Michael S Binkley, MD, MS

All Publications

• Investigating the tissue specificity and prognostic impact of cis-regulatory cancer risk variants. Human genetics Subramanian, A., Su, S., Moding, E. J., Binkley, M. S. 2023

  Abstract

  The tissue-specific incidence of cancers and their genetic basis are poorly understood. Although prior studies have shown global correlation across tissues for cancer risk single-nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS), any shared functional regulation of gene expression on a per SNP basis has not been well characterized. We set to quantify cis-mediated gene regulation and tissue sharing for SNPs associated with eight common cancers. We identify significant tissue sharing for individual SNPs and global enrichment for breast, colorectal, and Hodgkin lymphoma cancer risk SNPs in multiple tissues. In addition, we observe increasing tissue sharing for cancer risk SNPs overlapping with super-enhancers for breast cancer and Hodgkin lymphoma providing further evidence of tissue specificity. Finally, for genes under cis-regulation by breast cancer SNPs, we identify a phenotype characterized by low expression of tumor suppressors and negative regulators of the WNT pathway associated with worse freedom from progression and overall survival in patients who eventually develop breast cancer. Our results introduce a paradigm for functionally annotating individual cancer risk SNPs and will inform the design of future translational studies aimed to personalize assessment of inherited cancer risk across tissues.

  View details for DOI 10.1007/s00439-023-02586-6

  View details for PubMedID 37474751

  View details for PubMedCentralID 7388212

• KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer discovery Binkley, M. S., Jeon, Y. J., Nesselbush, M. n., Moding, E. J., Nabet, B. Y., Almanza, D. n., Kunder, C. n., Stehr, H. n., Yoo, C. H., Rhee, S. n., Xiang, M. n., Chabon, J. J., Hamilton, E. n., Kurtz, D. M., Gojenola, L. n., Owen, S. G., Ko, R. B., Shin, J. H., Maxim, P. G., Lui, N. S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M. n., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. n. 2020

  Abstract

  Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

  View details for DOI 10.1158/2159-8290.CD-20-0282

  View details for PubMedID 33071215

• Stage I-II Nodular Lymphocyte-Predominant Hodgkin Lymphoma: a Multi-institutional Experience of Adult Patients by ILROG. Blood Binkley, M. S., Rauf, M. S., Milgrom, S. A., Pinnix, C. C., Tsang, R. W., Dickinson, M. n., Ng, A. n., Roberts, K. B., Gao, S. n., Balogh, A. G., Ricardi, U. n., Levis, M. n., Casulo, C. n., Stolten, M. n., Specht, L. n., Plastaras, J. P., Wright, C. n., Kelsey, C. R., Brady, J. L., Mikhaeel, N. G., Hoppe, B. S., Terezakis, S. n., Picardi, M. n., Della Pepa, R. n., Kirova, Y. n., Akhtar, S. n., Maghfoor, I. n., Koenig, J. L., Jackson, C. n., Song, E. n., Sehgal, S. n., Advani, R. n., Natkunam, Y. n., Constine, L. S., Eich, H. T., Wirth, A. n., Hoppe, R. T. 2020

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment for stage I-II NLPHL is undefined. We conducted a multi-center retrospective study including patients ≥16 years with stage I-II NLPHL diagnosed from 1995-2018 receiving all forms of management including radiotherapy (RT), combined modality therapy (CMT=RT+chemotherapy), chemotherapy (CT), observation after excision, rituximab and RT, and single agent rituximab (R). End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age 39 years, 72.3% being male, and 54.9% having stage I disease. Median follow up was 5.5 years (IQR=3.1-10.1). 5-year PFS and OS for the entire cohort were 87.1% (95%CI=83.6-90.0%) and 98.3% (95%CI=96.4-99.2%), respectively. Primary management was RT alone (n=257, 46.0%), CMT (n=184, 32.9%), CT alone (n=47, 8.4%), observation (n=37, 6.6%), rituximab and RT (n=19, 3.4%), and rituximab alone (n=15, 2.7%). 5-year PFS rates were 91.1% (95%CI=85.3-94.7%) after RT, 90.5% (95%CI=84.8-94.1%) after CMT, 77.8% (95%CI=61.3-88.0%) after chemotherapy, 73.5% (95%CI=50.6-87.0%) after observation, 80.8% (95%CI=41.0-95.1%) after rituximab and RT, and 38.5% (95%CI=14.0-62.8%) after rituximab alone. For the RT cohort but not the CMT cohort, variant immunoarchitectural pattern and number of sites>2 were associated with worse PFS (P<0.05). Overall, 21 patients (3.8%) developed large cell transformation, with a significantly higher transformation rate for those with variant immunoarchitectural pattern (P=0.049) and number of involved sites >2 (P=0.0006). OS for patients with stage I-II NLPHLwas excellent following all managements.

  View details for DOI 10.1182/blood.2019003877

  View details for PubMedID 32211877

• Salvage treatment and survival for relapsed follicular lymphoma following primary radiotherapy: A collaborative study on behalf of ILROG. International journal of radiation oncology, biology, physics Binkley, M. S., Brady, J. L., Hajj, C., Chelius, M., Chau, K., Balogh, A., Levis, M., Filippi, A. R., Jones, M., Ahmed, S., MacManus, M., Wirth, A., Oguchi, M., Vistisen, A. K., Andraos, T. Y., Ng, A., Aleman, B. M., Choi, S. H., Kirova, Y., Hardy, S., Reinartz, G., Eich, H., Bratman, S., Constine, L. S., Suh, C., Dabaja, B., El-Galaly, T., Hodgson, D., Ricardi, U., Yahalom, J., Mikhaeel, N. G., Hoppe, R. T. 2019

  Abstract

  PURPOSE/OBJECTIVE(S): We previously reported 30% of patients with localized follicular lymphoma (FL) staged by 18F-FDG-PET-CT (PET-CT) receiving primary radiotherapy (RT) will relapse within 5 years. We sought to report outcomes for those who relapsed.MATERIALS/METHODS: We conducted a multicenter retrospective study of patients who received RT≥24Gy for stage I-II FL grade 1-3A FL, with age≥18 years, and PET-CT staging. Observation was defined as >6 months without treatment from relapse. Overall survival (OS) and freedom from progression (FFP) were estimated with Kaplan-Meier, and uni- and multivariable analyses (MVA) with Cox regression.RESULTS: Of 512 patients with median follow up of 52 months, 149 (29.1%) developed recurrent lymphoma at a median 23 months (range, 1-143) after primary RT. Median follow up was 33 months post relapse. 3-year OS was 91.4% after recurrence. OS was significantly worse for those with relapse ≤12 months from date of diagnosis versus all others, 88.7% versus 95.8%, respectively (p=0.01), and remained significantly worse on MVA (FLIPI-adjusted HR=3.61, p=0.009). Histology at relapse included: 93 indolent (grade 1-3A), 3 FL grade 3B/NOS, 18 diffuse large B-cell lymphoma (DLBCL); 35 patients were not biopsied. Of those with follow up ≥3 months and biopsied (n=74) or presumed (n=23) indolent recurrence, 58 patients (59.8%) were observed, 19 (19.6%) had systemic therapy, 16 (16.5%) RT, and 4 (4.1%) systemic therapy+RT. For patients with indolent recurrences that were observed, 3-year FFP or freedom from treatment was 56.6% (median, 48 months). For all patients with biopsied/presumed indolent recurrence receiving salvage treatment (n=59, including 20 initially observed) 3-year FFP was 73.9%.CONCLUSIONS: Prognosis for patients with relapsed FL following primary radiotherapy is excellent supporting the role of primary radiation in the management of early stage disease. Patients with localized FL treated with primary RT who experience early relapse (<12 months) have inferior survival to those with longer disease-free interval.

  View details for PubMedID 30858143

• Definitive radiotherapy for localized follicular lymphoma staged by F-18-FDG PET-CT: a collaborative study by ILROG BLOOD Brady, J. L., Binkley, M. S., Hajj, C., Chelius, M., Chau, K., Balogh, A., Levis, M., Filippi, A., Jones, M., Mac Manus, M., Wirth, A., Oguchi, M., Vistisen, A., Andraos, T., Ng, A. K., Aleman, B. P., Choi, S., Kirova, Y., Hardy, S., Reinartz, G., Eich, H. T., Bratman, S. V., Constine, L. S., Suh, C., Dabaja, B., El-Galaly, T. C., Hodgson, D. C., Ricardi, U., Yahalom, J., Hoppe, R. T., Mikhaeel, G. 2019; 133 (3): 237–45

  View details for DOI 10.1182/blood-2018-04-843540

  View details for Web of Science ID 000456614700011

• Lisocabtagene maraleucel for treatment of relapsed and refractory primary mediastinal large B-cell lymphoma in an adolescent patient. EJHaem Lee, D., Goyal, A., Wang, W. L., Ananth, S., Lau, E., Binkley, M. S., Bharadwaj, S., Dahiya, S. 2024; 5 (1): 153-156

  Abstract

  The safety and efficacy of CAR T-cell therapy are unknown in pediatric and adolescent patients with relapsed or refractory primary mediastinal large B-cell lymphoma (R/R PMBCL) which is associated with dismal prognosis. Here, we present a case report of a 16-year-old patient with R/R PMBCL treated with lisocabtagene maraleucel including correlative studies. Patient achieved complete response at 6 months without cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. She only experienced mild cytopenias, requiring filgrastim once. This report highlights the safety and efficacy of lisocabtagene maraleucel in this population, warranting prospective studies to improve clinical outcomes.

  View details for DOI 10.1002/jha2.859

  View details for PubMedID 38406546

• Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling. Nature Alig, S. K., Esfahani, M. S., Garofalo, A., Li, M. Y., Rossi, C., Flerlage, T., Flerlage, J. E., Adams, R., Binkley, M. S., Shukla, N., Jin, M. C., Olsen, M., Telenius, A., Mutter, J. A., Schroers-Martin, J. G., Sworder, B. J., Rai, S., King, D. A., Schultz, A., Bögeholz, J., Su, S., Kathuria, K. R., Liu, C. L., Kang, X., Strohband, M. J., Langfitt, D., Pobre-Piza, K. F., Surman, S., Tian, F., Spina, V., Tousseyn, T., Buedts, L., Hoppe, R., Natkunam, Y., Fornecker, L. M., Castellino, S. M., Advani, R., Rossi, D., Lynch, R., Ghesquières, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., André, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. 2023

  Abstract

  The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells hamper tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). Liquid biopsies, in contrast, show promise for molecular profiling of cHL due to relatively high circulating tumor DNA (ctDNA) levels1-4. Here, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate HRS ctDNA shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, using PhasED-Seq5 we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential.

  View details for DOI 10.1038/s41586-023-06903-x

  View details for PubMedID 38081297

• Predicting Adverse Cardiac Events After Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer. JACC. CardioOncology No, H. J., Guo, F. B., Park, N. J., Kastelowitz, N., Rhee, J. W., Clark, D. E., Chin, A. L., Vitzthum, L. K., Horst, K. C., Moding, E. J., Loo, B. W., Diehn, M., Binkley, M. S. 2023; 5 (6): 775-787

  Abstract

  Radiotherapy may cause grade ≥3 cardiac events, necessitating a better understanding of risk factors. The potential predictive role of imaging biomarkers with radiotherapy doses for cardiac event occurrence has not been studied.The aim of this study was to establish the associations between cardiac substructure dose and coronary artery calcium (CAC) scores and cardiac event occurrence.A retrospective cohort analysis included patients with locally advanced non-small cell lung cancer treated with radiotherapy (2006-2018). Cardiac substructures, including the left anterior descending coronary artery, left main coronary artery, left circumflex coronary artery, right coronary artery, and TotalLeft (left anterior descending, left main, and left circumflex coronary arteries), were contoured. Doses were measured in 2-Gy equivalent units, and visual CAC scoring was compared with automated scoring. Grade ≥3 adverse cardiac events were recorded. Time-dependent receiver-operating characteristic modeling, the log-rank statistic, and competing-risk models were used to measure prediction performance, threshold modeling, and the cumulative incidence of cardiac events, respectively.Of the 233 eligible patients, 61.4% were men, with a median age of 68.1 years (range: 34.9-90.7 years). The median follow-up period was 73.7 months (range: 1.6-153.9 months). Following radiotherapy, 22.3% experienced cardiac events, within a median time of 21.5 months (range: 1.7-118.9 months). Visual CAC scoring showed significant correlation with automated scoring (r = 0.72; P < 0.001). In a competing-risk multivariable model, TotalLeft volume receiving 15 Gy (per 1 cc; HR: 1.38; 95% CI: 1.11-1.72; P = 0.004) and CAC score >5 (HR: 2.51; 95% CI: 1.08-5.86; P = 0.033) were independently associated with cardiac events. A model incorporating age, TotalLeft CAC (score >5), and volume receiving 15 Gy demonstrated a higher incidence of cardiac events for a high-risk group (28.9%) compared with a low-risk group (6.9%) (P < 0.001).Adverse cardiac events associated with radiation occur in more than 20% of patients undergoing thoracic radiotherapy within a median time of <2 years. The present findings provide further evidence to support significant associations between TotalLeft radiotherapy dose and cardiac events and define CAC as a predictive risk factor.

  View details for DOI 10.1016/j.jaccao.2023.08.007

  View details for PubMedID 38205000

  View details for PubMedCentralID PMC10774791

• Genomic, Transcriptional, and Immunological Validation of Distinct Molecular Subtypes of Classic Hodgkin Lymphoma through Tissue-Based and Noninvasive Methods Alig, S. K., Esfahani, M., Garofalo, A., Li, M., Rossi, C., Flerlage, T., Flerlage, J. E., Adams, R., Binkley, M. S., Shukla, N., Jin, M., Olsen, M., Telenius, A., Mutter, J. A., Schroers-Martin, J., Sworder, B. J., Rai, S., King, D., Schultz, A., Bogeholz, J., Su, S., Kathuria, K. R., Liu, C., Kang, X., Langfitt, D. M., Pobre-Piza, K., Tian, F., Strohband, M. J., Spina, V., Tousseyn, T., Buedts, L., Fornecker, L., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Ghesquieres, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186810

  View details for Web of Science ID 001159306700178

• Inferred Gene Expression By Cell-Free DNA Profiling Allows Noninvasive Lymphoma Classification Mutter, J. A., Esfahani, M., Schroers-Martin, J., Alig, S. K., Hamilton, M. P., Sworder, B. J., Tessoulin, B., Boegeholz, J., Flerlage, T., Flerlage, J. E., Binkley, M. S., Sugio, T., Rossi, C., Olsen, M., Liu, C., Le Gouill, S., Kurtz, D. M., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186853

  View details for Web of Science ID 001159306701002

• Analysis of PET-CT Derived Radiomic Biomarkers with Efficacy, Safety, and Expansion of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL) Bharadwaj, S., Lau, E., Hashmi, A., Hamilton, M. P., Jensen, A., Goyal, A., Marar, M., Lee, C., Ananth, S., Sahaf, B., Mallampet, J., Ehlinger, Z., Syal, S., Patil, S., Guo, H., Smith, M., Weng, W., Frank, M. J., Binkley, M. S., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187617

  View details for Web of Science ID 001159306708098

• The pathobiology of select adolescent young adult lymphomas. EJHaem Steidl, C., Kridel, R., Binkley, M., Morton, L. M., Chadburn, A. 2023; 4 (4): 892-901

  Abstract

  Lymphoid cancers are among the most frequent cancers diagnosed in adolescents and young adults (AYA), ranging from approximately 30%-35% of cancer diagnoses in adolescent patients (age 10-19) to approximately 10% in patients aged 30-39 years. Moreover, the specific distribution of lymphoid cancer types varies by age with substantial shifts in the subtype distributions between pediatric, AYA, adult, and older adult patients. Currently, biology studies specific to AYA lymphomas are rare and therefore insight into age-related pathogenesis is incomplete. This review focuses on the paradigmatic epidemiology and pathogenesis of select lymphomas, occurring in the AYA patient population. With the example of posttransplant lymphoproliferative disorders, nodular lymphocyte-predominant Hodgkin lymphoma, follicular lymphoma (incl. pediatric-type follicular lymphoma), and mediastinal lymphomas (incl. classic Hodgkin lymphoma, primary mediastinal large B cell lymphoma and mediastinal gray zone lymphoma), we here illustrate the current state-of-the-art in lymphoma classification, recent molecular insights including genomics, and translational opportunities. To improve outcome and quality of life, international collaboration in consortia dedicated to AYA lymphoma is needed to overcome challenges related to siloed biospecimens and data collections as well as to develop studies designed specifically for this unique population.

  View details for DOI 10.1002/jha2.785

  View details for PubMedID 38024596

  View details for PubMedCentralID PMC10660115

• Treatment Approaches for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Clinical lymphoma, myeloma & leukemia Binkley, M. S., Advani, R. H. 2023

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare variant of Hodgkin lymphoma characterized by a persistent risk of relapse but an excellent overall survival. Historically, it was treated similarly to classic Hodgkin lymphoma, but efforts have been made to deintensify treatment due to risk of late toxicity associated with intensive therapy. For patients with completely resected stage IA NLPHL, no further treatment may be considered, particularly for pediatric patients. For those with stage I-II NLPHL without risk factors such as B symptoms, sites>2, or variant pattern histology, lower intensity treatment with radiotherapy or chemotherapy alone may be sufficient. However, combined modality therapy is a standard treatment for favorable and unfavorable risk stage I-II NLPHL associated with excellent progression-free and overall survival rates. For patients with advanced stage NLPHL, the optimal chemotherapy is not defined, but R-CHOP appears to be an effective treatment. Efforts to study NLPHL through multicenter collaborative efforts are crucial to develop evidence based and individualized treatments for patients with NLPHL.

  View details for DOI 10.1016/j.clml.2023.03.014

  View details for PubMedID 37076366

• Spatial phenotyping of Nodular Lymphocyte Predominant Hodgkin Lymphoma and T-cell/Histiocyte-Rich Large B-cell Lymphoma using PhenoCycler (formerly CODEX) Younes, S., Subramanian, A., Khan, A., Zhao, S., Binkley, M., Natkunam, Y. ELSEVIER SCIENCE INC. 2023: S1261-S1262

  View details for Web of Science ID 000990969802359

• Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents. Blood Spinner, M. A., Sica, R. A., Tamaresis, J. S., Lu, Y., Chang, C., Lowsky, R., Frank, M. J., Johnston, L. J., Miklos, D. B., Muffly, L., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Weng, W. K., Binkley, M. S., Hoppe, R. T., Advani, R. H., Arai, S. 2023

  Abstract

  The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade following the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for R/R cHL patients who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011-2020 (N=183) compared to 2001-2010 (N=159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era (4-year estimates 89.1% vs 79.0%, HR 0.53, 95% CI 0.33-0.85, p=0.011) with a trend towards lower non-relapse mortality beyond 2 years post-transplant. Among patients who progressed after AHCT, 4-year post-progression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients transplanted in the modern era, age ³45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, while receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS (HR 0.21, 95% CI 0.05-0.80, p=0.030). Extranodal disease at relapse was associated with inferior OS (HR 3.12, 95% CI 1.25-7.77, p=0.014). Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.

  View details for DOI 10.1182/blood.2022018827

  View details for PubMedID 36857637

• Investigating and modeling positron emission tomography factors associated with large cell transformation from low-grade lymphomas. EJHaem Obeid, J. P., Hiniker, S. M., Schroers-Martin, J., Guo, H. H., No, H. J., Moding, E. J., Advani, R. H., Alizadeh, A. A., Hoppe, R. T., Binkley, M. S. 2023; 4 (1): 90-99

  Abstract

  Low-grade lymphomas have a 1%-3% annual risk of transformation to a high-grade histology, and prognostic factors remain undefined. We set to investigate the role of positron emission tomography (PET) metrics in identification of transformation in a retrospective case-control series of patients matched by histology and follow-up time. We measured PET parameters including maximum standard uptake value (SUV-max) and total lesion glycolysis (TLG), and developed a PET feature and lactate dehydrogenase (LDH)-based model to identify transformation status within discovery and validation cohorts. For our discovery cohort, we identified 53 patients with transformation and 53 controls with a similar distribution of follicular lymphoma (FL). Time to transformation and control follow-up time was similar. We observed a significant incremental increase in SUV-max and TLG between control, pretransformation and post-transformation groups (P < 0.05). By multivariable analysis, we identified a significant interaction between SUV-max and TLG such that SUV-max had highest significance for low volume cases (P = 0.04). We developed a scoring model incorporating SUV-max, TLG, and serum LDH with improved identification of transformation (area under the curve [AUC] = 0.91). Our model performed similarly for our validation cohort of 23 patients (AUC = 0.90). With external and prospective validation, our scoring model may provide a specific and noninvasive tool for risk stratification for patients with low-grade lymphoma.

  View details for DOI 10.1002/jha2.615

  View details for PubMedID 36819184

  View details for PubMedCentralID PMC9928791

• STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer. JCO precision oncology Katipally, R. R., Spurr, L. F., Gutiontov, S. I., Turchan, W. T., Connell, P., Juloori, A., Malik, R., Binkley, M. S., Jiang, A. L., Rouhani, S. J., Chervin, C. S., Wanjari, P., Segal, J. P., Ng, V., Loo, B. W., Gomez, D. R., Bestvina, C. M., Vokes, E. E., Ferguson, M. K., Donington, J. S., Diehn, M., Pitroda, S. P. 2023; 7: e2200273

  Abstract

  Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC.This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62).Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local.In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

  View details for DOI 10.1200/PO.22.00273

  View details for PubMedID 36603171

• Investigating Metabolic Response after CAR-T Therapy and Bridging Radiotherapy for Relapsed/Refractory B-Cell Lymphoma Marar, M., Hiniker, S., Hoppe, R., Binkley, M. AMER SOC HEMATOLOGY. 2022: 12786-12787

  View details for DOI 10.1182/blood-2022-165302

  View details for Web of Science ID 000893230305405

• Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma. Cureus Hui, C., Wu, Y. F., Liu, K., Sandhu, N., Blomain, E., Binkley, M. S., Gephart, M. H., Chang, S. D., Li, G. H., Reddy, S. A., Soltys, S. G., Pollom, E. 2022; 14 (11): e31838

  Abstract

  Purpose/Objectives Combination BRAF (vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited. We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis. DF was defined as any new intracranial lesions. Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of the diameters of the five largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308, p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients with BRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.

  View details for DOI 10.7759/cureus.31838

  View details for PubMedID 36579260

  View details for PubMedCentralID PMC9788920

• Analysis of Metabolic Tumor Volume in Patients Undergoing Radiotherapy Prior to or After CAR-T Therapy for Relapsed/refractory Aggressive B Cell Lymphoma Marar, M., Hiniker, S., Hoppe, R., Binkley, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: S12-S13

  View details for Web of Science ID 000847787800028

• Characterizing the immune microenvironment for nodular lymphocyte-predominant Hodgkin lymphoma. British journal of haematology Binkley, M. S. 2022

  Abstract

  The microenvironment of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and its relationship to presentation and outcomes has not been widely investigated. In a large cohort of patients with NLPHL, Hartmann and colleagues showed an association between microenvironmental factors and clinical presentation serving to inform future studies evaluating the prognostic impact of the immunoarchitectural patterns and cell types present. Commentary on: Hartmann et al. Tumor cell characteristics and microenvironment composition correspond to clinical presentation in newly diagnosed nodular lymphocyte predominant Hodgkin lymphoma. Br J Haematol 2022 (Online ahead of print). doi: 10.1111/bjh.18376.

  View details for DOI 10.1111/bjh.18406

  View details for PubMedID 35993185

• The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer. Cancer research communications Sodji, Q. H., Nambiar, D. K., Viswanathan, V., von Eyben, R., Colburg, D., Binkley, M. S., Li, C. G., Olcina, M. M., Chang, D. T., Le, Q., Giaccia, A. J. 2022; 2 (7): 725-738

  Abstract

  Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral NK cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer. Mechanistically, NK cell exclusion is regulated in part by complement C3a and its receptor signaling. Inhibition of the C3a receptor enhances NK cell infiltration in syngeneic mouse models of pancreatic cancer resulting in tumor growth delay. However, tumor growth inhibition mediated by NK cells is not sufficient alone for complete tumor regression, but is potentiated when combined with radiation therapy. Our findings indicate that although C3a inhibition is a promising approach to enhance NK cell-based immunotherapy against pancreatic cancer, its combination with radiation therapy hold greater therapeutic benefit.

  View details for DOI 10.1158/2767-9764.crc-22-0069

  View details for PubMedID 35937458

• Inferring gene expression from cell-free DNA fragmentation profiles. Nature biotechnology Esfahani, M. S., Hamilton, E. G., Mehrmohamadi, M., Nabet, B. Y., Alig, S. K., King, D. A., Steen, C. B., Macaulay, C. W., Schultz, A., Nesselbush, M. C., Soo, J., Schroers-Martin, J. G., Chen, B., Binkley, M. S., Stehr, H., Chabon, J. J., Sworder, B. J., Hui, A. B., Frank, M. J., Moding, E. J., Liu, C. L., Newman, A. M., Isbell, J. M., Rudin, C. M., Li, B. T., Kurtz, D. M., Diehn, M., Alizadeh, A. A. 2022

  Abstract

  Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. Here we describe promoter fragmentation entropy as an epigenomic cfDNA feature that predicts RNA expression levels at individual genes. We developed 'epigenetic expression inference from cell-free DNA-sequencing' (EPIC-seq), a method that uses targeted sequencing of promoters of genes of interest. Profiling 329 blood samples from 201 patients with cancer and 87 healthy adults, we demonstrate classification of subtypes of lung carcinoma and diffuse large B cell lymphoma. Applying EPIC-seq to serial blood samples from patients treated with PD-(L)1 immune-checkpoint inhibitors, we show that gene expression profiles inferred by EPIC-seq are correlated with clinical response. Our results indicate that EPIC-seq could enable noninvasive, high-throughput tissue-of-origin characterization with diagnostic, prognostic and therapeutic potential.

  View details for DOI 10.1038/s41587-022-01222-4

  View details for PubMedID 35361996

• Practice patterns for the management of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL): an international survey by the Global NLPHL One Working Group (GLOW). Leukemia & lymphoma Lo, A. C., Major, A., Super, L., Appel, B., Shankar, A., Constine, L. S., Marks, L. J., Kelly, K. M., Metzger, M. L., Buhtoiarov, I. N., Mauz-Korholz, C., Costa, A. R., Binkley, M. S., Flerlage, J. 2022: 1-4

  View details for DOI 10.1080/10428194.2022.2053533

  View details for PubMedID 35357263

• Radiotherapy for brain metastases from thyroid cancer: an institutional and national retrospective cohort study. Thyroid : official journal of the American Thyroid Association Blomain, E. S., Berta, S., Hug, N. F., Giao, D. M., Meola, A., Binkley, M. S., Hui, C., Churilla, T., Shahsavari, N., Desai, K., Chang, S. D., Soltys, S., Pollom, E. L. 2022

  Abstract

  BACKGROUND: Stereotactic radiosurgery (SRS) is the standard of care for patients with a limited number of brain metastases. Despite the fact that the seminal studies regarding SRS for brain metastases were largely tissue agnostic, several current national guidelines do not uniformly recommend SRS in thyroid cancer. We therefore investigated oncologic outcomes in a cohort of patients with brain metastases from thyroid cancer who received radiotherapy at our institution as well as those in a nationally representative cancer cohort, the national cancer database (NCDB).METHODS: We identified patients with thyroid cancer and brain metastases treated with radiotherapy at our institution from 2002 through 2020. For the NCDB cohort, the national database of patients with thyroid cancer was screened on the basis of brain-directed radiotherapy or brain metastases. For the institutional cohort, the cumulative risk of local failure, distant intracranial failure and radiation necrosis were calculated, adjusted for the competing risk of death. Overall survival (OS) in both cohorts was analyzed using Kaplan-Meier method. Univariate analysis was accomplished via clustered competing risks regression.RESULTS: For the institutional cohort, we identified 33 patients with 212 treated brain metastases. Overall survival was 6.6 months. The 1-year cumulative incidences of local failure and distant intracranial failures were 7.0% and 38%, respectively. The 1-year risk of radiation necrosis was 3.3%. In the NCDB cohort, there were 289 patients and median survival was 10.2 months. NCDB national practice patterns analysis showed an increasing use of SRS over time in both the entire cohort and the subset of anaplastic patients. Univariate analysis was performed for overall survival, risk of local failure, risk of regional intracranial failure and risk of radiation necrosis.CONCLUSIONS: SRS is a safe, effective and increasingly-utilized treatment for thyroid cancer brain metastases of any histology and should be the standard of care treatment.

  View details for DOI 10.1089/thy.2021.0628

  View details for PubMedID 35229625

• Digital Spatial Profiling Reveals Spatial Heterogeneity in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Rojansky, R., Younes, S., Subramanian, A., Binkley, M., Natkunam, Y. SPRINGERNATURE. 2022: 1008-1009

  View details for Web of Science ID 000770361802277

• Digital Spatial Profiling Reveals Spatial Heterogeneity in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Rojansky, R., Younes, S., Subramanian, A., Binkley, M., Natkunam, Y. SPRINGERNATURE. 2022: 1008-1009

  View details for Web of Science ID 000770360202277

• Acute and Late Esophageal Toxicity Following Stereotactic Ablative Radiotherapy to Thoracic Tumors near or Abutting the Esophagus. International journal of radiation oncology, biology, physics Sodji, Q. H., Ko, R., von Eyben, R., Owen, S. G., Capaldi, D. P., Bush, K., Binkley, M. S., Alrowais, F., Pickthorn, B., Maxim, P. G., Gensheimer, M. F., Diehn, M., Loo, B. W. 1800

  Abstract

  PURPOSE: To evaluate the incidence of acute and late esophageal toxicity in patients with thoracic tumors near or abutting the esophagus treated with stereotactic ablative radiotherapy (SABR).METHODS AND MATERIALS: Among patients with thoracic tumors treated with SABR, we identified those with tumors near or abutting the esophagus. Using the linear-quadratic model with an alpha/SS ratio of 10, we determined the correlation between dosimetric parameters and esophageal toxicity graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.RESULTS: Out of 2200 patients treated with thoracic SABR, 767 patients were analyzable for esophageal dosimetry. We identified 55 patients with tumors near the esophagus (52 evaluable for esophagitis grade), 28 with PTV overlapping the esophagus. Median follow-up and overall survival were 16 and 23 months respectively. Thirteen patients (25%) developed temporary grade 2 acute esophageal toxicity, 11 (85%) of whom had PTV overlapping the esophagus. Symptoms resolved within 1-3 months in 12 patients, and 6 months in all patients. No grade 3-5 toxicity was observed. Only 3 patients (6%) developed late or persistent grade 2 dysphagia or dyspepsia of uncertain relationship to SABR. Cumulative incidence of acute esophagitis was 15% and 25% at 14 days and 60 days respectively. Acute toxicity correlated on univariate analysis with esophageal Dmax, D1cc, D2cc, Dmax/Dprescription and whether the PTV was overlapping the esophagus. Esophageal Dmax (BED10) < 62 Gy, D1cc (BED10) < 48 Gy, D2cc (BED10) < 43 Gy, and Dmax/Dprescription < 85% was associated with <20% risk of grade 2 acute esophagitis. Only 2 local recurrences occurred.CONCLUSIONS: Although 25% of patients with tumors near the esophagus developed acute esophagitis (39% of those with PTV overlapping the esophagus), these toxicities were all grade 2 and all temporary. This suggests the safety and efficacy of thoracic SABR for tumors near or abutting the esophagus when treating with high conformity and sharp dose gradients.

  View details for DOI 10.1016/j.ijrobp.2021.12.008

  View details for PubMedID 34942312

• RADIOTHERAPY FOR BRAIN METASTASES FROM THYROID CANCER: A RETROSPECTIVE COHORT STUDY Blomain, E., Berta, S., Hug, N., Giao, D., Meola, A., Binkley, M., Shahsavari, N., Desai, K., Chang, S., Soltys, S., Pollom, E. OXFORD UNIV PRESS INC. 2021: 42

  View details for Web of Science ID 000757356200166

• Intracranial Response to Combination BRAF and MEK Inhibitor Therapy in Patients with Metastatic Melanoma Hui, C., Wu, Y., Liu, K., Sandhu, N., Blomain, E., Binkley, M., Gephart, M., Chang, S., Li, G., Reddy, S., Gibbs, I., Soltys, S., Pollom, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S48-S49

  View details for Web of Science ID 000701779700077

• Radiotherapy for Management of Brain Metastases from Thyroid Cancer: A National Cancer Database Study Blomain, E., Binkley, M., Giao, D., Churilla, T., Soltys, S., Pollom, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S48

  View details for Web of Science ID 000701779700076

• Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D., Yoo, C., Kurtz, D. M., Owen, S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600087

• Stage I-II diffuse large B-cell lymphoma treated with rituximab and chemotherapy with or without radiotherapy. Leukemia & lymphoma Binkley, M. S., Hiniker, S. M., Younes, S., Yoo, C., Wignarajah, A., Jin, M., Guo, H. H., Gupta, N. K., Natkunam, Y., Advani, R. H., Hoppe, R. T. 2021: 1–15

  Abstract

  We set to identify prognostic factors in a retrospective cohort of consecutive patients with stage I-II diffuse large B-cell lymphoma treated with rituximab-chemotherapy with or without radiotherapy from 2001 through 2017 at our institution. We identified 143 patients with median follow-up of 7.7years. The majority were male (59.4%), had stage II (53.1%), had stage-modified IPI 0-1 (smIPI, 58.1%), and had non-bulky disease (<7cm, 68.5%). 99 patients (69.2%) received rituximab-chemotherapy followed by radiotherapy, and 44 patients (30.8%) received rituximab-chemotherapy alone. The 5-year progression-free survival (PFS) and overall survival (OS) were 81.2% and 88.9%, respectively. The 5-year PFS for those with smIPI 0-1 versus 2-4 was 89.5% versus 69.7%, respectively (P=0.005). Bulky disease (≥7cm) was associated with worse PFS and OS on univariable and multivariable analyses (P<0.05). Patients with smIPI 0-1 without bulky disease have excellent outcomes. However, patients with smIPI 2-4 or bulky disease have a high risk of progression.

  View details for DOI 10.1080/10428194.2021.1876859

  View details for PubMedID 33622155

• Single Cell Analysis Can Define Distinct Evolution of Tumor Sites in Follicular Lymphoma. Blood Haebe, S. E., Shree, T. n., Sathe, A. n., Day, G. n., Czerwinski, D. K., Grimes, S. n., Lee, H. n., Binkley, M. S., Long, S. R., Martin, B. A., Ji, H. P., Levy, R. n. 2021

  Abstract

  Tumor heterogeneity complicates biomarker development and fosters drug resistance in solid malignancies. In lymphoma, our knowledge of site-to-site heterogeneity and its clinical implications is still limited. Here, we profiled two nodal, synchronously-acquired tumor samples from ten follicular lymphoma patients using single cell RNA, B cell receptor (BCR) and T cell receptor sequencing, and flow cytometry. By following the rapidly mutating tumor immunoglobulin genes, we discovered that BCR subclones were shared between the two tumor sites in some patients, but in many patients the disease had evolved separately with limited tumor cell migration between the sites. Patients exhibiting divergent BCR evolution also exhibited divergent tumor gene expression and cell surface protein profiles. While the overall composition of the tumor microenvironment did not differ significantly between sites, we did detect a specific correlation between site-to-site tumor heterogeneity and T follicular helper (Tfh) cell abundance. We further observed enrichment of particular ligand-receptor pairs between tumor and Tfh cells, including CD40 and CD40LG, and a significant correlation between tumor CD40 expression and Tfh proliferation. Our study may explain discordant responses to systemic therapies, underscores the difficulty of capturing a patient's disease with a single biopsy, and furthers our understanding of tumor-immune networks in follicular lymphoma.

  View details for DOI 10.1182/blood.2020009855

  View details for PubMedID 33728464

• KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D. S., Yoo, C., Kurtz, D., Owen, S., Backhus, L., Berry, M. F., Shrager, J. B., Ramchandran, K., Padda, S., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303348

• Predicting per-lesion local recurrence in locally advanced non-small cell lung cancer following definitive radiation therapy using pre- and mid-treatment metabolic tumor volume. Radiation oncology (London, England) Binkley, M. S., Koenig, J. L., Kashyap, M. n., Xiang, M. n., Liu, Y. n., Sodji, Q. n., Maxim, P. G., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2020; 15 (1): 114

  Abstract

  We evaluated whether pre- and mid-treatment metabolic tumor volume (MTV) predicts per lesion local recurrence (LR) in patients treated with definitive radiation therapy (RT, dose≥60 Gy) for locally advanced non-small cell lung cancer (NSCLC).We retrospectively reviewed records of patients with stage III NSCLC treated from 2006 to 2018 with pre- and mid-RT PET-CT. We measured the MTV of treated lesions on the pre-RT (MTVpre) and mid-RT (MTVmid) PET-CT. LR was defined per lesion as recurrence within the planning target volume. Receiver operating characteristic (ROC) curves, cumulative incidence rates, and uni- and multivariable (MVA) competing risk regressions were used to evaluate the association between MTV and LR.We identified 111 patients with 387 lesions (112 lung tumors and 275 lymph nodes). Median age was 68 years, 69.4% were male, 46.8% had adenocarcinoma, 39.6% had squamous cell carcinoma, and 95.5% received concurrent chemotherapy. Median follow-up was 38.7 months. 3-year overall survival was 42.3%. 3-year cumulative incidence of LR was 26.8% per patient and 11.9% per lesion. Both MTVpre and MTVmid were predictive of LR by ROC (AUC = 0.71 and 0.76, respectively) and were significantly associated with LR on MVA (P = 0.004 and P = 7.1e-5, respectively). Among lesions at lower risk of LR based on MTVpre, higher MTVmid was associated with LR (P = 0.001).Per-lesion, larger MTVpre and MTVmid predicted for increased risk of LR. MTVmid was more highly predictive of LR than MTVpre and if validated may allow for further discrimination of high-risk lesions at mid-RT informing dose painting strategies.

  View details for DOI 10.1186/s13014-020-01546-y

  View details for PubMedID 32429982

• Salvage Treatment and Survival for Relapsed Follicular Lymphoma Following Primary Radiation Therapy: A Collaborative Study on Behalf of ILROG INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Brady, J. L., Hajj, C., Chelius, M., Chau, K., Balogh, A., Levis, M., Filippi, A., Jones, M., Ahmed, S., MacManus, M., Wirth, A., Oguchi, M., Vistisen, A., Andraos, T., Ng, A. K., Aleman, B. P., Choi, S., Kirova, Y. M., Hardy, S., Reinartz, G., Eich, H. T., Bratman, S., Constine, L. S., Suh, C., Dabaja, B., El-Galaly, T. C., Hodgson, D. C., Ricardi, U., Yahalom, J., Mikhaeel, G., Hoppe, R. T. 2019; 104 (3): 522–29

  View details for DOI 10.1016/j.ijrobp.2019.03.004

  View details for Web of Science ID 000469337300012

• Detection of Solid Tumor Molecular Residual Disease(MRD) Using Circulating Tumor DNA (ctDNA) MOLECULAR DIAGNOSIS & THERAPY Chin, R., Chen, K., Usmani, A., Chua, C., Harris, P. K., Binkley, M. S., Azad, T. D., Dudley, J. C., Chaudhuri, A. A. 2019; 23 (3): 311–31

  View details for DOI 10.1007/s40291-019-00390-5

  View details for Web of Science ID 000471051200002

• Detection of Solid Tumor Molecular Residual Disease (MRD) Using Circulating Tumor DNA (ctDNA). Molecular diagnosis & therapy Chin, R. I., Chen, K. n., Usmani, A. n., Chua, C. n., Harris, P. K., Binkley, M. S., Azad, T. D., Dudley, J. C., Chaudhuri, A. A. 2019

  Abstract

  Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are typically low, particularly in patients with localized disease, requiring highly sophisticated methods for detection and quantification. Multiple liquid biopsy methods have been developed for ctDNA analysis in solid tumor malignancies and are now enabling detection and assessment of earlier stages of disease, post-treatment molecular residual disease (MRD), resistance to targeted systemic therapy, and tumor mutational burden. Understanding ctDNA biology, mechanisms of release, and clearance and size characteristics, in conjunction with the application of molecular barcoding and targeted error correction, have increased the sensitivity and specificity of ctDNA detection techniques. Combinatorial approaches including integration of ctDNA data with circulating protein biomarkers may further improve assay sensitivity and broaden the scope of ctDNA applications. Circulating viral DNA may be utilized to monitor disease in some virally induced malignancies. In spite of increasingly accurate methods of ctDNA detection, results need to be interpreted with caution given that somatic mosaicisms such as clonal hematopoiesis of indeterminate potential (CHIP) may give rise to genetic variants in the bloodstream unrelated to solid tumors, and the limited concordance observed between different commercial platforms. Overall, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumor malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance, and treatment personalization based on real-time assessment of the tumor genomic landscape.

  View details for PubMedID 30941670

• Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG. Blood Brady, J. L., Binkley, M. S., Hajj, C., Chelius, M., Chau, K., Balogh, A., Levis, M., Filippi, A. R., Jones, M., Mac Manus, M., Wirth, A., Oguchi, M., Krog Vistisen, A., Andraos, T. Y., Ng, A. K., Aleman, B. M., Choi, S. H., Kirova, Y., Hardy, S., Reinartz, G., Eich, H. T., Bratman, S. V., Constine, L. S., Suh, C., Dabaja, B., El-Galaly, T. C., Hodgson, D. C., Ricardi, U., Yahalom, J., Hoppe, R. T., Mikhaeel, N. G. 2018

  Abstract

  Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40-50%. As 18F-FDG PET-CT upstages 10-60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study. Inclusion criteria were: RT alone for untreated stage I-II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow up ≥3 months. Endpoints were freedom from progression (FFP), local control, and overall survival (OS). FFP and OS were estimated with Kaplan-Meier, and uni- and multivariable analyses of prognostic factors performed with Cox Regression. 512 patients treated from 2000-2017 at 16 centres were eligible for analysis. Median age was 58 years (range 20-90). 410 patients (80.1%) had stage I disease. Median RT dose was 30 Gy (24-52). Median follow up was 52 months (3.2-174.6). 5y-FFP and OS were 68.9% and 95.7%. For stage I, 5y-FFP was 74.1%, vs 49.1% for stage II (p<0.0001). 8 patients relapsed infield (1.6%).4 had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (HR=2.11, 95%CI=1.44-3.10) and BCL2 expression (HR =1.62, 95%CI 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

  View details for PubMedID 30446493

• F-18-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated With Highly Conformal Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Qian, Y., Von Eyben, R., Liu, Y., Chin, F. T., Miao, Z., Apte, S., Carter, J. N., Binkley, M. S., Pollom, E. L., Harris, J. P., Prionas, N. D., Kissel, M., Simmons, A., Diehn, M., Shultz, D. B., Brown, J., Maxim, P. G., Koong, A. C., Graves, E. E., Loo Jr, B. W. 2018; 102 (4): 1183–92

  View details for DOI 10.1016/j.ijrobp.2018.03.045

  View details for Web of Science ID 000447789700063

• 18F-EF5 Pet-Based Imageable Hypoxia Predicts for Local Control in Tumors Treated With Conformal Radiotherapy Qian, Y., Liu, Y., Von Eyben, R., Carter, J. N., Pollom, E. L., Harris, J. P., Prionas, N. D., Binkley, M. S., Simmons, A., Diehn, M., Chin, F. T., Shultz, D. B., Brown, J., Maxim, P. G., Koong, A. C., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2018: E17–E18

  View details for Web of Science ID 000432447200042

• 18F-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated With Highly Conformal Radiation Therapy. International journal of radiation oncology, biology, physics Qian, Y. n., Von Eyben, R. n., Liu, Y. n., Chin, F. T., Miao, Z. n., Apte, S. n., Carter, J. N., Binkley, M. S., Pollom, E. L., Harris, J. P., Prionas, N. D., Kissel, M. n., Simmons, A. n., Diehn, M. n., Shultz, D. B., Brown, J. M., Maxim, P. G., Koong, A. C., Graves, E. E., Loo, B. W. 2018

  Abstract

  Tumor hypoxia contributes to radiation resistance. A noninvasive assessment of tumor hypoxia would be valuable for prognostication and possibly selection for hypoxia-targeted therapies. 18F-pentafluorinated etanidazole (18F-EF5) is a nitroimidazole derivative that has demonstrated promise as a positron emission tomography (PET) hypoxia imaging agent in preclinical and clinical studies. However, correlation of imageable hypoxia by 18F-EF5 PET with clinical outcomes after radiation therapy remains limited.Our study prospectively enrolled 28 patients undergoing radiation therapy for localized lung or other tumors to receive pretreatment 18F-EF5 PET imaging. Depending on the level of 18F-EF5 tumor uptake, patients underwent functional manipulation of tumor oxygenation with either carbogen breathing or oral dichloroacetate followed by repeated 18F-EF5 PET. The hypoxic subvolume of tumor was defined as the proportion of tumor voxels exhibiting higher 18F-EF5 uptake than the 95th percentile of 18F-EF5 uptake in the blood pool. Tumors with a hypoxic subvolume ≥ 10% on baseline 18F-EF5 PET imaging were classified as hypoxic by imaging. A Cox model was used to assess the correlation between imageable hypoxia and clinical outcomes after treatment.At baseline, imageable hypoxia was demonstrated in 43% of all patients (12 of 28), including 6 of 16 patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy and 6 of 12 patients with other cancers. Carbogen breathing was significantly associated with decreased imageable hypoxia, while dichloroacetate did not result in a significant change under our protocol conditions. Tumors with imageable hypoxia had a higher incidence of local recurrence at 12 months (30%) than those without (0%) (P < .01).Noninvasive hypoxia imaging by 18F-EF5 PET identified imageable hypoxia in about 40% of tumors in our study population. Local tumor recurrence after highly conformal radiation therapy was higher in tumors with imageable hypoxia.

  View details for PubMedID 29859786

• Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Zhou, L., Liu, C., Scherer, F., Kurtz, D. M., Esfahani, M. S., Say, C., Carter, J. N., Merriott, D., Dudley, J., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Billy, W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: E4

  View details for DOI 10.1016/j.ijrobp.2017.02.048

  View details for Web of Science ID 000403079100013

• Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung. Radiotherapy and oncology Binkley, M. S., King, M. T., Shrager, J. B., Bush, K., Chaudhuri, A. A., Popat, R., Gensheimer, M. F., Maxim, P. G., Henry Guo, H., Diehn, M., Nair, V. S., Loo, B. W. 2017; 123 (2): 270-275

  Abstract

  To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors.We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (α/β=3Gy) isodose volume and that of the total lung volume (TLV).Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (ΔFEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse ΔFEV1/FEV1pre (median=-0.16, range=-0.230 to -0.20). Five had VR20BED3<1 (low regional ventilation) and improved ΔFEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing ΔFEV1/FEV1pre (R(2)=0.25, p=0.03).After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.

  View details for DOI 10.1016/j.radonc.2017.03.021

  View details for PubMedID 28460826

• Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H. n., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L. n., Scherer, F. n., Kurtz, D. M., Say, C. n., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L. n., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. n. 2017

  Abstract

  Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

  View details for PubMedID 28899864

• Partial orbit irradiation achieves excellent outcomes for primary orbital lymphoma. Practical radiation oncology Binkley, M. S., Hiniker, S. M., Donaldson, S. S., Hoppe, R. T. 2016; 6 (4): 255-261

  Abstract

  Primary radiation therapy (RT) achieves excellent local control and overall survival when treating localized orbital lymphoma. However, evidence supporting irradiation of partial orbit volumes to spare nearby critical structures is lacking. We sought to investigate outcomes for patients with localized orbital lymphoma treated with partial orbit irradiation.We retrospectively reviewed patients with orbital lymphoma treated with RT at our institution who met our inclusion criteria: biopsy-confirmed, low-grade lymphoma, localized disease, partial orbit treatment volumes, and follow-up >3months. The Kaplan-Meier method was used to measure overall survival (OS), and the cumulative incidence function adjusted for the competing risk of death was used to measure local failure (LF), contralateral orbit recurrence (COR), and progression. Patient characteristics were compared with outcomes using Fisher exact test for dichotomous variables and Wilcoxon rank-sum test for continuous variables.Thirty-two patients meeting inclusion criteria were identified with median follow-up of 45.8months (range, 3.6-171.9). The majority had stage IEA disease; their sites included conjunctiva (n=20) and retrobulbar or lacrimal gland (n=12). Median partial orbit RT dose was 30.6Gy (range, 22.5-36). Five-year OS was 100%. Five-year cumulative incidence of LF, COR, and overall disease progression was 5.3%, 5.9%, and 21.4%, respectively. Five-year cumulative incidence of LF was 8.3% for conjunctival disease versus 0.0% for retrobulbar or lacrimal gland involvement (P=.15). No significant association was observed between the outcomes of LF, COR, or progression and pretreatment characteristics. Acute and late toxicity included grade 2 periorbital edema (n=3, 9.4%), dry eye (n=3, 9.4%), retinal vascular disorder (n=1, 3.1%), conjunctivitis (n=2, 6.3%), and grade 3 cataract (n=1, 3.1%).Use of partial orbit irradiation in treating low-grade, localized orbital lymphoma achieves excellent survival with low rates of LF, COR, or progression.

  View details for DOI 10.1016/j.prro.2015.11.013

  View details for PubMedID 26935235

• Pre-treatment non-target lung FDG-PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR). Radiotherapy and oncology Chaudhuri, A. A., Binkley, M. S., Rigdon, J., Carter, J. N., Aggarwal, S., Dudley, S. A., Qian, Y., Kumar, K. A., Hara, W. Y., Gensheimer, M., Nair, V. S., Maxim, P. G., Shultz, D. B., Bush, K., Trakul, N., Le, Q., Diehn, M., Loo, B. W., Guo, H. H. 2016; 119 (3): 454-460

  Abstract

  To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ⩾ 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001).Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.

  View details for DOI 10.1016/j.radonc.2016.05.007

  View details for PubMedID 27267049

• Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery. Seminars in radiation oncology Hiniker, S. M., Modlin, L. A., Choi, C. Y., Atalar, B., Seiger, K., Binkley, M. S., Harris, J. P., Liao, Y. J., Fischbein, N., Wang, L., Ho, A., Lo, A., Chang, S. D., Harsh, G. R., Gibbs, I. C., Hancock, S. L., Li, G., Adler, J. R., Soltys, S. G. 2016; 26 (2): 97-104

  Abstract

  Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

  View details for DOI 10.1016/j.semradonc.2015.11.008

  View details for PubMedID 27000505

• Tracheal Diverticulum Following Paratracheal Hypofractionated Radiotherapy in the Setting of Prior and Subsequent Bevacizumab CUREUS Chaudhuri, A. A., Chen, J., Carter, J. N., Binkley, M. S., Kumar, K. A., Dudley, S. A., Sung, A. W., Loo, B. W. 2016; 8 (4)

  View details for DOI 10.7759/cureus.578

  View details for Web of Science ID 000453611400028

• Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery SEMINARS IN RADIATION ONCOLOGY Hiniker, S. M., Modlin, L. A., Choi, C. Y., Atalar, B., Seiger, K., Binkley, M. S., Harris, J. P., Liao, Y. J., Fischbein, N., Wang, L., Ho, A., Lo, A., Chang, S. D., Harsh, G. R., Gibbs, I. C., Hancock, S. L., Li, G., Adler, J. R., Soltys, S. G. 2016; 26 (2): 97-104

  Abstract

  Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

  View details for DOI 10.1016/j.semradonc.2015.11.008

  View details for Web of Science ID 000373242700003

• Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation. International journal of radiation oncology, biology, physics Binkley, M. S., Hiniker, S. M., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W., Shultz, D. B. 2016; 94 (4): 808-815

  Abstract

  We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation.We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2 Gy per fraction equivalent dose (EQD2; α/β = 2 for spinal cord; α/β = 3 for other critical structures).We identified 82 courses (44 for retreatment) in 38 patients reirradiated at a median 16 months (range: 1-71 months) following initial RT. Median follow-up was 17 months (range: 3-57 months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Critical structures receiving ≥75 Gy EQD2 included spinal cord (1 cm(3); n=1), esophagus (1 cm(3); n=10), trachea (1 cm(3); n=11), heart (1 cm(3); n=9), aorta (1 cm(3); n=16), superior vena cava (1 cm(3); n=12), brachial plexus (0.2 cm(3); n=2), vagus nerve (0.2 cm(3); n=7), sympathetic trunk (0.2 cm(3); n=4), chest wall (30 cm(3); n=12), and proximal bronchial tree (1 cm(3); n=17). Cumulative dose-volume (D cm(3)) toxicity following reirradiation data included esophagitis grade ≥2 (n=3, D1 cm(3) range: 41.0-100.6 Gy), chest wall grade ≥2 (n=4; D30 cm(3) range: 35.0-117.2 Gy), lung grade 2 (n=7; V20combined-lung range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2 cm(3) range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm(3) = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm(3) = 130.8 Gy). No grade ≥4 toxicity was observed.Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

  View details for DOI 10.1016/j.ijrobp.2015.12.007

  View details for PubMedID 26831903

• Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors RADIATION ONCOLOGY Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. 2016; 11

  Abstract

  Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction.We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n = 21, V60BED3 ≥4.1 % TLV).Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01-13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (-4.6-9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX = 20-100 Gy, R (2)  = 0.52-0.55, p < 0.0001) and smaller with lower pre-treatment FEV1% (R (2)  = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted.We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

  View details for DOI 10.1186/s13014-016-0616-8

  View details for Web of Science ID 000372776500001

  View details for PubMedCentralID PMC4791793

• A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy LEUKEMIA & LYMPHOMA Binkley, M. S., Hiniker, S. M., Wu, S., Natkunam, Y., Mittra, E. S., Advani, R. H., Hoppe, R. T. 2016; 57 (3): 604-608

  Abstract

  As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  View details for DOI 10.3109/10428194.2015.1067700

  View details for Web of Science ID 000372499800016

• A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy. Leukemia & lymphoma Binkley, M. S., Hiniker, S. M., Wu, S., Natkunam, Y., Mittra, E. S., Advani, R. H., Hoppe, R. T. 2016; 57 (3): 604-608

  Abstract

  As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  View details for DOI 10.3109/10428194.2015.1067700

  View details for PubMedID 26159046

• Severe Chest Wall Toxicity From Cryoablation in the Setting of Prior Stereotactic Ablative Radiotherapy CUREUS Chaudhuri, A. A., Binkley, M. S., Aggarwal, S., Qian, Y., Carter, J. N., Shah, R., Loo, B. W. 2016; 8 (2)

  View details for DOI 10.7759/cureus.477

  View details for Web of Science ID 000453610500005

• Tracheal Diverticulum Following Paratracheal Hypofractionated Radiotherapy in the Setting of Prior and Subsequent Bevacizumab. Cure¯us Chaudhuri, A. A., Chen, J. J., Carter, J. N., Binkley, M. S., Kumar, K. A., Dudley, S. A., Sung, A. W., Loo, B. W. 2016; 8 (4)

  Abstract

  We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions (70 Gy equivalent dose in 2 Gy fractions). The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI-bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy.

  View details for DOI 10.7759/cureus.578

  View details for PubMedID 27226939

• Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors. Radiation oncology Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. 2016; 11 (1): 40-?

  Abstract

  Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction.We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n = 21, V60BED3 ≥4.1 % TLV).Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01-13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (-4.6-9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX = 20-100 Gy, R (2)  = 0.52-0.55, p < 0.0001) and smaller with lower pre-treatment FEV1% (R (2)  = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted.We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

  View details for DOI 10.1186/s13014-016-0616-8

  View details for PubMedID 26975700

• Severe Chest Wall Toxicity From Cryoablation in the Setting of Prior Stereotactic Ablative Radiotherapy. Cure¯us Chaudhuri, A. A., Binkley, M. S., Aggarwal, S., Qian, Y., Carter, J. N., Shah, R., Loo, B. W. 2016; 8 (2)

  Abstract

  We present the case of a 42-year-old woman with metastatic synovial sarcoma of parotid origin, treated definitively with chemoradiation, who subsequently developed oligometastatic disease limited to the lungs. She underwent multiple left and right lung wedge resections and left lower lobectomy, followed by right lower lobe stereotactic ablative radiotherapy (SABR), 54 Gy in three fractions to a right lower lobe lesion abutting the chest wall. Two years later, she was treated with cryoablation for a separate right upper lobe nodule abutting the chest wall. Two months later, she presented with acute shortness of breath, pleuritic chest pain, decreased peripheral blood O2 saturation, and productive cough. A computed tomography (CT) scan demonstrated severe chest wall necrosis in the area of recent cryoablation that, in retrospect, also received a significant radiation dose from her prior SABR. This case demonstrates that clinicians should exercise caution in using cryoablation when treating lung tumors abutting a previously irradiated chest wall. Note: Drs. Loo and Shah contributed equally as co-senior authors.

  View details for DOI 10.7759/cureus.477

  View details for PubMedID 27004154

  View details for PubMedCentralID PMC4780688

• Predicting Radiotherapy Responses and Treatment Outcomes Through Analysis of Circulating Tumor DNA. Seminars in radiation oncology Chaudhuri, A. A., Binkley, M. S., Osmundson, E. C., Alizadeh, A. A., Diehn, M. 2015; 25 (4): 305-312

  Abstract

  Tumors continually shed DNA into the blood where it can be detected as circulating tumor DNA (ctDNA). Although this phenomenon has been recognized for decades, techniques that are sensitive and specific enough to robustly detect ctDNA have only become available recently. Quantification of ctDNA represents a new approach for cancer detection and disease burden quantification that has the potential to revolutionize response assessment and personalized treatment in radiation oncology. Analysis of ctDNA has many potential applications, including detection of minimal residual disease following radiotherapy, noninvasive tumor genotyping, and early detection of tumor recurrence. Ultimately, ctDNA-based assays could lead to personalization of therapy based on identification of somatic alterations present in tumors and changes in ctDNA concentrations before and after treatment. In this review, we discuss methods of ctDNA detection and clinical applications of ctDNA-based biomarkers in radiation oncology, with a focus on recently developed techniques that use next-generation sequencing for ctDNA quantification.

  View details for DOI 10.1016/j.semradonc.2015.05.001

  View details for PubMedID 26384278

  View details for PubMedCentralID PMC4575502

• Colorectal Histology Is Associated With an Increased Risk of Local Failure in Lung Metastases Treated With Stereotactic Ablative Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Trakul, N., Jacobs, L. R., von Eyben, R., Quynh-Thu Le, Q. T., Maxim, P. G., Loo, B. W., Shultz, D. B., Diehn, M. 2015; 92 (5): 1044-1052

  Abstract

  Stereotactic ablative radiation therapy (SABR) is increasingly used to treat lung oligometastases. We set out to determine the safety and efficacy of this approach and to identify factors associated with outcomes.We conducted a retrospective study of patients treated with SABR for metastatic lung tumors at our institution from 2003 to 2014. We assessed the association between various patient and treatment factors with local failure (LF), progression, subsequent treatment, systemic treatment, and overall survival (OS), using univariate and multivariate analyses.We identified 122 tumors in 77 patients meeting inclusion criteria for this study. Median follow-up was 22 months. The 12- and 24-month cumulative incidence rates of LF were 8.7% and 16.2%, respectively; the 24-month cumulative incidence rates of progression, subsequent treatment, and subsequent systemic treatment were 75.2%, 64.5%, and 35.1%, respectively. Twenty-four-month OS was 74.6%, and median OS was 36 months. Colorectal metastases had a significantly higher cumulative incidence of LF at 12 and 24 months (25.5% and 42.2%, respectively), than all other histologies (4.4% and 9.9%, respectively; P<.0004). The 24-month cumulative incidences of LF for colorectal metastases treated with a biologically effective dose at α/β = 10 (BED10) of <100 Gy versus BED10 of ≥100 Gy were 62.5% and 16.7%, respectively (P=.08). Toxicity was minimal, with only a single grade 3 or higher event observed.SABR for metastatic lung tumors appears to be safe and effective with excellent local control, treatment-free intervals, and OS. An exception is metastases from colorectal cancer, which have a high LF rate consistent with a radioresistant phenotype, suggesting a potential role for dose escalation.

  View details for DOI 10.1016/j.ijrobp.2015.04.004

  View details for Web of Science ID 000357900600024

  View details for PubMedID 26025776

• Stereotactic ablative radiotherapy (SABR) for treatment of central and ultra-central lung tumors LUNG CANCER Chaudhuri, A. A., Tang, C., Binkley, M. S., Jin, M., Wynne, J. F., von Eyben, R., Hara, W. Y., Trakul, N., Loo, B. W., Diehn, M. 2015; 89 (1): 50-56

  Abstract

  Treatment of central and ultra-central lung tumors with stereotactic ablative radiotherapy (SABR) remains controversial due to risks of treatment-related toxicities compared with peripheral tumors. Here we report our institution's experience in treating central and ultra-central lung tumor patients with SABR.We retrospectively reviewed outcomes in 68 patients with single lung tumors, 34 central and 34 peripheral, all treated with SABR consisting of 50 Gy in 4-5 fractions. Tumor centrality was defined per the RTOG 0813 protocol. We defined "ultra-central" tumors as those with GTV directly abutting the central airway.Median follow-up time was 18.4 months and median overall survival was 38.1 months. Two-year overall survival was similar between ultra-central, central, and peripheral NSCLC (80.0% vs. 63.2% vs. 86.6%, P=0.62), as was 2-year local failure (0% vs. 10.0% vs. 16.3%, P=0.64). Toxicity rates were low and comparable between the three groups, with only two cases of grade 3 toxicity (chest wall pain), and one case of grade 4 toxicity (pneumonitis) observed. Patients with ultra-central tumors experienced no symptomatic toxicities over a median follow-up time of 23.6 months. Dosimetric analysis revealed that RTOG 0813 central airway dose constraints were frequently not achieved in central tumor treatment plans, but this did not correlate with increased toxicity rate.Patients with central and ultra-central lung tumors treated with SABR (50 Gy in 4-5 fractions) experienced few toxicities and good outcomes, similar to patients with peripheral lung tumors.

  View details for DOI 10.1016/j.lungcan.2015.04.014

  View details for Web of Science ID 000356546300010

  View details for PubMedID 25997421

• Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223

  Abstract

  Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema.We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3).27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001).We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

  View details for DOI 10.1016/j.ijrobp.2014.05.025

  View details for Web of Science ID 000341456500029

• Lung volume reduction after stereotactic ablative radiation therapy of lung tumors: potential application to emphysema. International journal of radiation oncology, biology, physics Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223

  Abstract

  Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema.We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3).27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001).We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

  View details for DOI 10.1016/j.ijrobp.2014.05.025

  View details for PubMedID 25015205