Academic Appointments


  • Clinical Assistant Professor, Pathology

Professional Education


  • 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


  • 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

    Abstract

    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 ClinicalTrials.gov, 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
  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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)

    Abstract

    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

  • 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

    Abstract

    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

    Abstract

    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

    Abstract

    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 < 0.05). Fluorescence histopathology positively correlated with EGFR expression by immunohistochemistry, which also increased proportionally with increasing degree of dysplasia.CONCLUSION: Molecular imaging with an anti-EGFR agent can successfully discriminate high-grade dysplastic lesions from low-grade dysplasia and normal epithelium.

    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 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

    Abstract

    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

  • Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging 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. 2019

    Abstract

    PURPOSE: To identify the optimal dosing strategy for fluorescence-guided surgery in patients with head and neck squamous cell carcinoma, we conducted a dose-ranging study evaluating the anti-epidermal growth factor receptor (EGFR) therapeutic antibody, panitumumab, that was fluorescently labeled with the near-infrared dye IRDye800CW.PROCEDURES: Patients (n=24) received either 0.5 or 1.0mg/kg panitumumab-IRDye800CW in the weight-based dosing group or 25 or 50mg panitumumab-IRDye800CW in the fixed dosing group. Following surgery, whole primary specimens were imaged in a closed-field device and the mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were assessed. Clinical variables, including dose, time of infusion-to-surgery, age, unlabeled dose, gender, primary tumor site, and tumor size, were analyzed to evaluate the factors affecting the fluorescence intensity in order to identify the optimal dose for intraoperative fluorescence imaging.RESULTS: A total of 24 primary tumor specimens were imaged and analyzed in this study. Although no correlations between TBR and dose of panitumumab-IRDye800CW were found, there were moderate-strong correlations between the primary tumor MFI and panitumumab-IRDye800CW dose for fixed dose (mg) (R2=0.42) and for dose/weight (mg/kg) (R2=0.54). Results indicated that the optimal MFI was at approximately 50mg for fixed dose and 0.75mg/kg for dose/weight. No significant differences were found for the primary tumor MFI and TBRs between the weight-based dosing and the fixed dosing groups. MFIs significantly increased when the infusion-to-surgery window was reduced to within 2days (vs. 3days or more, p<0.05).CONCLUSIONS: Antibody-based imaging for surgical resection is under investigation in multiple clinical trials. Our data suggests that a fixed dose of 50mg is an appropriate diagnostic dose for successful surgical fluorescence imaging.

    View details for PubMedID 31054001

  • The Clinical Application of Fluorescence-Guided Surgery in Head and Neck Cancer. Journal of nuclear medicine : official publication, Society 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, D., van den Berg, N. S., Rosenthal, E. L. 2019

    Abstract

    Although surgical resection has been the primary treatment modality of solid tumors for decades, surgeons still rely on visual cues and palpation to delineate healthy from cancerous tissue. This may contribute to the high rate (up to 30%) of positive margins in head and neck cancer resections. Margin status in these patients is the most important prognostic factor for overall survival. In addition, second primary lesions may be present at the time of surgery. Although often unnoticed by the medical team, these lesions can have significant survival ramifications. We hypothesize that real-time fluorescence imaging can enhance intraoperative decision-making by aiding the surgeon in detecting close or positive margins and visualizing unanticipated regions of primary disease. The purpose of this study was to assess the clinical utility of real-time fluorescence imaging for intraoperative decision-making. Methods: Head and neck cancer patients (n = 14) scheduled for curative resection were enrolled in a clinical trial evaluating panitumumab-IRDye800CW for surgical guidance (NCT02415881). Open-field fluorescence imaging was performed throughout the surgical procedure. The fluorescence signal was quantified as signal-to-background ratios to characterize the fluorescence contrast of regions of interest relative to background. Results: Fluorescence imaging was able to improve surgical decision-making in three cases (21.4%); identification of a close margin (n = 1) and unanticipated regions of primary disease (n = 2). Conclusion: This study demonstrates the clinical applications of fluorescence imaging on intraoperative decision-making. This information is required for designing phase III clinical trials using this technique. Furthermore, this study is the first to demonstrate this application for intraoperative decision-making during resection of primary tumors.

    View details for PubMedID 30733319

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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. 2018

    View details for PubMedID 30097892

  • 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. S., Gomez, A. J., Holsinger, F. C., Kong, C. S., Colevas, A. D., Warram, J. M., Rosenthal, E. L. 2018

    Abstract

    For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor-mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. 21 adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n=3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n=5) received 0.5mg/kg, cohort 2B (n=7) received 1mg/kg, and cohort 3 (n=6) received 50 mg. Patients were followed 30 days post-infusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2-3, compared to ex vivo specimen imaging TBR of 5-6. We obtained clear differentiation between tumor and normal tissue, with a three-fold signal difference between positive and negative specimens (p<0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy which are otherwise less amenable to image guidance.

    View details for PubMedID 29967260

  • 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

  • 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

    Abstract

    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

    Abstract

    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

  • 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

    Abstract

    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