Publications by authors named "Itaru Endo"

641 Publications

MELK expression in breast cancer is associated with infiltration of immune cell and pathological compete response (pCR) after neoadjuvant chemotherapy.

Am J Cancer Res 2021 15;11(9):4421-4437. Epub 2021 Sep 15.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.

In experimental settings, maternal embryonic leucine zipper kinase (), an apical member of the snf1/AMPK serine-threonine kinases family, plays a role in tumor growth. We investigated the clinical relevance of expression by performing silico analyses of 7,135 breast cancer patients using multiple independent large cohorts. In triple negative breast cancer (TNBC) found that elevated expression significantly correlates with Nottingham histologic grade and tumor growth according to American Joint Committee Cancer (AJCC) stage. High tumor enriched cell proliferation-related gene sets as well as DNA repair, unfolded protein response, and MTORC signaling gene sets. In two independent cohorts a high mutation rate and worse survival was significantly associated with high tumor. In immune-related gene sets including, allograft rejection, interferon (IFN)-α response, and IFN-γ response, high tumor significantly enriched. Pro-cancer regulatory T cells, T helper type 2 cells and anti-cancer immune cells including CD4 memory T cells, T helper type1 cells, CD8 T cells, M1 macrophages, gamma-delta T cells, and dendritic cells with high levels of cytolytic activity (CYT) were highly infiltrated. expression did not correlate with the responses to any of the drugs tested in cell lines. However, pathologic complete response was significantly associated with high following NAC in both TNBC and ER-positive plus HER2-negative breast cancer. In conclusion, cell proliferation, immune response, and NAC breast cancer response was associated with expression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493385PMC
September 2021

Increased intratumor heterogeneity, angiogenesis and epithelial to mesenchymal transition pathways in metaplastic breast cancer.

Am J Cancer Res 2021 15;11(9):4408-4420. Epub 2021 Sep 15.

Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY, USA.

Metaplastic breast cancer (MBC) constitutes a rare but unique histologic entity with poor prognosis. We hypothesized that MBC possesses unique genetic profile and tumor immune microenvironment. MBC cases were identified from a total of 10827 breast cancer entries in the Cancer Genome Atlas Data Set (TCGA) and the AACR-GENIE (Genomics Evidence Neoplasia Information Exchange) cohorts. Tumor infiltrated immune cells were estimated by xCell. Baseline clinical characteristics were compared, and gene set enrichment analysis (GSEA) was performed. MBC comprised 0.66% of the cohorts (1.2% of TCGA and 0.6% of GENIE). MBC cases were predominantly triple-negative (TNBC) (8 (61.5%) vs 151 (14.4%), P<0.001), and high Nottingham histological grade (8 (61.5%) vs 222 (21.1%), P=0.02) compared to non-MBC in the TCGA cohort. Increased infiltration of M1 macrophages (P=0.012), dendritic cells (P<0.001) and eosinophils (P=0.036) was noted in the MBC cohort however there was no difference in cytolytic activity (P=0.806), CD4 memory (P=0.297) or CD8 T-cells (P=0.864). Tumor mutation burden was lower in the MBC compared to the non-MBC, median: 0.4 vs 1.6/Mb in the TCGA-TNBC cohort (P=0.67) and 3.0 vs 4.0/Mb (P=0.1) in the GENIE-cohort. MBC had increased intratumor heterogeneity (P<0.001), macrophage regulation (P=0.008) and TGF-beta response (P<0.001). Disease-specific survival was decreased in MBC (P=0.018). Angiogenesis and epithelial-to-mesenchymal transition pathways were enriched in triple-negative MBC by GSEA (P=0.004 and P<0.001, respectively). Our results suggest that high intratumor heterogeneity, enriched angiogenesis and EMT pathway expression represent possible mechanisms leading to worse disease-specific survival found in metaplastic breast cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493380PMC
September 2021

Sphingosine 1-phosphate (S1P) produced by sphingosine kinase 1 (SphK1) and exported via ABCC1 is related to hepatocellular carcinoma (HCC) progression.

Am J Cancer Res 2021 15;11(9):4394-4407. Epub 2021 Sep 15.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY 14263, USA.

Sphingosine-1-Phosphate (S1P) is produced by Sphingosine Kinase 1 (SphK1) in the cell and is transported out of the cells by ABCC1 transporter. S1P induces inflammation, angiogenesis and modulates tumor immune microenvironment (TIME) in autocrine and paracrine manner. We hypothesized that high S1P export is associated with hepatocellular carcinoma (HCC) progression and worse survival. Transcriptome linked with clinical data were obtained from a total of 533 patients from TCGA (The Cancer Genome Atlas)-HCC (n = 350), GSE6764 (n = 75), and GSE89377 (n = 108) cohorts. Both SphK1 and ABCC1 were expressed higher in aggressive HCC than normal liver or cirrhosis and correlated with MKi67 expression. High S1P export by high expression of both SphK1 and ABCC1 enriched gene sets related with cell proliferation (E2F targets, G2M checkpoint, MYC targets), inflammation (Inflammatory response, TNFα, IL6), angiogenesis, metastasis (TGF-β, epithelial-mesenchymal transition), and immune response (allograft rejection, complement, interferon-gamma) in gene set enrichment analysis. High S1P export was associated with elevation of HGF, HSP90AA1, TRAF2, and AKR1B10. It was also associated with high intratumor heterogeneity, leucocyte fraction, macrophage regulation and lymphocyte infiltration, as well as T helper type2 cells, macrophages, dendritic cells, CD4 T memory activated cells, B-cells and cytolytic activity score in TIME. High S1P export was associated with significantly worse disease specific survival ( = 0.034) and overall survival ( = 0.004) compared to low S1P export group. In conclusion, simultaneous high expression of SphK1 and ABCC1 that reflect S1P export is associated with enhancement of both HCC progression and immune response. Given that S1P export was also associated with worse survival, we cannot help but speculate that pro-cancer pathways activated by S1P may overwhelm the anti-cancer immune response mediated by S1P.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493375PMC
September 2021

Mutant KRAS as a prognostic biomarker after hepatectomy for rectal cancer metastases: Does the primary disease site matter?

J Hepatobiliary Pancreat Sci 2021 Oct 6. Epub 2021 Oct 6.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: The prognostic implication of mutant KRAS (mKRAS) among patients with primary disease in the rectum remains unknown.

Methods: From 2000 to 2018, patients undergoing hepatectomy for colorectal liver metastases at 10 collaborating international institutions with documented KRAS status were surveyed.

Results: A total of 834 (65.8%) patients with primary colon cancer and 434 (34.2%) patients with primary rectal cancer were included. In patients with primary colon cancer, mKRAS served as a reliable prognostic biomarker of poor overall survival (OS) (hazard ratio [HR]: 1.58, 95% CI 1.28-1.95) in the multivariable analysis. Although a trend towards significance was noted, mKRAS was not found to be an independent predictor of OS in patients with primary rectal tumors (HR 1.34, 95% CI 0.98-1.80). For colon cancer, the specific codon impacted in mKRAS appears to reflect underlying disease biology and oncologic outcomes, with codon 13 being associated with particularly poor OS in patients with left-sided tumors (codon 12, HR 1.56, 95% CI 1.22-1.99; codon 13, HR 2.10 95% CI 1.43-3.08;). Stratifying the rectal patient population by codon mutation did not confer prognostic significance following hepatectomy.

Conclusions: While the left-sided colonic disease is frequently grouped with rectal disease, our analysis suggests that there exist fundamental biologic differences that drive disparate outcomes. Although there was a trend toward significance of KRAS mutations for patients with primary rectal cancers, it failed to achieve statistical significance.
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http://dx.doi.org/10.1002/jhbp.1054DOI Listing
October 2021

Surgical outcomes in gastroenterological surgery in Japan: Report of the National Clinical Database 2011-2019.

Ann Gastroenterol Surg 2021 Sep 9;5(5):639-658. Epub 2021 Apr 9.

The Japanese Society of Gastroenterological Surgery Tokyo Japan.

Background: We aimed to present the 2019 annual report of the gastroenterological section of the National Clinical Database (NCD).

Methods: We reviewed 609,589 cases recorded in 2019 and 5,029,764 cases registered from 2011 to 2019 for the 115 selected gastroenterological surgical procedures.

Results: The main features of gastroenterological surgery in Japan were similar to those described in the 2018 annual report, namely, that 1) operative numbers gradually increased in all procedures, except gastrectomy and hepatectomy, which decreased in these years; 2) in all eight major gastroenterological surgeries, the age distribution tended toward older patients; 3) the morbidity of esophagectomy, hepatectomy, and pancreaticoduodenectomy increased, but mortality was minimized in all procedures; 4) all eight major gastroenterological procedures have increasingly been performed under laparoscopy; and 5) board-certified surgeons were increasingly involved. These trends in recent years were more prominent in 2019.

Conclusions: Thanks to the continuous cooperation and dedication of the surgeons, medical staff, and surgical clinical reviewers who registered the clinical data into the NCD, it is possible to understand the comprehensive landscape of surgery in Japan and to disclose new evidence in this field. The Japanese Society of Gastroenterological Surgery will continue to promote the value of this database and encourage the use of feedback and clinical studies using the NCD, now and in the future. Generating further approaches to surgical quality improvement are important directions for future research.
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http://dx.doi.org/10.1002/ags3.12462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452469PMC
September 2021

New criteria of resectability for pancreatic cancer: A position paper by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS).

J Hepatobiliary Pancreat Sci 2021 Sep 27. Epub 2021 Sep 27.

Department of Gastroenterological Surgery, Yokohama City University Graduate School Medicine, Yokohama, Japan.

The symposium "New criteria of resectability for pancreatic cancer" was held during the 33nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) in 2021 to discuss the potential modifications that could be made in the current resectability classification. The meeting focused on setting the foundation for developing a new prognosis-based resectability classification that is based on the tumor biology and the response to neoadjuvant treatment (NAT). The symposium included selected experts from Western and Eastern high-volume centers who have discussed their concept of resectability status through published literature. During the symposium, presenters reported new resectability classifications from their respective institutions based on tumor biology, conditional status, pathology, and genetics, in addition to anatomical tumor involvement. Interestingly, experts from all the centers reached the agreement that anatomy alone is insufficient to define resectability in the current era of effective NAT. On behalf of the JSHBPS, we would like to summarize the content of the conference in this position paper. We also invite global experts as internal reviewers of this paper for intercontinental cooperation in creating an up-to-date, prognosis-based resectability classification that reflects the trends of contemporary clinical practice.
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http://dx.doi.org/10.1002/jhbp.1049DOI Listing
September 2021

Study protocol: a multicenter randomized controlled trial of the multifaceted workload reduction of the anti-adhesion barrier for diverting ileostomy in laparoscopic rectal surgery, YCOG 2005 (ADOBARRIER study).

Int J Colorectal Dis 2021 Sep 20. Epub 2021 Sep 20.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background: There are few randomized controlled trials on the efficacy of spray-type anti-adhesion material during diverting ileostomy in laparoscopic rectal cancer surgery.

Purpose: This study will assess whether or not spraying an anti-adhesion material during diverting ileostomy could reduce the surgeon's multifaceted workload in ileostomy closure.

Methods: Patients with laparoscopic or robotic surgery for rectal cancer scheduled for low anterior resection and diverting ileostomy will be enrolled in the ADOBARRIER study (multicenter, single-blind, randomized controlled trial). The target sample size is set at 120 cases, which will be randomly divided into an anti-adhesion material-using group and a non-using group at a ratio of 1:1. The primary endpoint is the multifaceted workload of the surgeon of ileostomy closure using SURG-TLX between groups with and without usage of the anti-adhesion material during diverting ileostomy construction; the secondly endpoint is the operative time, amount of intraoperative blood loss, degree of adhesions, and extent of intra-abdominal adhesions when the ileostomy is closed.

Conclusions: This RCT will evaluate the efficacy and safety of spray-type anti-adhesion material for diverting ileostomy construction. The results of this study are expected to facilitate decision-making regarding the use of anti-adhesion material.

Trial Registration: This trial was registered with the Japan Registry of Clinical Trials (jRCT) in October 2020 as jRCTs032200155.
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http://dx.doi.org/10.1007/s00384-021-04032-3DOI Listing
September 2021

The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma.

Cancers (Basel) 2021 Sep 3;13(17). Epub 2021 Sep 3.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.
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http://dx.doi.org/10.3390/cancers13174443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430652PMC
September 2021

Plastic or self-expandable metal stent: Which is the most suitable for patients with pancreatic head cancer in the upcoming era of neoadjuvant chemotherapy? A review.

Dig Endosc 2021 Aug 13. Epub 2021 Aug 13.

Division of, Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Kanagawa, Japan.

Obstructive jaundice is a major symptom of pancreatic head cancer, and although its amelioration is required before scheduling chemotherapy, the decision to perform biliary drainage for resectable pancreatic cancer has remained controversial. In recent years, the effectiveness of neoadjuvant therapy for pancreatic cancer has been reported. Preoperative biliary drainage has become increasingly necessary, making the choice of stent an important one; thus, the longer the waiting period extends through neoadjuvant chemotherapy, the more durable stents - such as self-expandable metallic stents, rather than plastic stents - would be desired as an option. Still, there is insufficient evidence regarding surgical outcomes and long-term prognosis, and further confirmatory studies are needed. Through this review, we aim to provide an update on the characteristics of biliary stents and preoperative biliary drainage for potentially resectable pancreatic cancer.
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http://dx.doi.org/10.1111/den.14107DOI Listing
August 2021

Preoperative risk factors of incisional surgical site infection in severe or intractable ulcerative colitis.

Surg Today 2021 Aug 13. Epub 2021 Aug 13.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Purpose: The present study explored preoperative risk factors (predictors) of incisional surgical site infection (I-SSI) in severe or intractable ulcerative colitis (UC).

Methods: This was a retrospective study of 230 consecutive patients who underwent primary surgery for UC. Patients whose surgical indications were UC with cancer or dysplasia were excluded. SSI was defined as an infection according to the Centers for Disease Control and Prevention Guidelines. Preoperative variables were examined by univariate, receiver operating characteristic curve, and multivariate analyses.

Results: We analyzed 208 patients in this study. In a multivariate logistic analysis, C-reactive protein (CRP) ≥ 1.7 mg/dl [odds ratio (OR) 5.35; 95% confidence interval (CI) 1.50-19.06; p = 0.01), albumin ≤ 2.4 g/dl (OR 5.77; 95% CI 1.41-23.57; p = 0.02), and preoperative blood transfusion (OR 3.21; 95% CI 1.04-9.96; p = 0.04) were predictors of I-SSI. Patients with all predictors had a more than 50% incidence of I-SSI, a higher incidence of all severe complications (13.6% vs. 3.2%; p = 0.02), and a longer postoperative hospital stay (19.5 vs. 17.0 days, p = 0.04) than the other patients.

Conclusions: CRP ≥ 1.7 mg/dl, albumin ≤ 2.4 g/dl, and transfusion are predictors of I-SSI in severe or intractable UC. Clinician should carefully evaluate the surgical options before these predictors appear.
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http://dx.doi.org/10.1007/s00595-021-02354-xDOI Listing
August 2021

Postoperative Infectious Complications Worsen Long-Term Survival After Curative-Intent Resection for Hepatocellular Carcinoma.

Ann Surg Oncol 2021 Aug 10. Epub 2021 Aug 10.

Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.

Background: Postoperative infectious complications may be associated with a worse long-term prognosis for patients undergoing surgery for a malignant indication. The current study aimed to characterize the impact of postoperative infectious complications on long-term oncologic outcomes among patients undergoing resection for hepatocellular carcinoma (HCC).

Methods: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The relationship between postoperative infectious complications, overall survival (OS), and recurrence-free survival (RFS) was analyzed.

Results: Among 734 patients who underwent HCC resection, 269 (36.6%) experienced a postoperative complication (Clavien-Dindo grade 1 or 2 [n = 197, 73.2%] vs grade 3 and 4 [n = 69, 25.7%]). An infectious complication was noted in 81 patients (11.0%) and 188 patients (25.6%) had non-infectious complications. The patients with infectious complications had worse OS (median: infectious complications [46.5 months] vs no complications [106.4 months] [p < 0.001] and non-infectious complications [85.7 months] [p < 0.05]) and RFS (median: infectious complications [22.1 months] vs no complications [45.5 months] [p < 0.05] and non-infectious complications [38.3 months] [p = 0.139]) than the patients who had no complication or non-infectious complications. In the multivariable analysis, infectious complications remained an independent risk factor for OS (hazard ratio [HR], 1.7; p = 0.016) and RFS (HR, 1.6; p = 0.013). Among the patients with infectious complications, patients with non-surgical-site infection (SSI) had even worse OS and RFS than patients with SSI (median OS: 19.5 vs 70.9 months [p = 0.010]; median RFS: 12.8 vs 33.9 months [p = 0.033]).

Conclusion: Infectious complications were independently associated with an increased long-term risk of tumor recurrence and death. Patients with non-SSI versus SSI had a particularly worse oncologic outcome.
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http://dx.doi.org/10.1245/s10434-021-10565-2DOI Listing
August 2021

Increased apoptosis is associated with robust immune cell infiltration and cytolytic activity in breast cancer.

Am J Cancer Res 2021 15;11(7):3674-3687. Epub 2021 Jul 15.

Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.

Tumor infiltrating immune cells plays a critical role in cancer progression. Apoptosis is an autonomous cell death that counteracts tumor growth. To this end, we hypothesized that increased apoptosis in breast cancer is associated with immune cell killing. Apoptosis score of MSigDB Hallmark collection was used to analyze METABRIC cohort (n=1904) and TCGA (n=1069) as validation cohort. High apoptosis tumors enriched cancer promoting signaling pathways; hypoxia, KRAS, TGF-β, PI3K signaling, and was associated with low MKI67 expression and less cell proliferation gene sets, less homologous recombination defects, and less altered fraction. High apoptosis tumors also enriched angiogenesis and high infiltration of vascular endothelial cells, pericytes and stromal cells and significantly enriched inflammation and immune response-related gene sets and high infiltration of CD8, CD4 memory, dendritic cells, M1 and M2 macrophages and significant elevation of cytolytic activity and immune checkpoint molecules, consistently in both cohorts. In conclusion, breast cancer patients with high apoptosis are associated with angiogenesis, immune response, high immune cell infiltration and cytolytic activity. To the best of our knowledge, this is the first study to utilize in silico translational approach to demonstrate the clinical relevance of apoptosis in breast cancer patients in large cohorts.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8332871PMC
July 2021

Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer.

Am J Cancer Res 2021 15;11(7):3628-3644. Epub 2021 Jul 15.

Department of Surgical Oncology, Roswell Park Cancer Institute Buffalo, NY 14263, USA.

Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8332854PMC
July 2021

A novel five-gene score to predict complete pathological response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer.

Am J Cancer Res 2021 15;11(7):3611-3627. Epub 2021 Jul 15.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York, USA.

Neoadjuvant Chemotherapy (NAC) is not frequently used in ER-positive/HER2-negative breast cancer (BC) because around 10% patients achieve pathological complete response (pCR). Since NAC can result in cancer downstaging both in the breast and axilla and prevent a morbid surgery, thus a score to predict pCR in this population will be crucial to identify patients who can benefit from this approach. A total of 4038 patients from cohorts; GSE25066, GSE20194, Hess, GSE20181, TCGA-BRCA and METBRIC were analyzed. The score was generated by the 5 most highly expressed genes in the Hallmark E2F targets gene set amongst patients in the GSE25066 cohort with ER-positive/HER2-negative BC who achieved pCR. The area under the curve was significantly higher in the score than that for the E2F targets score. High score ER-positive/HER2-negative BCs were significantly associated with higher Nottingham pathological grade, AJCC cancer stage, expression levels, intratumor heterogeneity, homologous recombination defects, mutation burden, neoantigen load, and infiltration of anti-cancer immune cells (CD4, T helper type1, plasmacytoid dendritic cells, M1 macrophages). They also expressed lower abundance of stromal cells including fibroblasts, lymphatic endothelial cells, pericytes and adipocytes consistently in GSE25066, TCGA and METABRIC cohorts. All cell proliferation-related gene sets, G2M checkpoint, E2F targets, MYC targets v1 and v2, Mitotic Spindle, were strongly enriched in high score BCs consistently in 3 cohorts. The gene score was significantly associated with high pCR rate consistently in the GSE25066 (38%, < 0.001), GSE20194 (16%, = 0.006), and Hess cohort (23%, = 0.037). In conclusion, the 5-gene score reflects cancer cell proliferation and immune cell infiltration, and predicts pCR after NAC in ER-positive/HER2-negative breast cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8332850PMC
July 2021

Impact of Tumor Burden Score on Conditional Survival after Curative-Intent Resection for Hepatocellular Carcinoma: A Multi-Institutional Analysis.

World J Surg 2021 Nov 2;45(11):3438-3448. Epub 2021 Aug 2.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Background: The impact of tumor burden score (TBS) on conditional survival (CS) among patients undergoing curative-intent resection of hepatocellular carcinoma (HCC) has not been examined to date.

Methods: Patients who underwent liver resection of HCC between 2000 and 2017 were identified from a multi-institutional database. The impact of TBS and other clinicopathologic factors on 3-year conditional survival (CS) was examined.

Results: Among 1,040 patients, 263 (25.3%) patients had low TBS, 668 (64.2%) had medium TBS and 109 (10.5%) had high TBS. TBS was strongly associated with OS; 5-year OS was 39.0% among patients with high TBS compared with 61.1% and 79.4% among patients with medium and low TBS, respectively (p < 0.001). While actuarial survival decreased as time elapsed from resection, CS increased over time irrespective of TBS. The largest differences between 3-year actuarial survival and CS were noted among patients with high TBS (5-years postoperatively; CS: 78.7% vs. 3-year actuarial survival: 30.7%). The effect of adverse clinicopathologic factors including high TBS, poor/undifferentiated tumor grade, microvascular invasion, liver capsule involvement, and positive margins on prognosis decreased over time.

Conclusions: CS rates among patients who underwent resection for HCC increased as patients survived additional years, irrespective of TBS. CS estimates can be used to provide important dynamic information relative to the changing survival probability after resection of HCC.
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http://dx.doi.org/10.1007/s00268-021-06265-3DOI Listing
November 2021

Systemic therapy and prognosis of older patients with stage II/III breast cancer: A large-scale analysis of the Japanese Breast Cancer Registry.

Eur J Cancer 2021 Sep 19;154:157-166. Epub 2021 Jul 19.

Department of Breast Oncology, Aichi Cancer Center, Nagoya, Japan. Electronic address:

Aim: This study aimed at investigating the real-world prognostic impact of systemic treatment in older patients with stage II/III breast cancer (BC).

Methods: This retrospective cohort study included patients with stage II/III primary BC, aged ≥55 years, and registered in the Japanese Breast Cancer Registry from 2004 to 2011. The clinicopathological characteristics, treatments, and prognosis of patients aged ≥75 years (older) were compared to those of younger patients.

Results: In total, 56,093 patients (12,727, ≥75 years; 17,860, 65-74 years; 25,506, 55-64 years) were enrolled. In the older group, 9.2% with a luminal (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), 32.9% with a triple-negative (TN, HR-/HER2-), and 27.4% with a HER2-positive (any-HR/HER2+) receptor were administered chemotherapy. In those with luminal cancer, the 5-year breast cancer-specific survival (BCSS) was approximately 95% in all age groups. Meanwhile, among those with TN and HER2-positive BC, the older group had a poorer BCSS. The 5-year overall survival (OS) was also poorer in the older group across all subtypes. Among older patients matched using clinicopathological factors, chemotherapy use was associated with improved OS in the luminal and HER2-positive subtypes.

Conclusions: Chemotherapy use was lower among older patients with stage II/III breast cancer. Those with TN and HER2-positive BC had a lower BCSS than their younger counterparts. Chemotherapy may be beneficial in improving the OS in older patients with luminal and HER2-positive BCs. Treatment for older patients should be individualized, based on tumor-related factors, quality of life, and the patient's health status.
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http://dx.doi.org/10.1016/j.ejca.2021.06.006DOI Listing
September 2021

Feasibility of esophagectomy for esophageal cancer in elderly patients: a case-control study.

Langenbecks Arch Surg 2021 Jul 14. Epub 2021 Jul 14.

Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Purpose: Surgery in elderly patients with esophageal cancer is challenging due to high mortality and limited survival. This study aimed to evaluate the safety and effectiveness of curative esophagectomy in elderly patients with esophageal cancer.

Methods: This study included 77 and 112 patients with esophageal cancer aged ≥ 70 and 40-64 years, respectively, who underwent R0 esophagectomy between January 1998 and December 2016. Patient characteristics, intraoperative outcomes, postoperative complications, and long-term survival were compared.

Results: The proportions of comorbid diseases (85.7% vs. 57.1%; P < 0.001), the American Society of Anesthesiologists score (1/2/3; 2.6%/94.8%/2.6% vs. 42.9%/57.1%/0%; P < 0.001), the preoperative systemic inflammation score (SIS) (0/1/2; 20.8%/48.1%/31.2% vs. 38.4%/38.4%/23.2%; P = 0.036), and postoperative complications (Clavien-Dindo grade ≥ III) (33.8% vs. 20.5%; P = 0.041) were significantly higher in the elderly group than those in the non-elderly group. However, long-term overall survival (OS) and relapse-free survival were not significantly different between the groups. On multivariate analysis, SIS (hazard ratio, 3.06; P = 0.037) and severe postoperative complications (hazard ratio, 2.01; P = 0.039) were significantly correlated with OS in the elderly group.

Conclusions: As SIS and severe postoperative complications lead to poor prognosis after R0 esophagectomy in elderly patients, selecting appropriate patients for esophagectomy and preventing severe postoperative complications is essential.
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http://dx.doi.org/10.1007/s00423-021-02271-0DOI Listing
July 2021

G2M checkpoint pathway alone is associated with drug response and survival among cell proliferation-related pathways in pancreatic cancer.

Am J Cancer Res 2021 15;11(6):3070-3084. Epub 2021 Jun 15.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.

Given the severe side effects of the treatments and poor survival, prognostic and predictive biomarkers to guide management of pancreatic cancer are in critical need. We hypothesized that cell proliferation-related pathways are associated with drug response and survival in pancreatic cancer. Six Hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis were evaluated in 3 independent cohorts- TCGA-PAAD ( = 176), GSE57495 ( = 63), and GSE62452 ( = 69). G2M and E2F, as well as Mitotic and p53 pathway correlated highly with other gene sets. All pathways were significantly correlated with expression and its proliferation score, but none with cytolytic activity and the rate of pathologically complete resection (R0). All pathways were significantly associated with high alteration and expression of KRAS gene except for MYC v1. G2M, E2F, and p53 pathway were significantly associated with high alteration of TP53 gene. Interestingly, different pathways correlated with the AUC of different cancer therapeutics, such as Gemcitabine (Mitotic: = 0.706 [ = 0.01]), Paclitaxel (MYC v2: = -0.636 [ < 0.05]), Apatinib (Mitotic: = -0.556 [ = 0.03]), Palbociclib (E2F: = 0.675 [ < 0.01]), and Sorafenib (G2M: = -0.593 [ = 0.03]). Among all six pathways, only G2M was consistently associated with worse patient survival in all three cohorts. In conclusion, each cell proliferation-related pathway was predictive of a unique agent, and the G2M score alone predicts survival in pancreatic cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263638PMC
June 2021

Preoperative prevalence and risk factors of deep-vein thrombosis in Japanese surgical patients with ulcerative colitis: a retrospective investigational study.

Surg Today 2021 Jul 8. Epub 2021 Jul 8.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0024, Japan.

Purpose: The purpose of this study was to clarify the perioperative deep-vein thrombosis (DVT) prevalence and its risk factors in surgical ulcerative colitis (UC) patients by comparing the results with those in surgical colorectal cancer (CRC) patients at a high risk of perioperative venous thrombosis.

Methods: This retrospective, observational study included patients who underwent surgery for UC or CRC between January 2013 and October 2019. Consecutive surgical patients with a positive D-dimer assay result (≥ 1.0 µg/ml) underwent lower-extremity venous ultrasonography. The prevalence and risk factors for preoperative DVT were examined in UC patients.

Results: A total of 101 UC patients and 593 CRC patients were deemed eligible. Among the D-dimer positive cases, there were no significant differences between the two groups in the preoperative DVT prevalence (UC: 21.8% vs. CRC: 28.8%, p = 0.151), distal type (18.8% vs. 27.2%, p = 0.086), or proximal type (5.9% vs. 4.2%, p = 0.434). Furthermore, multivariate analyses showed that an older age, overweight status, poor ASA status, and a high preoperative dose of steroid were independent risk factors for preoperative DVT in UC surgical patients.

Conclusions: The risk of perioperative thrombosis in UC patients was considered similar to that in CRC, so active thromboprophylaxis should be administered to UC patients while paying attention to bleeding.

Trial Registration: This study was registered with the Japanese Clinical Trials Registry as UMIN000042004 ( http://www.umin.ac.jp/ctr/index.htm ).
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http://dx.doi.org/10.1007/s00595-021-02335-0DOI Listing
July 2021

Bromodomain-containing Protein 4 Is a Favourable Prognostic Factor in Breast Cancer Patients.

Anticancer Res 2021 Jul;41(7):3597-3606

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Aim: To evaluate the association between bromodomain-containing protein 4 (BRD4) expression and clinicopathological factors and prognosis in human breast cancer specimens.

Patients And Methods: We used tissue microarrays constructed from samples of patients (n=183) who underwent surgery. We validated the association between BRD4 expression and prognosis in solid tumours, including breast cancer, using The Cancer Genome Atlas (TCGA) database.

Results: Immunohistochemical staining showed that BRD4 was widely distributed in breast cancer tissues. BRD4 was strongly expressed in 19.7% of patients but BRD4 staining intensity was not correlated with other clinicopathological factors. Most importantly, patients with a strong BRD4 expression had a significantly longer disease-specific survival than those with a weak BRD4 expression (100.0% vs. 91.3% at 5 years, p=0.027). mRNA expression analysis showed similar results (91.2% vs. 80.2% at 6 years, p=0.047).

Conclusion: Strong BRD4 expression was associated with a significantly better prognosis in breast cancer tumours.
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http://dx.doi.org/10.21873/anticanres.15148DOI Listing
July 2021

Octogenarians' Breast Cancer Is Associated with an Unfavorable Tumor Immune Microenvironment and Worse Disease-Free Survival.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Elderly patients are known to have a worse prognosis for breast cancer. This is commonly blamed on their medical comorbidities and access to care. However, in addition to these social issues, we hypothesized that the extreme elderly (octogenarians-patients over 80 years old) have biologically worse cancer with unfavorable tumor immune microenvironment. The Cancer Genomic Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were analyzed. The control (aged 40-65) and octogenarians numbered 668 and 53 in TCGA and 979 and 118 in METABRIC, respectively. Octogenarians had significantly worse breast cancer-specific survival in both cohorts ( < 0.01). Octogenarians had a higher ER-positive subtype rate than controls in both cohorts. Regarding PAM50 classification, luminal-A and -B subtypes were significantly higher in octogenarians, whereas basal and claudin-low subtypes were significantly lower ( < 0.05) in octogenarians. There was no difference in tumor mutation load, intratumor heterogeneity, or cytolytic activity by age. However, the octogenarian cohort was significantly associated with high infiltration of pro-cancer immune cells, M2 macrophage, and regulatory T cells in both cohorts ( < 0.05). Our results demonstrate that octogenarians' breast cancer is associated with worse survival and with an unfavorable tumor immune microenvironment.
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http://dx.doi.org/10.3390/cancers13122933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230790PMC
June 2021

Primary breast lymphoma initially diagnosed as invasive ductal carcinoma: A case report.

Clin Case Rep 2021 Jun 5;9(6):e04189. Epub 2021 May 5.

Department of Gastroenterological Surgery Yokohama City University Graduate School of Medicine Yokohama Japan.

A malignant tumor in the breast may not be conclusive of breast cancer. It is important to keep the possibility of primary breast lymphoma in rare scenarios. For the diagnosis of primary breast lymphoma, immunohistochemical staining is necessary.
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http://dx.doi.org/10.1002/ccr3.4189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222742PMC
June 2021

Clinical Impact of a Novel Model Predictive of Oncotype DX Recurrence Score in Breast Cancer.

In Vivo 2021 Jul-Aug;35(4):2439-2444

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background/aim: Oncotype DX recurrence score (RS) for breast cancer is a useful tool for determining chemotherapy indication but it is expensive and time-consuming. We determined whether four immuno-histochemical markers, namely human epidermal growth factor 2 (HER2), estrogen receptor (ER), progesterone receptor (PgR), and Ki-67, are predictive of an RS ≥26 in Japanese patients.

Patients And Methods: The study included 95 Japanese patients evaluated for RS. A predictive model was created using logistic regression analysis.

Results: The discriminant function was calculated as follows: p=1/{1+exp [-(4.611+1.2342×HER2-0.0813×ER- 0.0489 ×PgR+0.0857×Ki67)]}. Using a probability of 0.5 as the cutoff, the accuracy, sensitivity, specificity, positive predictive and negative predictive values were 90.5%, 72.2%, 94.8%, 76.4% and 93.5%, respectively.

Conclusion: The model had a high negative predictive value in predicting RS ≥26 in Japanese patients, indicating that Oncotype DX testing may be omitted in patients with a negative result according to the predictive model.
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http://dx.doi.org/10.21873/invivo.12522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286534PMC
June 2021

Validation study of the ACS NSQIP surgical risk calculator for two procedures in Japan.

Am J Surg 2021 Jun 23. Epub 2021 Jun 23.

American College of Surgeons, Division of Research and Optimal Patient Care, 633 N. Saint Clair St., Chicago, IL, 60611-3211, USA.

Introduction: The ACS NSQIP Surgical Risk Calculator (SRC) assesses risk to support goal-concordant care. While it accurately predicts US outcomes, its performance internationally is unknown. This study evaluates SRC accuracy in predicting mortality following low anterior resection (LAR) and pancreaticoduodenectomy (PD) in NSQIP patients and accuracy retention when applied to native Japanese patients (National Clinical Database, NCD).

Methods: NSQIP (41,260 LAR; 15,114 PD) and NCD cases (61,220 LAR; 27,901 PD) from 2015 to 2017 were processed through the SRC mortality model. Country-specific calibration and discrimination were assessed with and without an intercept correction applied to the Japanese data.

Results: The SRC exhibited acceptable calibration for LAR and PD when applied to NSQIP data but miscalibration for NCD data. A simple correction to the model intercept, motivated by lower mortality rates in the Japanese data, successfully remediated the miscalibration.

Conclusions: The SRC may inaccurately predict surgical risk when applied to the native Japanese population. An intercept correction method is suggested when miscalibration is encountered; it is simple to implement and may permit effective international use of the SRC.
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http://dx.doi.org/10.1016/j.amjsurg.2021.06.008DOI Listing
June 2021

High postoperative neutrophil-lymphocyte ratio and low preoperative lymphocyte-monocyte ratio predict poor prognosis in gastric cancer patients receiving gastrectomy with positive lavage cytology: a retrospective cohort study.

Langenbecks Arch Surg 2021 Jun 17. Epub 2021 Jun 17.

Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama City, Kanagawa, 236-0004, Japan.

Background: Long-term outcomes in gastric cancer patients with positive lavage cytology (CY1) are generally poor. This multi-institutional retrospective cohort study aims to evaluate the clinical significance of the neutrophil-lymphocyte ratio (NLR) and the lymphocyte-monocyte ratio (LMR) in CY1 gastric cancer patients.

Methods: A total of 121 CY1 gastric cancer patients without other non-curative factors, who underwent macroscopically curative resection, were enrolled in this study. The cutoff values of preoperative NLR (pre-NLR), postoperative NLR (post-NLR), preoperative LMR (pre-LMR), and postoperative LMR (post-LMR) were defined by the Contal and O'Quigley method as 2.3, 3.0, 2.5, and 3.2, respectively. A Cox proportional hazard model was used to identify the independent prognostic factors among NLR, LMR, and other clinicopathological factors.

Results: There were significant differences in the overall survival (OS) between the two groups: high post-NLR groups vs. low post-NLR group (median survival time, months) (10.9 vs. 22.8, P = 0.006) and high pre-LMR group vs. low pre-LMR group (21.3 vs. 11.0, P = 0.001). The LMR value elevated significantly after gastrectomy (P = 0.020), although not in the NLR value (P = 0.733). On multivariate analysis, high post-NLR (hazard ratio = 1.506; 95% confidence interval = 1.047-2.167; P = 0.027), low pre-LMR (1.773; 1.135-2.769, 0.012), and no postoperative chemotherapy (1.558; 1.053-2.305, 0.027) were found to be independent prognostic factors for adverse OS.

Conclusions: Because a combination of high post-NLR and low pre-LMR may be an adverse prognostic marker in resectable CY1 gastric cancer patients, it is necessary to conduct a prospective trial to confirm a useful perioperative chemotherapeutic regimen for these patients.
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http://dx.doi.org/10.1007/s00423-021-02233-6DOI Listing
June 2021

Adipogenesis in triple-negative breast cancer is associated with unfavorable tumor immune microenvironment and with worse survival.

Sci Rep 2021 06 15;11(1):12541. Epub 2021 Jun 15.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA.

Cancer-associated adipocytes are known to cause inflammation; however, the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. We hypothesized that intra-tumoral adipogenesis reflects a different cancer biology than abundance of intra-tumoral adipocytes. The Molecular Signatures Database Hallmark adipogenesis gene set of gene set variant analysis was used to quantify adipogenesis. Total of 5,098 breast cancer patients in multiple cohorts (training; GSE96058 (n = 3273), validation; TCGA (n = 1069), treatment response; GSE25066 (n = 508) and GSE20194 (n = 248)) were analyzed. Adipogenesis did not correlate with abundance of adipocytes. Adipogenesis was significantly lower in triple negative breast cancer (TNBC). Elevated adipogenesis was significantly associated with worse survival in TNBC, but not in the other subtypes. High adipogenesis TNBC was significantly associated with low homologous recombination deficiency, but not with mutation load. High adipogenesis TNBC enriched metabolism-related gene sets, but neither of cell proliferation- nor inflammation-related gene sets, which were enriched to adipocytes. High adipogenesis TNBC was infiltrated with low CD8 T cells and high M2 macrophages. Although adipogenesis was not associated with neoadjuvant chemotherapy response, high adipogenesis TNBC was significantly associated with low expression of PD-L1 and PD-L2 genes, and immune checkpoint molecules index. In conclusion, adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes.
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http://dx.doi.org/10.1038/s41598-021-91897-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206113PMC
June 2021

Relationship between stromal regulatory T cells and the response to neoadjuvant chemotherapy for locally advanced rectal cancer.

Surg Today 2021 Jun 3. Epub 2021 Jun 3.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Background: In addition to the direct power of anticancer drugs, the effectiveness of anticancer therapy depends on the host immune function. The present study investigated whether or not the reduction rate and histological response of preoperative chemotherapy were related to the immune microenvironment surrounding a primary tumor of the rectum.

Methods: Sixty-five patients received preoperative chemotherapy followed by resection from 2012 to 2014; all of these patients were retrospectively analyzed. CD3, CD8, and FoxP3 were immunohistochemically examined as markers for T lymphocytes, cytotoxic T lymphocytes, and regulatory T lymphocytes (Treg), respectively. The correlation between the tumor-infiltrating lymphocyte composition and the tumor reduction rate and histological response to neoadjuvant chemotherapy was investigated.

Results: The average tumor reduction rate was 41.5% ± 18.8%. According to RECIST, 47 patients (72.3%) achieved a partial response (PR), and 1 patient (1.5%) achieved a complete response (CR). Eight patients (12.3%) showed a grade 2 histological response, and 2 (3.1%) showed a grade 3 response. A multivariate analysis demonstrated that a low Treg infiltration in stromal cell areas was significantly associated with the achievement of a PR or CR [odds ratio (OR) 7.69; 95% confidence interval (CI) 1.96-33.33; p < 0.01] and a histological grade 2 or 3 response (OR 11.11; 95% CI 1.37-98.04; p = 0.02).

Conclusion: A low Treg infiltration in the stromal cell areas may be a marker of a good response to neoadjuvant chemotherapy in patients with locally advanced rectal cancer.
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http://dx.doi.org/10.1007/s00595-021-02311-8DOI Listing
June 2021

Urine as a Source of Liquid Biopsy for Cancer.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Tissue biopsy is the gold standard for diagnosis and morphological and immunohistochemical analyses to characterize cancer. However, tissue biopsy usually requires an invasive procedure, and it can be challenging depending on the condition of the patient and the location of the tumor. Even liquid biopsy analysis of body fluids such as blood, saliva, gastric juice, sweat, tears and cerebrospinal fluid may require invasive procedures to obtain samples. Liquid biopsy can be applied to circulating tumor cells (CTCs) or nucleic acids (NAs) in blood. Recently, urine has gained popularity due to its less invasive sampling, ability to easily repeat samples, and ability to follow tumor evolution in real-time, making it a powerful tool for diagnosis and treatment monitoring in cancer patients. With the development and advancements in extraction methods of urinary substances, urinary NAs have been found to be closely related to carcinogenesis, metastasis, and therapeutic response, not only in urological cancers but also in non-urological cancers. This review mainly highlights the components of urine liquid biopsy and their utility and limitations in oncology, especially in non-urological cancers.
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http://dx.doi.org/10.3390/cancers13112652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199052PMC
May 2021
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