Publications by authors named "Junko Kishikawa"

39 Publications

Predictive factors of survival of colorectal cancer patients after para-aortic lymph node metastasis.

Int J Clin Oncol 2021 Nov 27. Epub 2021 Nov 27.

Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Para-aortic lymph node (PALN) metastasis is an ominous manifestation indicating a poor prognosis in colorectal cancer (CRC) patients; however, some treatments prolong survival. In this study, we investigated predictors of prolonged survival in CRC patients after PALN metastasis.

Methods: We examined 141 patients with CRC that metastasized to the PALNs from CRC with or without extra-PALN metastasis. Among clinicopathological parameters, factors associated with survival after PALN metastasis were identified by multivariate analyses using Cox's proportional hazard models.

Results: The mean hemoglobin and albumin values at diagnosis were 12.3 g/dL and 3.7 g/dL, respectively. Rectal cancer was predominant (n = 81). Mutated RAS was detected in 43%. One hundred and four patients had differentiated adenocarcinoma. Patients underwent PALN dissection (n = 11), radiotherapy (n = 6), and systemic therapy (n = 120). Biologics were administered to 95 patients. The median survival time was 29.1 months. On multivariate analysis, independent factors associated with reduced survival after PALN metastasis were low albumin (hazard ratio [HR] 2.33 per -1 g/dL), mutated RAS (HR 2.55), other than differentiated adenocarcinoma (HR 2.75), rectal cancer (HR 3.38 against right-sided colon, and 3.48 against left-sided colon), the presence of extra-PALN metastasis (HR 6.56), and no use of biologics (HR 3.04).

Conclusions: This study revealed that hypoalbuminemia as well as RAS mutation, undifferentiated histology, rectal cancer, other site metastasis, and no use of biologics contribute to poor prognosis in CRC patients with PALN metastasis. Nutritional management may be important for improving survival of these patients.
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http://dx.doi.org/10.1007/s10147-021-02095-4DOI Listing
November 2021

Prognoses in Pathologically Confirmed T1 Lower Rectal Cancer Patients with or without Preoperative Therapy: An Analysis Using the Surveillance, Epidemiology, and End Results Database.

Oncology 2021 Nov 24. Epub 2021 Nov 24.

Introduction Preoperative chemoradiotherapy (CRT) is the standard therapy for downstaging in locally advanced lower rectal cancer. However, it remains unclear whether rectal cancers down-staged by preoperative therapy show similar prognoses to those of the same stage without preoperative therapy. We previously demonstrated that preoperative CRT did not affect prognosis of rectal cancer with pathological T1N0 (pT1N0) stage in a single institute. Here, using a larger dataset, we compared prognoses of (y)pT1 rectal cancer stratified by the use of preoperative therapy and analyzed prognostic factors. Methods Cases of pT1N0 rectal cancer, registered between 2004 and 2016, were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized as the 'ypT1 group' if they had undergone preoperative therapy before surgery or as the 'pT1 group' if they had undergone surgery alone. overall survival (OS) and cancer-specific survival (CSS) between these groups of patients was compared. Factors associated with CSS and OS were identified by univariate and multivariate analyses. Results Among 3,757 eligible patients, ypT1 and pT1 groups comprised 720 and 3,037 patients, respectively. While ypT1 patients showed poorer CSS than ypT1 patients, there was no significant difference in OS. Preoperative therapy was not an independent prognostic factor for CSS or OS. Multivariate analysis identified age and histological type as significant factors associated with CSS. Sex, age, race, and number of lymph nodes dissected were identified as significant factors associated with OS. Conclusions Prognosis among patients with (y)p T1N0 rectal cancer was similar irrespective of whether they underwent preoperative therapy, which is consistent with our previous observations.
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http://dx.doi.org/10.1159/000521033DOI Listing
November 2021

Preoperative sarcopenia is a poor prognostic factor in lower rectal cancer patients undergoing neoadjuvant chemoradiotherapy: a retrospective study.

Int J Clin Oncol 2021 Nov 6. Epub 2021 Nov 6.

Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: This study aimed to investigate the effect of sarcopenia on the prognosis of advanced lower rectal cancer patients receiving neoadjuvant chemoradiotherapy (CRT). Sarcopenia has been recognized as an adverse factor for surgical outcomes in several malignancies. However, the impact of preoperative sarcopenia on rectal cancer patients receiving CRT is still unknown.

Methods: This retrospective study included cT3-T4 anyN M0 lower rectal cancer patients who underwent CRT followed by R0 resection at our institution between October 2003 and December 2016. CRT consisted of 5-fluorouracil-based oral chemotherapy and long course radiation (50.4 Gy/28 fr). The psoas muscle area at the third lumbar vertebra level was evaluated by computed tomography before and after CRT, and was adjusted by the square of the height to obtain the psoas muscle mass index (PMI). Sarcopenia was defined as the sex-specific lowest quartile of the PMI. We assessed the association between pre- and post-CRT sarcopenia and postoperative prognosis.

Results: Among 234 patients, 55 and 179 patients were categorized as sarcopenia and non-sarcopenia patients, respectively. Although post-CRT sarcopenia correlated with residual tumor size, it had no association with other pathological features. The median follow-up period was 72.9 months, and the 5-year DFS and OS were 67.0% and 85.8%, respectively. Multivariate analysis showed that post-CRT sarcopenia was independently associated with poor DFS (HR: 1.76; P = 0.036), OS (HR: 2.01; P = 0.049), and recurrence in the liver (HR: 3.01; P = 0.025).

Conclusions: Sarcopenia is a poor prognostic indicator in lower advanced rectal cancer patients treated with CRT.
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http://dx.doi.org/10.1007/s10147-021-02062-zDOI Listing
November 2021

Poor nutrition and sarcopenia are related to systemic inflammatory response in patients with rectal cancer undergoing preoperative chemoradiotherapy.

Int J Colorectal Dis 2021 Oct 11. Epub 2021 Oct 11.

Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: Preoperative chemoradiotherapy (CRT) is the standard therapy for locally advanced rectal cancer (LARC). However, the changes that the patient's physical status during CRT, such as host systemic inflammatory response, nutritional status, and muscle depletion, are still unclear. We evaluated the clinical significance of malnutrition and sarcopenia for patients with LARC undergoing CRT.

Patients And Methods: Patients with LARC treated with CRT following radical surgery at our institution between 2006 and 2016 (N = 225) were retrospectively analyzed. A new prognostic score (PNSI) was devised based on the prognostic nutritional index (PNI) and the psoas muscle mass index (PMI): patients with malnutrition/sarcopenia were scored 2; patients with one and neither abnormality were scored 1 and 0, respectively.

Results: Neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, and platelet/lymphocyte ratio increased, whereas PNI and PMI decreased after CRT. There were 130, 73, and 22 patients in the PNSI 0, 1, and 2 groups, respectively. Patients with higher PNSI had higher residual tumor size (p = 0.003), yT stage (p = 0.007), ypStage (p < 0.001), post-CRT platelet/lymphocyte ratio (p = 0.027), and post-CRT C-reactive protein/albumin ratio (p < 0.001). Post-CRT PNSI was associated with overall survival and was an independent poor prognosis factor (PNSI 1 to 0, hazard ratio 2.40, p = 0.034, PNSI 2 to 0, hazard ratio 2.66, p = 0.043) together with mesenteric lymph node metastasis, lateral lymph node metastasis, and histology.

Conclusion: A combined score of post-CRT malnutrition/sarcopenia is promising for predicting overall survival in LARC.
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http://dx.doi.org/10.1007/s00384-021-04039-wDOI Listing
October 2021

Impact of Inferior Mesenteric Artery Occlusion on the Calibre of Collateral Arteries of the Colon.

Anticancer Res 2021 Oct;41(10):5189-5193

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background/aim: The inferior mesenteric arteries (IMA) are occluded in some colorectal cancer patients. This study evaluated the impact of IMA occlusion on the calibre of collateral arteries.

Patients And Methods: As an IMA obstruction model, 20 patients who underwent abdominal aortic aneurysm surgery, with ligated, excluded, or embolised IMA, were enrolled. Changes in the calibre of the left colic arteries (LCAs) and marginal arteries after surgeries were evaluated.

Results: The cross-sectional area of the LCA significantly increased after surgery (4.34 mm vs. 6.34 mm, p=0.0009) and that of the marginal artery did not change significantly (2.69 mm vs. 3.01 mm, p=0.33).

Conclusion: The calibre of the LCA increased after IMA occlusion. The descending branch of the LCA should be confirmed preoperatively to preserve blood flow during a low tie procedure.
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http://dx.doi.org/10.21873/anticanres.15337DOI Listing
October 2021

Women are predisposed to early dose-limiting toxicities during adjuvant CAPOX for colorectal cancer.

Int J Clin Pract 2021 Nov 18;75(11):e14863. Epub 2021 Sep 18.

Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: Oxaliplatin-based adjuvant chemotherapy was demonstrated to be beneficial for stage III or high-risk stage II colorectal cancer (CRC). Moreover, a recent international collaborative trial suggested 3-months CAPOX as an alternative regimen for low-risk stage III colorectal cancer (CRC) patients. Thus, it is important to clarify the frequency and predictive markers of dose-limiting toxicities (DLTs) developed within the short-course CAPOX cycles.

Methods: We investigated CRC patients who underwent radical surgery and adjuvant CAPOX therapy at our hospital between December 2010 and February 2021. Patients who received initially reduced doses of CAPOX and those who had early recurrence were excluded. We reviewed the age, sex, comorbidities, physical, laboratory and oncological data and other perioperative factors. The associations between these variables and early DLTs within four cycles of CAPOX were examined by multivariate analyses using logistic regression models.

Results: Among 168 patients (96 men, mean age: 58.3 years), 120 (71%) developed early DLTs. Patients with early DLTs were predominantly women and sarcopenic and habitual alcohol consumers. On multivariate analyses, only the female sex was an independent predictive factor for early DLTs (odds ratio: 2.61, P = .027).

Conclusion: Women were prone to early DLTs during adjuvant CAPOX in the current study. Doctors should be aware of the sex difference in the incidence of early DLTs, adjust the CAPOX dosage and provide supportive care for female CRC patients.
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http://dx.doi.org/10.1111/ijcp.14863DOI Listing
November 2021

Vascular anatomy of the splenic flexure: a review of the literature.

Surg Today 2021 Aug 4. Epub 2021 Aug 4.

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Surgical treatment of the transverse colon is difficult because of the many variations of blood vessels. We reviewed the patterns of vascular anatomy and the definition of the vessels around the splenic flexure. We searched the PubMed database for studies on the vascular anatomy of the splenic flexure that were published from January 1990 to October 2020. After screening of full texts, 33 studies were selected. The middle colic arteries were reported to arise independently without forming a common trunk in 8.9-33.3% of cases. The left colic artery was absent in 0-7.5% of cases. The accessory middle colic artery was present in 6.7-48.9% of cases and was present in > 80% of cases without a left colic artery. The reported frequency of Riolan's arch was 7.5-27.8%. The frequency was found to vary widely across studies, partially due to the ambiguous definition of Riolan's arch. A comprehensive preoperative knowledge of the branching patterns of the middle colic artery and left colic artery and the presence of collateral arteries would be helpful in surgery for colon cancer in the splenic flexure.
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http://dx.doi.org/10.1007/s00595-021-02328-zDOI Listing
August 2021

Risk of extracolonic malignancies and metachronous rectal cancer after colectomy and ileorectal anastomosis in familial adenomatous polyposis.

Asian J Surg 2021 Jul 27. Epub 2021 Jul 27.

Department of Surgical Oncology, Faculty of Medicine, the University of Tokyo, Japan.

Background: Analysis of long-term clinical outcomes of patients with familial adenomatous polyposis is critical in reducing or preventing the incidence of extracolonic malignancies after initial surgery. The aim of the present study was to clarify the long-term outcomes, and establish a surveillance strategy for surgically treated familial adenomatous polyposis patients.

Methods: Between January 1967 and March 2020, retrospective data were collected from 37 patients with familial adenomatous polyposis treated or monitored in our department. Occurrence of metachronous cancers, including rectal cancers and extracolonic malignancies, and other diseases was analyzed.

Results: The median follow-up duration after the first surgery was 13.8 years. Initially, 16 patients underwent total proctocolectomy with ileal pouch-anal anastomosis, 18 underwent total colectomy with ileorectal anastomosis, and three underwent other procedures. A secondary proctectomy was performed for 9 of the 18 patients who underwent ileorectal anastomosis. Rectal cancer was diagnosed in 6 patients who underwent ileorectal anastomosis. In addition, 5 gastric cancer, 2 duodenal cancer, 1 gallbladder cancer, and 1 thyroid cancer cases were diagnosed. The age at which the extracolonic malignancies were diagnosed was >50 years. 4 patients died due to metachronous rectal cancer, gastric cancer, or gallbladder cancer.

Conclusion: Careful consideration should be paid before choosing ileorectal anastomosis as the treatment procedure for familial adenomatous polyposis patients because completion proctectomy was eventually necessary for half of the patients. Long-term surveillance, with more frequent gastric surveillance for patients over 50 years, is important for the prevention and treatment of extracolonic malignancies in familial adenomatous polyposis patients.
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http://dx.doi.org/10.1016/j.asjsur.2021.06.034DOI Listing
July 2021

Smoking and Incidence of Colorectal Cancer Subclassified by Tumor-Associated Macrophage Infiltrates.

J Natl Cancer Inst 2021 Jul 15. Epub 2021 Jul 15.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Background: Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates.

Methods: Utilizing the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence [for CD68, CD86, IRF5, MAF, and MRC1 (CD206)] combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability-weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias due to tissue data availability. All statistical tests were 2-sided.

Results: During follow-up of 131,144 participants (3,648,370 person-years), we documented 3,092 incident colorectal cancer cases including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity=.003). Compared to never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for ≥40 pack-years (Ptrend=.004). In contrast, pack-years smoked were not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend>.009, with the α level of 0.005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages.

Conclusions: The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.
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http://dx.doi.org/10.1093/jnci/djab142DOI Listing
July 2021

Expression of Lysophosphatidylinositol Signaling-relevant Molecules in Colorectal Cancer.

Anticancer Res 2021 May;41(5):2349-2355

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background/aim: Lysophosphatidylinositol (LPI) is a subspecies of the lysophospholipid mediators produced when phospholipase hydrolyzes membrane phosphatidylinositol. Previously, we used mass spectrometry-based lipidomics to demonstrate that LPI is selectively elevated in colorectal cancer (CRC) tissues. Here, we hypothesized that the expression levels of the LPI biosynthetic enzyme and LPI receptor - DDHD domain containing 1 (DDHD1) and G protein-coupled receptor 55 (GPR55), respectively - may be correlated with malignant potential, and we evaluated their roles in the context of CRC.

Materials And Methods: Colorectal specimens from 92 CRC patients underwent DDHD1 and GPR55 immunolabeling. Correlation between protein expression levels and clinicopathological variables was examined.

Results: Depth of tumor invasion was positively correlated with DDHD1 expression. Regardless of the degree of invasion depth, GPR55 was highly expressed in CRC tissues. Neither DDHD1 nor GPR55 expression levels were associated with disease-free survival.

Conclusion: DDHD1 expression is associated with depth of tumor invasion in CRC tissues and may be involved in tumor progression.
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http://dx.doi.org/10.21873/anticanres.15009DOI Listing
May 2021

Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment.

J Immunother Cancer 2021 04;9(4)

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

Background: Myeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood.

Methods: We used multiplexed immunofluorescence combined with digital image analysis to identify CD14 monocytic and CD15 granulocytic cells and to evaluate their maturity (HLA-DR and CD33), immunosuppressive potential (ARG1) and proximity to cytokeratin (KRT)-positive tumor cells in 913 colorectal carcinomas. Using covariate data of 4465 incident colorectal cancers in two prospective cohort studies, the inverse probability weighting method was used with multivariable-adjusted Cox proportional hazards models to assess cancer-specific mortality according to ordinal quartiles (Q1-Q4) of myeloid cell densities. Immune cell-tumor cell proximity was measured with the nearest neighbor method and the G-cross function, which determines the likelihood of any tumor cell having at least one immune cell of the specified type within a certain radius.

Results: Higher intraepithelial ( =0.0002; HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal ( <0.0001; HR for Q4 (vs Q1), 0.42, 95% CI 0.29 to 0.63) densities of CD14HLA-DR cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14HLA-DR cells were associated with higher colorectal cancer-specific mortality ( =0.0003; HR for Q4 (vs Q1), 1.78, 95% CI 1.25 to 2.55). Spatial analyses indicated that CD15 cells were located closer to tumor cells than CD14 cells, and CD14HLA-DR cells were closer to tumor than CD14HLA-DR cells (p<0.0001). The G-cross proximity measurement, evaluating the difference in the likelihood of any tumor cell being colocated with at least one CD14HLA-DR cell versus CD14HLA-DR cell within a 20 µm radius, was associated with lower colorectal cancer-specific mortality ( <0.0001; HR for Q4 (vs Q1), 0.37, 95% CI 0.24 to 0.57).

Conclusions: Myeloid cell populations occur in spatially distinct distributions and exhibit divergent, subset-specific prognostic significance in colorectal cancer, with mature CD14HLA-DR and immature CD14HLA-DR monocytic phenotypes most notably showing opposite associations. These results highlight the prognostic utility of multimarker evaluation of myeloid cell infiltrates and reveal a previously unrecognized degree of spatial organization for myeloid cells in the immune microenvironment.
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http://dx.doi.org/10.1136/jitc-2020-002297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098931PMC
April 2021

Tumor Long Interspersed Nucleotide Element-1 (LINE-1) Hypomethylation in Relation to Age of Colorectal Cancer Diagnosis and Prognosis.

Cancers (Basel) 2021 Apr 22;13(9). Epub 2021 Apr 22.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Evidence indicates the pathogenic role of epigenetic alterations in early-onset colorectal cancers diagnosed before age 50. However, features of colorectal cancers diagnosed at age 50-54 (hereafter referred to as "intermediate-onset") remain less known. We hypothesized that tumor long interspersed nucleotide element-1 (LINE-1) hypomethylation might be increasingly more common with decreasing age of colorectal cancer diagnosis. In 1356 colorectal cancers, including 28 early-onset and 66 intermediate-onset cases, the tumor LINE-1 methylation level measured by bisulfite-PCR-pyrosequencing (scaled 0 to 100) showed a mean of 63.6 (standard deviation (SD) 10.1). The mean tumor LINE-1 methylation level decreased with decreasing age (mean 64.7 (SD 10.4) in age ≥70, 62.8 (SD 9.4) in age 55-69, 61.0 (SD 10.2) in age 50-54, and 58.9 (SD 12.0) in age <50; < 0.0001). In linear regression analysis, the multivariable-adjusted β coefficient (95% confidence interval (CI)) (vs. age ≥70) was -1.38 (-2.47 to -0.30) for age 55-69, -2.82 (-5.29 to -0.34) for age 50-54, and -4.54 (-8.24 to -0.85) for age <50 ( = 0.0003). Multivariable-adjusted hazard ratios (95% CI) for LINE-1 methylation levels of ≤45, 45-55, and 55-65 (vs. >65) were 2.33 (1.49-3.64), 1.39 (1.05-1.85), and 1.29 (1.02-1.63), respectively ( = 0.0005). In conclusion, tumor LINE-1 hypomethylation is increasingly more common with decreasing age of colorectal cancer diagnosis, suggesting a role of global DNA hypomethylation in colorectal cancer arising in younger adults.
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http://dx.doi.org/10.3390/cancers13092016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122644PMC
April 2021

Coffee Intake and Colorectal Cancer Incidence According to T-Cell Response.

JNCI Cancer Spectr 2020 Dec 7;4(6):pkaa068. Epub 2020 Sep 7.

Department of Pathology, Brigham and Women's Hospital, Program in MPE Molecular Pathological Epidemiology, Harvard Medical School, Boston, MA, USA.

We hypothesized that the associations between coffee intake and colorectal cancer (CRC) incidence might differ by immune cell densities in CRC tissue. Using the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of coffee intake with incidence of CRC classified by intraepithelial or stromal T-cell subset densities by multiplex immunofluorescence assay for CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3. We applied an inverse probability-weighted Cox proportional hazardsregression model to control for selection bias and potential confounders. During follow-up of 133 924 participants (3 585 019 person-years), we documented 3161 incident CRC cases, including 908 CRC cases with available data on T-cell densities in tumor tissue. The association between coffee intake and CRC was not statistically significantly different by intraepithelial or stroma T-cell subset ( > .38). Hence, there is no sufficient evidence for differential effect of coffee intake on incidence of CRC subtypes classified by T-cell infiltrates.
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http://dx.doi.org/10.1093/jncics/pkaa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771005PMC
December 2020

Epithelial-mesenchymal transition and metastatic ability of CD133 colorectal cancer stem-like cells under hypoxia.

Oncol Lett 2021 Jan 9;21(1):19. Epub 2020 Nov 9.

Department of Surgical Oncology, The University of Tokyo, Tokyo 113-8655, Japan.

Although CD133 is a representative cancer stem cell marker, its function in tumor aggressiveness under hypoxia remains unclear. Therefore, the present study aimed to investigate the associations between CD133, the epithelial-mesenchymal transition and distant metastasis in colorectal cancer. CD133 and CD133 cells were isolated from a single colorectal cancer cell line LoVo, and their adhesive and migratory properties were compared under hypoxic conditions. Immunostaining analysis was performed to determine CD133 expression in clinical samples of primary tumors, as well as liver and peritoneal metastases. Under hypoxia, the expression levels of hypoxia-inducible factor (HIF)-1α and the epithelial-mesenchymal transition markers N-cadherin and vimentin were significantly higher in the CD133 compared with those in the CD133 cells. Furthermore, the migratory ability of the CD133 cells was higher compared with that of the CD133 cells under hypoxia. By contrast, the expression levels of β1 integrin were significantly lower in the CD133 cells under hypoxia compared with those in the CD133 cells. Immunohistochemical analysis of clinical samples revealed that the levels of CD133 expression in metastatic tissues from the liver were significantly higher compared with those in the corresponding primary tumors, whereas CD133 expression levels in peritoneal metastatic tissues were significantly lower compared with those in the corresponding primary tumors. In conclusion, compared with the CD133 cells, the CD133 colorectal cancer cells exhibited enhanced levels of HIF-1α expression and tumor cell migration during hypoxia. This was associated with an increased ability of epithelial-mesenchymal transition, possibly leading to the acquisition of an increased hematogenous metastatic potential and eventually resulting in liver metastasis. High β1 integrin expression levels in the CD133 cells under hypoxia may serve a key role in cell adhesion to the peritoneum, resulting in peritoneal metastasis.
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http://dx.doi.org/10.3892/ol.2020.12280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681219PMC
January 2021

The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment.

Cancer Immunol Res 2021 01 6;9(1):8-19. Epub 2020 Oct 6.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor stromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Overall macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single-cell resolution within the tumor microenvironment.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785652PMC
January 2021

Smoking Status at Diagnosis and Colorectal Cancer Prognosis According to Tumor Lymphocytic Reaction.

JNCI Cancer Spectr 2020 Aug 14;4(5):pkaa040. Epub 2020 May 14.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Smoking has been associated with worse colorectal cancer patient survival and may potentially suppress the immune response in the tumor microenvironment. We hypothesized that the prognostic association of smoking behavior at colorectal cancer diagnosis might differ by lymphocytic reaction patterns in cancer tissue.

Methods: Using 1474 colon and rectal cancer patients within 2 large prospective cohort studies (Nurses' Health Study and Health Professionals Follow-up Study), we characterized 4 patterns of histopathologic lymphocytic reaction, including tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral lymphocytic reaction, and Crohn's-like lymphoid reaction. Using covariate data of 4420 incident colorectal cancer patients in total, an inverse probability weighted multivariable Cox proportional hazards regression model was conducted to adjust for selection bias due to tissue availability and potential confounders, including tumor differentiation, disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, and , , and mutations.

Results: The prognostic association of smoking status at diagnosis differed by TIL status. Compared with never smokers, the multivariable-adjusted colorectal cancer-specific mortality hazard ratio for current smokers was 1.50 (95% confidence interval = 1.10 to 2.06) in tumors with negative or low TIL and 0.43 (95% confidence interval = 0.16 to 1.12) in tumors with intermediate or high TIL (2-sided = .009). No statistically significant interactions were observed in the other patterns of lymphocytic reaction.

Conclusions: The association of smoking status at diagnosis with colorectal cancer mortality may be stronger for carcinomas with negative or low TIL, suggesting a potential interplay of smoking and lymphocytic reaction in the colorectal cancer microenvironment.
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http://dx.doi.org/10.1093/jncics/pkaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477375PMC
August 2020

Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer.

EBioMedicine 2020 Jul 8;57:102860. Epub 2020 Jul 8.

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

Background: Tumour budding and poorly differentiated clusters (PDC) represent forms of tumour invasion. We hypothesised that T-cell densities (reflecting adaptive anti-tumour immunity) might be inversely associated with tumour budding and PDC in colorectal carcinoma.

Methods: Utilising 915 colon and rectal carcinomas in two U.S.-wide prospective cohort studies, and multiplex immunofluorescence combined with machine learning algorithms, we assessed CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 co-expression patterns in lymphocytes. Tumour budding and PDC at invasive fronts were quantified by digital pathology and image analysis using the International tumour Budding Consensus Conference criteria. Using covariate data of 4,420 incident colorectal cancer cases, inverse probability weighting (IPW) was integrated with multivariable logistic regression analysis that assessed the association of T-cell subset densities with tumour budding and PDC while adjusting for selection bias due to tissue availability and potential confounders, including microsatellite instability status.

Findings: Tumour budding counts were inversely associated with density of CD3CD8 [lowest vs. highest: multivariable odds ratio (OR), 0.50; 95% confidence interval (CI), 0.35-0.70; P < 0.001] and CD3CD8CD45RO cells (lowest vs. highest: multivariable OR, 0.44; 95% CI, 0.31-0.63; P < 0.001) in tumour epithelial region. Tumour budding levels were associated with higher colorectal cancer-specific mortality (multivariable hazard ratio, 2.13; 95% CI, 1.57-2.89; P < 0.001) in Cox regression analysis. There were no significant associations of PDC with T-cell subsets.

Interpretation: Tumour epithelial naïve and memory cytotoxic T cell densities are inversely associated with tumour budding at invasive fronts, suggesting that cytotoxic anti-tumour immunity suppresses tumour microinvasion.
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http://dx.doi.org/10.1016/j.ebiom.2020.102860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347996PMC
July 2020

Prognostic Significance of Immune Cell Populations Identified by Machine Learning in Colorectal Cancer Using Routine Hematoxylin and Eosin-Stained Sections.

Clin Cancer Res 2020 08 21;26(16):4326-4338. Epub 2020 May 21.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Purpose: Although high T-cell density is a well-established favorable prognostic factor in colorectal cancer, the prognostic significance of tumor-associated plasma cells, neutrophils, and eosinophils is less well-defined.

Experimental Design: We computationally processed digital images of hematoxylin and eosin (H&E)-stained sections to identify lymphocytes, plasma cells, neutrophils, and eosinophils in tumor intraepithelial and stromal areas of 934 colorectal cancers in two prospective cohort studies. Multivariable Cox proportional hazards regression was used to compute mortality HR according to cell density quartiles. The spatial patterns of immune cell infiltration were studied using the G function, which estimates the likelihood of any tumor cell in a sample having at least one neighboring immune cell of the specified type within a certain radius. Validation studies were performed on an independent cohort of 570 colorectal cancers.

Results: Immune cell densities measured by the automated classifier demonstrated high correlation with densities both from manual counts and those obtained from an independently trained automated classifier (Spearman's ρ 0.71-0.96). High densities of stromal lymphocytes and eosinophils were associated with better cancer-specific survival [ < 0.001; multivariable HR (4th vs 1st quartile of eosinophils), 0.49; 95% confidence interval, 0.34-0.71]. High G area under the curve (AUC; = 0.002) and high G AUC ( < 0.001) also showed associations with better cancer-specific survival. High stromal eosinophil density was also associated with better cancer-specific survival in the validation cohort ( < 0.001).

Conclusions: These findings highlight the potential for machine learning assessment of H&E-stained sections to provide robust, quantitative tumor-immune biomarkers for precision medicine.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442724PMC
August 2020

Metabolic Profiling of Formalin-Fixed Paraffin-Embedded Tissues Discriminates Normal Colon from Colorectal Cancer.

Mol Cancer Res 2020 06 12;18(6):883-890. Epub 2020 Mar 12.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Accumulating evidence suggests that metabolic reprogramming has a critical role in carcinogenesis and tumor progression. The usefulness of formalin-fixed paraffin-embedded (FFPE) tissue material for metabolomics analysis as compared with fresh frozen tissue material remains unclear. LC/MS-MS-based metabolomics analysis was performed on 11 pairs of matched tumor and normal tissues in both FFPE and fresh frozen tissue materials from patients with colorectal carcinoma. Permutation test was applied to identify metabolites with differential abundance between tumor and normal tissues. A total of 200 metabolites were detected in the FFPE samples and 536 in the fresh frozen samples. The preservation of metabolites in FFPE samples was diverse according to classes and chemical characteristics, ranging from 78% (energy) to 0% (peptides). Compared with the normal tissues, 34 (17%) and 174 (32%) metabolites were either accumulated or depleted in the tumor tissues derived from FFPE and fresh frozen samples, respectively. Among them, 15 metabolites were common in both FFPE and fresh frozen samples. Notably, branched chain amino acids were highly accumulated in tumor tissues. Using KEGG pathway analyses, glyoxylate and dicarboxylate metabolism, arginine and proline, glycerophospholipid, and glycine, serine, and threonine metabolism pathways distinguishing tumor from normal tissues were found in both FFPE and fresh frozen samples. This study demonstrates that informative data of metabolic profiles can be retrieved from FFPE tissue materials. IMPLICATIONS: Our findings suggest potential value of metabolic profiling using FFPE tumor tissues and may help to shape future translational studies through developing treatment strategies targeting metabolites.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272267PMC
June 2020

Immunohistochemical Expression of CD133 and LGR5 in Ulcerative Colitis-associated Colorectal Cancer and Dysplasia.

In Vivo 2019 Jul-Aug;33(4):1279-1284

Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Background/aim: Cluster of differentiation 133 (CD133) and leu cine-rich orphan G-protein-coupled receptor 5 (LGR5) are the most putative stem cell markers for colorectal cancer (CRC), and are associated with poor prognosis of patients with CRC. However, the role of CD133 and LGR5 in the inflammation-dysplasia-carcinoma sequence has not been fully elucidated. We examined the expression of CD133 and LGR5 in ulcerative colitis-associated CRC (UC-CRC; n=20) and UC-associated colorectal dysplasia (n=16) by immunohistochemistry.

Results: The rate of CD133-positive cases in UC-CRC was significantly higher than that in dysplasia (p=0.026), but that of LGR5 expression was not. Moreover, LGR5 expression was significantly positively associated with p53 expression (p=0.03), whereas CD133 expression positively correlated with p53 expression, but not significantly (p=0.10).

Conclusion: CD133 may play an important role in tumor development in the context of the inflammation-dysplasia-carcinoma sequence. LGR5-positive cancer stem cells may play a critical role in the development of UC-CRC, particularly upon loss of p53 function.
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http://dx.doi.org/10.21873/invivo.11600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689354PMC
December 2019

LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer.

Br J Cancer 2019 05 19;120(10):996-1002. Epub 2019 Apr 19.

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background: The aim of this study was to clarify whether a cancer stem cell marker could be an indicator of post-operative peritoneal recurrence of colon cancer.

Methods: Expression of four putative markers (CD133, CD44 variant 6, aldehyde dehydrogenase-1 and leucine-rich repeating G-protein-coupled receptor-5 (LGR5)) was evaluated immunohistochemically in primary tumour samples from 292 patients who underwent curative resection for non-metastasised pT4 colon cancer at the University of Tokyo Hospital between 1997 and 2015.

Results: Peritoneal recurrence was significantly higher in LGR5-negative cases (5-year cumulative incidence: 27.5% vs. 14.4%, p = 0.037). Multivariable analysis confirmed that negative LGR5 expression was an independent risk factor for peritoneal recurrence (hazard ratio (HR) 2.79, p = 0.005) in addition to poor differentiation, positive lymph node metastasis, preoperative carcinoembryonic antigen > 5 ng/mL and anastomotic leakage. The addition of LGR5 significantly improved the predictive value of the multivariable model (net reclassification improvement: 0.186, p = 0.028: integrated discrimination improvement: 0.047, p = 0.008).

Conclusions: Negative LGR5 expression was a significant predictor of peritoneal recurrence in patients with pT4 colon cancer. Therefore, LGR5 might be a promising biomarker to identify patients at high risk of post-operative peritoneal metastasis.
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http://dx.doi.org/10.1038/s41416-019-0442-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734652PMC
May 2019

CD133 expression predicts post-operative recurrence in patients with colon cancer with peritoneal metastasis.

Int J Oncol 2018 Mar 8;52(3):721-732. Epub 2018 Jan 8.

Department of Surgical Oncology, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.

Despite extensive research on cancer stem cells in colorectal cancer, the impact of stem cell markers on patient survival remains unclear, particularly in those with distant metastasis. In this study, we focused on colon cancer with peritoneal metastasis and investigated the association between the expression of CD133, aldehyde dehydrogenase-1 (ALDH1) and leucine-rich repeating G-protein coupled receptor-5 (Lgr5), and disease prognosis. Putative stem cell marker expression was immunohistochemically evaluated in samples from 142 primary tumours and 75 peritoneal nodules. The associations between the expression of these markers and clinicopathological characteristics, overall survival and disease-free survival were analysed. The expression of CD133, ALDH1 and Lgr5 was found to be positive in 55.6, 47.2 and 78.9% of the primary tumour samples, respectively. While their expression was not associated with overall survival, disease-free survival was significantly worse in the CD133‑negative group (36.1 vs. 13.7%, P=0.041). Multivariable analysis confirmed that a negative CD133 expression was an independent risk factor for a reduced disease-free survival (P=0.005). Furthermore, the benefit of systemic chemotherapy was significantly greater in the CD133-negative group (P=0.039). On the whole, our data indicated that patients with colon cancer with CD133-negative expression had a reduced disease-free survival. Thus, we propose that CD133 expression may be a useful clinical biomarker in the treatment of colon cancer with peritoneal metastasis.
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http://dx.doi.org/10.3892/ijo.2018.4240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807045PMC
March 2018

Results of a 36-year surveillance program for ulcerative colitis-associated neoplasia in the Japanese population.

Dig Endosc 2018 Mar 2;30(2):236-244. Epub 2017 Nov 2.

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background And Aim: Surveillance colonoscopy has been carried out for patients with long-standing ulcerative colitis who have an increased risk for colorectal cancer. The aim of the present study was to determine the incidence of and the risk factors for neoplasia.

Methods: We evaluated 289 ulcerative colitis patients who underwent surveillance colonoscopy between January1979 and December 2014. Cumulative incidence of neoplasia and its risk factors were investigated. Clinical stage and overall survival were compared between the surveillance and non-surveillance groups.

Results: Cumulative risk of dysplasia was 3.3%, 12.1%, 21.8%, and 29.1% at 10, 20, 30 and 40 years after the onset of ulcerative colitis, respectively. Cumulative risk of colorectal cancer was 0.7%, 3.2%, 5.2%, and 5.2% at 10, 20, 30 and 40 years from the onset of ulcerative colitis, respectively. Total colitis was a risk factor for neoplasia (P = 0.015; hazard ratio, 2.96).

Conclusions: Our surveillance colonoscopy program revealed the incidence and risk factors of ulcerative colitis-associated neoplasias in the Japanese population. Total colitis is a risk factor for neoplasia.
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http://dx.doi.org/10.1111/den.12955DOI Listing
March 2018

Allele Is Associated with Concomitant Anti-tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians.

Front Pharmacol 2017 27;8:90. Epub 2017 Feb 27.

Department of Laboratory Medicine, Karolinska Institutet-Karolinska University Hospital Stockholm, Sweden.

Drug-induced liver injury (DILI) is a known adverse effect of both anti-tuberculosis (anti-TB) and antiretroviral (ARV) drugs. Recent studies highlight the implications of genetic predispositions to DILI. We performed a case-control study to identify Human Leukocyte Antigen-B (HLA-B) variant alleles associated with anti-TB and ARV co-treatment induced liver toxicity in Ethiopian TB and HIV co-infected patients. A total of 495 newly diagnosed TB and HIV co-infected patients were enrolled and received rifampicin based anti-TB and efavirenz based ARV therapy. Change in liver enzyme level from baseline was monitored 1st, 2nd, 4th, 8th, 12th, and 24th weeks after treatment initiation to identify patients who developed DILI (cases) and those who did not (treatment tolerants). Genomic DNA from 46 cases and 46 sex and age matched treatment tolerants were genotyped for HLA-B variant alleles using Olerup SSP®HLA-B DNA Typing Kits. The proportion of allele carriers in DILI cases (37.0%), particularly in those who developed cholestatic type of DILI (44.8%) was significantly higher compared with those who tolerated the treatment (2.2%). The allele frequency was significantly higher in cases (25%) than treatment tolerants (1.1%). In a multivariate logistic analysis, the proportion of patients carrying ( = 0.002) and ( = 0.014) alleles were significantly higher in DILI cases compared with treatment tolerants. was significantly associated with cholestatic ( = 0.001) and mixed ( = 0.017) types of liver toxicity, and mild-to-moderate severity ( = 0.001). Of all alleles detected, accounted 58.3% and accounted 41.7%. was not detected. The variant allele frequencies of (15.2 vs. 0%) and (9.8 vs. 1.1%) were significantly higher in the DILI cases than treatment tolerants ( < 0.03). We conclude that alleles ( and ) confer susceptibility to the development of anti-TB and ARV drugs co-treatment induced liver toxicity, which is mainly of cholestatic type. The possible association of with anti-TB and ARV drugs co-treatment induced liver toxicity requires further investigations.
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http://dx.doi.org/10.3389/fphar.2017.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326775PMC
February 2017

Expression of the stem cell marker CD133 is related to tumor development in colorectal carcinogenesis.

Asian J Surg 2018 May 10;41(3):274-278. Epub 2017 Feb 10.

Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background/objective: CD133 is currently considered the most robust surface marker for colorectal cancer stem cells. Two meta-analysis reports have suggested that CD133 expression is significantly associated with shorter survival, and CD133 may play an important role in the progression of colorectal cancer. However, the role of CD133 in colorectal adenoma has not been fully elucidated.

Methods: We used immunohistochemistry to evaluate CD133 expression in 200 endoscopically resected colorectal polyps from 200 patients and 20 normal mucosae between January 1993 and December 1996.

Results: CD133 staining was positive in 17.9% of the colorectal adenomas. Moreover, CD133 expression was associated with differentiation status (p = 0.003) and tumor size (p = 0.03).

Conclusion: CD133 might play an important role in tumor development.
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http://dx.doi.org/10.1016/j.asjsur.2016.12.002DOI Listing
May 2018

Pouchitis after ileal pouch-anal anastomosis in ulcerative colitis: Diagnosis, management, risk factors, and incidence.

Dig Endosc 2017 Jan 7;29(1):26-34. Epub 2016 Nov 7.

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Restorative proctocolectomy with ileal pouch-anal anastomosis has been the surgical treatment of choice for patients with ulcerative colitis who require surgery. Quality of life after this procedure is satisfactory in most cases; however, pouchitis is a troublesome condition involving inflammation of the ileal pouch. When a patient presents with symptoms of pouchitis, such as increased bowel movements, mucous and/or bloody exudates, abdominal cramps, and fever, endoscopy is essential for a precise diagnosis. The proximal ileum and rectal cuff, as well as the ileal pouch, should be endoscopically observed. The reported incidence of pouchitis ranges from 14% to 59%, and antibiotic therapy is the primary treatment for acute pouchitis. Chronic pouchitis includes antibiotic-dependent and refractory pouchitis. Intensive therapy including antitumor necrosis factor antibodies and steroids may be necessary for antibiotic-refractory pouchitis, and pouch failure may occur despite such intensive treatment. Reported risk factors for the development of pouchitis include presence of extraintestinal manifestations, primary sclerosing cholangitis, non-smoking, and postoperative non-steroidal anti-inflammatory drug usage. In the present review, we focus on the diagnosis, endoscopic features, management, incidence, and risk factors of pouchitis in patients with ulcerative colitis who underwent ileal pouch-anal anastomosis.
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http://dx.doi.org/10.1111/den.12744DOI Listing
January 2017

Incidence of neoplasias and effectiveness of postoperative surveillance endoscopy for patients with ulcerative colitis: comparison of ileorectal anastomosis and ileal pouch-anal anastomosis.

World J Surg Oncol 2016 Mar 9;14:75. Epub 2016 Mar 9.

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.

Background: The incidence of neoplasia after surgery has not been sufficiently evaluated in patients with ulcerative colitis (UC), particularly in the Japanese population, and it is not clear whether surveillance endoscopy is effective in detecting dysplasia/cancer in the remnant rectum or pouch. The aims of this study were to assess and compare postoperative development of dysplasia/cancer in patients with UC who underwent ileorectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA) and to evaluate the effectiveness of postoperative surveillance endoscopy.

Methods: One hundred twenty patients who received postoperative surveillance endoscopy were retrospectively reviewed for development of dysplasia/cancer in the remnant rectal mucosa or pouch.

Results: Three hundred seventy-nine endoscopy sessions were conducted for 30 patients after IRA, while 548 pouch endoscopy sessions were conducted for 90 patients after IPAA. In the IRA group, 5 patients developed dysplasia/cancer during postoperative surveillance and in all cases, neoplasia was detected at an early stage. In the IRA group, no patient developed neoplasia within 10 years of diagnosis; the cumulative incidence of neoplasia after disease onset was 7.2, 12.0, and 23.9% at 15, 20, and 25 years, respectively. In one case after stapled IPAA, dysplasia was found at the ileal pouch; a subsequent 9 endoscopy sessions in 8 years did not detect any dysplasia. Neoplasia was found more frequently during postoperative surveillance in the IRA group than in the IPAA group (p = .0028). The cumulative incidence of neoplasia after IRA was 3.8, 8.7, and 21.7% at 10, 15, and 20 years, respectively, and that after IPAA was 1.6% at 20 years.

Conclusions: The cumulative incidence of neoplasia after IPAA was minimal. Those who underwent IRA had a greater risk of developing neoplasia than those who underwent IPAA, although postoperative surveillance endoscopy was able to detect dysplasia/cancer at an early stage. IRA can be the surgical procedure of choice only in selected cases in which it would be of benefit to the patient, with more careful surveillance.
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http://dx.doi.org/10.1186/s12957-016-0833-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784460PMC
March 2016

Ulcerative colitis with hepatitis B virus infection treated successfully by granulocyte monocyte apheresis.

J Clin Apher 2016 Dec 15;31(6):584-586. Epub 2016 Feb 15.

Department of Hemodialysis and Apheresis, the University of Tokyo Hospital, Tokyo, Japan.

Ulcerative colitis (UC) is a major type of idiopathic inflammatory bowel disease (IBD). Immunosuppressive therapies are used to treat IBD patients. Clinicians have strong concerns about using immunosuppressive therapies for IBD patients with hepatitis B virus (HBV) infection because aggressive immunosuppressive therapy can promote reactivation of HBV. For that reason, physicians hesitate to use steroids or other immunosuppressive drugs for IBD patients with HBV infection. Granulocyte monocyte apheresis (GMA) is a safe and effective therapy for UC patients. In Japan, a maximum of 11 sessions of GMA are allowed for moderate-to-severe, steroid-resistant UC patients. However, the effects of GMA on HBV remain unclear. This case report describes a 39-year-old man with active UC complicated by HBV infection. Although his symptoms improved with steroid treatment while under entecavir therapy, clinical remission could not be maintained after the steroid dosage was decreased, so GMA was started. After GMA initiation, the frequency of diarrhea decreased and his symptoms improved, and the steroid dosage could be decreased. During the course of GMA, the patient did not experience deterioration in his hepatitis and the HBV DNA level gradually decreased, although GMA itself did not affect the HBV DNA level during each session of GMA. Results show that GMA is a safe and efficacious strategy against UC complicated by HBV without affecting hepatitis because GMA had no remarkable effect on HBV activity. J. Clin. Apheresis 31:584-586, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jca.21450DOI Listing
December 2016

CD133 Expression at the Metastatic Site Predicts Patients' Outcome in Colorectal Cancer with Synchronous Liver Metastasis.

Ann Surg Oncol 2016 06 29;23(6):1916-23. Epub 2016 Jan 29.

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Background: CD133 is a transmembrane protein that is proposed to be a stem cell marker of colorectal cancer (CRC); however, the correlation between CD133 expression and survival of CRC patients with liver metastasis has not been fully examined.

Methods: CD133 expression was evaluated immunohistochemically, both in primary tumors and synchronous liver metastases of 88 consecutive CRC patients, as well as recurrent lesions in the remnant liver of 27 of these 88 patients. The relationship between CD133 expression and clinicopathological characteristics, recurrence-free survival, and overall survival (OS) was analyzed.

Results: CD133 expression in liver metastases (mCD133) was detected in 50 of 88 patients (56.8 %), and had significant correlation with CD133 expression in primary lesions (pCD133) (p < 0.001). CD133 expression in liver recurrent lesions (recCD133) also had a significant correlation with mCD133 (p < 0.001). mCD133+ patients had significantly longer disease-free survival (p = 0.043) and OS (p = 0.014) than mCD133- patients. In addition, mCD133+ patients had a significantly lower rate of extrahepatic recurrence (p < 0.001).

Conclusions: Patients without CD133 expression in liver metastasis had significantly shorter survival, perhaps because mCD133- patients had a significantly higher rate of extrahepatic recurrence.
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http://dx.doi.org/10.1245/s10434-016-5099-1DOI Listing
June 2016

Hereditary gastrointestinal cancer.

Surg Today 2016 Oct 16;46(10):1115-22. Epub 2015 Dec 16.

Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome.
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http://dx.doi.org/10.1007/s00595-015-1283-3DOI Listing
October 2016
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