Publications by authors named "Masayuki Nagahashi"

174 Publications

Low expression of miR-195 is associated with cell proliferation, glycolysis and poor survival in estrogen receptor (ER)-positive but not in triple negative breast cancer.

Am J Cancer Res 2021 15;11(6):3320-3334. Epub 2021 Jun 15.

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

MiR-195 is a tumor suppressive microRNA in breast cancer. Its clinical relevance remains debatable as it has only been studied via in vitro experiments or small cohort studies. We analyzed a total of 2,038 patients in the TCGA and METABRIC cohorts to assess whether low miR-195 expressing tumors are associated with aggressive cancer characteristics and poor prognostic outcomes. The median cutoff of miR-195 expression was used to split the groups into miR-195 high and low groups. Low miR-19 expressing tumors demonstrated high cell proliferating features by enriching the gene sets associated with cell proliferation, MKI67 expression and pathological grade. One-third of the top target miR-195 genes were related to cell proliferation. Low miR-195 expressing tumors were associated with both pro-cancerous and anti-cancerous immune cells. Low miR-195 expressing tumors were associated with enhanced glycolysis and poor survival in ER-positive tumors, but not other subtypes of breast cancer. In conclusion, low expression of miR-195 in ER-positive breast cancer was associated with enhanced cancer cell proliferation, glycolysis, and worse overall survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263660PMC
June 2021

Profiling of host genetic alterations and intra-tumor microbiomes in colorectal cancer.

Comput Struct Biotechnol J 2021 4;19:3330-3338. Epub 2021 Jun 4.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.

Some bacteria are symbiotic in tumor tissues, and metabolites of several bacterial species have been found to cause DNA damage. However, to date, the association between bacteria and host genetic alterations in colorectal cancer (CRC) has not been fully investigated. We evaluated the association between the intra-tumor microbiome and host genetic alterations in 29 Japanese CRC patients. The tumor and non-tumor tissues were extracted from the patients, and 16S rRNA genes were sequenced for each sample. We identified enriched bacteria in tumor and non-tumor tissues. Some bacteria, such as , which is already known to be enriched in CRC, were found to be enriched in tumor tissues. Interestingly, , which is also known to be enriched in CRC, was enriched in non-tumor tissues. Furthermore, it was shown that certain bacteria that often coexist within tumor tissue were enriched in the presence of a mutated gene or signal pathway with mutated genes in the host cells. was associated with many mutated genes, as well as cell cycle-related pathways including mutated genes. In addition, the patients with a high abundance of were suggested to be associated with mutational signature 3 indicating failure of double-strand DNA break repairs. These results suggest that CRC development may be partly caused by DNA damage caused by substances released by bacterial infection. Taken together, the identification of distinct gut microbiome patterns and their host specific genetic alterations might facilitate targeted interventions, such as modulation of the microbiome in addition to anticancer agents or immunotherapy.
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http://dx.doi.org/10.1016/j.csbj.2021.05.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202188PMC
June 2021

Angiogenesis is associated with an attenuated tumor microenvironment, aggressive biology, and worse survival in gastric cancer patients.

Am J Cancer Res 2021 15;11(4):1659-1671. Epub 2021 Apr 15.

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

Angiogenesis is a cornerstone of cancer as it allows tumors to receive oxygen and nutrients. A high level of angiogenesis within a tumor may therefore be indicative of its aggressiveness. In this study, we examined this hypothesis in gastric cancer. Gene set variation analysis was used to measure the level of angiogenesis in tumors in 1,348 gastric cancer patients using the Hallmark_angiogenesis gene set to score tumor transcriptomes. As we predicted, there was a significant correlation between angiogenesis score and expression of angiogenesis-related genes. The score moderately correlated with abundance of vessel-related stromal cells, fibroblasts and chondrocytes in the tumor microenvironment (TME). Tumors with high score had low infiltration of T helper type 1 and 2 cells but a greater infiltration of M1 macrophages and dendritic cells. They also had enriched expression of gene sets for coagulation, hypoxia, epithelial mesenchymal transition (EMT), and TGF-β signaling. High angiogenesis score was significantly associated with advanced AJCC stage and higher T- but not N-parameters in the TNM staging system. Patients with a high score also had shorter survival. In conclusion, bulk tumor transcriptome-based quantification of tumor angiogenesis using a computational algorithm may serve to identify patients with worse survival in gastric cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085878PMC
April 2021

Histopathological characteristics and artificial intelligence for predicting tumor mutational burden-high colorectal cancer.

J Gastroenterol 2021 Jun 28;56(6):547-559. Epub 2021 Apr 28.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.

Background: Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides.

Methods: We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images.

Results: Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934.

Conclusions: TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.
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http://dx.doi.org/10.1007/s00535-021-01789-wDOI Listing
June 2021

Anatomic location of residual disease after initial cholecystectomy independently determines outcomes after re-resection for incidental gallbladder cancer.

Langenbecks Arch Surg 2021 Apr 10. Epub 2021 Apr 10.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.

Purpose: This study aimed to elucidate the impact of anatomic location of residual disease (RD) after initial cholecystectomy on survival following re-resection of incidental gallbladder cancer (IGBC).

Methods: Patients with pT2 or pT3 gallbladder cancer (36 with IGBC and 171 with non-IGBC) who underwent resection were analyzed. Patients with IGBC were classified as follows according to the anatomic location of RD after initial cholecystectomy: no RD (group 1); RD in the gallbladder bed, stump of the cystic duct, and/or regional lymph nodes (group 2); and RD in the extrahepatic bile duct and/or distant sites (group 3).

Results: Timing of resection (IGBC vs. non-IGBC) did not affect survival in either multivariate or propensity score matching analysis. RD was found in 16 (44.4%) of the 36 patients with IGBC; R0 resection following re-resection was achieved in 32 patients (88.9%). Overall survival (OS) following re-resection was worse in group 3 (n = 7; 5-year OS, 14.3%) than in group 2 (n = 9; 5-year OS, 55.6%) (p = 0.035) or in group 1 (n = 20; 5-year OS, 88.7%) (p < 0.001). There was no survival difference between groups 1 and 2 (p = 0.256). Anatomic location of RD was independently associated with OS (group 2, HR 2.425, p = 0.223; group 3, HR 9.627, p = 0.024).

Conclusion: The anatomic location of RD independently predicts survival following re-resection, which is effective for locoregional disease control in IGBC, similar to resection for non-IGBC. Not all patients with RD have poor survival following re-resection for IGBC.
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http://dx.doi.org/10.1007/s00423-021-02165-1DOI Listing
April 2021

NQO1 as a Marker of Chemosensitivity and Prognosis for Colorectal Liver Metastasis.

Anticancer Res 2021 Mar;41(3):1563-1570

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background/aim: This study aimed to evaluate how NAD(P)H: quinone oxidoreductase-1 (NQO1) affects survival after hepatectomy in patients with colorectal liver metastasis (CRLM).

Patients And Methods: A retrospective analysis was conducted of 88 consecutive patients who underwent hepatectomy for CRLM. Of the 88 patients, preoperative chemotherapy was administered to 30 patients. Immunohistochemistry of the resected specimens was conducted using monoclonal anti-NQO1 antibody.

Results: NQO1-positive expression in tumor cells of CRLM was associated with worse overall survival (p=0.026) and was an independent adverse prognostic factor in multivariate analysis (hazard ratio=5.296, p=0.007). Among 30 patients who received preoperative chemotherapy, patients with loss of NQO1 expression in non-neoplastic epithelial cells of the bile ducts (NQO1 polymorphism: n=19) showed significantly better response to preoperative chemotherapy for CRLM (p=0.004).

Conclusion: NQO1-positive expression in tumor cells of CRLM may be an adverse prognostic factor after hepatectomy for CRLM.
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http://dx.doi.org/10.21873/anticanres.14916DOI Listing
March 2021

Mutational signatures in squamous cell carcinoma of the lung.

J Thorac Dis 2021 Feb;13(2):1075-1082

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Tumor mutational burden (TMB) has been identified as one of the predictors for the response to anti-programmed cell death-1 (anti-PD-1) antibody therapy and reported to correlate with smoking history in lung adenocarcinoma. However, in squamous cell carcinoma of the lung, the association between TMB and clinicopathological background factors, such as smoking history, has not been reported, including in our previous study. The mutational signature is a tool to identify the mutagens that are contributing to the mutational spectrum of a tumor by investigating the pattern of DNA changes. Here, we analyzed the mutational signature in lung squamous cell carcinoma to identify mutagens affecting the TMB.

Methods: Seven representative mutational signatures including signature 7 (SI7) [ultraviolet (UV)-related], SI4 (smoking), SI6/15 [mismatch repair (MMR)], SI2/13 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)], and SI5 (clock-like) were analyzed in Japanese patients with lung squamous cell carcinoma (n=67) using data generated by next-generation sequencing consisting of a 415-gene panel. The relationships between signatures and clinico-pathological data including TMB and programmed death-ligand 1 (PD-L1) expression were analyzed.

Results: Although the reconstructed mutational counts were small with targeted sequencing (median: 30.1, range: 13.3-98.7), the distributions of signatures were comparable among samples, with 56 cases containing more than four signatures. The smoking-related SI4 was found in 45 cases and was significantly related with pack-year index (PYI) (P=0.026). The reconstructed mutation counts were highly correlated with SI4 (r=0.51, P<0.0001), whereas the correlation was weak with SI6/15 (MMR-related) and SI2/13 (APOBEC-related). There was no mutational signature related with PD-L1 expression. Some patients exhibited unique signatures; the patient with the highest mutational counts had a MMR signature, and another patient with a prominent UV signature had occupational exposure to UV, as he was employed as a neon sign engineer.

Conclusions: Mutational signatures can predict the cause of lung squamous cell carcinoma. Tobacco smoking is the mutagen most related with TMB.
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http://dx.doi.org/10.21037/jtd-20-2602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947495PMC
February 2021

Dysregulation of sphingolipid metabolic enzymes leads to high levels of sphingosine-1-phosphate and ceramide in human hepatocellular carcinoma.

Hepatol Res 2021 May 9;51(5):614-626. Epub 2021 Mar 9.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan.

Aim: Sphingosine-1-phosphate (S1P) and ceramide are bioactive sphingolipids known to be important in regulating numerous processes involved in cancer progression. The aim of this study was to determine the absolute levels of sphingolipids in hepatocellular carcinoma (HCC) utilizing data obtained from surgical specimens. In addition, we explored the clinical significance of S1P in patients with HCC and the biological role of S1P in HCC cells.

Methods: Tumors and normal liver tissues were collected from 20 patients with HCC, and sphingolipids were measured by mass spectrometry. The Cancer Genome Atlas (TCGA) cohort was utilized to evaluate gene expression of enzymes related to sphingolipid metabolism. Immunohistochemistry of phospho-sphingosine kinase 1 (SphK1), an S1P-producing enzyme, was performed for 61 surgical specimens. CRISPR/Cas9-mediated SphK1 knockout cells were used to examine HCC cell biology.

Results: S1P levels were substantially higher in HCC tissue compared with normal liver tissue. Levels of other sphingolipids upstream of S1P in the metabolic cascade, such as sphingomyelin, monohexosylceramide and ceramide, were also considerably higher in HCC tissue. Enzymes involved in generating S1P and its precursor, ceramide, were found in higher levels in HCC compared with normal liver tissue. Immunohistochemical analysis found that phospho-SphK1 expression was associated with tumor size. Finally, in vitro assays indicated that S1P is involved in the aggressiveness of HCC cells.

Conclusions: Sphingolipid levels, including S1P and ceramide, were elevated in HCC compared with surrounding normal liver tissue. Our findings suggest S1P plays an important role in HCC tumor progression, and further examination is warranted.
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http://dx.doi.org/10.1111/hepr.13625DOI Listing
May 2021

Clinicopathological Characteristics and Surgical Outcomes of Primary Cystic Duct Carcinoma: A Multi-institutional Study.

World J Surg 2021 05 11;45(5):1613-1615. Epub 2021 Feb 11.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

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http://dx.doi.org/10.1007/s00268-021-05991-yDOI Listing
May 2021

Oncological outcomes of surgery for recurrent biliary tract cancer: who are the best candidates?

HPB (Oxford) 2021 Jan 22. Epub 2021 Jan 22.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

Background: This study aimed to investigate the impact of surgery on outcomes in patients with recurrent biliary tract cancer (BTC) and elucidate factors affecting survival after surgery for this disease.

Methods: A single-center study was undertaken in 178 patients with recurrent BTC, of whom 24 underwent surgery for recurrence, 85 received chemotherapy, and 69 received best supportive care. Then, we carried out a multicenter study in 52 patients undergoing surgery for recurrent BTC (gallbladder cancer, 39%; distal cholangiocarcinoma, 27%; perihilar cholangiocarcinoma, 21%; intrahepatic cholangiocarcinoma, 13%).

Results: In the single-center study, 3-year survival after recurrence was 53% in patients who underwent surgery, 4% in those who received chemotherapy, and 0% in those who received best supportive care (p < 0.001). Surgery was an independently prognostic factor (p < 0.001). In the multicenter series, the respective 3-year and 5-year survival after surgery for recurrence was 50% and 29% in the 52 patients. Initial site of recurrence was the only independent prognostic factor (p = 0.019). Five-year survival after surgery for recurrence in patients with single distant, multifocal distant, and locoregional recurrence was 51%, 0%, and 0%, respectively (p = 0.002). Sites of single distant recurrence included the liver (n = 13, 54%), distant lymph nodes (all from gallbladder cancer, n = 7, 29%), lung (n = 2, 9%), peritoneum (n = 1, 4%), and abdominal wall (n = 1, 4%).

Conclusion: Surgery may be an effective option for patients with less aggressive tumor biology characterized by single distant recurrence in recurrent BTC.
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http://dx.doi.org/10.1016/j.hpb.2021.01.007DOI Listing
January 2021

Efficacy of preoperative frailty assessment in patients with gastrointestinal disease.

Geriatr Gerontol Int 2021 Mar 27;21(3):327-330. Epub 2021 Jan 27.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Aim: The role of preoperative frailty assessment in patients with gastrointestinal (GI) disease remains unclear. This study aimed to clarify the relationship between frailty and postoperative outcomes in patients with GI disease.

Methods: This study investigated 42 patients (aged ≥65 years) with GI disease who underwent abdominal surgery. The frailty status was analyzed using the Japanese version of the Cardiovascular Health Study criteria. We also investigated postoperative outcomes.

Results: Of the 42 patients, seven (16.7%) were robust, 24 (57.1%) were prefrail and 11 (26.2%) were frail. Postoperative complications were observed in 45.5% and 63.6% of prefrail and frail patients, respectively, whereas no complications were found in robust patients (P = 0.026). The median hospital stay was 15, 19.5 and 27 days in robust, prefrail and frail patients, respectively (P < 0.01).

Conclusion: Preoperative frailty status based on the Japanese version of the Cardiovascular Health Study criteria is associated with postoperative complication incidence and hospital stay extension in patients with GI disease. Geriatr Gerontol Int 2021; ••: ••-••.
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http://dx.doi.org/10.1111/ggi.14134DOI Listing
March 2021

[A Case of Umbilical Metastasis from Pancreatic Cancer after Surgery].

Gan To Kagaku Ryoho 2020 Dec;47(13):2409-2411

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.

The patient was a 63-year-old woman with diagnosis of pancreatic cancer. Abdominal CT showed pancreatic head tumor and paraaortic lymph node metastasis. We performed chemotherapy with nab-paclitaxel plus gemcitabine. After 5 courses of chemotherapy, the tumor reduced in size. Pancreaticoduodenectomy followed by adjuvant chemotherapy with S-1 was performed. Fourteen months after surgery, umbilical metastasis(Sister Mary Joseph's nodule: SMJN)was found in the umbilicus near the abdominal incisional hernia. There was no evidence of metastasis except in the umbilicus, we performed the umbilical tumor resection and abdominal incisional hernia repair. Pathological diagnosis was pancreatic cancer metastasis. Although following chemotherapy, multiple skin metastases was found in the lower abdomen 3 months after umbilical resection. We performed skin metastases resection to relieve pain and symptoms of bleeding. But she died 29 months after the initial therapy(7 months after umbilical resection).
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December 2020

[Long-Term Survival after Surgery with Postoperative Chemotherapy for Perihilar Cholangiocarcinoma with Residual Invasive Carcinoma at Ductal Resection Margins-A Case Report].

Gan To Kagaku Ryoho 2020 Dec;47(13):1899-1901

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.

A 64-year-old man with liver dysfunction was given a diagnosis of perihilar cholangiocarcinoma(Bismuth type Ⅳ). The tumor was predominantly right-sided and invaded to the bifurcation of the right and left portal veins. After confirming sufficient liver functional reserve and future liver remnant, the patient underwent extended right hepatectomy, extrahepatic bile duct resection, and portal vein resection and reconstruction. Intraoperative examination of frozen sections revealed the presence of residual invasive carcinoma on both the hepatic and duodenal sides of the ductal resection margins. However, we did not perform pancreaticoduodenectomy or additional resection of the margin-positive proximal bile duct considering the curability and invasiveness of these procedures. He received postoperative chemotherapy with biweekly gemcitabine plus cisplatin for 1 year, followed by gemcitabine monotherapy for 1 year, and S-1 monotherapy has been performed since then. He remains alive and well with no evidence of disease 63 months after surgery.
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December 2020

[Amelanotic Malignant Melanoma of the Esophagogastric Junction-A Case Report].

Gan To Kagaku Ryoho 2020 Dec;47(13):2083-2085

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.

A 73-year-old man presented with anemia, and gastroscopy showed a nonpigmented tumor in the esophagogastric junction. The result of the tumor biopsy initially suspected poorly differentiated adenocarcinoma. However, additional immunohistochemical examination revealed malignant melanoma. The final diagnosis was amelanotic malignant melanoma of the esophagogastric junction with adrenal and spinal metastasis. Although immunotherapy was performed, the patient died 132 days after diagnosis.
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December 2020

[A Case of Invasive Lobular Carcinoma of Accessory Mammary Gland That Was Difficult for Evaluate for Lesion Spread].

Gan To Kagaku Ryoho 2020 Dec;47(13):2044-2046

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.

A 48-year-old female discovered a mass in her left axilla. A thorough examination resulted in a diagnosis of left invasive lobular carcinoma(ILC)of the accessory mammary gland with wide ductal spread. Considering the wide ductal spread, massive resection of the left axilla mass, left lymph node dissection, and a latissimus dorsi musculocutaneous flap procedure were performed. However, histological analysis revealed ILC measuring 80×50 mm with lymph node metastases(5/23)and extensive cancer spread, resulting in a positive surgical margin. It is important to recognize the characteristics of ILC, axillary accessory breast cancer, and the axilla in a treatment strategy.
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December 2020

[A Case of a"Watch and Wait Therapy"Approach after Preoperative Chemoradiotherapy for Rectal Cancer Accompanied by Severe Emphysema].

Gan To Kagaku Ryoho 2020 Dec;47(13):1960-1962

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.

A 72-year-old man was referred to our hospital for treatment for rectal cancer. Digital rectal examination and colonoscopy revealed a 4 cm tumor located at the anterior rectal wall 5 cm away from the anal verge, and pathological examination confirmed that the tumor was adenocarcinoma. A computed tomography scan detected neither regional lymph node metastasis nor distant metastasis. Hence, he was diagnosed with cT3N0M0, cStage Ⅱa rectal cancer. The preoperative general examination revealed bradyarrhythmia and severe emphysema, and he was considered to be high risk for general anesthesia. After placement of a pacemaker, preoperative capecitabine-based chemoradiotherapy(CRT)(50.4 Gy in 28 fractions of 1.8 Gy each)was implemented. The digital rectal examination and imaging evaluation 4 weeks after preoperative CRT revealed that the tumor disappeared, and pathological examination showed no malignant findings. Considering the risks of general anesthesia, the"watch and wait therapy"approach was adopted with sufficient informed consent. At present, 15 months after preoperative CRT, no evidence of regrowth or distant metastasis has been detected under rigorous follow- up evaluations.
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December 2020

Activin a Receptor Type 2A Mutation Affects the Tumor Biology of Microsatellite Instability-High Gastric Cancer.

J Gastrointest Surg 2021 Jan 8. Epub 2021 Jan 8.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.

Background: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations.

Methods: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated.

Results: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival.

Conclusions: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.
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http://dx.doi.org/10.1007/s11605-020-04889-9DOI Listing
January 2021

Outcome of radical surgery for gallbladder carcinoma according to TNM stage: implications for adjuvant therapeutic strategies.

Langenbecks Arch Surg 2021 May 4;406(3):801-811. Epub 2021 Jan 4.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.

Purpose: Outcomes following surgery for advanced gallbladder carcinoma remain unsatisfactory. This study aimed to determine the surgical outcome and effectiveness of adjuvant chemotherapy according to TNM stage in patients with gallbladder carcinoma.

Methods: A total of 200 patients undergoing surgery for gallbladder carcinoma were enrolled. Clinicopathological data were evaluated and surgical outcomes were compared between patients with and without adjuvant chemotherapy according to TNM stage.

Results: The 5-year overall survival (OS) after resection for patients with stage I (n = 27), IIA (n = 18), IIB (n = 28), IIIA (n = 25), IIIB (n = 43), IVA (n = 7), and IVB (n = 52) disease was 90.8%, 94.4%, 73.6%, 33.7%, 57.7%, 14.3%, and 11.8%, respectively (p < 0.001). R0 resection was performed in all patients with stage I or II disease, in 89.7% of those with stage III disease, and 69.5% of those with stage IV disease. For patients with stage III disease, adjuvant chemotherapy was associated with improved OS (5-year OS, 60.9% vs. 41.1%; p = 0.028) and was an independent prognostic factor (hazard ratio, 2.045; p = 0.039). For patients with stage IV disease, adjuvant chemotherapy appeared to affect OS (5-year OS, 25.1% vs. 5.3%; p = 0.041); R0 resection (hazard ratio, 1.882; p = 0.040) was the only independent prognostic factor.

Conclusion: TNM stage clearly predicts survival after resection of gallbladder carcinoma. R0 resection with adjuvant chemotherapy is recommended for long-term survival in the multimodal management of patients with stage III or IV gallbladder carcinoma.
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http://dx.doi.org/10.1007/s00423-020-02068-7DOI Listing
May 2021

A giant pelvic solitary fibrous tumor with Doege-Potter syndrome successfully treated with transcatheter arterial embolization followed by surgical resection: a case report.

Surg Case Rep 2020 Nov 25;6(1):299. Epub 2020 Nov 25.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.

Background: Solitary fibrous tumor (SFT), a mesenchymal fibroblastic tumor with a hypervascular nature, rarely develops in the pelvis. Resection of a giant SFT occupying the pelvic cavity poses an increased risk of developing massive hemorrhage during resection, although surgical resection is the most effective treatment method for this tumor to achieve a potential cure. SFT rarely develops with Doege-Potter syndrome, which is known as a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia (NICTH) secondary to SFT that secretes insulin-like growth factor-II (IGF-II). We present a case of a giant pelvic SFT with Doege-Potter syndrome, which was successfully treated with transcatheter arterial embolization (TAE) followed by surgical resection.

Case Presentation: A 46-year-old woman presented with a disorder of consciousness due to refractory hypoglycemia. Images of the pelvis showed a giant and heterogeneously hypervascular mass displacing and compressing the rectum. Endocrinological evaluation revealed low serum levels of insulin and C-peptide consistent with NICTH. Angiography identified both the inferior mesenteric artery and the bilateral internal iliac artery as the main feeders of the tumor. To avoid intraoperative massive bleeding, super-selective TAE was performed for the tumor 2 days prior to surgery. Hypoglycemia disappeared after TAE. The tumor was resected completely, with no massive hemorrhage during resection. Histologically, it was diagnosed as IGF-II-secreting SFT. Partial necrosis of the rectum in the specimen was observed due to TAE. The patient was followed up for 2 years and no evidence of disease has been reported.

Conclusions: Preoperative angiography followed by TAE is an exceedingly helpful method to reduce intraoperative hemorrhage when planning to resect SFT occupying the pelvic cavity. Complications related to ischemia should be kept in mind after TAE, which needs to be planned within 1 or 2 days before surgery. TAE for tumors may be an option in addition to medical and surgical treatment for persistent hypoglycemia in Doege-Potter syndrome.
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http://dx.doi.org/10.1186/s40792-020-01076-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688842PMC
November 2020

Clinical Utility of ypTNM Stage Grouping in the 8th Edition of the American Joint Committee on Cancer TNM Staging System for Esophageal Squamous Cell Carcinoma.

Ann Surg Oncol 2021 Feb 6;28(2):650-660. Epub 2020 Oct 6.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: The 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system provided a specific 'ypTNM' stage grouping for patients with esophageal cancer.

Objective: This study aimed to evaluate the clinical utility of the AJCC 8th edition ypTNM stage grouping for patients with esophageal squamous cell carcinoma (ESCC).

Methods: We enrolled 152 patients with ESCC who underwent surgery after neoadjuvant cisplatin plus 5-fluorouracil (CF) therapy between June 2005 and December 2011. ypStage was evaluated according to the AJCC 7th and 8th editions. Predictive performance for disease-specific survival (DSS) and overall survival (OS) was compared between both editions. The prognostic significance of ypTNM stage grouping was evaluated using univariate and multivariate analyses.

Results: Revision of the AJCC 7th edition to the 8th edition was associated with a change in ypStage in 96 patients (63.2%). The AJCC 8th edition revealed a better predictive performance than the 7th edition in terms of DSS (Akaike's information criterion [AIC] 499 vs. 513; Bayesian information criterion [BIC] 505 versus 519; concordance index [C-index] 0.725 versus 0.679) and OS (AIC 662 vs. 674; BIC 669 vs. 681; C-index 0.662 vs. 0.622). On univariate and multivariate analyses, ypStage in the 8th edition was an independent prognostic factor for both DSS and OS.

Conclusions: ypTNM stage grouping in the AJCC 8th edition provided a better predictive performance for DSS and OS than that in the 7th edition. ypStage in the 8th edition was the most reliable prognostic factor for ESCC patients who underwent surgery after neoadjuvant CF therapy.
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http://dx.doi.org/10.1245/s10434-020-09181-3DOI Listing
February 2021

Intra-Tumoral Angiogenesis Is Associated with Inflammation, Immune Reaction and Metastatic Recurrence in Breast Cancer.

Int J Mol Sci 2020 Sep 13;21(18). Epub 2020 Sep 13.

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

Angiogenesis is one of the hallmarks of cancer. We hypothesized that intra-tumoral angiogenesis correlates with inflammation and metastasis in breast cancer patients. To test this hypothesis, we generated an angiogenesis pathway score using gene set variation analysis and analyzed the tumor transcriptome of 3999 breast cancer patients from The Cancer Genome Atlas Breast Cancer (TCGA-BRCA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE20194, GSE25066, GSE32646, and GSE2034 cohorts. We found that the score correlated with expression of various angiogenesis-, vascular stability-, and sphingosine-1-phosphate (S1P)-related genes. Surprisingly, the angiogenesis score was not associated with breast cancer subtype, Nottingham pathological grade, clinical stage, response to neoadjuvant chemotherapy, or patient survival. However, a high score was associated with a low fraction of both favorable and unfavorable immune cell infiltrations except for dendritic cell and M2 macrophage, and with Leukocyte Fraction, Tumor Infiltrating Lymphocyte Regional Fraction and Lymphocyte Infiltration Signature scores. High-score tumors had significant enrichment for unfavorable inflammation-related gene sets (interleukin (IL)6, and tumor necrosis factor (TNF)α- and TGFβ-signaling), as well as metastasis-related gene sets (epithelial mesenchymal transition, and Hedgehog-, Notch-, and WNT-signaling). High score was significantly associated with metastatic recurrence particularly to brain and bone. In conclusion, using the angiogenesis pathway score, we found that intra-tumoral angiogenesis is associated with immune reaction, inflammation and metastasis-related pathways, and metastatic recurrence in breast cancer.
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http://dx.doi.org/10.3390/ijms21186708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555442PMC
September 2020

Sphingosine Kinase 1 is Associated With Immune Cell-Related Gene Expressions in Human Breast Cancer.

J Surg Res 2020 12 15;256:645-656. Epub 2020 Aug 15.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan.

Background: Although previous experiments have implicated sphingosine-1-phosphate (S1P) as a links between immune reactions and cancer progression, the exact mechanism of this interaction has not comprehensively studied in clinical human samples. This study sought to evaluate the S1P regulation by sphingosine kinase 1 (SPHK1), an S1P-producing enzyme, in the immunity/immuno-reactivity of clinical human breast cancer surgical specimens.

Methods: S1P levels were examined in tumor, peritumoral, and normal human breast samples using mass spectrometry. Genomics Data Commons data portal of The Cancer Genome Atlas cohort was used to assess the expression of S1P-related and immune-related genes.

Results: S1P levels were significantly higher in tumor samples compared to peritumoral (P < 0.05) or normal human breast samples (P < 0.001). SPHK1 gene expression was elevated in tumoral samples compared to normal breast samples (P < 0.01). Furthermore, the elevated expression of SPHK1 in breast cancer tissue was associated with an increased expression of the different kinds of immune-related genes, such as CD68, CD163, CD4, and FOXP3 (forkhead box P3), in HER2-negative breast cancer. Network analysis showed the central role of SPHK1 in the interaction of S1P signaling and expression of immune cell-related proteins.

Conclusions: We demonstrated that S1P is mainly produced by tumor tissue, rather than peritumoral tissue, in breast cancer patients. Our data revealed the involvement of S1P signaling in the regulation of immune-related genes, suggesting the links between S1P and complicated immune-cancer interactions in breast cancer patients.
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http://dx.doi.org/10.1016/j.jss.2020.06.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882641PMC
December 2020

Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

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

Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as "intratumoral adipocyte". These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.
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http://dx.doi.org/10.3390/ijms21165744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461211PMC
August 2020

Genetic analysis in the clinical management of biliary tract cancer.

Ann Gastroenterol Surg 2020 Jul 14;4(4):316-323. Epub 2020 Apr 14.

Division of Digestive and General Surgery Niigata University Graduate School of Medical and Dental Sciences Niigata Japan.

Biliary tract cancer (BTC) is clinically and pathologically heterogeneous and responds inadequately to treatment. A small section of patients develop resectable disease, although the relapse rates are high; the benefits of adjuvant capecitabine chemotherapy for BTC are now understood, and gemcitabine-based combination chemotherapy is the first line of therapeutic strategy for BTC; however, alternative therapy for BTC is not known. Genomic profiling can provide detailed information regarding the carcinogenesis, identification, and therapy for BTC. Currently, confirmed restorative targets for BTC are lacking. In this review, we aimed to analyze the preclinical and clinical implications of a spectrum of genomic alterations associated with new potentially remedial targets. We focused on eight draggable genes for BTC, which were described as having evidence of therapeutic impact (evidence level 2A-3B) based on the clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment; these include ERBB2, NTRK1, RNF43, CDK6, CDKN2B, FGFR2, IDH1, and IDH2. Moreover, some of the BTC present microsatellite instability, hypermutation, and germline variants, which we also reviewed. Finally, we discussed the therapeutic options based on the next-generation sequencing findings in BTC. Studies have demonstrated that BTC includes subgroups with individually distinct driver mutations, most of which will be targeted with new treatment plans.
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http://dx.doi.org/10.1002/ags3.12334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382432PMC
July 2020

Annual report of the Japanese Breast Cancer Registry for 2017.

Breast Cancer 2020 Sep 24;27(5):803-809. Epub 2020 Jul 24.

Department of Breast Surgery, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.

Background: The Japanese Breast Cancer Society Registry started in 1975; it was transferred to the registry platform of the National Clinical Database in 2012. We provide the annual data and an analysis of the Breast Cancer Registry for 2017.

Methods: Patients' characteristics and pathological data of the 95,203 registered Japanese breast cancer patients from 1,427 institutes in 2017 were obtained. Trends in age at diagnosis and pathological stage were determined during the most recent 6 years (2012-2017).

Results: The mean onset age was 60.2 years with bimodal peaks at 45-49 years and 65-69 years. A short-term trend of the most recent 6 years of data caused the second, older peak. At diagnosis, 32.4% of breast cancer patients were premenopausal. The distribution of stages revealed that the proportion of early stage breast cancer (stage 0-I) increased up to 60%. At the initial diagnosis, 2.2% of patients presented with metastatic disease. Sentinel node biopsy without axillary node dissection was performed without neoadjuvant chemotherapy (NAC) in 68.8%, and with NAC in 31.1%, of patients. For patients without NAC, lymph node metastasis was less than 3% if the tumor size was less than 1 cm. The proportion of node-negativity decreased to 79.5% when tumor size was 2.1-5 cm.

Conclusions: This analysis of the registry provides new information for effective treatment in clinical practice, cancer prevention, and the conduct of clinical trials. Further development of the registry and progress in collecting prognostic data will greatly enhance its scientific value.
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http://dx.doi.org/10.1007/s12282-020-01139-3DOI Listing
September 2020

[A Case of High-Frequency Microsatellite Instability in Colorectal Cancer with MSH2 Mutation Detected Using Gene Panel Testing with a Next-Generation Sequencer].

Gan To Kagaku Ryoho 2020 Jul;47(7):1113-1115

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.

Here, we report about a woman in her 30s who had peritoneal dissemination and multiple colon cancer with high-frequency microsatellite instability(MSI-H). Her father, paternal grandfather, and maternal grandmother had a history of colorectal cancer treatment. Thus, Lynch syndrome was suspected. We performed R0 resection for peritoneal dissemination and subsequent peritoneal dissemination. A 435-gene panel testing using a next-generation sequencer identified MSH2 and other mutations in the tumor. Hence, we speculated that she could have a germline mutation of MSH2, which causes Lynch syndrome. In the future, if she wishes to receive genetic counseling and undergo germline testing for variants to confirm the diagnosis of Lynch syndrome, we will perform them after receiving informed consent.
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July 2020

The E2F Pathway Score as a Predictive Biomarker of Response to Neoadjuvant Therapy in ER+/HER2- Breast Cancer.

Cells 2020 07 8;9(7). Epub 2020 Jul 8.

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

E2F transcription factors play critical roles in the cell cycle. Therefore, their activity is expected to reflect tumor aggressiveness and responsiveness to therapy. We scored 3905 tumors of nine breast cancer cohorts for this activity based on their gene expression for the Hallmark E2F targets gene set. As expected, tumors with a high score had an increased expression of cell proliferation-related genes. A high score was significantly associated with shorter patient survival, greater MKI67 expression, histological grade, stage, and genomic aberrations. Furthermore, metastatic tumors had higher E2F scores than the primary tumors from which they arose. Although tumors with a high score had greater infiltration by both pro- and anti-cancerous immune cells, they had an increased expression of immune checkpoint genes. Estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative cancer with a high E2F score achieved a significantly higher pathological complete response (pCR) rate to neoadjuvant chemotherapy. The E2F score was significantly associated with the expression of cyclin-dependent kinase (CDK)-related genes and strongly correlated with sensitivity to CDK inhibition in cell lines. In conclusion, the E2F score is a marker of breast cancer aggressiveness and predicts the responsiveness of ER-positive/HER2-negative patients to neoadjuvant chemotherapy and possibly to CDK and immune checkpoint inhibitors.
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http://dx.doi.org/10.3390/cells9071643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407968PMC
July 2020

Clinicopathological Characteristics and Surgical Outcomes of Primary Cystic Duct Carcinoma: A Multi-institutional Study.

World J Surg 2020 Nov;44(11):3875-3883

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

Background: The role of surgery in the management of primary cystic duct carcinoma (CDC) remains unclear especially in advanced disease. This study aimed to evaluate long-term outcomes in patients undergoing surgery for primary CDC.

Methods: From a multi-institutional database, we identified 41 patients who underwent surgery for primary CDC, defined as a part of gallbladder carcinoma with the tumor centre located in the cystic duct.

Results: Of the 41 patients, 31 (75.6%) underwent preoperative biliary drainage for jaundice. Twenty-eight (68.3%) patients underwent extensive resection including major hepatectomy (n = 21), pancreaticoduodenectomy (n = 4), or both procedures (n = 3). Thirty-four (82.9%) patients had ≥ pT3 tumor, while 31 (75.6%) patients had involvement of contiguous organs/structures. Nodal and distant metastasis was found in 26 (63.4%) and 7 (17.1%) patients, respectively. Most patients (90.2%) had perineural invasion. Median overall survival was 23.7 months in all 41 patients. Factors independently associated with both overall and disease-specific survival were pN (P = 0.003 and P = 0.007, respectively) and pM (P = 0.003 and P = 0.013, respectively) classification. Median survival was 75.3, 17.7, and 5.2 months for patients with pN0M0 (n = 14), pN1/2pM0 or pN0pM1 (n = 21), and pN1/2pM1 (n = 6) disease, respectively (P < 0.001).

Conclusions: Primary CDC is characterized by locally advanced disease with aggressive histopathological characteristics at surgery, leading to extensive resection during treatment. Surgery provides potential benefits for patients with pN0pM0 disease, whereas pN1/2 and/or pM1 status appear to have strong adverse effects on survival.
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http://dx.doi.org/10.1007/s00268-020-05656-2DOI Listing
November 2020

Inguinal Herniation After Living Donor Kidney Transplantation: A Case Report.

Transplant Proc 2020 Jul - Aug;52(6):1940-1943. Epub 2020 May 21.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

A 68-year-old male patient received a living donor kidney transplantation 8 years earlier for end-stage kidney disease secondary to IgA nephropathy. His post-transplantation follow-up had been routinely performed with laboratory examinations, ultrasound, and computed tomography (CT). His kidney graft function had been excellent and stable, as shown by a baseline serum creatinine level of 1.0 mg/dL. At referral, regular follow-up ultrasound and CT showed allograft hydroureteronephrosis. He did not have any complaints, but his physical examination revealed right inguinal bulging that was 3.5 × 3.5 cm. Abdominal enhanced CT revealed transplant allograft hydroureteronephrosis due to ipsilateral herniation of ureteroneocystostomy into the right inguinal canal. His serum creatinine level was slightly elevated (1.1 mg/dL). Then, he underwent an open right inguinal hernia repair. Paraperitoneal allograft hydroureteronephrosis and bladder herniation was confirmed at surgery, and hernioplasty with polypropylene mesh reinforcement was successfully performed. The postoperative course was uneventful. He was discharged on the seventh day after surgery. Six weeks after surgery, CT revealed disappearance of allograft hydroureteronephrosis and no sign of inguinal hernia recurrence with the serum creatinine stable at 1.0 mg/dL. Transplant ureteral obstruction due to inguinal hernia is a rare complication after kidney transplantation. However, transplant ureter or bladder herniation should be considered in the differential diagnosis of graft hydroureteronephrosis for preventing allograft loss.
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http://dx.doi.org/10.1016/j.transproceed.2020.02.131DOI Listing
November 2020
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