Clinical Focus

  • Anatomic and Clinical Pathology

Academic Appointments

  • Clinical Assistant Professor, Pathology

Professional Education

  • Board Certification: American Board of Pathology, Cytopathology (2017)
  • Fellowship: Stanford University Department of Pathology (2017) CA
  • Fellowship: Stanford University Department of Pathology (2016) CA
  • Board Certification: American Board of Pathology, Anatomic and Clinical Pathology (2015)
  • Residency: Stanford University Department of Pathology (2015) CA
  • Medical Education: Indiana University School of Medicine (2011) IN
  • Fellowship, Stanford University, Cytopathology (2017)
  • Fellowship, Stanford University, Gastrointestinal Pathology (2016)
  • Residency, Stanford University, Anatomic and Clinical Pathology (2015)
  • MD, Indiana University School of Medicine (2011)
  • BA, Indiana University, Chemistry and Biology (2006)


All Publications

  • Deep learning model for the prediction of microsatellite instability in colorectal cancer: a diagnostic study. The Lancet. Oncology Yamashita, R., Long, J., Longacre, T., Peng, L., Berry, G., Martin, B., Higgins, J., Rubin, D. L., Shen, J. 2021; 22 (1): 132?41


    Detecting microsatellite instability (MSI) in colorectal cancer is crucial for clinical decision making, as it identifies patients with differential treatment response and prognosis. Universal MSI testing is recommended, but many patients remain untested. A critical need exists for broadly accessible, cost-efficient tools to aid patient selection for testing. Here, we investigate the potential of a deep learning-based system for automated MSI prediction directly from haematoxylin and eosin (H&E)-stained whole-slide images (WSIs).Our deep learning model (MSINet) was developed using 100 H&E-stained WSIs (50 with microsatellite stability [MSS] and 50 with MSI) scanned at 40× magnification, each from a patient randomly selected in a class-balanced manner from the pool of 343 patients who underwent primary colorectal cancer resection at Stanford University Medical Center (Stanford, CA, USA; internal dataset) between Jan 1, 2015, and Dec 31, 2017. We internally validated the model on a holdout test set (15 H&E-stained WSIs from 15 patients; seven cases with MSS and eight with MSI) and externally validated the model on 484 H&E-stained WSIs (402 cases with MSS and 77 with MSI; 479 patients) from The Cancer Genome Atlas, containing WSIs scanned at 40× and 20× magnification. Performance was primarily evaluated using the sensitivity, specificity, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUROC). We compared the model's performance with that of five gastrointestinal pathologists on a class-balanced, randomly selected subset of 40× magnification WSIs from the external dataset (20 with MSS and 20 with MSI).The MSINet model achieved an AUROC of 0·931 (95% CI 0·771-1·000) on the holdout test set from the internal dataset and 0·779 (0·720-0·838) on the external dataset. On the external dataset, using a sensitivity-weighted operating point, the model achieved an NPV of 93·7% (95% CI 90·3-96·2), sensitivity of 76·0% (64·8-85·1), and specificity of 66·6% (61·8-71·2). On the reader experiment (40 cases), the model achieved an AUROC of 0·865 (95% CI 0·735-0·995). The mean AUROC performance of the five pathologists was 0·605 (95% CI 0·453-0·757).Our deep learning model exceeded the performance of experienced gastrointestinal pathologists at predicting MSI on H&E-stained WSIs. Within the current universal MSI testing paradigm, such a model might contribute value as an automated screening tool to triage patients for confirmatory testing, potentially reducing the number of tested patients, thereby resulting in substantial test-related labour and cost savings.Stanford Cancer Institute and Stanford Departments of Pathology and Biomedical Data Science.

    View details for DOI 10.1016/S1470-2045(20)30535-0

    View details for PubMedID 33387492

  • Tough to Swallow: Dysphagia in a Child with an Aberrant Left Subclavian Artery. Digestive diseases and sciences Hsu, D., Martin, B., Forgó, E., Greene, E., Hassan, M., Bass, D. 2021

    View details for DOI 10.1007/s10620-020-06777-3

    View details for PubMedID 33433797

  • Intraoperative Fluorescence-Guided Surgery in Head and Neck Squamous Cell Carcinoma. The Laryngoscope Lee, Y. J., Krishnan, G., Nishio, N., van den Berg, N. S., Lu, G., Martin, B. A., van Keulen, S., Colevas, A. D., Kapoor, S., Liu, J. T., Rosenthal, E. L. 2021; 131 (3): 529?34


    The rate of positive margins in head and neck cancers has remained stagnant over the past three decades and is consistently associated with poor overall survival. This suggests that significant improvements must be made intraoperatively to ensure negative margins. We discuss the important role of fluorescence imaging to guide surgical oncology in head and neck cancer. This review includes a general overview of the principles of fluorescence, available fluorophores used for fluorescence imaging, and specific clinical applications of fluorescence-guided surgery, as well as challenges and future directions in head and neck surgical oncology. Laryngoscope, 131:529-534, 2021.

    View details for DOI 10.1002/lary.28822

    View details for PubMedID 33593036

  • Pulmonary large cell neuroendocrine carcinoma (LCNEC) with confirmed liver metastases negative on 18F-FDG and 68Ga-DOTATATE PET. Radiology case reports Ninatti, G., Duan, H., Ferri, V., Martin, B. A., Aparici, C. M. 2020; 15 (12): 2698?2700


    Lung neuroendocrine neoplasms (NENs) encompass the low-, intermediate-, and high-grade entities. Differentiated NENs overexpress somatostatin receptors, which are targeted by 68Ga-DOTA-conjugated peptides in molecular imaging with positron emission tomography. Less differentiated NENs may have lost their expression of somatostatin receptors and thus show lower uptake of 68Ga-DOTA-peptides; however, these tumors express GLUT-1 and can be imaged with (18)F-fluordeoxyglucose (FDG). We report the case of a 72-year-old patient with a poorly differentiated, high grade lung NEN, which was 18F-FDG-positive at initial diagnosis. After treatment and remission, the patient had histologically confirmed relapse in the liver. Interestingly, these hepatic metastases did not demonstrated radiopharmaceutical uptake at neither 18F-FDG nor 68Ga-DOTATATE positron emission tomography/computed tomography.

    View details for DOI 10.1016/j.radcr.2020.10.023

    View details for PubMedID 33117470

  • Effect of Formalin Fixation for Near-Infrared Fluorescence Imaging with an Antibody-Dye Conjugate in Head and Neck Cancer Patients. Molecular imaging and biology Kapoor, S., Lu, G., van den Berg, N. S., Krishnan, G., Pei, J., Zhou, Q., Martin, B. A., Baik, F. M., Rosenthal, E. L., Nishio, N. 2020


    PURPOSE: This study evaluated the effect of formalin fixation for near-infrared (NIR) fluorescence imaging of an antibody-dye complex (panitumumab-IRDye800CW) that was intravenously administered to patients with head and neck squamous cell carcinoma (HNSCC) scheduled to undergo surgery of curative intent.PROCEDURES: HNSCC patients were infused with 25 or 50mg of panitumumab-IRDye800CW followed by surgery 1-5days later. Following resection, primary tumor specimens were imaged in a closed-field fluorescence imaging device, before and after formalin fixation. The fluorescence images of formalin-fixed specimens were compared with images prior to formalin fixation. Regions of interest were drawn on the primary tumor and on the adjacent normal tissue on the fluorescence images. The mean fluorescence intensity (MFI) and tumor-to-background ratios (TBRs) of the fresh and formalin-fixed tissues were compared.RESULTS: Of the 30 enrolled patients, 20 tissue specimens were eligible for this study. Formalin fixation led to an average of 10% shrinkage in tumor specimen size (p<0.0001). Tumor MFI in formalin-fixed specimens was on average 10.9% lower than that in the fresh specimens (p=0.0002). However, no statistical difference was found between the TBRs of the fresh specimens and those of the formalin-fixed specimens (p=0.85).CONCLUSIONS: Despite the 11% decrease in MFI between fresh and formalin-fixed tissue specimens, the relative difference between tumor and normal tissue as measured in TBR remained unchanged. This data suggests that evaluation of formalin-fixed tissue for assessing the accuracy of fluorescence-guided surgery approaches could provide a valid, yet more flexible, alternative to fresh tissue analysis.TRIAL REGISTRATION: NCT02415881.

    View details for DOI 10.1007/s11307-020-01553-1

    View details for PubMedID 33078373

  • Photoacoustic Molecular Imaging for the Identification of Lymph Node Metastasis in Head and Neck Cancer using an anti-EGFR Antibody-Dye Conjugate. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Nishio, N., van den Berg, N. S., Martin, B. A., van Keulen, S., Fakurnejad, S., Rosenthal, E. L., Wilson, K. E. 2020


    The presence of lymph node (LN) metastases is an essential prognostic indicator in patients with head and neck squamous cell carcinoma (HNSCC). This study assessed photoacoustic molecular imaging (PAMI) of the anti-epidermal growth factor receptor (EGFR) antibody (panitumumab) conjugated to a near-infrared fluorescent dye, IRDye800CW (panitumumab-IRDye800CW; pan800) for the identification of occult metastatic LNs in patients with HNSCC (n=7). After in vitro photoacoustic imaging characterization of pan800, PAMI was performed on excised neck specimens of patients infused with pan800 prior to surgery. Freshly obtained neck specimens were imaged with three-dimensional, multiwavelength spectroscopic PAMI (680, 686, 740, 800, 860, 924, and 958 nm wavelengths). Harvested LNs were then imaged with a closed-field near-infrared fluorescence imager and histologically examined by the pathologist to determine their metastatic status. A total of 53 LNs with a maximum diameter of 10 mm were analyzed with photoacoustic and fluorescence imaging, of which four were determined to be metastatic on final histopathology. Photoacoustic signal in the LNs corresponding to accumulated pan800 were spectrally unmixed using a linear least square error classification algorithm. Metastatic LNs had a five-fold higher average thresholded photoacoustic signal intensity corresponding to pan800 compared to benign LNs (2.50 ± 1.09 a.u. vs. 0.53 ± 0.32 a.u., p<0.001). Fluorescence imaging showed that metastatic LNs had a two-fold increase in fluorescence signal compared to benign LNs ex vivo (p<0.01, 0.068 ± 0.027 a.u. vs. 0.035 ± 0.018 a.u.) Moreover, the ratio of the average of the highest 10% photoacoustic signal intensity over total average, representative of degree of heterogeneity of pan800 signal in LNs, showed a significant difference between metastatic LNs vs. benign LNs (11.6 ± 13.4 vs. 1.8 ± 0.7, p<0.01) and an area under the receiver operating characteristic (ROC) curve of 0.96 (95% CI; 0.91-1.00). The data indicate that PAMI of IRDye800-labeled tumor-specific antibody may have the potential to identify occult LN metastasis perioperatively in HNSCC patients.

    View details for DOI 10.2967/jnumed.120.245241

    View details for PubMedID 33008927

  • Tumour-specific fluorescence-guided surgery for pancreatic cancer using panitumumab-IRDye800CW: a phase 1 single-centre, open-label, single-arm, dose-escalation study. The lancet. Gastroenterology & hepatology Lu, G., van den Berg, N. S., Martin, B. A., Nishio, N., Hart, Z. P., van Keulen, S., Fakurnejad, S., Chirita, S. U., Raymundo, R. C., Yi, G., Zhou, Q., Fisher, G. A., Rosenthal, E. L., Poultsides, G. A. 2020


    BACKGROUND: Complete surgical resection remains the primary curative option for pancreatic ductal adenocarcinoma, with positive margins in 30-70% of patients. In this study, we aimed to evaluate the use of intraoperative tumour-specific imaging to enhance a surgeon's ability to detect visually occult cancer in real time.METHODS: In this single-centre, open-label, single-arm study, done in the USA, we enrolled patients who had clinically suspicious or biopsy-confirmed pancreatic ductal adenocarcinomas and were scheduled for curative surgery. Eligible patients were 19 years of age or older with a life expectancy of more than 12 weeks and a Karnofsky performance status of at least 70% or an Eastern Cooperative Oncology Group or Zubrod level of one or lower, who were scheduled to undergo curative surgery. Patients were sequentially enrolled into each dosing group and 2-5 days before surgery, patients were intravenously infused with 100 mg of unlabelled panitumumab followed by 25 mg, 50 mg, or 75 mg of the near-infrared fluorescently labelled antibody (panitumumab-IRDye800CW). The primary endpoint was to determine the optimal dose of panitumumab-IRDye800CW in identifying pancreatic ductal adenocarcinomas as measured by tumour-to-background ratio in all patients. The tumour-to-background ratio was defined as the fluorescence signal of the tumour divided by the fluorescence signal of the surrounding healthy tissue. The dose-finding part of this study has been completed. This study is registered with, NCT03384238.FINDINGS: Between April, 2018, and July, 2019, 16 patients were screened for enrolment onto the study. Of the 16 screened patients, two (12%) patients withdrew from the study and three (19%) were not eligible; 11 (69%) patients completed the trial, all of whom were clinically diagnosed with pancreatic ductal adenocarcinoma. The mean tumour-to-background ratio of primary tumours was 3·0 (SD 0·5) in the 25 mg group, 4·0 (SD 0·6) in the 50 mg group, and 3·7 (SD 0·4) in the 75 mg group; the optimal dose was identified as 50 mg. Intraoperatively, near-infrared fluorescence imaging provided enhanced visualisation of the primary tumours, metastatic lymph nodes, and small (<2 mm) peritoneal metastasis. Intravenous administration of panitumumab-IRDye800CW at the doses of 25 mg, 50 mg, and 75 mg did not result in any grade 3 or higher adverse events. There were no serious adverse events attributed to panitumumab-IRDye800CW, although four possibly related adverse events (grade 1 and 2) were reported in four patients.INTERPRETATION: To our knowledge, this study presents the first clinical use of panitumumab-IRDye800CW for detecting pancreatic ductal adenocarcinomas and shows that panitumumab-IRDye800CW is safe and feasible to use during pancreatic cancer surgery. Tumour-specific intraoperative imaging might have added value for treatment of patients with pancreatic ductal adenocarcinomas through improved patient selection and enhanced visualisation of surgical margins, metastatic lymph nodes, and distant metastasis.FUNDING: National Institutes of Health and the Netherlands Organization for Scientific Research.

    View details for DOI 10.1016/S2468-1253(20)30088-1

    View details for PubMedID 32416764

  • Interobserver Agreement Among Gastrointestinal Pathologists Using the Updated Sydney System for Gastric Biopsy Interpretation Pepper, M., Shandiz, A., Charville, G., Higgins, J., Longacre, T., Martin, B. NATURE PUBLISHING GROUP. 2020: 749?50
  • Utility of HER2 Testing in Fine Needle Aspiration and Core Biopsy Samples of Gastrointestinal and Pancreaticobiliary Tract Malignancies Chen, A., Scott, G., Martin, B. NATURE PUBLISHING GROUP. 2020: 333?34
  • Automated Screening of Medical Records for Drug-Induced Liver Injury Scott, G., Chen, A., Park, A., Higgins, J., Martin, B. NATURE PUBLISHING GROUP. 2020: 1548?49
  • Comprehensive genomic sequencing of high-grade neuroendocrine neoplasms Sun, T., Van Hummelen, P., Martin, B., Xia, C., Lee, H., Zhao, L., Hornbacker, K., Ji, H., Kunz, P. L. AMER SOC CLINICAL ONCOLOGY. 2020
  • Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer MOLECULAR IMAGING AND BIOLOGY Nishio, N., van den Berg, N. S., van Keulen, S., Martin, B. A., Fakurnejad, S., Zhou, Q., Lu, G., Chirita, S. U., Kaplan, M. J., Divi, V., Colevas, A. D., Rosenthal, E. L. 2020; 22 (1): 156?64
  • Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research Lu, G., Fakurnejad, S., Martin, B. A., van den Berg, N. S., van Keulen, S., Nishio, N., Zhu, A. J., Chirita, S. U., Zhou, Q., Gao, R. W., Kong, C. S., Fischbein, N., Penta, M., Colevas, A. D., Rosenthal, E. L. 2020


    PURPOSE: The efficacy of antibody-based therapeutics depends on successful drug delivery into solid tumors, therefore there is a clinical need to measure intratumoral antibody distribution. This study aims to develop and validate an imaging and computation platform to directly quantify and predict antibody delivery into human head and neck cancers in a clinical study.EXPERIMENTAL DESIGN: Twenty-four patients received systemic infusion of a near-infrared (NIR) fluorescence-labeled therapeutic antibody followed by surgical tumor resection. A computational platform was developed to quantify the extent of heterogeneity of intratumoral antibody distribution. Both univariate and multivariate regression analysis were used to select the most predictive tumor biological factors for antibody delivery. Quantitative image features from the pre-treatment magnetic resonance imaging (MRI) were extracted and correlated with fluorescence imaging of antibody delivery.RESULTS: This study not only confirmed heterogeneous intratumoral antibody distribution in line with many preclinical reports, but also quantified the extent of inter-patient, inter-tumor, and intra-tumor heterogeneity of antibody delivery. This study demonstrated the strong predictive value of tumor size for intratumoral antibody accumulation and its significant impact on antibody distribution in both primary tumor and lymph node metastasis. Furthermore, this study established the feasibility of using contrast-enhanced MRI to predict antibody delivery.CONCLUSIONS: This study provides a clinically translatable platform to measure antibody delivery into solid tumors and yields valuable insight into clinically relevant antibody tumor penetration, with implications in the selection of patients amenable to antibody therapy and the design of more effective dosing strategies.

    View details for DOI 10.1158/1078-0432.CCR-19-3717

    View details for PubMedID 31980465

  • Design of optical imaging probes by screening of diverse substrate libraries directly in disease tissue extracts. Angewandte Chemie (International ed. in English) Tholen, M., Yim, J. J., Groborz, K., Yoo, E., Martin, B. A., van den Berg, N. S., Drag, M., Bogyo, M. 2020


    Fluorescently-quenched probes that are specifically activated in the cancer microenvironment have great potential application for diagnosis, early detection and surgical guidance. These probes are often designed to target specific enzymes associated with disease by direct optimization using single purified enzymes. However, this can result in painstaking chemistry efforts to produce a probe with suboptimal performance when applied in vivo. We describe here an alternate, unbiased activity-profiling approach in which whole tissue extracts are used to directly identify optimal peptide sequences for probe design. Screening of tumor extracts with a hybrid combinatorial substrate library (HyCoSuL) identified a combination of natural and non-natural amino acid residues that was used to generate highly efficient tumor-specific probes. This new strategy simplifies and enhances the process of probe optimization without any a priori knowledge of enzyme targets and has the potential to be applied to diverse disease states using clinical or animal model tissues samples.

    View details for DOI 10.1002/anie.202006719

    View details for PubMedID 32589815

  • Impact of a deep learning assistant on the histopathologic classification of liver cancer. NPJ digital medicine Kiani, A., Uyumazturk, B., Rajpurkar, P., Wang, A., Gao, R., Jones, E., Yu, Y., Langlotz, C. P., Ball, R. L., Montine, T. J., Martin, B. A., Berry, G. J., Ozawa, M. G., Hazard, F. K., Brown, R. A., Chen, S. B., Wood, M., Allard, L. S., Ylagan, L., Ng, A. Y., Shen, J. 2020; 3: 23


    Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p?=?0.184, OR?=?1.281), it significantly improved the accuracy (p?=?0.045, OR?=?1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p?=?0.000, OR?=?4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p?=?0.000, OR?=?0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

    View details for DOI 10.1038/s41746-020-0232-8

    View details for PubMedID 32140566

    View details for PubMedCentralID PMC7044422

  • Origins and clonal convergence of gastrointestinal IgE+ B cells in human peanut allergy. Science immunology Hoh, R. A., Joshi, S. A., Lee, J. Y., Martin, B. A., Varma, S., Kwok, S., Nielsen, S. C., Nejad, P., Haraguchi, E., Dixit, P. S., Shutthanandan, S. V., Roskin, K. M., Zhang, W., Tupa, D., Bunning, B. J., Manohar, M., Tibshirani, R., Fernandez-Becker, N. Q., Kambham, N., West, R. B., Hamilton, R. G., Tsai, M., Galli, S. J., Chinthrajah, R. S., Nadeau, K. C., Boyd, S. D. 2020; 5 (45)


    B cells in human food allergy have been studied predominantly in the blood. Little is known about IgE+ B cells or plasma cells in tissues exposed to dietary antigens. We characterized IgE+ clones in blood, stomach, duodenum, and esophagus of 19 peanut-allergic patients, using high-throughput DNA sequencing. IgE+ cells in allergic patients are enriched in stomach and duodenum, and have a plasma cell phenotype. Clonally related IgE+ and non-IgE-expressing cell frequencies in tissues suggest local isotype switching, including transitions between IgA and IgE isotypes. Highly similar antibody sequences specific for peanut allergen Ara h 2 are shared between patients, indicating that common immunoglobulin genetic rearrangements may contribute to pathogenesis. These data define the gastrointestinal tract as a reservoir of IgE+ B lineage cells in food allergy.

    View details for DOI 10.1126/sciimmunol.aay4209

    View details for PubMedID 32139586

  • Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates. Nature communications Lu, G., Nishio, N., van den Berg, N. S., Martin, B. A., Fakurnejad, S., van Keulen, S., Colevas, A. D., Thurber, G. M., Rosenthal, E. L. 2020; 11 (1): 5667


    Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.

    View details for DOI 10.1038/s41467-020-19498-y

    View details for PubMedID 33168818

  • A Phase I/II Trial of Intratumoral CpG, Local Low-Dose Radiation, and Oral Ibrutinib in Patients with Low-Grade B-Cell Lymphoma Shree, T., Khodadoust, M. S., Czerwinski, D. K., Frank, M. J., Hong, W. X., Greenstein, R., Long, S. R., Martin, B., Levy, R. AMER SOC HEMATOLOGY. 2019
  • Optical molecular imaging can differentiate metastatic from benign lymph nodes in head and neck cancer. Nature communications Nishio, N., van den Berg, N. S., van Keulen, S., Martin, B. A., Fakurnejad, S., Teraphongphom, N., Chirita, S. U., Oberhelman, N. J., Lu, G., Horton, C. E., Kaplan, M. J., Divi, V., Colevas, A. D., Rosenthal, E. L. 2019; 10 (1): 5044


    Identification of lymph node (LN) metastasis is essential for staging of solid tumors, and as a result, surgeons focus on harvesting significant numbers of LNs during ablative procedures for pathological evaluation. Isolating those LNs most likely to harbor metastatic disease can allow for a more rigorous evaluation of fewer LNs. Here we evaluate the impact of a systemically injected, near-infrared fluorescently-labeled, tumor-targeting contrast agent, panitumumab-IRDye800CW, to facilitate the identification of metastatic LNs in the ex vivo setting for head and neck cancer patients. Molecular imaging demonstrates a significantly higher mean fluorescence signal in metastatic LNs compared to benign LNs in head and neck cancer patients undergoing an elective neck dissection. Molecular imaging to preselect at-risk LNs may thus allow a more rigorous examination of LNs and subsequently lead to improved prognostication than regular neck dissection.

    View details for DOI 10.1038/s41467-019-13076-7

    View details for PubMedID 31695030

  • Probe-based fluorescence dosimetry of an antibody-dye conjugate to identify head and neck cancer as a first step to fluorescence-guided tissue preselection for pathological assessment. Head & neck Nishio, N., van Keulen, S., van den Berg, N. S., Lu, G., LaRochelle, E. P., Davis, S. C., Martin, B. A., Fakurnejad, S., Zhou, Q., Birkeland, A. C., Kaplan, M. J., Divi, V., Colevas, A. D., Pogue, B. W., Rosenthal, E. L. 2019


    BACKGROUND: Despite the rapid growth of fluorescence imaging, accurate sampling of tissue sections remains challenging. Development of novel technologies to improve intraoperative assessment of tissue is needed.METHODS: A novel contact probe-based fluorescence dosimeter device, optimized for IRDye800CW quantification, was developed. After evaluation of the device in a phantom setup, its clinical value was defined ex vivo in patients with head and neck squamous cell carcinoma who received panitumumab-IRDye800CW.RESULTS: Ten patients were enrolled with a total of 216 data points obtained. Final histopathology showed tumor in 119 spots and normal tissue in 97 spots. Fluorescence-to-excitation ratios in tumor tissue were more than three times higher than those in normal tissue. The area under the curve was 0.86 (95% CI: 0.81-0.91) for tumor detection.CONCLUSIONS: Fluorescence-guided tissue preselection using a fluorescence dosimeter could have substantial impact on tissue sampling for frozen section analysis and potentially reduce sampling errors.

    View details for DOI 10.1002/hed.25964

    View details for PubMedID 31571335

  • Fluorescence molecular imaging for identification of high-grade dysplasia in patients with head and neck cancer. Oral oncology Fakurnejad, S., van Keulen, S., Nishio, N., Engelen, M., van den Berg, N. S., Lu, G., Birkeland, A., Baik, F., Colevas, A. D., Rosenthal, E. L., Martin, B. A. 2019; 97: 50?55


    OBJECTIVE: High-grade dysplasia is associated with a risk of malignant transformation, and it is necessary to distinguish from normal epithelium or low-grade dysplasia, especially in the intraoperative setting. We hypothesize that an anti-epidermal growth factor receptor (EGFR) contrast agent can be used to differentiate high-grade dysplasia from low-grade dysplasia and normal epithelium.MATERIALS AND METHODS: Patients with biopsy proven head and neck squamous cell carcinoma (HNSCC) were enrolled in a clinical trial using systemically injected fluorescently labeled anti-EGFR antibody (panitumumab-IRDye800CW) (NCT02415881). Paraffin embedded tumor specimens from 11 patients were evaluated by fluorescence histopathology. Hematoxylin and eosin (H&E) slides were reviewed by a board-certified pathologist, and regions of invasive squamous cell carcinoma, high-grade dysplasia and low-grade dysplasia were delineated. EGFR expression was assessed for each patient by way of immunohistochemistry.RESULTS: 11 patients were included in the study with a total of 219 areas on tissue sections analyzed; 68 normal epithelium, 53 low-grade dysplasia, 48 high-grade dysplasia, and 50 malignant regions. The signal-to-background ratio (SBR) increased proportionally with increasing grade of dysplasia; normal epithelium (1.5?±?0.1), low-grade dysplasia (1.8?±?0.1), high-grade dysplasia: (2.3?±?0.2). High-grade dysplasia had a significantly higher SBR when compared to normal or low-grade dysplasia (p?

    View details for DOI 10.1016/j.oraloncology.2019.08.008

    View details for PubMedID 31421471

  • Interim results of a Phase I/II trial of intratumoral CpG, local low-dose radiation, and oral ibrutinib in patients with low-grade B-cell lymphoma Shree, T., Khodadoust, M. S., Czerwinski, D., Frank, M. J., Hong, W. X., Greenstein, R., Guo, S., Long, S., Martin, B. A., Levy, R. AMER ASSOC CANCER RESEARCH. 2019
  • The Clinical Application of Fluorescence-Guided Surgery in Head and Neck Cancer JOURNAL OF NUCLEAR MEDICINE van Keulen, S., Nishio, N., Fakurnejad, S., Birkeland, A., Martin, B. A., Lu, G., Zhou, Q., Chirita, S. U., Forouzanfar, T., Colevas, A., van den Berg, N. S., Rosenthal, E. L. 2019; 60 (6): 758?63
  • The Sentinel Margin: Intraoperative ex-vivo Specimen Mapping Using Relative Fluorescence Intensity. Clinical cancer research : an official journal of the American Association for Cancer Research van Keulen, S., Nishio, N., Birkeland, A., Fakurnejad, S., Martin, B. A., Forouzanfar, T., Cunanan, K., Colevas, A. D., van den Berg, N. S., Rosenthal, E. L. 2019


    PURPOSE: Despite major advancements in surgical oncology, the positive margin rate for primary head and neck cancer resection remains around 15-30%. In particular, the deep surface margin is the most challenging to adequately assess. Inadequate margins are directly correlated to poor survival, and as such, mitigation of these rates is critical to improve patient outcomes. We have developed an ex vivo imaging strategy that utilizes fluorescence intensity-peaks (relative to background signal) of an injected anti-epidermal growth factor receptor antibody conjugated to a fluorescent probe to locate potential close or positive margins on the deep surface of the resected tumor specimen.EXPERIMENTAL DESIGN: Twelve patients with head and neck cancer scheduled for surgery received systemic administration of a tumor-specific contrast-agent (panitumumab-IRDye800). After surgical resection, the tumor specimen was imaged using a fluorescence imager. The three highest fluorescence intensity-peaks on the deep surface of the specimen were isolated and correlated to histology to determine the margin distance at these regions.RESULTS: Relative fluorescence peak-intensities identified the closest margin on the deep surface of the specimen within 2.5 minutes. The highest intensity-peak consistently (100%) detected the closest margin to the tumor. The difference in tumor margin distance between the first and second highest fluorescence intensity-peak averaged 2.1±1.4mm. The tumor-margin difference between the second and third highest peak averaged 1.6±0.6mm.CONCLUSIONS: Fluorescence intensity-peaks can identify the region on the specimen where tumor is closest to specimen's edge on the deep surface. This technique could have broad applications in obtaining adequate margins in oncological surgery.

    View details for DOI 10.1158/1078-0432.CCR-19-0319

    View details for PubMedID 31142505

  • Serial Fine Needle Aspiration (FNA) Allows Direct Sampling of Low-grade Lymphoma Tumor Nodules and Subsequent Analysis of the Tumor and Its Microenvironment in Clinical Trial Patients Receiving Immunotherapy Mooney, K., Long, S., Martin, B., Frank, M., Czerwinski, D., Levy, R., Guo, X., Shree, T., Greenstein, R. NATURE PUBLISHING GROUP. 2019
  • A novel group of HPV-related adenocarcinomas of the lower anogenital tract (vagina, vulva, and anorectum) in women and men resembling HPV-related endocervical adenocarcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Voltaggio, L., McCluggage, W. G., Iding, J. S., Martin, B., Longacre, T. A., Ronnett, B. M. 2019


    Human papillomavirus (HPV) is an oncogenic virus associated with the development of several human cancers. Primary vaginal, vulvar, and anal adenocarcinomas are rare and, to date, have rarely been shown to be associated with HPV infection. We report a series of nine HPV-related adenocarcinomas of the lower anogenital tract distal to the cervix. The tumors involved the vagina (4), anorectum (3), and vulva (2). Two of the three anorectal cases involved men. Patients presented with a vulvar or vaginal mass/nodule, painless rectal bleeding, or during screening colonoscopy. Lesions ranged in size from 3.2 to 8.4?cm. The most salient morphologic characteristic was the presence of papillary or villiform/villoglandular architecture in all cases. Tumors displayed features similar to those of usual type high-risk HPV-related endocervical adenocarcinoma, namely, mucinous or mucin-poor (pseudoendometrioid) features or a hybrid of these, with columnar cells with crowded, cigar-shaped to ovoid irregular nuclei. Mitoses (mostly apical) and apoptotic bodies were easily identified. Adenosis was present in two vaginal cases. One anal tumor featured abundant intracytoplasmic mucin that was multivacuolated in some areas imparting a "clear cell"-like appearance. All tumors were diffusely and strongly positive for p16. Seven of seven tested cases were positive for high-risk HPV by in situ hybridization or polymerase chain reaction. Follow-up information, available in five patients, revealed two local recurrences but no tumor related deaths or distant metastases. We report the first well-documented series of HPV-associated primary adenocarcinomas of the vagina, vulva, and anorectum and broaden the spectrum of HPV-related neoplasia involving the lower anogenital tract in both women and men.

    View details for DOI 10.1038/s41379-019-0437-z

    View details for PubMedID 31857682

  • The Runs: Sudden Copious Ostomy Output in an Acolonic Hirschsprung Disease Patient with Short Gut Syndrome DIGESTIVE DISEASES AND SCIENCES Nakayuenyongsuk, W., Barnes, D., Martin, B., Christofferson, M., Kerner, J. 2019; 64 (1): 56?59
  • Intraoperative Tumor Assessment Using Real-Time Molecular Imaging in Head and Neck Cancer Patients. Journal of the American College of Surgeons Keulen, S. v., Nishio, N., Fakurnejad, S., van den Berg, N. S., Lu, G., Birkeland, A., Martin, B. A., Forouzanfar, T., Dimitrios Colevas, A., Rosenthal, E. L. 2019


    In head and neck cancer, surgical resection using primarily visual and tactile feedback is considered gold standard for solid tumors. Due to high numbers of tumor-involved surgical margins which are directly correlated to poor clinical outcome, intraoperative optical imaging trials have rapidly proliferated over the past five years. However, few studies report on intraoperative in situ imaging data that could support surgical resection. To demonstrate the clinical application of in situ surgical imaging, we report on the imaging data that is directly (i.e. in real-time) available to the surgeon.Fluorescence intensities and tumor-to-background ratios (TBRs) were determined from the intraoperative imaging data - the view as seen by the surgeon during tumor resection - of 20 patients and correlated to patient and tumor characteristics including age, sex, tumor site, tumor size, histological differentiation and EGFR expression. Furthermore, different lighting conditions in regard to surgical workflow were evaluated.Under these circumstances, intraoperative TBRs of the primary tumors averaged 2.2±0.4 (range 1.5-2.9). Age, sex, tumor site, and tumor size did not have a significant effect on open-field intraoperative molecular imaging of the primary tumors (p>0.05). In addition, variation in EGFR expression levels or the presence of ambient light did not seem to alter TBRs.We present the results of successful in situ intraoperative imaging of primary tumors alongside the optimal conditions with respect to both molecular image acquisition and surgical workflow. This study illuminates the potentials of open-field molecular imaging to assist the surgeon in achieving successful cancer removal.

    View details for DOI 10.1016/j.jamcollsurg.2019.09.007

    View details for PubMedID 31568855

  • Rapid, non-invasive fluorescence margin assessment: Optical specimen mapping in oral squamous cell carcinoma. Oral oncology van Keulen, S., van den Berg, N. S., Nishio, N., Birkeland, A., Zhou, Q., Lu, G., Wang, H., Middendorf, L., Forouzanfar, T., Martin, B. A., Colevas, A. D., Rosenthal, E. L. 2019; 88: 58?65


    OBJECTIVE: Surgical resection remains the primary treatment for the majority of solid tumors. Despite efforts to obtain wide margins, close or positive surgical margins (<5?mm) are found in 15-30% of head and neck cancer patients. Obtaining negative margins requires immediate, intraoperative feedback of margin status. To this end, we propose optical specimen mapping of resected tumor specimens immediately after removal.MATERIALS AND METHODS: A first-in-human pilot study was performed in patients (n?=?8) after infusion of fluorescently labeled antibody, panitumumab-IRDye800 to allow surgical mapping of the tumor specimen. Patients underwent standard of care surgical resection for head and neck squamous cell carcinoma (HNSCC). Optical specimen mapping was performed on the primary tumor specimen and correlated with pathological findings after tissue processing.RESULTS: Optical mapping of the specimen had a 95% sensitivity and 89% specificity to detect cancer within 5?mm (n?=?160) of the cut surface. To detect tumor within 2?mm of the specimen surface, the sensitivity of optical specimen mapping was 100%. The maximal observed penetration depth of panitumumab-IRDye800 through human tissue in our study was 6.3?mm.CONCLUSION: Optical specimen mapping is a highly sensitive and specific method for evaluation of margins within <5?mm of the tumor mass in HNSCC specimens. This technology has potentially broad applications for ensuring adequate tumor resection and negative margins in head and neck cancers.

    View details for PubMedID 30616798

  • Intraoperative Molecular Imaging for ex vivo Assessment of Peripheral Margins in Oral Squamous Cell Carcinoma. Frontiers in oncology Fakurnejad, S., Krishnan, G., van Keulen, S., Nishio, N., Birkeland, A. C., Baik, F. M., Kaplan, M. J., Colevas, A. D., van den Berg, N. S., Rosenthal, E. L., Martin, B. A. 2019; 9: 1476


    Objective: Complete surgical resection is the standard of care for treatment of oral cancer although the positive margin rate remains 15-30%. Tissue sampling from the resected specimen and from the wound bed for frozen section analysis (FSA) remains the mainstay for intraoperative margin assessment but is subject to sampling error and can require the processing of multiple samples. We sought to understand if an ex vivo imaging strategy using a tumor-targeted fluorescently labeled antibody could accurately identify the closest peripheral margin on the mucosal surface of resected tumor specimen, so that this "sentinel margin" could be used to guide pathological sampling. Materials and Methods: Twenty-nine patients with oral squamous cell carcinoma scheduled for surgical resection were consented for the study and received systemic administration of a tumor-targeted fluorescently labeled antibody (Panitumumab IRDye800CW). After surgical resection, the tumor specimen was imaged using a closed-field fluorescent imaging device. Relevant pathological data was available for five patients on retrospective review. For each of these five patients, two regions of highest fluorescence intensity at the peripheral margin and one region of lowest fluorescence intensity were identified, and results were correlated with histology to determine if the region of highest fluorescence intensity along the mucosal margin (i.e., the sentinel margin) was truly the closest margin. Results: Imaging acquisition of the mucosal surface of the specimen immediately after surgery took 30 s. In all of the specimens, the region of highest fluorescence at the specimen edge had a significantly smaller margin distance than other sampled regions. The average margin distance at the closest, "sentinel," margin was 3.2 mm compared to a margin distance of 8.0 mm at other regions (p < 0.0001). Conclusions: This proof-of-concept study suggests that, when combined with routine FSA, ex vivo fluorescent specimen imaging can be used to identify the closest surgical margin on the specimen. This approach may reduce sampling error of intraoperative evaluation, which should ultimately improve the ability of the surgeon to identify the sentinel margin. This rapid sentinel margin identification improves the surgeon's orientation to areas most likely to be positive in the surgical wound bed and may expedite pathology workflow.

    View details for DOI 10.3389/fonc.2019.01476

    View details for PubMedID 31998640

    View details for PubMedCentralID PMC6965069

  • Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome. BMJ open gastroenterology Hitchins, M. P., Vogelaar, I. P., Brennan, K., Haraldsdottir, S., Zhou, N., Martin, B., Alvarez, R., Yuan, X., Kim, S., Guindi, M., Hendifar, A. E., Kalady, M. F., DeVecchio, J., Church, J. M., de la Chapelle, A., Hampel, H., Pearlman, R., Christensen, M., Snyder, C., Lanspa, S. J., Haile, R. W., Lynch, H. T. 2019; 6 (1): e000299


    The plasma-based methylated SEPTIN9 (mSEPT9) is a colorectal cancer (CRC) screening test for adults aged 50-75 years who are at average risk for CRC and have refused colonoscopy or faecal-based screening tests. The applicability of mSEPT9 for high-risk persons with Lynch syndrome (LS), the most common hereditary CRC condition, has not been assessed. This study sought preliminary evidence for the utility of mSEPT9 for CRC detection in LS.Firstly, SEPT9 methylation was measured in LS-associated CRC, advanced adenoma, and subject-matched normal colorectal mucosa tissues by pyrosequencing. Secondly, to detect mSEPT9 as circulating tumor DNA, the plasma-based mSEPT9 test was retrospectively evaluated in LS subjects using the Epi proColon 2.0 CE assay adapted for 1mL plasma using the "1/1 algorithm". LS case groups included 20 peri-surgical cases with acolonoscopy-based diagnosis of CRC (stages I-IV), 13 post-surgical metastatic CRC, and 17 pre-diagnosis cases. The control group comprised 31 cancer-free LS subjects.Differential hypermethylation was found in 97.3% (36/37) of primary CRC and 90.0% (18/20) of advanced adenomas, showing LS-associated neoplasia frequently produce the mSEPT9 biomarker. Sensitivity of plasma mSEPT9 to detect CRC was 70.0% (95% CI, 48%-88%)in cases with a colonoscopy-based CRC diagnosis and 92.3% (95% CI, 64%-100%) inpost-surgical metastatic cases. In pre-diagnosis cases, plasma mSEPT9 was detected within two months prior to colonoscopy-based CRC diagnosis in 3/5 cases. Specificity in controls was 100% (95% CI 89%-100%).These preliminary findings suggest mSEPT9 may demonstrate similar diagnostic performance characteristics in LS as in the average-risk population, warranting a well-powered prospective case-control study.

    View details for DOI 10.1136/bmjgast-2019-000299

    View details for PubMedID 31275589

    View details for PubMedCentralID PMC6577308

  • Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence CANCER RESEARCH Gao, R. W., Teraphongphom, N. T., van den Berg, N. S., Martin, B. A., Oberhelman, N. J., Divi, V., Kaplan, M. J., Hong, S. S., Lu, G., Ertsey, R., Tummers, W. J., Gomez, A. J., Holsinger, F., Kong, C. S., Colevas, A. D., Warram, J. M., Rosenthal, E. L. 2018; 78 (17): 5144?54
  • Practical Approach to the Use of Helicobacter Immunohistochemistry Based on a Single-Institution Retrospective Quality Assurance Review Forgo, E., Longacre, T., Martin, B. NATURE PUBLISHING GROUP. 2018: 774?75
  • Intractable Diarrhea in Two Brothers: Late Diagnosis of Tufting Enteropathy in Adolescence. Digestive diseases and sciences Haas, K., Martin, B., Martín, M., Kerner, J. 2016; 61 (2): 381-383

    View details for DOI 10.1007/s10620-015-3766-x

    View details for PubMedID 26115750

  • Pancreatic Metastases: Potential for Misdiagnosis on Fine Needle Aspiration Martin, B. A., Longacre, T. A., Kong, C. S. NATURE PUBLISHING GROUP. 2016: 108A
  • 46,XY disorders of sex development and congenital diaphragmatic hernia: a case with dysmorphic facies, truncus arteriosus, bifid thymus, gut malrotation, rhizomelia, and adactyly. American journal of medical genetics. Part A Esplin, E. D., Chaib, H., Haney, M., Martin, B., Homeyer, M., Urban, A. E., Bernstein, J. A. 2015; 167 (6): 1360-1364


    The association of 46,XY disorder of sex development (DSD) with congenital diaphragmatic hernia (CDH) is rare, but has been previously described with and without other congenital anomalies. Literature review identified five cases of 46,XY DSD associated with CDH and other congenital anomalies. These five cases share characteristics including CDH, 46,XY karyotype with external female appearing or ambiguous genitalia, cardiac anomalies, and decreased life span. The present case had novel features including truncus arteriosus, bifid thymus, gut malrotation, and limb anomalies consisting of rhizomelia and adactyly. With this case report, we present a review of the literature of cases of 46,XY DSD and CDH in association with multiple congenital abnormalities. This case may represent a unique syndrome of 46,XY DSD and diaphragmatic hernia or a more severe presentation of a syndrome represented in the previously reported cases. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.37037

    View details for PubMedID 25898814

  • Mistaken identity: Legionella micdadei appearing as acid-fast bacilli on lung biopsy of a hematopoietic stem cell transplant patient TRANSPLANT INFECTIOUS DISEASE Waldron, P. R., Martin, B. A., Ho, D. Y. 2015; 17 (1): 89-93


    Legionella micdadei is a potential cause of invasive lung infections in immunocompromised hosts. On biopsy specimens, it can appear as an acid-fast bacillus (AFB) and can be mistaken for a member of genus Mycobacterium. As Legionella requires selective media to grow in culture, and the commonly used, commercially available urine antigen test for Legionella only detects Legionella pneumophila serogroup-1, but not L. micdadei, it is important to consider this organism in the differential diagnosis for AFB in immunocompromised hosts. We report a case of L. micdadei infection, which was initially treated empirically for non-tuberculous mycobacteria based on AFB staining of biopsy tissue before the final diagnosis was made.

    View details for DOI 10.1111/tid.12334

    View details for Web of Science ID 000348532400013

    View details for PubMedID 25573597

    View details for PubMedCentralID PMC4368428

  • Lynch Syndrome Screening: Discordance in MMR and Germline Test Results Mafnas, C., Martin, B., Ford, J., Longacre, T. NATURE PUBLISHING GROUP. 2015: 177A
  • Universal Screening for Gynecologic and Colorectal Cancer: A Single Institution Experience Martin, B., Mafnas, C., Ford, J., Longacre, T. NATURE PUBLISHING GROUP. 2015: 297A
  • Evaluation of intestinal biopsies for pediatric enteropathy: a proposed immunohistochemical panel approach. American journal of surgical pathology Martin, B. A., Kerner, J. A., Hazard, F. K., Longacre, T. A. 2014; 38 (10): 1387-1395


    Congenital enteropathies are rare disorders with significant clinical consequences; however, definitive diagnosis based on morphologic assessment of duodenal biopsies with routine stains alone is often impossible. To determine the role of immunohistochemistry (IHC) in the evaluation for microvillous inclusion disease, congenital tufting enteropathy (intestinal epithelial dysplasia), and enteroendocrine cell dysgenesis, a series of duodenal biopsies from 26 pediatric patients with chronic/intractable diarrhea was retrospectively reviewed. IHC stains for CD10, EpCAM, chromogranin, and villin were performed on all biopsies, and the results were correlated with hematoxylin and eosin and ultrastructural findings using electron microscopy, when available. Biopsies from 2 patients diagnosed with microvillous inclusion disease at the time of original biopsy demonstrated diffuse CD10-positive cytoplasmic inclusions within enterocytes and normal expression of EpCAM and chromogranin. Biopsies from 3 patients, including 2 siblings with confirmed EPCAM mutations, demonstrated complete loss of EpCAM expression and normal expression of CD10 and chromogranin; electron microscopic evaluation revealed characteristic ultrastructural findings of tufting enteropathy. Biopsies from 1 patient with a confirmed NEUROG3 mutation demonstrated an absence of intestinal enteroendocrine cells by chromogranin staining, consistent with enteroendocrine cell dysgenesis. Four patients' biopsies displayed nonspecific staining patterns for CD10 and/or EpCAM with normal expression of chromogranin, and 16 patients' biopsies exhibited normal expression for all 3 markers. Villin stains demonstrated heterogenous brush border labeling with nonspecific cytoplasmic reactivity, a pattern variably present throughout the biopsy series. In conclusion, the routine use of an IHC panel of CD10, EpCAM, and chromogranin is warranted in patients meeting specific age and/or clinical criteria, as the morphologic findings of congenital enteropathies may be subtle, focal, or inapparent on routine stains.

    View details for DOI 10.1097/PAS.0000000000000314

    View details for PubMedID 25188866

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