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Papers - Oba, Junna

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Medical AI and AI for Medical Sciences.

Sakurada K, Ishikawa T, Oba J, Kuno M, Okano Y, Sakamaki T, Tamura T

JMA journal 8 ( 1 ) 26 - 37 2025.01

Research paper (scientific journal), Joint Work, ISSN 2433-328X

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Using a Systems Engineering Approach to Build a PCR Testing System at a Medical School During the COVID-19 Pandemic

J Oba, M Toriya, Y Uwamino, K Matsuo

Risk Management and Healthcare Policy, 649-662 17 649 - 662 2024

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 1179-1594

Background: During the COVID-19 pandemic, there was an increasing need to expand diagnostic testing in hospitals. At Keio University Hospital (KUH), clinical staff were concerned that the demand for PCR testing might exceed the capacity of the Clinical Laboratory. In response, basic researchers at Keio University School of Medicine (KUSM) set out to build a new, collaborative, PCR testing system. To be authorized to perform such diagnostic PCR testing, KUSM registered its core laboratory as an external clinical laboratory (ECL). Methods: In the pandemic, there was a pressure to build the PCR system quickly. Speed required discussions that developed a shared understanding of the unprecedented, new KUH/KUSM PCR system. To design, construct, and archive the new PCR testing system, we used a systems engineering (SE) approach. This included diagram visualization of functional flows and application of the Unified Architecture Framework (UAF), both of which are often used in system building. We considered daily demand for PCR testing at KUH and KUSM, and daily COVID-19 infections in Japan. Results: We operated the collaborative PCR testing system from August 2020 to June 2022. Given public health insurance reimbursement policies, KUH focused on individuals with suspicious symptoms, while the ECL at KUSM screened samples from asymptomatic individuals. KUSM performed about half as many tests as KUH. Interviewing KUH staff revealed that diagrams helped promote a better understanding of the KUH/KUSM PCR testing system. Conclusion: When designing temporary systems that may be repurposed in the future, we suggest using an SE approach with diagrams and UAF perspectives. This approach will enable stakeholders to understand what is being proposed to be built, and facilitate achieving an informed consensus on the proposed system. We suggest that SE approaches should be widely used in projects that involve building and operating complex, collaborative systems, and documenting the process.

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Multi-modal molecular programs regulate melanoma cell state

Andrews M.C., Oba J., Wu C.J., Zhu H., Karpinets T., Creasy C.A., Forget M.A., Yu X., Song X., Mao X., Robertson A.G., Romano G., Li P., Burton E.M., Lu Y., Sloane R.S., Wani K.M., Rai K., Lazar A.J., Haydu L.E., Bustos M.A., Shen J., Chen Y., Morgan M.B., Wargo J.A., Kwong L.N., Haymaker C.L., Grimm E.A., Hwu P., Hoon D.S.B., Zhang J., Gershenwald J.E., Davies M.A., Futreal P.A., Bernatchez C., Woodman S.E.

Nature Communications (Nature Communications) 13 ( 1 ) 4000 2022.07

Research paper (scientific journal), Joint Work, Lead author, Accepted

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate highly complex multi-omic regulation of melanoma cell intrinsic programs that provide key insights into the molecular maintenance of phenotypic states. These findings have implications for cancer biology and the identification of new therapeutic strategies. Further, these deeply characterized cell lines will serve as an invaluable resource for future research in the field.

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SARS-CoV-2 RT-qPCR testing of pooled saliva samples: A case study of 824 asymptomatic individuals and a questionnaire survey in Japan

Oba J., Taniguchi H., Sato M., Takanashi M., Yokemura M., Sato Y., Nishihara H.

PLoS ONE (PLoS ONE) 17 ( 5 May ) e0263700 2022.05

Research paper (scientific journal), Joint Work, Lead author, Accepted

From the beginning of the COVID-19 pandemic, the demand for diagnostic and screening tests has exceeded supply. Although the proportion of vaccinated people has increased in wealthier countries, breakthrough infections have occurred amid the emergence of new variants. Pooled-sample COVID-19 testing using saliva has been proposed as an efficient, inexpensive, and non-invasive method to allow larger-scale testing, especially in a screening setting. In this study, we aimed to evaluate pooled RT-qPCR saliva testing and to compare the results with individual tests. Employees of Philips Japan, Ltd. were recruited to participate in COVID-19 screening from October to December 2020. Asymptomatic individuals (n = 824) submitted self-collected saliva samples. Samples were tested for the presence of SARS-CoV-2 by RT-qPCR in both 10-sample pools and individual tests. We also surveyed participants regarding their thoughts and behaviors after the PCR screening project. Two of the 824 individuals were positive by RT-qPCR. In the pooled testing, one of these two had no measurable Ct value, but showed an amplification trend at the end of the PCR cycle. Both positive individuals developed cold-like symptoms, but neither required hospitalization. Of the 824 participants, 471 responded to our online questionnaire. Overall, while respondents agreed that PCR screening should be performed regularly, the majority were willing to undergo PCR testing only when it was provided for free or at low cost. In conclusion, pooled testing of saliva samples can support frequent large-scale screening that is rapid, efficient, and inexpensive.

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Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

CJ Terranova, M Tang, M Maitituoheti, AT Raman, AK Ghosh, J Schulz, ...

Cell reports 36 (3) (Cell Reports) 36 ( 3 ) 109410 2021.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 2211-1247

The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.

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The genetic and epigenetic basis of distinct melanoma types

Oba J., Woodman S.E.

Journal of Dermatology (Journal of Dermatology) 48 ( 7 ) 925 - 939 2021.07

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 03852407

Melanoma represents the deadliest skin cancer. Recent therapeutic developments, including targeted and immune therapies have revolutionized clinical management and improved patient outcome. This progress was achieved by rigorous molecular and functional studies followed by robust clinical trials. The identification of key genomic alterations and gene expression profiles have propelled the understanding of distinct characteristics within melanoma subtypes. The aim of this review is to summarize and highlight the main genetic and epigenetic findings of melanomas and highlight their pathological and therapeutic importance.

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RT-PCR screening tests for SARS-CoV-2 with saliva samples in asymptomatic people: Strategy to maintain social and economic activities while reducing the risk of spreading the virus

Oba J., Taniguchi H., Sato M., Takamatsu R., Morikawa S., Nakagawa T., Takaishi H., Saya H., Matsuo K., Nishihara H.

Keio Journal of Medicine (Keio Journal of Medicine) 70 ( 2 ) 35 - 43 2021.06

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 00229717

The year 2020 will be remembered for the coronavirus disease 2019 (COVID-19) pandemic, which continues to affect the whole world. Early and accurate identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental to combat the disease. Among the current diagnostic tests, real-time reverse transcriptase–polymerase chain reaction (RT-qPCR) is the most reliable and frequently used method. Herein, we discuss the interpretation of RT-qPCR results relative to viral infectivity. Although nasopharyngeal swab samples are often used for RT-qPCR testing, they require collection by trained medical staff. Saliva samples are emerging as an inexpensive and efficient alternative for large-scale screening. Pooled-sample testing of saliva has been applied for mass screening of SARS-CoV-2 infection. Current policies recommend isolating people with borderline cycle threshold (Ct) values (35<Ct <40), despite these Ct values indicating minimal infection risk. We propose the new concept of a “social cut-off” Ct value and risk stratification based on the correlation of Ct with infectivity. We also describe the experience of RT-qPCR screening of saliva samples at our institution. It is important to implement a scientific approach to minimize viral transmission while allowing economic and social activities to continue.

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Elevated endogenous SDHA drives pathological metabolism in highly metastatic uveal melanoma

Chattopadhyay C., Oba J., Roszik J., Marszalek J.R., Chen K., Qi Y., Eterovic K., Gordon Robertson A., Burks J.K., McCannel T.A., Grimm E.A., Woodman S.E.

Investigative Ophthalmology and Visual Science (Investigative Ophthalmology and Visual Science) 60 ( 13 ) 4187 - 4195 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 01460404

PURPOSE. Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. METHODS. We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. RESULTS. We identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. CONCLUSIONS. Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.

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Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma

McKean M., Oba J., Ma J., Roth K.G., Wang W.L., Macedo M.P., Carapeto F.C.L., Haydu L.E., Siroy A.E., Vo P., Hong D.S., Eterovic A.K., Patel K.P., Bassett R.L., Grimm E.A., Lazar A.J., Woodman S.E.

Journal of Investigative Dermatology (Journal of Investigative Dermatology) 139 ( 3 ) 728 - 731 2019.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022202X

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CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-l1 blockade

Chen L., Diao L., Yang Y., Yi X., Rodriguez B.L., Li Y., Villalobos P.A., Cascone T., Liu X., Tan L., Lorenzi P.L., Huang A., Zhao Q., Peng D., Fradette J.J., Peng D.H., Ungewiss C., Roybal J., Tong P., Oba J., Skoulidis F., Peng W., Carter B.W., Gay C.M., Fan Y., Class C.A., Zhu J., Rodriguez-Canales J., Kawakami M., Byers L.A., Woodman S.E., Papadimitrakopoulou V.A., Dmitrovsky E., Wang J., Ullrich S.E., Wistuba I.I., Heymach J.V., Qin F.X.F., Gibbons D.L.

Cancer Discovery (Cancer Discovery) 8 ( 9 ) 1156 - 1175 2018.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 21598274

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. SIGNIFICANCE: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8+ T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated.

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Targeting the HGF/MET Axis counters primary resistance to KIT inhibition in KIT-mutant melanoma

Oba J., Kim S.H., Wang W.L., Macedo M.P., Carapeto F., McKean M.A., Van Arnam J., Eterovic A.K., Sen S., Kale C.R., Yu X., Haymaker C.L., Routbort M., Haydu L.E., Bernatchez C., Lazar A.J., Grimm E.A., Hong D.S., Woodman S.E.

JCO Precision Oncology (JCO Precision Oncology) 2 1 - 8 2018

Research paper (scientific journal), Joint Work, Accepted

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Building a versatile medical test system in a pandemic

Oba J., Toriya M., Matsuo K.

Impact 2023 (2), 42-44 (Science Impact Ltd) ( 2 ) 42 - 44 2023.04

Joint Work, Lead author

The COVID-19 pandemic was unprecedented and forced countries to organise and combine resources and develop coordinated responses. Temporary systems were established with the support of researchers and other stakeholders. Dr Junna Oba, Assistant Professor at the Department of Extended Intelligence for Medicine at Keio University School of Medicine (KUSM) is devising methodologies for developing adjustable temporary systems that are quick and efficient to build, apply and dissemble when emergency situations have passed. KUSM helped to respond to the COVID-19 crisis by collaborating with basic science researches to reinforce the PCR testing system in hospitals. Among those involved in this effort were Professor Masako Toriya of Keio University Global Research Institute (KGRI) and Professor Koichi Matsuo from the KUSM's Collaborative Research Resources group. The researchers built from scratch a workflow for effective testing and information sharing. Since this time, the team has been working to build a cooperative network, developing a novel approach to planning, analysing and recording various processes and strategies to address emergency situations that will be shared with the wider healthcare community and policy makers. The researchers used systems engineering methods to launch an unprecedented collaborative system that offers the ability to gain an overall picture of the interrelationships between departments that are working together on the diagnosis, treatment and management of COVID-19.

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Integrative analysis identifies four molecular and clinical subsets in uveal melanoma

Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, Hess JM, Uzunangelov V, Walter V, Danilova L, Lichtenberg TM, Kucherlapati M, Kimes PK, Tang M, Penson A, Babur O, Akbani R, Bristow CA, Hoadley KA, Iype L, Chang MT, Cherniack AD, Benz C, Mills GB, Verhaak RGW, Griewank KG, Felau I, Zenklusen JC, Gershenwald JE, Schoenfield L, Lazar AJ, Abdel-Rahman MH, Roman-Roman S, Stern MH, Cebulla CM, Williams MD, Jager MJ, Coupland SE, Esmaeli B, Kandoth C, Woodman SE.

Cancer Cell 32 ( 2 ) 204 - 220 2017.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1535-6108

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Prediction of oral food challenge outcome using machine learning methods

T Arima, T Hirose, J Oba, T Ishikawa, Y Ichigi, M Ono, M Gondo, K Sugita, ...

Journal of Allergy and Clinical Immunology 155 (2), AB258 2025

Estimating copy number using next-generation sequencing to determine ERBB2 amplification status

K Nakamura, E Aimono, J Oba, H Hayashi, S Tanishima, T Hayashida, ...

Medical Oncology 38, 1-8 (Medical Oncology) 38 ( 4 ) 36 2021.04

Research paper (scientific journal), Accepted, ISSN 13570560

Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as “equivocal”, which means that some ERBB2 amplification cases diagnosed as “HER2 negative” might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

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Pulmonary metastasis secondary to abiraterone-resistant prostate cancer with homozygous deletions of BRCA2: First Japanese case

Izawa M., Kosaka T., Nakamura K., Oba J., Hishida T., Hongo H., Mikami S., Nishihara H., Oya M.

IJU Case Reports (IJU Case Reports) 4 ( 1 ) 14 - 17 2021.01

Research paper (scientific journal), Accepted

Introduction: Most metastatic prostate cancers acquire the capacity for androgen-independent growth and become resistant to androgen deprivation therapy. A patient-focused treatment strategy is needed for aggressive castration-resistant prostate cancer. Case presentation: We report the case of a 62-year-old man who presented with prostatic adenocarcinoma who was treated by radiation and combined androgen blockade. After completion of first-line therapy, he was diagnosed with multiple metastatic castration-resistant prostate cancer in the lung. Second-line therapy with abiraterone acetate resulted in partial remission of the lung metastases. Thoracic surgery was performed to remove the single lung metastasis remaining. Next-generation sequencing of the specimens demonstrated homozygous loss of BRCA2. We note in this case a heterogeneous response to abiraterone acetate may be related to the somatic BRCA2 deletions. Conclusions: We present the first Japanese case of a metastatic abiraterone acetate-resistant castration-resistant prostate cancer accompanied by BRCA2 mutation.

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Defining ERBB2 amplification status by Next-Generation Sequencing

K Nakamura, E Aimono, J Oba, A Ueki, M Imai, E Yanagita, H Yamada, ...

CANCER SCIENCE 112, 320-320 2021

The quality of DNA extracted from FFPE tissue is a critical factor for successful gene profiling test

E Yanagita, H Yamada, R Takamatsu, R Matsuoka, E Aimono, ...

CANCER SCIENCE 112, 324-324 2021

The diagnostic value of genomic screening test for the cancer patients at the initial treatment phase

E Aimono, K Nakamura, E Yanagita, H Yamada, E Sasaki, H Hayashi, ...

CANCER SCIENCE 112, 521-521 2021

Pulmonary metastasis secondary to abiraterone‐resistant prostate cancer with homozygous deletions of BRCA2: first Japanese case

M Izawa, T Kosaka, K Nakamura, J Oba, T Hishida, H Hongo, S Mikami, ...

IJU Case Reports 4 (1), 14-17 2021

Multi-modal cancer cell-intrinsic molecular programs correlate with immunotherapy efficacy

J Oba

CANCER SCIENCE 112, 150-150 2021

The expression of cd74-regulated inflammatory markers in stage iv melanoma: Risk of cns metastasis and patient survival

Ogata D., Roszik J., Oba J., Kim S.H., Bassett R.L., Haydu L.E., Tanese K., Grimm E.A., Ekmekcioglu S.

Cancers (Cancers) 12 ( 12 ) 1 - 13 2020.12

Research paper (scientific journal), Accepted

Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), macrophage migration inhibitory factor (MIF) and improved outcomes with CD74 expression in stage III melanoma. In our current study, we tested our hypothesis on CD74-regulated inflammatory markers’ expression in stage IV melanoma tumors whether the signature is associated with survival outcome and/or risk of developing CNS metastasis. We retrospectively identified 315 patients with stage IV melanoma. In a tissue microarray (TMA), we examined the expression of cells with CD74, its receptor MIF, and downstream inflammatory markers iNOS, nitrotyrosine (NT), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES1). We analyzed the association of those inflammatory markers with overall survival time (OS) and time to CNS metastasis using Kaplan–Meier survival analyses. Our data validates CD74 as a useful prognostic tumor cell protein marker associated with favorable OS as in stage III melanomas, while the tumor NT expression strongly predicts an increased risk of developing CNS metastasis (p = 0.0008) in those patients.

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Non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis

Takeuchi S., Oba J., Esaki H., Furue M.

Journal of Dermatology (Journal of Dermatology) 45 ( 2 ) 158 - 164 2018.02

Research paper (scientific journal), Accepted, ISSN 03852407

Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non-corticosteroid adherence. As such, non-corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non-corticosteroid users and 225 with moderate to severe itch who were defined as non-corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non-corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.

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Trends in hepatocyte growth factor, insulin-like growth factor 1, thyroid-stimulating hormone, and leptin expression levels in uveal melanoma patient serum and tumor tissues: correlation to disease progression

Oba, J., Esmaeli, B., Ellerhorst, J. A., Lyons, G. R., Milton, D. R., Wang, W. L., Macedo, M. P., Lazar, A. J., Grimm, E. A. and Chattopadhyay, C.

Melanoma Res 27 ( 2 ) 126 - 133 2017.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1473-5636

This exploratory study was carried out to determine the expression levels of hepatocyte growth factor (HGF), insulin-like growth factor 1, thyroid-stimulating hormone (TSH), and leptin in serum and tumor samples from patients with uveal melanoma and to investigate the potential association of these expression levels with disease progression and patient survival. Seventeen patients, including nine nonmetastatic and eight metastatic, were included in the study. Eighteen healthy individuals served as controls. The levels of these four proteins in serum and tissue samples were determined by enzyme-linked immunosorbent assays and immunohistochemical staining, respectively. Associations between protein levels and survival, disease progression, and other clinicopathological factors were analyzed statistically. Serum levels of HGF were significantly higher and TSH levels were lower in uveal melanoma patients than in healthy individuals, but the level of neither protein differed significantly between metastatic and nonmetastatic groups. Of the four proteins tested, only serum TSH was significantly associated with patient survival. No correlation was observed between the tissue and serum levels of each protein. The levels of HGF in serum may be markers of uveal melanoma development. The prognostic and predictive values of these potential markers need to be determined in a larger cohort.

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Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set

Roszik, J., Haydu, L. E., Hess, K. R., Oba, J., Joon, A. Y., Siroy, A. E., Karpinets, T. V., Stingo, F. C., Baladandayuthapani, V., Tetzlaff, M. T., Wargo, J. A., Chen, K., Forget, M. A., Haymaker, C. L., Chen, J. Q., Meric-Bernstam, F., Eterovic, A. K., Shaw, K. R., Mills, G. B., Gershenwald, J. E., Radvanyi, L. G., Hwu, P., Futreal, P. A., Gibbons, D. L., Lazar, A. J., Bernatchez, C., Davies, M. A. and Woodman, S. E.

BMC Med 14 ( 1 ) 168 2016.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1741-7015

BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R(2) = 0.73 and R(2) = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.

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Uveal melanoma: From diagnosis to treatment and the science in between

Chattopadhyay, C., Kim, D. W., Gombos, D. S., Oba, J., Qin, Y., Williams, M. D., Esmaeli, B., Grimm, E. A., Wargo, J. A., Woodman, S. E. and Patel, S. P.

Cancer 122 ( 15 ) 2299 - 312 2016.08

Research paper (scientific journal), Accepted, ISSN 1097-0142

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. (c) 2016 American Cancer Society.

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Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma

Oba, J., Wei, W., Gershenwald, J. E., Johnson, M. M., Wyatt, C. M., Ellerhorst, J. A. and Grimm, E. A.

Medicine (Baltimore) 95 ( 11 ) e3073 2016.03

Research paper (scientific journal), Accepted, ISSN 1536-5964

The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and that leptin stimulates proliferation of cultured melanoma cells. Here, we tested the hypothesis that leptin contributes to early melanoma progression by assessing its association with sentinel node positivity in cutaneous melanoma patients. The study enrolled 72 patients who were scheduled to undergo lymphatic mapping and sentinel node biopsy. Fasting blood was obtained before surgery, and serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) with a "raw" (assay value) and an "adjusted" value (raw value divided by body mass index). Leptin levels and other clinicopathologic parameters were compared between sentinel node positive and negative groups. Logistic regression models were used to predict sentinel node status using leptin and other relevant clinical parameters. The raw and adjusted leptin levels were significantly higher in the 15 patients with positive sentinel nodes. These findings could not be attributed to differences in body mass indices. Univariate models revealed raw leptin, adjusted leptin, Breslow thickness, and mitotic rate as significant predictors of sentinel node status. Leptin levels and Breslow thickness remained significant in multivariate models. Survival and follow-up analysis revealed more aggressive disease in diabetic patients. Elevated serum leptin levels predict sentinel node metastasis in melanoma. Validation of this finding in larger cohorts should enable better stratification of early stage melanoma patients.

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Early Tumor-Infiltrating Dendritic Cells Change their Characteristics Drastically in Association with Murine Melanoma Progression

Nakahara, T., Oba, J., Shimomura, C., Kido-Nakahara, M. and Furue, M.

J Invest Dermatol 136 ( 1 ) 146 - 53 2016.01

Research paper (scientific journal), Accepted, ISSN 1523-1747

Dendritic cells (DCs) have a critical effect on the outcome of adaptive immune responses against growing tumors. Tumor-infiltrating dendritic cells (TIDCs) play diverse roles in the regulation of tumor regression or growth, but the characteristics that distinguish those effects are obscure. In this study, we investigated the frequency, phenotype, and function of TIDCs over time from early stages of melanoma growth in mice. Flow cytometric analysis revealed that the tumors were infiltrated by a significant population of CD11c(+) major histocompatibility complex II(+) DCs, especially at an early stage of tumor growth. The allogeneic stimulatory capacity of TIDCs increased with tumor growth, whereas this capacity of DCs in lymph nodes decreased. TIDCs harvested at an early stage of melanoma (early TIDCs) accelerated tumor growth, but those harvested at a late stage (late TIDCs) delayed tumor progression when they were coinjected with melanoma cells. Furthermore, coinjection of early TIDCs failed to induce full immunocompetent maturation of CD8(+) T cells, with much lower expression of IFN-gamma, granzyme B, and perforin within the tumor microenvironment. In conclusion, TIDCs change their characteristics from an immunoinhibitory to an immunostimulatory phenotype over time in association with tumor progression.

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CD10-Equipped Melanoma Cells Acquire Highly Potent Tumorigenic Activity: A Plausible Explanation of Their Significance for a Poor Prognosis

Oba, J., Nakahara, T., Hashimoto-Hachiya, A., Liu, M., Abe, T., Hagihara, A., Yokomizo, T. and Furue, M.

PLoS One 11 ( 2 ) e0149285 2016

Research paper (scientific journal), Accepted, ISSN 1932-6203

CD10 has been widely used in cancer diagnosis. We previously demonstrated that its expression in melanoma increased with tumor progression and predicted poor patient survival. However, the mechanism by which CD10 promotes melanoma progression remains unclear. In order to elucidate the role of CD10 in melanoma, we established CD10-overexpressing A375 melanoma cells and performed DNA microarray and qRT-PCR analyses to identify changes in the gene expression profile. The microarray analysis revealed that up-regulated genes in CD10-A375 were mostly involved in cell proliferation, angiogenesis, and resistance to apoptosis; down-regulated genes mostly belonged to the categories associated with cell adhesion and migration. Accordingly, in functional experiments, CD10-A375 showed significantly greater cell proliferation in vitro and higher tumorigenicity in vivo; CD10 enzymatic inhibitors, thiorphan and phosphoramidon, significantly blocked the tumor growth of CD10-A375 in mice. In migration and invasion assays, CD10-A375 displayed lower migratory and invasive capacity than mock-A375. CD10 augmented melanoma cell resistance to apoptosis mediated by etoposide and gemcitabine. These findings indicate that CD10 may promote tumor progression by regulating the expression profiles of genes related to cell proliferation, angiogenesis, and resistance to apoptosis.

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Pruritus of patients with atopic dermatitis in daily life and their experience of therapeutic effects: results of a web-based questionnaire survey

Takeuchi, S., Oba, J., Esaki, H. and Furue, M.

Br J Dermatol 173 ( 1 ) 250 - 2 2015.07

Research paper (scientific journal), Accepted, ISSN 1365-2133

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Inflammatory IL-1beta-driven JNK activation in stage III melanoma

Qin, Y., Milton, D. R., Oba, J., Ding, Z., Lizee, G., Ekmekcioglu, S. and Grimm, E. A.

Pigment Cell Melanoma Res 28 ( 2 ) 236 - 9 2015.03

Research paper (scientific journal), Accepted, ISSN 1755-148X (Electronic)

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Expression of programmed death receptor ligand 1 in melanoma may indicate tumor progression and poor patient survival

Oba, J., Nakahara, T., Abe, T., Hagihara, A., Moroi, Y. and Furue, M.

J Am Acad Dermatol 70 ( 5 ) 954 - 6 2014.05

Research paper (scientific journal), Accepted, ISSN 1097-6787

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The prognostic value of a reverse transcriptase-PCR assay of sentinel lymph node biopsy for patients with cutaneous melanoma: a single-center analysis in Japan

Ito, T., Moroi, Y., Oba, J., Nakahara, T., Takeuchi, S., Uchi, H., Takahara, M., Masuda, T. and Furue, M.

Melanoma Res 22 ( 1 ) 38 - 44 2012.02

Research paper (scientific journal), Accepted, ISSN 1473-5636

Sentinel lymph node biopsy (SLNB) is the standard of care for staging melanoma. However, limited research has been carried out on the prognostic value of SLNB in patients with primary cutaneous melanoma in Asian countries. The objective is to evaluate the efficacy of SLNB in Japanese patients with primary cutaneous melanoma and to elucidate whether reverse transcriptase (RT)-PCR analysis of sentinel lymph nodes (SLNs) is valuable for predicting patient outcome. A total of 101 patients with primary cutaneous melanoma underwent SLNB at the Department of Dermatology, Kyushu University (Fukuoka, Japan), between May 2001 and December 2009. The removed nodes were stained with hematoxylin-eosin and with immunohistochemical stains for HMB-45, tyrosinase, MART-1, and MITF and multiple-mRNA marker (MART-1, tyrosinase, and GP-100) RT-PCR assays were conducted. The following clinicopathological variables were evaluated: age, sex, histological type, tumor site, Breslow thickness, disease-free survival (DFS), and melanoma-specific survival (MSS). Several parameters were analyzed for DFS and MSS using the Kaplan-Meier method and Cox proportional hazards model. The success rate of identifying SLNs was 98% (99 of 101 cases). Tumor-positive SLNs were significantly correlated with higher Breslow thickness, stage, tumor subtype, and tumor site. Patients with tumor-positive SLNs had a significantly shorter MSS and DFS than those with tumor-negative SLNs (P=0.0153 and 0.0004, respectively). Patients with at least two positive markers in the RT-PCR assay had a significantly shorter DFS than those with less than one marker (P=0.013). SLNB and multimarker RT-PCR analysis are useful for predicting the prognosis of patients with melanoma.

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Expression of CD10 predicts tumor progression and unfavorable prognosis in malignant melanoma

Oba, J., Nakahara, T., Hayashida, S., Kido, M., Xie, L., Takahara, M., Uchi, H., Miyazaki, S., Abe, T., Hagihara, A., Moroi, Y. and Furue, M.

J Am Acad Dermatol 65 ( 6 ) 1152 - 60 2011.12

Research paper (scientific journal), Accepted, ISSN 1097-6787

BACKGROUND: CD10 expression in malignant melanoma (MM) has been reported to increase according to tumor progression and metastasis; however, its association with patient outcome has not been clarified. OBJECTIVE: We examined the immunohistochemical expression of CD10 in MM to determine whether or not it could serve as a marker for tumor progression and prognosis. METHODS: A total of 64 formalin-fixed, paraffin-embedded samples of primary MM were immunostained for CD10. Similarly, 40 samples of melanocytic nevus and 20 of metastatic MM were analyzed for comparison. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark level, the presence or absence of ulceration and tumor-infiltrating lymphocytes, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: Immunohistochemical analysis revealed that 34 of 64 cases (53%) of primary MM expressed CD10, compared with 15 of 20 cases (75%) of metastatic MM and only 4 of 40 cases (10%) of nevus. There was a significant positive relationship between CD10 expression and Breslow thickness, Clark level, and ulceration. Univariate analysis revealed 4 significant factors for shorter survival periods: CD10 expression, high Breslow thickness, high Clark level, and the presence of ulceration (P < .01 each). In multivariate analysis, CD10 expression was revealed to be a statistically significant and independent prognostic factor. LIMITATIONS: The major limitation was the small sample size. CONCLUSION: CD10 expression may serve as a progression marker and can predict unfavorable prognosis in patients with MM.

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Clinicopathologic and prognostic significance of SATB1 in cutaneous malignant melanoma

Chen, H., Takahara, M., Oba, J., Xie, L., Chiba, T., Takeuchi, S., Tu, Y., Nakahara, T., Uchi, H., Moroi, Y. and Furue, M.

J Dermatol Sci 64 ( 1 ) 39 - 44 2011.10

Research paper (scientific journal), Accepted, ISSN 1873-569X (Electronic)

BACKGROUND: Special AT-rich sequence-binding protein-1 (SATB1), a new type of gene regulator, has been reported to be expressed in several human cancers and may have malignant potential. However, no data on SATB1 expression and its relationship to tumor progression in cutaneous malignant melanoma (CMM) has yet been reported. OBJECTIVE: We examined the immunohistochemical expression of SATB1 in CMM to determine whether it could serve as a prognostic marker. METHODS: A total of 97 samples of primary CMM and controls were immunostained for SATB1. The following clinicopathologic variables were evaluated: age, gender, subtype, SATB1 expression, Breslow thickness, Clark level, presence of ulceration, lymph node metastasis, distant metastasis, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional-hazards model. RESULTS: Forty cases (85.1%) of CMM showed positive staining for SATB1 by immunohistochemistry. The intensity of SATB1 staining was significantly higher in CMM than in nevus NV and normal skin (NS) (P < 0.01). High SATB1 expression was significantly correlated with Breslow thickness, Clark level, mortality, presence of ulceration, and lymph node metastasis (P < 0.01). Moreover, Kaplan-Meier analysis revealed that SATB1 overexpression was significantly associated with worse survival (P < 0.01). Further univariate analysis and multivariate regression analysis indicated that SATB1 expression was an independent prognostic marker for CMM (P = 0.03). CONCLUSIONS: The overexpression of SATB1 correlated with metastatic potential of CMM and is a novel independent prognostic marker for predicting outcome.

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Expression of milk fat globule epidermal growth factor-VIII may be an indicator of poor prognosis in malignant melanoma

Oba, J., Moroi, Y., Nakahara, T., Abe, T., Hagihara, A. and Furue, M.

Br J Dermatol 165 ( 3 ) 506 - 12 2011.09

Research paper (scientific journal), Accepted, ISSN 1365-2133

BACKGROUND: Milk fat globule epidermal growth factor-VIII (MFG-E8) is a secreted protein that binds phosphatidylserine and promotes apoptotic cell ingestion by phagocytes, mediating the immune tolerance and maintenance of homeostasis. A recent study has shown that MFG-E8 expression in human melanoma is increased with tumour progression; however, the effect of its expression on patient survival has not yet been clarified. OBJECTIVE: To analyse MFG-E8 expression in melanoma, and to determine whether it can serve as a marker for diagnosis, tumour progression and/or prognosis. METHODS: MFG-E8 expression was examined by immunohistochemistry in 60 primary melanomas, 22 metastatic lesions and 30 benign naevi. The following clinicopathological variables were evaluated: age, gender, histological type, tumour site, Breslow thickness, Clark's level, the presence or absence of ulceration and tumour-infiltrating lymphocytes, and survival periods. Statistical analyses were performed to assess associations and melanoma-specific survival. RESULTS: MFG-E8 expression was significantly higher in primary and metastatic melanoma than in naevus. Furthermore, it increased according to tumour progression and metastasis. Patients with MFG-E8 expression in primary tumours had significantly shorter survival periods than those without MFG-E8 expression. Univariate and multivariate analyses revealed that MFG-E8 expression was a statistically significant and independent prognostic factor. CONCLUSION: MFG-E8 expression may serve as a tumour progression marker and can predict an unfavourable prognosis in patients with melanoma.

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CD10 expressed by fibroblasts and melanoma cells degrades endothelin-1 secreted by human keratinocytes

Xie, L., Moroi, Y., Takahara, M., Tsuji, G., Oba, J., Hayashida, S., Takeuchi, S., Shan, B., Uchi, H. and Furue, M.

Eur J Dermatol 21 ( 4 ) 505 - 9 2011.07

Research paper (scientific journal), Accepted, ISSN 1167-1122

Endothelin-1 (ET-1) is a potent multifunctional peptide linked to wound healing, pigmentation, carcinogenesis, and fibrosclerotic processes in the skin. Whereas ET-1 was thought to be digested by receptor-mediated endocytosis, it is also reported to be biochemically degraded by the neutral endopeptidase CD10 using kidney homogenates. Although keratinocytes (KC) and fibroblasts (Fb) are sources of both ET-1 and CD10, respectively, there is no report investigating the direct association between CD10 expression and its function in relation to ET-1 degradation in the skin. CD10 expression in melanoma cells is associated with clinical prognosis, suggesting an important role in the invasive and metastatic potential of melanoma cells. Here, cultured KC produced much higher amounts of ET-1 than did cultured Fb or melanoma cells. In contrast, KC and A375 melanoma cells did not express CD10, while Fb, SK-MEL-28 and G361 melanoma cells constitutively expressed CD10. KC-derived ET-1 was down-modulated by both CD10-positive Fb and CD10-positive melanoma cells, and the inhibition was partially reversed under substitution conditions using CD10-knockdown Fb or CD10-knockdown melanoma cells. This indicates that CD10 on cultured Fb and melanoma cells is biochemically active in the degradation or down-modulation of ET-1 secreted from KC. These findings may lead to better understanding of skin homeostasis and of the malignant potential of melanoma.

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Expression of c-Kit, p-ERK and cyclin D1 in malignant melanoma: an immunohistochemical study and analysis of prognostic value

Oba, J., Nakahara, T., Abe, T., Hagihara, A., Moroi, Y. and Furue, M.

J Dermatol Sci 62 ( 2 ) 116 - 23 2011.05

Research paper (scientific journal), Accepted, ISSN 1873-569X (Electronic)

BACKGROUND: The mitogen-activated protein kinase (MAPK) signaling pathway is one of the major cascades that are crucial for the initiation and progression of melanoma; however, the influence of these signaling molecules on patient survival has not been clarified. OBJECTIVE: The purpose of this study was to analyze the protein expression of MAPK signaling molecules in melanoma, and to correlate the expression status with clinicopathologic parameters. METHODS: Expression of c-Kit, phosphorylated ERK (p-ERK), and cyclin D1 was examined by immunohistochemistry in 78 primary melanomas, 24 metastatic lesions, and in 42 benign nevi. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark's level, ulceration, and survival period. Statistical analyses were performed for assessment of associations and melanoma-specific survival. RESULTS: The expression of c-Kit, p-ERK, and cyclin D1 was significantly higher in primary melanomas than in nevi. c-Kit immunoreactivity was highest in thin (Tis-pT2) melanomas, and showed a significant reduction with tumor progression and metastasis. The expression of p-ERK was high in all stages of melanoma. Cyclin D1 positivity increased significantly according to tumor progression, but decreased in metastases. A significant correlation between p-ERK and cyclin D1 expression was observed. Survival analysis failed to detect any trends towards shorter or longer survival among patients expressing either c-Kit, p-ERK or cyclin D1. CONCLUSIONS: The expression of c-Kit, p-ERK, and cyclin D1 might help to differentiate thin melanoma from melanocytic nevus, but it appears to lack prognostic potential.

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CD10-bearing fibroblasts may inhibit skin inflammation by down-modulating substance P

Xie, L., Takahara, M., Nakahara, T., Oba, J., Uchi, H., Takeuchi, S., Moroi, Y. and Furue, M.

Arch Dermatol Res 303 ( 1 ) 49 - 55 2011.01

Research paper (scientific journal), Accepted, ISSN 1432-069X (Electronic)

Substance P (SP) is a multipotent neuropeptide that affects the proliferation, activation and motility of keratinocytes and fibroblasts (Fbs). SP in pulmonary and synovial cells is degraded by CD10, a 90- to 110-kDa cell surface zinc-dependent metalloprotease. However, the expression and function of CD10 in human dermal Fbs have not yet been investigated in vivo and in vitro specifically with reference to SP. Our immunohistologic study revealed moderate to strong fibroblastic CD10 expression in the majority of psoriasis vulgaris (16/16), chronic eczema (15/16), lichen planus (18/20) and atopic dermatitis (4/5). Keratinocytes showed no CD10 expression in vivo and in vitro. Cultured Fbs constitutively expressed CD10 and SP. CD10 expression was augmented by external interleukin (IL)-1beta and IL-22, but not by IL-8 and IL-17A in Fbs. SP production was enhanced in CD10 knockdown-Fbs (CD10ND-Fbs) compared with control-Fbs. In the presence of IL-1beta or IL-22, the enhancement of SP production was more prominent in CD10ND-Fbs than in control-Fbs, suggesting the down-modulating activity of CD10 on SP in cytokine-mediated inflammation. In conclusion, fibroblastic CD10 expression may down-regulate skin inflammation by degrading SP or reducing its level in the dermal microenvironment.

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Aberrant expression of CD10 in ground-glass-like multinucleated giant cells of multicentric reticulohistiocytosis

Tashiro, A., Takeuchi, S., Nakahara, T., Oba, J., Tsujita, J., Fukushi, J., Kiryu, H., Oda, Y., Xie, L., Yan, X., Takahara, M., Moroi, Y. and Furue, M.

J Dermatol 37 ( 11 ) 995 - 7 2010.11

Research paper (scientific journal), Accepted, ISSN 1346-8138

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Hair follicle nevus - A dermoscopic approach

Okada, J., Moroi, Y., Tsujita, J., Takahara, M., Urabe, K., Kiryu, H. and Furue, M.

Eur J Dermatol 18 ( 2 ) 185 - 7 2008.03

Research paper (scientific journal), Accepted, ISSN 1167-1122

We report the case of a 26-year-old man who presented with small soft nodules with tiny hairs that had been present on his nose since childhood. The nodules were initially diagnosed as melanocytic nevi. However, dermoscopy showed many uniform hair follicles and an interfollicular 'pseudo-pigment network' in the nodules. Histologically, many well-differentiated hair follicles and sebaceous glands were seen in the dermis. Serial sectioning revealed neither central cysts nor a central canal. We therefore diagnosed this case as hair follicle nevus. Dermoscopy is now widely used as a non-invasive, in vivo technique for the diagnosis of pigmented skin lesions. Hair follicle nevus is a very rare disease and this is the first report to demonstrate the manifestation of this clinical entity by dermoscopy.

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Case of adult T-cell leukemia/lymphoma manifesting marked purpura

Okada, J., Imafuku, S., Tsujita, J., Moroi, Y., Urabe, K. and Furue, M.

J Dermatol 34 ( 11 ) 782 - 5 2007.11

Research paper (scientific journal), Accepted, ISSN 0385-2407

We present a case of a 62-year-old woman with marked purpura, first appearing on both legs, then spreading over the whole body, including the face. At presentation, the patient was thought to have Henoch-Schonlein purpura. However, a skin biopsy from a purpuric lesion revealed prominent infiltrations of atypical lymphocytes into the papillary dermis and marked extravasation of erythrocytes through the epidermis and upper dermis. Antibody to human T-lymphotropic virus type 1 (HTLV-1) was present in the serum and samples from skin lesions revealed HTLV-1 proviral DNA integration, as well as a clonal T-cell receptor Cbeta1 gene rearrangement. We therefore diagnosed this case as adult T-cell leukemia/lymphoma (ATL), and the purpuric lesions as ATL-specific. Soon after the initiation of chemotherapy, these purpuric lesions began to resolve with pigmentation.

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