Publications by authors named "Kentaro Inamura"

110 Publications

Adjuvant Chemotherapy in Patients With Early-Stage Non-Small Cell Lung Cancer.

Authors:
Kentaro Inamura

JAMA Oncol 2021 Feb 25. Epub 2021 Feb 25.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.1001/jamaoncol.2020.8189DOI Listing
February 2021

Tumor B7-H3 expression in diagnostic biopsy specimens and survival in patients with metastatic prostate cancer.

Prostate Cancer Prostatic Dis 2021 Feb 8. Epub 2021 Feb 8.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Prostate cancer spans a broad spectrum from indolent to deadly disease. In the management of prostate cancer, diagnostic biopsy specimens are important sources of data that inform the selection of treatment. B7-H3 (CD276), an immune checkpoint molecule, has emerged as a promising immunotherapy target. B7-H3 expression is related to adverse clinical outcomes in various types of cancer; however, little is known concerning the association between tumor B7-H3 expression in diagnostic biopsy specimens and clinical outcome in patients with metastatic prostate cancer.

Methods: We evaluated tumor B7-H3 expression levels in diagnostic biopsy specimens from 135 patients with metastatic prostate cancer and 113 patients with localized prostate cancer.

Results: High B7-H3 expression was more frequently observed in patients with metastatic cancer than in those with localized cancer (31 vs. 12%; p = 0.0003). In patients with localized cancer, the B7-H3 expression status was not associated with biochemical recurrence-free survival. However, among patients with metastatic cancer, high B7-H3 expression was independently associated with high disease-specific mortality (multivariable hazard ratio [HR] = 2.72; p = 0.047) and overall mortality rates (multivariable HR = 2.04; p = 0.025).

Conclusions: Tumor B7-H3 expression in diagnostic biopsy specimens may be a useful biomarker for identifying highly aggressive metastatic prostate cancer. Given the potential utility of anti-B7-H3 immunotherapy, this information may aid in stratifying prostate cancer based on its responsiveness to B7-H3-targeted treatment.
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http://dx.doi.org/10.1038/s41391-021-00331-6DOI Listing
February 2021

Ki-67 Labeling Index Variability Between Surgically Resected Primary and Metastatic Hepatic Lesions of Gastroenteropancreatic Neuroendocrine Neoplasms.

Int J Surg Pathol 2021 Feb 5:1066896921990715. Epub 2021 Feb 5.

13609Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

. A higher Ki-67 labeling index is associated with a poorer prognosis in gastroenteropancreatic neuroendocrine neoplasms. It has also been proposed that the Ki-67 labeling index may increase during disease progression from the primary site to metastatic sites. Although biopsy specimens are used to measure the Ki-67 labeling index, heterogeneity in lesions is thought to affect the assessment of the Ki-67 labeling index. To overcome tumor heterogeneity, we evaluated the variability in the Ki-67 labeling index between primary lesions and hepatic metastases by analyzing only surgically resected specimens. We conducted a single-center retrospective study to analyze the variability in the Ki-67 labeling index and the change in tumor grade between the primary site and metastatic hepatic sites in 19 patients diagnosed with gastroenteropancreatic neuroendocrine neoplasms at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 1998 to 2018. Both the primary site and metastatic hepatic sites were surgically resected. Among the 19 patients with gastroenteropancreatic neuroendocrine neoplasms, 12 patients (63%) showed higher levels of the Ki-67 labeling index at metastatic hepatic sites than at the primary site. The median Ki-67 labeling index levels for the primary lesion and metastatic hepatic lesions were 5% and 10%, respectively. The Ki-67 labeling index levels were significantly elevated in the metastatic hepatic lesions compared to the primary lesion ( = .002). This study addressed the heterogeneity of the Ki-67 labeling index by analyzing only surgically resected specimens. We observed a statistically significant increase in the Ki-67 labeling index in hepatic metastases compared to the primary lesion.
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http://dx.doi.org/10.1177/1066896921990715DOI Listing
February 2021

Ethical Considerations about Genomic Medicine Implementation: Lessons Learned from the eMERGE III Study.

Authors:
Kentaro Inamura

J Pers Med 2020 Oct 26;10(4). Epub 2020 Oct 26.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.

The development of high-throughput techniques has permitted the accumulation of enormous amounts of genomic information. As increasing numbers of studies aim to utilize individual genomic information for diagnostic, preventive, or therapeutic purposes, Institutional Review Boards (IRBs) have a greater opportunity to review such types of study protocols. An article published in the titled, "Ethical Considerations Related to Return of Results from Genomic Medicine Projects: The eMERGE Network (Phase III) Experience" identified the common concerns of IRBs in the process of reviewing such studies, and some concerns included the readability of informed consent materials, potential risks to participants, information sharing with family members, options for withdrawal or receiving limited results, and provisions to clear participant questions. Since there is an increase in the number of genomic medicine implementation studies worldwide, the insights provided by this study would assist future researchers in protocol preparation as well as aid project review by IRB members.
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http://dx.doi.org/10.3390/jpm10040195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712392PMC
October 2020

Is hypervascular papillary renal cell carcinoma present?

Abdom Radiol (NY) 2020 Oct 12. Epub 2020 Oct 12.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Purpose: We aimed to investigate atypical papillary renal cell carcinoma (PRCC) presenting with early contrast enhancement and late washout and to investigate the correlation between the CT attenuation value of the corticomedullary phase (CMP) of contrast-enhanced CT in PRCCs and the endothelial cell counts of these tumors.

Methods: Twenty-two patients with pathologically confirmed PRCC were enrolled in this study. PRCCs were categorized into 18 typical PRCCs and 4 atypical PRCCs. The CT attenuation value of the lesion in the CMP was measured in the maximal section of the tumor using the region of interest. Microvessel density (MVD) was evaluated as a histopathologic parameter using tissue specimens immunohistochemically stained with an anti-ERG antibody. The CT attenuation value and MVD were compared between atypical and typical PRCCs using the Mann-Whitney U test, where p < 0.05 was considered significant. The correlations between CT attenuation value and MVD were evaluated in all PRCCs using single linear regression analysis.

Results: The mean CT attenuation value and the MVD were significantly higher in atypical than in typical PRCCs. Correlation analyses revealed a weak positive correlation between the CT attenuation value and MVD.

Conclusions: We confirmed several cases of atypical PRCC that present with early contrast enhancement, such as clear cell renal cell carcinoma. In addition, a positive correlation was found between the CT attenuation value in the CMP of PRCCs and the vascular endothelial cell count.
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http://dx.doi.org/10.1007/s00261-020-02809-8DOI Listing
October 2020

Testicular seminoma with a progressing pulmonary nodule and mediastinal lymphadenopathy without retroperitoneal metastasis.

IJU Case Rep 2020 Sep 7;3(5):211-214. Epub 2020 Jul 7.

Department of Urology Cancer Institute Hospital Japanese Foundation for Cancer Research Tokyo Japan.

Introduction: Testicular germ cell cancer has a relatively good prognosis even if visceral and/or lymph node metastases are present thanks to chemotherapy. Yet chemotherapy can lead to various adverse events. Therefore, it is crucial to distinguish whether a suspected metastatic disease is metastasis or not.

Case Presentation: A 33-year-old male visited our hospital to receive subsequent therapy for suspected recurrent seminoma with a progressing pulmonary nodule and mediastinal lymphadenopathy after orchiectomy. The pathological diagnosis of needle aspiration and resected specimen of the several lesions was consistent with epithelioid cell granuloma without caseous necrosis. Based on these findings, the lung and mediastinal lymph node lesions were diagnosed as sarcoidosis.

Conclusion: In cases where the simultaneous occurrence of other benign or malignant diseases is suspected, pathological confirmation is necessary for appropriate decision-making.
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http://dx.doi.org/10.1002/iju5.12191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469829PMC
September 2020

Frequent expression of conventional endothelial markers in pleural mesothelioma: usefulness of claudin-5 as well as combined traditional markers to distinguish mesothelioma from angiosarcoma.

Lung Cancer 2020 10 30;148:20-27. Epub 2020 Jul 30.

Division of Pathology, The Cancer Institute, Departments of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan; Department of Pathology, School of Medicine, International University of Health and Welfare, Tokyo 108-8329, Japan. Electronic address:

Objectives: Distinguishing pleural sarcomatoid mesotheliomas from true sarcomas is challenging because the former does not always express the mesothelial markers, and diagnosis is often made on the basis of keratin expression. Consequently, sarcomas such as angiosarcomas that express keratin complicate the differential diagnosis. Furthermore, some mesotheliomas have been reported to express endothelial markers. The aim of this study is to identify useful markers for distinguishing pleural sarcomatoid mesothelioma from angiosarcoma.

Materials And Methods: This study enrolled 147 patients with pleural mesothelioma-93 with epithelioid, 25 with biphasic, and 29 with sarcomatoid subtypes-and 41 patients with angiosarcomas in various organs. The expression levels of cytokeratin, mesothelial, and endothelial markers were assayed in both groups to identify the markers that could assist in distinguishing mesothelioma from angiosarcoma. Cytokeratin (AE1/AE3, CAM 5.2), endothelial (CD31, CD34, ERG, factor VIII, and claudin-5), and mesothelial (calretinin, WT-1, podoplanin (D2-40), EMA, and CK5/6) markers were immunohistochemically assayed using tissue blocks.

Results: More than 90% of the mesotheliomas and less than 20% of the angiosarcomas expressed cytokeratin. Calretinin was expressed in 82% of all types of mesotheliomas but in only 48% of sarcomatoid mesotheliomas. Endothelial markers were expressed in mesothelioma tissues-CD31 in 10.3%, CD34 in 3.5%, ERG in 29%, and factor VIII in 3.4%-and the positivity was higher in sarcomatoid than in epithelioid and biphasic mesotheliomas. Claudin-5 was expressed in all the angiosarcomas, but not in any of the mesotheliomas.

Conclusion: We found overlapping immunophenotypes in pleural mesotheliomas and angiosarcomas, but the sensitivity and specificity of claudin-5 expression were sufficient to distinguish between them. The differential diagnosis of mesothelioma should therefore include claudin-5 in a panel of immunohistochemical markers to distinguish mesothelioma from angiosarcoma.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.029DOI Listing
October 2020

Gut microbiota contributes towards immunomodulation against cancer: New frontiers in precision cancer therapeutics.

Authors:
Kentaro Inamura

Semin Cancer Biol 2021 May 21;70:11-23. Epub 2020 Jun 21.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Electronic address:

The microbiota influences human health and the development of diverse diseases, including cancer. Microbes can influence tumor initiation and development in either a positive or negative manner. In addition, the composition of the gut microbiota affects the efficacy and toxicity of cancer therapeutics as well as therapeutic resistance. The striking impact of microbiota on oncogenesis and cancer therapy provides compelling evidence to support the notion that manipulating microbial networks represents a promising strategy for treating and preventing cancer. Specific microbes or the microbial ecosystem can be modified via a multiplicity of processes, and therapeutic methods and approaches have been evolving. Microbial manipulation can be applied as an adjunct to traditional cancer therapies such as chemotherapy and immunotherapy. Furthermore, this approach displays great promise as a stand-alone therapy following the failure of standard therapy. Moreover, such strategies may also benefit patients by avoiding the emergence of toxic side effects that result in treatment discontinuation. A better understanding of the host-microbial ecosystem in patients with cancer, together with the development of methodologies for manipulating the microbiome, will help expand the frontiers of precision cancer therapeutics, thereby improving patient care. This review discusses the roles of the microbiota in oncogenesis and cancer therapy, with a focus on efforts to harness the microbiota to fight cancer.
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http://dx.doi.org/10.1016/j.semcancer.2020.06.006DOI Listing
May 2021

Impact of Serum γ-Glutamyltransferase on Overall Survival in Patients with Metastatic Renal Cell Carcinoma in the Era of Targeted Therapy.

Target Oncol 2020 06;15(3):347-356

Department of Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Background: γ-Glutamyltransferase (GGT) is a marker of oxidative stress. Elevated serum GGT is linked to poor survival in various malignancies; however, there are no data on metastatic renal cell carcinoma (mRCC). Additionally, GGT expression in cancer tissues remains largely unknown.

Objective: The present study was designed to determine the prognostic role of serum GGT in patients with mRCC and the association between systemic and local GGT levels.

Patients And Methods: Pretherapeutic serum GGT and other clinicopathological parameters were retrospectively compared with overall survival (OS) in 146 consecutive patients with mRCC receiving tyrosine kinase inhibitor therapy. GGT expression was analyzed in 65 resected specimens using immunohistochemistry.

Results: A total of 82 patients (56%) died during the follow-up period (median 34.9 months). Median OS was 16.0 months and 36.8 months in patients with elevated GGT levels and without elevated GGT, respectively (P < 0.001). On multivariable analysis, elevated serum GGT was an independent adverse prognostic factor (hazard ratio [HR] 4.04, P < 0.001), together with high neutrophils (HR 2.06, P = 0.041), low albumin (HR 2.00, P = 0.006), high lactate dehydrogenase (HR 2.68, P < 0.001), and high De Ritis ratio (HR 1.97, P = 0.004). Preoperative serum GGT levels were 29, 48, and 109 U/l in patients whose renal cancer cells showed negative to weak, moderate, and strong GGT expression, respectively (P = 0.004).

Conclusions: Elevated serum GGT was an unfavorable prognostic factor in mRCC, and overexpression of GGT in renal cancer cells might be responsible for elevation of serum GGT.
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http://dx.doi.org/10.1007/s11523-020-00719-9DOI Listing
June 2020

Insulinoma-associated Protein 1 (INSM1) Is a Better Marker for the Diagnosis and Prognosis Estimation of Small Cell Lung Carcinoma Than Neuroendocrine Phenotype Markers Such as Chromogranin A, Synaptophysin, and CD56.

Am J Surg Pathol 2020 06;44(6):757-764

Division of Pathology, The Cancer Institute.

To diagnose small cell lung carcinoma (SCLC), neuroendocrine (NE) phenotype markers such as chromogranin A, synaptophysin, and CD56 are helpful. However, because they are dispensable, SCLCs occur without apparent NE phenotypes. Insulinoma-associated protein 1 (INSM1) is a transcription factor for NE differentiation and has emerged as a single practical marker for SCLC. Using the surgical samples of 141 pulmonary NE tumors (78 SCLCs, 44 large cell NE carcinomas, and 19 carcinoids), and 246 non-NE carcinomas, we examined the immunohistochemical expression and prognostic relevance of INSM1 in association with NE phenotype markers. We evaluated its sensitivity and specificity for SCLC diagnosis, as well as its usefulness to diagnose SCLC without NE marker expression and to estimate the prognosis. INSM1 was expressed in SCLCs (92%, 72/78), large cell NE carcinomas (68%, 30/44), and carcinoids (95%, 18/19). In addition, among SCLCs with no expression of NE phenotype markers (n=12), 9 (75%) were positive for INSM1. These data suggest the superiority of INSM1 to the phenotype markers. Only 7% of adenocarcinomas (9/134) and 4% of squamous cell carcinomas (4/112) were positive for INSM1. SCLC with low-INSM1 expression (n=28) had a significantly better prognosis (P=0.040) than the high-INSM1 group (n=50). Our study revealed that INSM1 is highly sensitive and specific to detect SCLC and can estimate prognosis. INSM1 will be a promising marker for SCLC.
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http://dx.doi.org/10.1097/PAS.0000000000001444DOI Listing
June 2020

Calretinin-expressing lung adenocarcinoma: Distinct characteristics of advanced stages, smoker-type features, and rare expression of other mesothelial markers are useful to differentiate epithelioid mesothelioma.

Pathol Res Pract 2020 Mar 10;216(3):152817. Epub 2020 Jan 10.

Division of Pathology, The Cancer Institute, Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Pathology, School of Medicine, International University of Health and Welfare, Tokyo, Japan. Electronic address:

Calretinin, a mesothelioma marker, is sometimes expressed in lung cancer, which may complicate the differential diagnosis of mesothelioma. Here, the clinicopathological and immunohistochemical characteristics of calretinin-positive lung cancer were examined to reduce confusion with malignant mesothelioma. Calretinin expression in 307 consecutive cases of lung cancer was evaluated immunohistochemically. Survival was analyzed using the Kaplan-Meier method and log-rank test. Calretinin expression was identified in 67 (22%) tumors, including those with partial and weak expression [15% (37/250) of adenocarcinomas, 54% (25/46) of squamous cell carcinomas, 75% (3/4) of adenosquamous carcinomas, and 29% (2/7) of sarcomatoid carcinomas]. In calretinin-positive adenocarcinoma (n = 37), expression percentages of Wilms tumor-1, podoplanin, thyroid transcription factor-1, and claudin-4 were 6, 3, 52, 82%, respectively, whereas in calretinin-positive squamous cell carcinoma (n = 25) the percentages were 8, 12, 12, 68%, respectively, indicating that other mesothelial markers were only rarely expressed and that claudin-4 expression was common. Although not an independent marker, calretinin expression was associated with a poor prognosis for stage I tumors of adenocarcinoma (p < 0.001) and of all histological subtypes (p < 0.001). In conclusion, calretinin-positive lung tumors share characteristics with those of smokers and advanced stages and can be differentiated from mesothelioma with the use of other mesothelial and epithelial markers.
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http://dx.doi.org/10.1016/j.prp.2020.152817DOI Listing
March 2020

Roles of microbiota in response to cancer immunotherapy.

Authors:
Kentaro Inamura

Semin Cancer Biol 2020 10 3;65:164-175. Epub 2020 Jan 3.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. Electronic address:

Immunotherapy, which shows great promise for treating patients with metastatic malignancies, has dramatically changed the therapeutic landscape of cancer, particularly subsequent to the discovery of immune checkpoint inhibitors. However, the responses to immunotherapy are heterogeneous and often transient. More problematic is that a high proportion of patients with cancer are resistant to such therapy. Much effort has been expended to identify reliable biomarkers that accurately predict clinical responses to immunotherapy. Unfortunately, such tools are lacking, and our knowledge of the mechanisms underlying its efficacy and safety is insufficient. The microbiota is increasingly recognized for its influence on human health and disease. Microbes create a pro- or an anti-inflammatory environment through complex interactions with host cells and cytokines. Emerging evidence indicates that microbes alter the efficacy and toxicity of immunotherapy by modulating the host's local and systemic immune responses. It is therefore critically important to exploit the microbiota to develop biomarkers as well as to identify therapeutic targets that can be applied to cancer immunotherapy. This review provides insights into the challenges that must be addressed to achieve these goals.
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http://dx.doi.org/10.1016/j.semcancer.2019.12.026DOI Listing
October 2020

Mucinous lung adenocarcinoma, particularly referring to EGFR-mutated mucinous adenocarcinoma.

Pathol Int 2020 Feb 20;70(2):72-83. Epub 2019 Dec 20.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.

The current 2015 World Health Organization (WHO) classification of lung tumors does not adequately categorize mucinous lung adenocarcinoma. Thus far, only two variants of mucinous adenocarcinoma have been studied: invasive mucinous adenocarcinoma and colloid adenocarcinoma. Moreover, common types of invasive adenocarcinoma when they produce mucin are yet to be elucidated, particularly epidermal growth factor receptor (EGFR)-mutated mucinous adenocarcinoma. In this study, we extracted mucinous adenocarcinoma of both the common types and the two variants. Further, we immunohistochemically and molecular-biologically examined their clinicopathological characteristics, mutation patterns, and expressions of thyroid transcription factor-1 (TTF-1), hepatocyte nuclear factor-4 alpha (HNF-4a) and mucins, particularly referring to EGFR-mutated adenocarcinoma. Among 1159 surgically resected invasive adenocarcinomas, 189 mucinous adenocarcinomas (16%) were identified. Among these, 20%, 34% and 9.5% were EGFR mutated, KRAS mutated and ALK rearranged, respectively. Compared with EGFR-mutated nonmucinous adenocarcinoma, EGFR-mutated mucinous adenocarcinoma had no female predominance, lower grades of histological differentiation and lower TTF-1 and higher HNF-4a expressions. Moreover, for the first time, we indicated that mucin production was an independent prognostic factor for EGFR-mutated adenocarcinomas and the mucin-staining pattern of negative MUC5AC and positive MUC5B was characteristic in these adenocarcinomas. We suggest that EGFR-mutated mucinous adenocarcinoma has a different tumorigenic pathway than nonmucinous EGFR-mutated adenocarcinoma.
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http://dx.doi.org/10.1111/pin.12879DOI Listing
February 2020

Identification of a specific ultrasonographic finding for differentiating hepatic angiomyolipoma from hepatocellular carcinoma.

Clin Imaging 2020 Feb 27;59(2):104-108. Epub 2019 Nov 27.

Division of Clinical Examination Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan. Electronic address:

Objective: To identify specific ultrasonographic features that differentiate hepatic angiomyolipoma (HAML) from hepatocellular carcinoma (HCC).

Methods: Twelve patients with HAML and 73 patients with HCC, whose diagnosis were pathologically confirmed at a single center in Japan between 2006 and 2016, were included in this study. The HAML and HCC cases were histologically evaluated and their histological growth patterns were compared. Using ultrasonographic data, we evaluated the imaging features representing the distinct histological differences. Ultrasonographic findings, reviewed by two examiners, were compared via interobserver variability analysis. This retrospective study was approved by the institutional ethics committee at our institute (No. 2017-1004).

Results: The enrolled patients were carefully divided into two case sets: discovery case set (6 HAML patients and 37 HCC patients) and validation case set (6 HAML patients and 36 HCC patients). In the discovery case set, half of the HAML cases had intratumoral regions showing a reticular growth pattern. None of the HCC cases appeared as a region with the reticular growth pattern. The regions with the reticular growth pattern present as an intratumoral hyper echoic foci on ultrasound images. The presence of the intratumoral hyper echoic foci was significantly associated with HAML (P < .01). In the validation case set, the intratumoral hyper echoic foci predicted HAML at a specificity of 100% and a sensitivity of 50%.

Conclusions: Intratumoral hyper echoic foci, representing reticular growth pattern, can be a promising ultrasonographic finding to help differentiate HAML from HCC.
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http://dx.doi.org/10.1016/j.clinimag.2019.10.020DOI Listing
February 2020

Efficacy and safety profile of nivolumab for Japanese patients with metastatic renal cell cancer.

Int J Clin Oncol 2020 Jan 14;25(1):151-157. Epub 2019 Sep 14.

Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan.

Background: Nivolumab, which has a promising anti-tumor efficacy and a manageable safety profile, has being rapidly introduced in metastatic renal cell cancer therapy in Japan. We evaluated the efficacy and adverse events of nivolumab in real world clinical practice in Japan.

Methods: The medical records of 45 consecutive patients who started treatment with nivolumab, up to September 2018, were reviewed and statistically analyzed.

Results: The median follow-up period was 22.3 months. The best responses were a complete response in three patients (8%), a partial response in 14 patients (36%), stable disease in 14 patients (36%), and progressive disease in eight patients (20%). The median progression-free survival period and 1 year progression-free survival rate were 14.9 months and 54.5%, respectively. The estimated overall survival period and 1-year and 2-year overall survival rates from initiation of nivolumab were not reached, and 91.1%, and 86.2%, respectively. Twenty-seven patients (60%) experienced adverse events including four (10%) severe adverse events (Grade 3 or 4). The most common adverse event was rash (n = 9, 20%). Five patients discontinued nivolumab therapy, because of an adverse event (Grade 3 diarrhea, one patient; Grade 2 fatigue, one patient; Grade 3 uveitis, two patients; and Grade 3 adrenal insufficiency, one patient).

Conclusions: Nivolumab has a relatively favorable efficacy and safety profile for Japanese metastatic renal cell cancer patients in clinical practice.
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http://dx.doi.org/10.1007/s10147-019-01542-7DOI Listing
January 2020

Relationship of B7-H3 expression in tumor cells and tumor vasculature with FOXP3+ regulatory T cells in renal cell carcinoma.

Cancer Manag Res 2019 25;11:7021-7030. Epub 2019 Jul 25.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: B7-H3 (CD276), an immune checkpoint molecule, regulates the tumor-immune microenvironment and controls the aggressiveness of various tumors. Although B7-H3 expression has been associated with the number of tumor-infiltrating FOXP3+ regulatory T cells, little information is available about this association in clear cell renal cell carcinoma (ccRCC).

Methods: Using 252 consecutive cases of ccRCC, we examined the association of B7-H3 expression in both the tumor cells and tumor vasculature with the number of tumor-infiltrating FOXP3+ cells and assessed whether the effects of B7-H3 expression on survival differ according to FOXP3+ cell number.

Results: High B7-H3 expression was observed in the tumor cells and tumor vasculature in 15% and 54% of ccRCC cases, respectively. High FOXP3+ cell number was positively associated with B7-H3 expression in both the tumor cells (odds ratio [OR] =2.93; =0.0041) and tumor vasculature (OR=2.45; =0.0007). Tumor cell B7-H3 expression was associated with increased disease-specific mortality in high FOXP3+ cell number group (hazard ratio [HR] =2.98; =0.017), but not in low FOXP3+ group (=0.71). Tumor vasculature B7-H3 expression was also associated with increased disease-specific mortality in high FOXP3+ cell number group (HR=4.86; =0.0025), but not in low FOXP3+ group (=0.48).

Conclusion: We demonstrate that B7-H3 expression in both tumor cells and the tumor vasculature is positively associated with FOXP3+ cell number. Such expression is also associated with increased mortality in high FOXP3+ cell number group, but not in low FOXP3+ cell number group. These findings suggest that B7-H3-expressing ccRCCs may exert tumor-promoting immunity by interacting with FOXP3+ regulatory T cells in the tumor microenvironment.
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http://dx.doi.org/10.2147/CMAR.S209205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664858PMC
July 2019

Physical Activity and Colorectal Cancer Prognosis According to Tumor-Infiltrating T Cells.

JNCI Cancer Spectr 2018 Oct 9;2(4):pky058. Epub 2019 Jan 9.

Department of Oncologic Pathology.

Background: Evidence suggests that high-level physical activity may potentially reduce cancer mortality through its immune enhancement effect. We therefore hypothesized that survival benefits associated with physical activity might be stronger in colorectal carcinomas with lower immune reaction at diagnosis.

Methods: Using molecular pathological epidemiology databases of 470 colon and rectal carcinoma cases in the Nurses' Health Study and the Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis physical activity in strata of densities of CD3 cells, CD8 cells, CD45RO (PTPRC) cells, or FOXP3 cells in tumor tissue. Cox proportional hazards regression model was used to adjust for potential confounders, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, , , and mutations, and expression of CTNNB1 (beta-catenin), PTGS2 (cyclooxygenase-2), and .

Results: The association of postdiagnosis physical activity with colorectal cancer-specific mortality differed by CD3 cell density ( < .001). Multivariable-adjusted colorectal cancer-specific mortality hazard ratios for a quartile-unit increase in physical activity were 0.56 (95% confidence interval = 0.38 to 0.83) among cases with the lowest quartile of CD3 cell density compared with 1.14 (95% confidence interval = 0.79 to 1.65) in cases with the highest quartile. We observed no differential survival association of physical activity by densities of CD8 cells, CD45RO cells, or FOXP3 cells.

Conclusions: The association between postdiagnosis physical activity and colorectal cancer survival appeared stronger for carcinomas with lower T cell infiltrates, suggesting an interactive effect of exercise and immunity on colorectal cancer progression.
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http://dx.doi.org/10.1093/jncics/pky058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591576PMC
October 2018

Preparation of metal phthalocyanine (MPc)-polymer complexes: the possible anti-cancer properties of FePc-polymer complexes.

Heliyon 2019 Mar 29;5(3):e01383. Epub 2019 Mar 29.

Department of Materials Science, Faculty of Science and Engineering, Shimane University, Matsue 690-8504, Japan.

We have succeeded in preparing various water-soluble metal phthalocyanine (MPc)-polymer complexes, wherein the metal moiety is lithium, iron, cobalt, copper, zinc, or tin, and the polymer is one of the following water-soluble polymers: polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), or polyvinyl alcohol (PVA). Among all MPc-polymer complexes, the iron phthalocyanine (FePc)-PVP complex in water showed the largest and sharpest absorption peak at ∼700 nm in UV-Vis absorption spectrum, which indicates that FePc-polymer complexes in water are easily prepared and the degree of stacking of FePc in the complexes, very small, such as that of a monomer or a similar structure. Conversely, the polymer chains including those of PEG, PVP, and dextran have high biological affinity as well as flexibility. Speculatively, the FePc-polymer (e.g., PEG, PVP, and dextran) complexes adsorbed onto the surface of a cancer cell might break it via the irradiation of near-infrared light having a wavelength of ∼700 nm. Furthermore, chlorophyll a-polymer complexes, previously prepared by our group, might similarly break a cancer cell because these complexes showed a large and sharp absorption peak at ∼700 nm in UV-Vis spectrum.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441755PMC
March 2019

Cerebral Thromboembolism after Lobectomy for Lung Cancer: Pathological Diagnosis and Mechanism of Thrombus Formation.

Cancers (Basel) 2019 04 5;11(4). Epub 2019 Apr 5.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.

Lung cancer is the leading cause of cancer-related deaths worldwide. Although molecular therapies have emerged as efficacious strategies for the treatment of lung cancer, surgical resection is still recommended as a radical therapeutic option. Currently, lobectomy is regarded as the most reliable radical treatment of primary lung cancer. Among the various complications after lobectomy, cerebral thromboembolism requires attention as a life-threatening complication during the early postoperative period. It occurs in 0.2⁻1.2% of surgical cases of lung cancer and typically develops following left upper lobectomy with a long pulmonary vein stump (PVS). PVS-associated thrombosis is known to cause cerebral thromboembolism after such procedures; however, distinguishing this specific complication from that caused by postoperative atrial fibrillation is challenging. We summarize herein the diagnostic pathology of thrombus formation in accordance with its thrombogenic mechanism. We focus on the potential utility of the pathological assessment of thrombectomy specimens. The morphological information obtained from these specimens enables the presumption of thrombogenic etiology and provides useful clues to both select an appropriate pharmacotherapy and determine a follow-up treatment for cerebral thromboembolism.
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http://dx.doi.org/10.3390/cancers11040488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521235PMC
April 2019

A case report on 111In chloride bone marrow scintigraphy in management of adrenal myelolipoma.

Medicine (Baltimore) 2019 Feb;98(8):e14625

Pathology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research.

Rationale: Adrenal myelolipoma is a benign hormone-inactive tumor composed of hematopoietic tissue and mature adipose tissue. Because this tumor tends to be rich in fat, in many cases it can be diagnosed based on computed tomography (CT) or magnetic resonance imaging (MRI) findings alone. However, in the presence of much necrosis, calcification and hematopoietic tissue and/or the absence of much fat, and in cases with tumor apoplexy, this tumor becomes difficult to differentiate from other tumors. In such cases, a bone marrow scan may be informative as a non-invasive imaging diagnostic method for preoperative diagnosis of the tumor and determination of the method for the surgical treatment. We herein report a case of huge adrenal myelolipoma with the non-adipose portion identified using an Indium chloride (InCl3) bone marrow scan.

Patient Concerns: A 69-year-old woman was referred to our hospital because of a left peritoneal mass detected on a medical checkup. Abdominal CT revealed a mass measuring 14.3 cm in diameter located between the left kidney and the left adrenal gland, which showed coexistence of fat and soft tissue densities.

Diagnoses: A bone marrow scan is a nuclear medicine examination to assess hematopoietic activity. To avoid excessive resection of the tumor, we thought that a bone marrow scan could be applied for differentiation between myelolipoma and retroperitoneal liposarcoma by evaluating the hematopoietic activity of the tumor. Tumor enucleation was performed, and pathological examination showed a diagnosis of adrenal myelolipoma.

Intervention: The patient was treated with laparoscopic enucleation.

Outcomes: No metastatic recurrence was found during 8 months of follow-up.

Lessons: Diagnosis of myelolipoma by CT and MRI becomes difficult in the presence of a high volume of hematopoietic tissue. In such cases, a bone marrow scan may be informative as a non-invasive imaging diagnostic method for preoperative diagnosis of the tumor and determination of the method of surgical treatment.
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http://dx.doi.org/10.1097/MD.0000000000014625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408009PMC
February 2019

Mesenchymal tumors of the lung: diagnostic pathology, molecular pathogenesis, and identified biomarkers.

J Thorac Dis 2019 Jan;11(Suppl 1):S9-S24

Division of Pathology, The Cancer Institute, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Lung cancers are mainly composed of epithelial tumors such as carcinomas. Since mesenchymal tumors that arise in the lung are very rare, they have garnered little attention. The 2015 World Health Organization (WHO) classification of lung tumors has undergone revision, not only for carcinomas but also for mesenchymal tumors. The current version now includes PEComatous tumors, myoepithelial tumors, and pulmonary myxoid sarcomas with translocation as new disease entities. To date, no review article has comprehensively summarized what is known about pulmonary mesenchymal tumors in accordance with the latest WHO classification. In this review, we attempt to summarize the data about these tumors in line with the 2015 WHO classification (except for pediatric tumors), focusing on their diagnostic pathology, molecular pathogenesis, and identified biomarkers for differential diagnoses. We also address the recently recognized pulmonary mesenchymal tumors that have not yet been included in the WHO classification. An increased understanding of the molecular characteristics of pulmonary mesenchymal tumors has the potential to provide clinicians with the best therapeutic options for patients with these tumors.
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http://dx.doi.org/10.21037/jtd.2018.12.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353741PMC
January 2019

Identification of Multisialylated LacdiNAc Structures as Highly Prostate Cancer Specific Glycan Signatures on PSA.

Anal Chem 2019 02 23;91(3):2247-2254. Epub 2019 Jan 23.

Cancer Proteomics Group, Cancer Precision Medicine Center , Japanese Foundation for Cancer Research , Tokyo 135-8550 , Japan.

Serum prostate-specific antigen (PSA) test is the current gold standard for screening and diagnosis of prostate cancer (PCa), while overdiagnosis and overtreatment are social problems. In order to improve the specificity and exclude a false positive diagnosis in PSA test, PCa-specific glycosylation subtypes of PSA were explored using in-depth quantitative profiling of PSA glycoforms based on mass spectrometric oxonium ion monitoring technology. As a result of analysis using sera from 15 PCa or 15 benign prostate hyperplasia (BPH) patients whose PSA levels were in the "gray zone" (4.0-10.0 ng/mL), 52 glycan structures on PSA were quantitatively observed. We found that abundance of multisialylated LacdiNAc (GalNAcβ1-4GlcNAc) structures were significantly upregulated in the PCa group compared to the BPH group. A couple of those glycoforms were then extracted and subjected to establish a novel PCa-specific diagnosis model (PSA G-index). When the diagnostic power was assessed using an independent validation sample set (15 PCa and 15 BPH patients in the PSA gray zone), an AUC of PSA G-index was 1.00, while that of total PSA or PSA f/T ratio was 0.50 or 0.60, respectively. Moreover, both PSA glycoforms showed significant correlation with Gleason scores. Lectin histochemical staining analysis also showed that PCa cells overexpressed glycoproteins containing LacdiNAc and sialic acids moieties. Thus, PSA G-index could serve as not only an effective secondary screening method to exclude false positive diagnosis in PSA screening, but also a potential grading biomarker for PCa.
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http://dx.doi.org/10.1021/acs.analchem.8b04829DOI Listing
February 2019

Gut microbiome: a key player in cancer immunotherapy.

Hepatobiliary Surg Nutr 2018 Dec;7(6):479-480

Division of Pathology, The Cancer Institute, Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.21037/hbsn.2018.10.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295395PMC
December 2018

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

Clin Cancer Res 2019 03 26;25(6):1948-1956. Epub 2018 Dec 26.

Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance.

Results: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all < 0.04). SMAD4 loss was associated with worse RFS ( = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS ( = 0.002 and = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival.

Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421131PMC
March 2019

Unique MicroRNA and mRNA Interactions in -Mutated Lung Adenocarcinoma.

J Clin Med 2018 Nov 6;7(11). Epub 2018 Nov 6.

Division of Pathology, The Cancer Institute; Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ward, Tokyo 135-8550, Japan.

The gene was one of the first molecules to be selected for targeted gene therapy. -mutated lung adenocarcinoma, which is responsive to inhibitors, is characterized by a distinct oncogenic pathway in which unique microRNA (miRNA)⁻mRNA interactions have been observed. However, little information is available about the miRNA⁻mRNA regulatory network involved. Both miRNA and mRNA expression profiles were investigated using microarrays in 155 surgically resected specimens of lung adenocarcinoma with a known mutation status (52 mutated and 103 wild-type cases). An integrative analysis of the data was performed to identify the unique miRNA⁻mRNA regulatory network in -mutated lung adenocarcinoma. Expression profiling of miRNAs and mRNAs yielded characteristic miRNA/mRNA signatures (19 miRNAs/431 mRNAs) in -mutated lung adenocarcinoma. Five of the 19 miRNAs were previously listed as -mutation-specific miRNAs (i.e., miR-532-3p, miR-500a-3p, miR-224-5p, miR-502-3p, and miR-532-5p). An integrative analysis of miRNA and mRNA expression revealed a refined list of putative miRNA⁻mRNA interactions, of which 63 were potentially involved in -mutated tumors. Network structural analysis provided a comprehensive view of the complex miRNA⁻mRNA interactions in -mutated lung adenocarcinoma, including DUSP4 and MUC4 axes. Overall, this observational study provides insight into the unique miRNA⁻mRNA regulatory network present in -mutated tumors. Our findings, if validated, would inform future research examining the interplay of miRNAs and mRNAs in -mutated lung adenocarcinoma.
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http://dx.doi.org/10.3390/jcm7110419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262391PMC
November 2018

Impact of CDX2 expression status on the survival of patients after curative resection for colorectal cancer liver metastasis.

BMC Cancer 2018 Oct 16;18(1):980. Epub 2018 Oct 16.

Department of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.

Background: The prognostic biomarker for patients undergoing curative liver metastasectomy for colorectal cancer (CRC) is lacking. The purpose was to investigate the prognostic role of a lack of CDX2 expression, which has been proposed as a potential biomarker for high-risk relapse in early-stage CRC, in patients undergoing curative liver metastasectomy.

Methods: A total of 396 consecutive patients with CRC liver metastasis who underwent potentially curative liver metastasectomy at a single center in Japan between 2005 and 2015 were included. For the immunohistochemical analysis of nuclear CDX2 expression, we adopted the tissue microarray approach using the resected metastatic liver CRCs. Patient subgroups were compared with respect to disease-free survival (DFS) and overall survival (OS) by applying the Kaplan-Meier curve, log-rank tests, and multivariate analyses based on the Cox proportional hazards method. OS is defined as the period from the date of curative liver resection for metastatic CRC until death. DFS is defined as the length of time from curative liver resection to either the first recurrence or death. In patients without recurrence, the latest imaging inspection date was used as the censored date.

Results: Thirty-six of the 396 CRCs (9.1%) reduced CDX2 expression. The reduced expression of CDX2 was associated with poor differentiation (P = 0.02). DFS in days was lower in the patients with CDX2-low CRC than in the patients with CDX2-high CRC (median DFS: 245 days versus 420 days; hazard ratio for disease recurrence: 1.64; 95% confidence interval: 1.08-2.38; P = 0.02). OS in days was lower in the patients with CDX2-low CRC than in the patients with CDX2-high CRC (median OS: 1024 days versus 3145 days; hazard ratio: 2.41; 95% confidence interval: 1.52-3.85; P <  0.001). In patients with CDX2-low CRC, both DFS and OS were similar between the with and without pre- or post-operative chemotherapy groups (median DFS: 243 versus 247 days; P = 0.73, median OS: 1016 versus 1363 days; P = 0.69).

Conclusions: Reduced expression of CDX2 indicates poor DFS and OS, however, it might not represent chemosensitivity in patients undergoing curative liver metastasectomy. (339/350).
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http://dx.doi.org/10.1186/s12885-018-4902-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192098PMC
October 2018

in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status.

Cancer Immunol Res 2018 11 18;6(11):1327-1336. Epub 2018 Sep 18.

Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

The presence of () in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between status and histopathologic lymphocytic reactions or density of CD3 cells, CD8 cells, CD45RO (PTPRC) cells, or FOXP3 cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and , and mutations. The association of with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status ( = 0.002). The presence of was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22-0.92], but positively associated with TIL in non-MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12-3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that and MSI status interact to affect antitumor immune reactions. .
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215508PMC
November 2018

Vitamin D status after colorectal cancer diagnosis and patient survival according to immune response to tumour.

Eur J Cancer 2018 11 13;103:98-107. Epub 2018 Sep 13.

Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Background: High-level plasma 25-hydroxyvitamin D [25(OH)D] has been associated with lower colorectal cancer incidence and mortality. Considering evidence indicating immunomodulatory effects of vitamin D, we hypothesised that survival benefits from high systemic vitamin D level might be stronger for colorectal carcinoma with lower immune response to tumour.

Methods: Using 869 colon and rectal cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis 25(OH)D score [derived from diet and lifestyle variables to predict plasma 25(OH)D level] in strata of levels of histopathologic lymphocytic reaction. The Cox proportional hazards regression model was adjusted for potential confounders, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, PTGS2 (cyclooxygenase-2) expression and KRAS, BRAF and PIK3CA mutations.

Results: The association of postdiagnosis 25(OH)D score with colorectal cancer-specific mortality differed by levels of peritumoural lymphocytic reaction (p = 0.001). Multivariable-adjusted mortality hazard ratios for a quintile-unit increase of 25(OH)D score were 0.69 [95% confidence interval (CI), 0.54-0.89] in cases with negative/low peritumoural lymphocytic reaction, 1.08 (95% CI, 0.93-1.26) in cases with intermediate peritumoural reaction and 1.25 (95% CI, 0.75-2.09) in cases with high peritumoural reaction. The survival association of the 25(OH)D score did not significantly differ by Crohn's-like lymphoid reaction, intratumoural periglandular reaction or tumour-infiltrating lymphocytes.

Conclusions: The association between the 25(OH)D score and colorectal cancer survival is stronger for carcinomas with lower peritumoural lymphocytic reaction. Our results suggesting interactive effects of vitamin D and immune response may contribute to personalised dietary and lifestyle intervention strategies.
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http://dx.doi.org/10.1016/j.ejca.2018.07.130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195453PMC
November 2018

CSF1R-Expressing Tumor-Associated Macrophages, Smoking and Survival in Lung Adenocarcinoma: Analyses Using Quantitative Phosphor-Integrated Dot Staining.

Cancers (Basel) 2018 Jul 31;10(8). Epub 2018 Jul 31.

Division of Pathology, The Cancer Institute, Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.

CSF1R-expressing tumor-associated macrophages (TAMs) induce a tumor-promoting microenvironment by regulating immunity. Evidence demonstrates that the expression and single nucleotide polymorphisms of relate with survival and risk of lung cancer in never smokers. However, no previous studies have examined the association of CSF1R expression in TAMs with mortality or whether the prognostic association differs according to smoking status in lung adenocarcinoma. Quantitative phosphor-integrated dot staining was used to precisely assess CSF1R expression in TAMs. Using 195 consecutive cases of lung adenocarcinoma, we examined the association of CSF1R expression with mortality and whether the prognostic association differs according to smoking status. We observed high expression levels of CSF1R in TAMs in 65 of 195 (33%) cases of lung adenocarcinoma. High expression levels of CSF1R were associated with high lung cancer-specific mortality (log-rank = 0.037; hazard ratio (HR) = 1.61, 95% confidence interval (CI) = 1.02-2.52, = 0.043). This prognostic association differed according to smoking status ( for interaction = 0.049, between never-smoking and ever-smoking patients). The association between high expression levels of CSF1R and lung cancer-specific mortality was stronger in never-smoking patients (log-rank = 0.0027; HR = 2.90, 95% CI = 1.41-6.11, = 0.0041) than in ever-smoking patients (log-rank = 0.73; HR = 1.11, 95% CI = 0.59-2.00, = 0.73). The findings suggest that CSF1R-expressing TAMs may exert stronger tumor-promoting immunity in never-smoking patients with lung adenocarcinoma and serve as a therapeutic target in precision immunotherapies.
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http://dx.doi.org/10.3390/cancers10080252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115958PMC
July 2018

Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer.

J Clin Med 2018 Jul 10;7(7). Epub 2018 Jul 10.

Division of Pathology, The Cancer Institute, Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.

B7-H3 (CD276), a member of the family of immune modulators, orchestrates antitumor immunity. To date, only small-sized studies have examined the association of B7-H3 expression with survival in pancreatic cancer, yielding inconclusive results. We evaluated tumor B7-H3 expression in 150 consecutive patients with pancreatic ductal adenocarcinoma using immunohistochemistry. B7-H3 expression was positive (≥10% tumor cells) in 99 of 150 (66%) cases of pancreatic cancer. We classified the tumors into four groups depending on B7-H3 expression (negative, low, intermediate, and high) and found that higher B7-H3 expression was independently associated with lower disease-free survival (DFS; for high vs. negative B7-H3 expression: multivariable hazard ratio (HR) = 3.12; 95% confidence interval (CI) = 1.48⁻6.15; = 0.0026). Furthermore, the association of B7-H3 expression with survival differed according to the pathological stage (p-stage) ( = 0.048, between p-stages I⁻II and III⁻IV). The association of B7-H3 positivity with lower DFS was stronger in tumors with p-stage I⁻II (multivariable HR = 3.10, 95% CI = 1.75⁻5.69; < 0.0001) than in those with p-stage III⁻IV (multivariable HR = 1.20, 95% CI = 0.67⁻2.28; = 0.55). We demonstrated that tumor high B7-H3 expression is independently associated with poor survival in patients with pancreatic cancer and that this association is stronger in tumors with p-stage I⁻II than in those with p-stage III⁻IV. B7-H3 expression may be a useful prognostic biomarker for identifying aggressive early-stage pancreatic cancer.
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http://dx.doi.org/10.3390/jcm7070172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069252PMC
July 2018