Publications by authors named "Toshifumi Wakai"

332 Publications

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.csbj.2021.05.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202188PMC
June 2021

The effects of ARID1A mutations on colorectal cancer and associations with PD-L1 expression by stromal cells.

Cancer Rep (Hoboken) 2021 May 27:e1420. Epub 2021 May 27.

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

Background: ARID1A is a component of the SWI/SNF complex, which controls the accessibility of proteins to DNA. ARID1A mutations are frequently observed in colorectal cancers (CRCs) and have been reported to be associated with high mutational burden and tumor PD-L1 expression in vitro.

Aim: To clarify the role of ARID1A mutation in CRC.

Method And Results: We used next generation sequencing (NGS) and immunohistochemistry on clinically obtained samples. A total of 201 CRC tissues from Niigata University and Niigata Center Hospital were processed by NGS using the CANCERPLEX panel. Immunohistochemistry for ARID1A, PD-L1, MLH1, and MSH2 was performed on 66 propensity-matched (33 microsatellite instability-high [MSI-H] and 33 microsatellite-stable [MSS]) cases among 499 cases from Kyushu University. TCGA data were downloaded from cBioPortal. NGS showed significantly more mutations in ARID1A mutated CRCs (p = 0.01), and the trend was stronger for right-sided CRCs than left-sided. TCGA data confirmed these findings (p < 0.01). BRAF V600E and ATM mutations were also found at higher frequencies. Immunohistochemistry showed that 30% of MSI-H CRCs had ARID1A loss, while this was true in only 6% of MSS CRCs. In both MSI-H and MSS, PD-L1 expression by stromal cells was enhanced in the ARID1A-mutant groups (90% vs 39% in MSI-H, 100% vs 26% in MSS).

Conclusion: We found a higher mutational burden in ARID1A-mutant CRCs, and IHC study showed that ARID1A loss was correlated with high PD-L1 expression in stromal cells regardless of MSI status. These data support the idea that mutant ARID1A is a potential biomarker for CRCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cnr2.1420DOI Listing
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00423-021-02165-1DOI Listing
April 2021

Clinical Significance of Mesenteric Lymph Node Involvement in the Pattern of Liver Metastasis in Patients with Ovarian Cancer.

Ann Surg Oncol 2021 Apr 5. Epub 2021 Apr 5.

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

Background: Mesenteric lymph node (MLN) involvement is often observed in ovarian cancer (OC) with rectosigmoid invasion. This study aimed to investigate the clinical significance of MLN involvement in the pattern of liver metastasis in patients with OC.

Methods: We included 85 stage II-IV OC patients who underwent primary or interval debulking surgery. Twenty-seven patients underwent rectosigmoid resection, whose status of MLN involvement was judged from hematoxylin and eosin (H&E) staining of resected specimens. The prognostic significance of clinicopathological characteristics, including MLN involvement, was evaluated using univariate and multivariate analyses.

Results: MLN involvement was detected in 14/85 patients with stage II-IV OC. Residual tumor status, cytology of ascites, and MLN involvement were independent prognostic factors for progression-free survival (PFS; p = 0.033, p = 0.014, and p = 0.008, respectively). When patients were classified into three groups (no MLN, one MLN, two or more MLNs), the number of MLNs involved corresponded to three distinct groups in PFS (p = 0.001). The 3-year cumulative incidence of liver metastasis of patients with MLN involvement was significantly higher than that of patients without MLN involvement (61.1% vs. 8.9%, p < 0.001). MLN involvement was significantly associated with liver metastasis of hematogenous origin (p < 0.001) compared with peritoneal disseminated origin.

Conclusion: MLN involvement is an important prognostic factor in OC, predicting poor prognosis and liver metastasis of hematogenous origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-09899-8DOI Listing
April 2021

ASO Author Reflections: Clinical Significance of Mesenteric Lymph Node Involvement in Patients with Ovarian Cancer.

Ann Surg Oncol 2021 Mar 31. Epub 2021 Mar 31.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-09919-7DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14916DOI Listing
March 2021

Adipose most abundant 2 protein is a predictive marker for cisplatin sensitivity in cancers.

Sci Rep 2021 Mar 18;11(1):6255. Epub 2021 Mar 18.

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

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85498-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973578PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hepr.13625DOI Listing
May 2021

Massive perianal skin ulcer due to long-standing amoebic infection in an HIV-negative, heterosexual man.

J Dermatol 2021 Apr 13;48(4):e198-e200. Epub 2021 Feb 13.

Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15800DOI Listing
April 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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hpb.2021.01.007DOI Listing
January 2021

Urokinase-type Plasminogen Activator Is a Therapeutic Target for Overcoming Sorafenib Resistance in Hepatoma Cells.

Anticancer Res 2021 Feb;41(2):645-660

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

Background/aim: Sorafenib is a multikinase inhibitor approved as a first-line therapy for hepatocellular carcinoma. This study examined the sorafenib resistance mechanism.

Materials And Methods: Hepatoma HepG2 cells were exposed to sorafenib, and the biological activity of the conditioned media was analyzed using cell proliferation/apoptosis assays, multiplex immunoassays, ELISA, and western blot analyses. The effect of urokinase-type plasminogen activator (uPA) inhibitors or siRNA-mediated gene silencing was examined in culture experiments and a mouse xenograft tumor model.

Results: Sorafenib increased uPA secretion, which was abrogated by an Akt inhibitor. The growth-inhibitory effect of sorafenib was significantly enhanced by the uPA inhibitors UK122 and amiloride. Sorafenib-induced apoptosis was increased 2.4-fold in uPA siRNA-transduced cells (p<0.05). Combined therapy with sorafenib and amiloride significantly decreased tumor volumes [mean volume: 759 mm (sorafenib) vs. 283 mm (sorafenib plus amiloride), p<0.05].

Conclusion: uPA may play a critical role in sorafenib resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14816DOI Listing
February 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; ••: ••-••.
View Article and Find Full Text PDF

Download full-text PDF

Source
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).
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2020

Evaluation of intestinal microbiota, short-chain fatty acids, and immunoglobulin a in diversion colitis.

Biochem Biophys Rep 2021 Mar 30;25:100892. Epub 2020 Dec 30.

Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

It is reported that an increase in aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon are major causes of diversion colitis. However, the precise pathogenesis of this condition remains unclear. The aim of the present study was to examine the microbiota, intestinal SCFAs, and immunoglobulin A (IgA) in the diverted colon. Eight patients underwent operative procedures for colostomies. We assessed the diverted colon using endoscopy and obtained intestinal samples from the diverted colon and oral colon in these patients. We analyzed the microbiota and SCFAs of the intestinal samples. The bacterial communities were investigated using a 16S rRNA gene sequencing method. The microbiota demonstrated a change in the proportion of some species, especially , which significantly decreased in the diverted colon at the genus level. We also showed that intestinal SCFA values were significantly decreased in the diverted colon. Furthermore, intestinal IgA levels were significantly increased in the diverted colon. This study was the first to show that intestinal SCFAs were significantly decreased and intestinal IgA was significantly increased in the diverted colon. Our data suggest that SCFAs affect the microbiota and may play an immunological role in diversion colitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrep.2020.100892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797511PMC
March 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00423-020-02068-7DOI Listing
May 2021

Clinical practice guidelines for the management of biliary tract cancers 2019: The 3rd English edition.

J Hepatobiliary Pancreat Sci 2021 Jan 23;28(1):26-54. Epub 2020 Dec 23.

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

Background: The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014.

Methods: In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as Grade 1 (strong) or Grade 2 (weak) according to the concepts of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.

Results: The 31 CQs covered the six topics: (a) prophylactic treatment, (b) diagnosis, (c) biliary drainage, (d) surgical treatment, (e) chemotherapy, and (f) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded.

Conclusions: This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jhbp.870DOI Listing
January 2021

Genetic profiling for diffuse type and genomically stable subtypes in gastric cancer.

Comput Struct Biotechnol J 2020 29;18:3301-3308. Epub 2020 Oct 29.

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

Gastric cancer is one of the most common and clinically important diseases worldwide. The traditional Laeuren classification divides gastric cancer into two histopathological subtypes: diffuse and intestinal. Recent cancer genomics research has led to the development of a new classification based on molecular characteristics. The newly defined genomically stable (GS) subtype shares many cases with the histopathologically diffuse type. In this study, we performed genetic profiling of recurrently and significantly mutated genes in diffuse type and GS subtype tumors. We observed significantly different genetic characteristics, although the two subtypes overlapped in many cases. In addition, based on the profiles of the significantly mutated genes, we identified molecular functions and mutational signatures characteristic of each subtype. These results will advance the clinical application of the diffuse type and GS subtype gastric cancer in precision medicine for treating gastric cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.csbj.2020.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666323PMC
October 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40792-020-01076-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688842PMC
November 2020

Esophageal High-Resolution Manometry for Diagnosing the Severity of the Chronic Intestinal Pseudo-Obstruction: A Case Series.

Dig Dis Sci 2020 Nov 12. Epub 2020 Nov 12.

Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan.

Background: Chronic intestinal pseudo-obstruction (CIPO) is a severe and refractory intestinal motility disorder. However, due to its rarity and difficult histological investigation, its pathophysiology has not been characterized.

Aim: Therefore, in this study, we aimed to determine the role of esophageal high-resolution manometry (HRM) in CIPO and the histological and clinical characteristics of the disease.

Methods: Patients with CIPO were analyzed for clinical characteristics; histological findings; and clinical courses after therapeutic intervention. In addition, HRM was performed to determine the esophageal involvement.

Results: Eleven patients were diagnosed with CIPO, and five required the long period of parenteral nutrition showing impaired esophageal motility including achalasia and absent contractility diagnosed with HRM. The four of these five cases showed acute onset of the CIPO following the triggering events of pregnancy, appendicitis, and surgery. In contrast, other six patients with normal or Jackhammer esophagus on HRM had moderate severity of CIPO with gradual onset. The histological analyses revealed that the loss of the intestinal neural ganglion cells and layers by inflammation, destruction, and atrophy are related to the severity of the clinical course of the disease and esophageal HRM findings of achalasia and absent contractility.

Conclusions: HRM may be useful to diagnose the severity of the clinical course and to determine the therapeutic options for CIPO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-020-06701-9DOI Listing
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09181-3DOI Listing
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jss.2020.06.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882641PMC
December 2020
-->