable patient population? Journal of surgical oncology Gingrich, A. A., Bateni, S. B., Monjazeb, A. M., Thorpe, S. W., Kirane, A. R., Bold, R. J., Canter, R. J. 2019; 119 (8): 1087-1098

  Abstract

  As the U.S. population ages, differences in oncologic outcomes among the elderly have been recognized. Our objective was to analyze the clinical, pathologic, and treatment outcomes for elderly soft tissue sarcoma (STS) patients, hypothesizing significant differences in the management and response to therapy.Using the National Cancer Database, we identified 33 859 patients with nonmetastatic extremity STS. We defined elderly as ≥74 years in age and compared patient and treatment variables between adult and elderly patients. Cox-proportional hazards analysis was used to determine predictors of overall survival (OS).We identified 8504 elderly patients. Significant differences in histologic subtype, grade, and facility type between elderly and nonelderly patients (P < 0.05) exist. Elderly patients were less likely to undergo R0 resection (P = 0.001) and had a higher 90-day mortality (P = 0.001). Surgical elderly patients experienced superior OS compared with nonsurgical patients (P = 0.001). Among elderly patients, younger age, and female sex, lower Charlson-Deyo score, lower grade, smaller tumors, surgical resection, negative surgical margins, and radiation therapy were associated with better OS.Key differences exist in elderly extremity STS patients, including a narrower benefit/risk ratio with surgical management. These data highlight that elderly patients represent a distinct cohort for whom more careful selection appears indicated.

  View details for DOI 10.1002/jso.25470

  View details for PubMedID 30977916

• Role of Radiation Therapy in Adult Extraskeletal Ewing's Sarcoma Patients Treated with Chemotherapy and Surgery. Sarcoma Saiz, A. M., Gingrich, A. A., Canter, R. J., Kirane, A. R., Monjazeb, A. M., Randall, R. L., Thorpe, S. W. 2019; 2019: 5413527

  Abstract

  Radiation therapy (RT) is advocated in the multimodal treatment of high-grade soft tissue sarcoma (STS), but its role may be less clear in chemotherapy-sensitive STS such as extraskeletal Ewing sarcoma (EES). The purpose of this study was to determine the role of RT on overall survival (OS) in localized EES adult patients treated with chemotherapy and surgery. Adult patients diagnosed with EES and reported to the National Cancer Database from 2004 to 2014 were evaluated. All patients were treated with surgical resection. Patient demographics, tumor characteristics, treatments received, resection margins, and survival were examined for the 232 patients identified. Using multivariate analysis and Cox proportional hazard analysis, predictors of OS were determined. In the overall cohort, 40 percent of patients received RT and 78 percent received chemotherapy, with 31 percent receiving both. The addition of RT to the patients receiving surgery + chemotherapy did not improve OS (p < 0.05). Twenty-four percent of patients who achieved R0 resection after surgery still received RT without any improvement in OS. Patients treated at community cancer centers were more likely to receive additional RT compared with Comprehensive Cancer Centers (p < 0.05). In adult EES patients with localized disease treated with chemotherapy and surgery, the addition of RT does not improve overall survival.

  View details for DOI 10.1155/2019/5413527

  View details for PubMedID 31178655

  View details for PubMedCentralID PMC6507246

• Tumor Symbiosis: Gastrointestinal Stromal Tumor as a Host for Primary Peritoneal Mesothelioma. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract de la Torre, J., Banerjee, S., Baumgartner, J., Lin, G. Y., Burgoyne, A. M., Kirane, A., Sicklick, J. 2019; 23 (4): 879-881

  View details for DOI 10.1007/s11605-018-3918-3

  View details for PubMedID 30132292

  View details for PubMedCentralID PMC6384158

• Cyclooxygenase-2 Inhibition Potentiates the Efficacy of Vascular Endothelial Growth Factor Blockade and Promotes an Immune Stimulatory Microenvironment in Preclinical Models of Pancreatic Cancer. Molecular cancer research : MCR Zhang, Y., Kirane, A., Huang, H., Sorrelle, N. B., Burrows, F. J., Dellinger, M. T., Brekken, R. A. 2019; 17 (2): 348-355

  Abstract

  Resistance to standard therapy remains a major challenge in the treatment of pancreatic ductal adenocarcinoma (PDA). Although anti-VEGF therapy delays PDA progression, therapy-induced hypoxia results in a less differentiated mesenchymal-like tumor cell phenotype, which reinforces the need for effective companion therapies. COX-2 inhibition has been shown to promote tumor cell differentiation and improve standard therapy response in PDA. Here, we evaluate the efficacy of COX-2 inhibition and VEGF blockade in preclinical models of PDA. In vivo, the combination therapy was more effective in limiting tumor growth and metastasis than single-agent therapy. Combination therapy also reversed anti-VEGF-induced epithelial-mesenchymal transition and collagen deposition and altered the immune landscape by increasing tumor-associated CD8+ T cells while reducing FoxP3+ T cells and FasL expression on the tumor endothelium. IMPLICATIONS: Together, these findings demonstrate that COX-2 inhibition enhances the efficacy of anti-VEGF therapy by reducing hypoxia-induced epithelial plasticity and promoting an immune landscape that might facilitate immune activation.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/2/348/F1.large.jpg.

  View details for DOI 10.1158/1541-7786.MCR-18-0427

  View details for PubMedID 30333153

  View details for PubMedCentralID PMC6359969

• Serum C-reactive Protein and Neutrophil/Lymphocyte Ratio After Neoadjuvant Radiotherapy in Soft Tissue Sarcoma. Anticancer research Yanagisawa, M., Gingrich, A. A., Judge, S., Li, C. S., Wang, N., Thorpe, S. W., Kirane, A. R., Bold, R. J., Monjazeb, A. M., Canter, R. J. 2018; 38 (3): 1491-1497

  Abstract

  The predictive value of serum C-reactive protein (CRP) and neutrophil/lymphocyte (N/L) ratio in soft tissue sarcoma (STS) patients receiving neoadjuvant radiotherapy (RT) has not been analyzed.From 2007 to 2015, we identified 98 STS patients from a prospective database. Using multivariate analysis, we analyzed CRP and N/L ratios as predictors of overall survival (OS).Mean age of patients was 59 years, 46% were female, and 55% of tumors were located at the extremity. A total of 15 histologies were represented. Fifty percent received preoperative RT. Except for extremity location, characteristics were similar between the preoperative RT and upfront surgery cohorts, including baseline CRP levels and N/L ratios. Multivariate analysis of upfront surgery revealed histological grade, tumor size, and baseline N/L ratio to be predictors of OS, while for preoperative RT, baseline CRP and N/L ratio were not predictive.Baseline CRP and N/L ratio did not predict poor clinical outcome in STS patients receiving neoadjuvant RT.

  View details for DOI 10.21873/anticanres.12376

  View details for PubMedID 29491077

  View details for PubMedCentralID PMC5836802

• T Cells Dominate the Local Immune Response Induced by Intralesional IL-2 in Combination with Imiquimod and Retinoid for In-Transit Metastatic Melanoma. The Journal of investigative dermatology Ogawa, H. n., Luxardi, G. n., Kirane, A. n., Kulkarni, R. n., Monjazeb, A. M., Cheng, M. Y., Ma, C. n., Maverakis, E. n. 2018; 138 (6): 1442–45

  View details for DOI 10.1016/j.jid.2017.12.027

  View details for PubMedID 29291382

• Size and Location are the Most Important Risk Factors for Malignant Behavior in Resected Solitary Fibrous Tumors. Annals of surgical oncology Gholami, S., Cassidy, M. R., Kirane, A., Kuk, D., Zanchelli, B., Antonescu, C. R., Singer, S., Brennan, M. 2017; 24 (13): 3865-3871

  Abstract

  While previously thought to be clinically indolent, recent data suggest significant late metastatic capacity of solitary fibrous tumors (SFTs). We define prognostic factors for recurrence and disease-specific death (DSD) in resected primary SFTs.Resected primary SFTs from 1982 to 2015 were identified from a prospective, single institutional database. Risk factors for local (LR) and distant recurrence (DR), and DSD were assessed using competing risk analysis.A total of 219 patients with median follow-up of 6.1 (0.1-22) years were included. Five- and 10-year cumulative DSD was 9 and 11%, respectively. Size greater than the median 8 cm, gender, location, and complete gross resection were significantly associated with DSD (p < 0.05). Five- and 10-year cumulative risk (CR) of LR was 4 and 7%, whereas 5- and 10-year CR of DR was 13 and 16%, respectively. LR was associated with location (p = 0.02) and tumor size (p = 0.02), and DR was associated with size (p < 0.01). Histopathologic classification did not predict long-term behavior with both malignant and benign tumors demonstrating capacity for DR and associated death. Tumors in the thoracic cavity and abdomen/retroperitoneum presented the greatest risk of DR (16 and 27% 10-year CR). On multivariate analysis, size ≥ 8 cm (hazard ratio 2.89, p = 0.05) and tumor location in chest or abdominal/retroperitoneal cavity (hazard ratio 2.68, p = 0.01) significantly impacted DSD.Recurrence is highly associated with DSD and events occur as late as 16 years after initial presentation, including in patients with initially considered benign tumors. Patients with large (≥ 8 cm) tumors in the chest or abdominal/retroperitoneal cavity are at greatest risk.

  View details for DOI 10.1245/s10434-017-6092-z

  View details for PubMedID 29039030

• Neoadjuvant Radiotherapy is Associated with R0 Resection and Improved Survival for Patients with Extremity Soft Tissue Sarcoma Undergoing Surgery: A National Cancer Database Analysis. Annals of surgical oncology Gingrich, A. A., Bateni, S. B., Monjazeb, A. M., Darrow, M. A., Thorpe, S. W., Kirane, A. R., Bold, R. J., Canter, R. J. 2017; 24 (11): 3252-3263

  Abstract

  Neoadjuvant radiotherapy (RT) is increasingly advocated for the management of soft tissue sarcoma (STS). Therefore, this study sought to characterize the impact of neoadjuvant RT on rates of R0 resection and overall survival (OS) in extremity STS patients undergoing surgery.From January 2003 to December 2012, the study identified patients with a diagnosis of extremity STS from the National Cancer Database. After exclusion of patients younger than 18 years, not treated by surgery, who had metastases at diagnosis, intraoperative RT, and missing or unknown data, 27,969 patients were identified. Logistic regression and Cox-proportional hazard analysis were used to compare rates of R0 resection among preoperative, postoperative, and no-RT cohorts and to determine predictors of R0 resection and OS.The mean age of the patients was 59.5 ± 17.1 years, and 45.9% were female. The median tumor size was 10.5 cm. The data showed that 51% of the patients did not receive RT, 11.8% received preoperative RT, and 37.2% received postoperative RT. The rates of R0 resection were 90.1% for the preoperative RT cohort, 74.9% for the postoperative RT cohort, and 79.9% for the no-RT cohort (P < 0.001). The independent predictors for achievement of R0 resection included academic facility type (odds ratio [OR] 1.36; 95% confidence interval [CI] 1.20-1.55), histologic subtype, tumor size (OR 0.99; 95% CI 0.99-0.99), Charlson score (OR 0.92; 95% CI 0.84-0.99), and preoperative RT (OR 1.83; 95% CI 1.61-2.07). Both R0 resection and RT (pre- or post-operative) were associated with increased OS.Preoperative RT independently predicts higher rates of R0 resection for patients with extremity STS undergoing surgical resection. Negative surgical margins and pre- or postoperative RT are associated with improved OS.

  View details for DOI 10.1245/s10434-017-6019-8

  View details for PubMedID 28741123

  View details for PubMedCentralID PMC5693726

• The modified frailty index to predict morbidity and mortality for retroperitoneal sarcoma resections. The Journal of surgical research Park, J. S., Bateni, S. B., Bold, R. J., Kirane, A. R., Canter, D. J., Canter, R. J. 2017; 217: 191-197

  Abstract

  The modified frailty index (mFI) is an important method to risk-stratify surgical patients and has been validated for general surgery and selected surgical subspecialties. However, there are currently no data assessing the efficacy of the mFI to predict acute morbidity and mortality in patients undergoing surgery for retroperitoneal sarcoma.Using the American College of Surgeons' National Surgical Quality Improvement Program from 2007 to 2012, we performed a retrospective analysis of patients with a diagnosis of primary malignant retroperitoneal neoplasm who underwent surgical resection. The mFI was calculated according to standard published methods. Univariate and multivariate statistical analyses including χ2 and logistic regression were used to identify predictors of 30-d overall morbidity, 30-d severe morbidity (Clavien III/IV), and 30-d mortality.We identified 846 patients with the diagnosis of primary malignant retroperitoneal neoplasm who underwent surgical resection. The distribution mFI scores was 0 (48.5%) or 1 (36.3%), with only 4.5% of patients presenting with a score ≥3. Rates of 30-d overall morbidity, serious morbidity, and mortality were 22.6%, 12.9%, and 1.2%, respectively. Only selected mFI scores were associated with serious morbidity and overall morbidity on multivariate analysis (P < 0.05), and mFI did not predict 30-d mortality (P > 0.05).Our data demonstrate that the majority of patients undergoing retroperitoneal sarcoma resections have few, if any, comorbidities. The mFI was a limited predictor of overall and serious complications and was not a significant predictor of mortality. Better discriminators of preoperative risk stratification may be needed for this patient population.

  View details for DOI 10.1016/j.jss.2017.05.025

  View details for PubMedID 28587892

  View details for PubMedCentralID PMC5603411

• The importance of surgical margins in retroperitoneal sarcoma. Journal of surgical oncology Kirane, A., Crago, A. M. 2016; 113 (3): 270-6

  Abstract

  Surgery is the "gold-standard" treatment for retroperitoneal sarcomas, but local recurrence is common, and can cause disease-related death. Complete gross resection is associated with improved survival, but debate exists as to whether resection of adjacent organs to improve margins or prescription of neoadjuvant radiation leads to better outcomes. This review summarizes data addressing prognostic value of margin, extent of surgery necessary to optimize treatment of retroperitoneal sarcomas, and role of histology in optimizing therapy.

  View details for DOI 10.1002/jso.24135

  View details for PubMedID 26707028

• Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis. Cancer research Kirane, A., Ludwig, K. F., Sorrelle, N., Haaland, G., Sandal, T., Ranaweera, R., Toombs, J. E., Wang, M., Dineen, S. P., Micklem, D., Dellinger, M. T., Lorens, J. B., Brekken, R. A. 2015; 75 (18): 3699-705

  Abstract

  Repurposing "old" drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors.

  View details for DOI 10.1158/0008-5472.CAN-14-2887-T

  View details for PubMedID 26206560

  View details for PubMedCentralID PMC4572915

• Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Kirane, A., Toombs, J. E., Ostapoff, K., Carbon, J. G., Zaknoen, S., Braunfeld, J., Schwarz, R. E., Burrows, F. J., Brekken, R. A. 2012; 18 (18): 5031-42

  Abstract

  COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/erlotinib in preclinical models of pancreatic cancer.Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib ± standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined.COX-2 inhibition reduced the IC(50) of gemcitabine ± erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression.Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer.

  View details for DOI 10.1158/1078-0432.CCR-12-0453

  View details for PubMedID 22829202

  View details for PubMedCentralID PMC3777527

• Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib. Carcinogenesis Kirane, A., Toombs, J. E., Larsen, J. E., Ostapoff, K. T., Meshaw, K. R., Zaknoen, S., Brekken, R. A., Burrows, F. J. 2012; 33 (9): 1639-46

  Abstract

  Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 µM and remained sufficient to completely inhibit prostaglandin E(2) production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity.

  View details for DOI 10.1093/carcin/bgs195

  View details for PubMedID 22678114

  View details for PubMedCentralID PMC3514897

• Intraduodenal sarcoma recurrence of retroperitoneal origin: an unusual cause for a duodenal obstruction. World journal of surgical oncology Bao, J. J., Mansour, J. C., Timmerman, R. D., Kirane, A., Ewing, G. E., Schwarz, R. E. 2012; 10: 59

  Abstract

  Soft tissue sarcomas are uncommon tumors, and intraduodenal soft tissue sarcoma manifestation is even more rare. Only three cases of intraduodenal sarcomas have been reported in the literature thus far. Here, we report a case of an intraduodenal recurrence of a retroperitoneal sarcoma causing bowel obstruction. This unusual recurrence pattern likely relates to the patient's previous resection and radiation treatment, and highlights the benefits, limitations and follow-up strategies after multimodality treatment.

  View details for DOI 10.1186/1477-7819-10-59

  View details for PubMedID 22520024

  View details for PubMedCentralID PMC3478974

• Smac mimetic-derived augmentation of chemotherapeutic response in experimental pancreatic cancer. BMC cancer Awasthi, N., Kirane, A., Schwarz, M. A., Toombs, J. E., Brekken, R. A., Schwarz, R. E. 2011; 11: 15

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy, in part due to the overexpression of inhibitors of apoptosis proteins (IAPs). Smac is an endogenous IAP-antagonist, which renders synthetic Smac mimetics attractive anticancer agents. We evaluated the benefits of combining a Smac mimetic, JP1201 (JP), with conventional chemotherapy agents used for PDAC management.Cell viability assays and protein expression analysis were performed using WST-1 reagent and Western blotting, respectively. Apoptosis was detected by annexin V/propidium iodide staining. In vivo tumor growth and survival studies were performed in murine PDAC xenografts.JP and gemcitabine (Gem) inhibited PDAC cell proliferation with additive effects in combination. The percentage of early apoptotic cells in controls, JP, Gem and JP + Gem was 17%, 26%, 26% and 38%, respectively. JP-induced apoptosis was accompanied by PARP-1 cleavage. Similar additive anti-proliferative effects were seen for combinations of JP with doxorubicin (Dox) and docetaxel (DT). The JP + Gem combination caused a 30% decrease in tumor size in vivo compared to controls. Median animal survival was improved significantly in mice treated with JP + Gem (38 d) compared to controls (22 d), JP (28 d) or Gem (32 d) (p = 0.01). Animal survival was also improved with JP + DT treatment (32 d) compared to controls (16 d), JP (21 d) or DT alone (27 d).These results warrant further exploration of strategies that promote chemotherapy-induced apoptosis of tumors and highlight the potential of Smac mimetics in clinical PDAC therapy.

  View details for DOI 10.1186/1471-2407-11-15

  View details for PubMedID 21226944

  View details for PubMedCentralID PMC3034706