Publications by authors named "Hironori Yamaguchi"

170 Publications

Metformin combined with local irradiation provokes abscopal effects in a murine rectal cancer model.

Sci Rep 2022 May 4;12(1):7290. Epub 2022 May 4.

Department of Gastrointestinal Surgery, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan.

Although preoperative chemoradiation therapy can down-stage locally advanced rectal cancer (LARC), it has little effect on distant metastases. Metformin exerts an anti-cancer effect partly through the activation of host immunity. LuM1, a highly lung metastatic subclone of colon 26, was injected subcutaneously (sc) in BALB/c mice and treated with metformin and/or local radiation (RT). Lung metastases and the primary tumors were evaluated and the phenotypes of immune cells in the spleen and lung metastases were examined with flow cytometry and immunohistochemistry. Local RT, but not metformin, partially delayed the growth of sc tumor which was augmented with metformin. Lung metastases were unchanged in metformin or RT alone, but significantly reduced in the combined therapy. The ratios of splenic T cells tended to be low in the RT group, which were increased by the addition of metformin. IFN-γ production of the splenic CD4(+) and CD8(+) T cells was enhanced and CD49b (+) CD335(+) activated NK cells was increased after combined treatment group. Density of NK cells infiltrating in lung metastases was increased after combination treatment. Metformin effectively enhances local and abscopal effects of RT though the activation of cell-mediated immunity and might be clinically useful for LARC.
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http://dx.doi.org/10.1038/s41598-022-11236-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9068771PMC
May 2022

Programmed death ligand (PD-L1) expression on monocytes is inversely correlated with tumour response to preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer.

Colorectal Dis 2022 May 3. Epub 2022 May 3.

Department of Surgery, Jichi Medical University.

Aim: The clinical efficacy of chemoradiotherapy (CRT) is largely dependent on host immune status. The aim of this study was to identify possible markers expressed on circulating mononuclear cells to predict tumour response in patients with locally advanced rectal cancer (LARC) METHODS: Peripheral blood samples were obtained from 47 patients diagnosed with LARC before and after CRT. The numbers of lymphocytes and monocyte subsets were analyzed using flow cytometry. Based on clinical and pathological findings, patients were classified as high or low responders.

Results: Lymphocyte counts were markedly decreased after CRT. Total numbers of lymphocytes (p=0.030) and CD4(+) T cells (p=0.041) in post-CRT samples were significantly lower in low responders than in high responders. In contrast, monocyte counts were not reduced and the number of CD14 (+) CD16(+) non-classical (patrolling) monocytes were somewhat increased after CRT (p=0.050). Moreover, the ratios of PD-L1 (+) cells on patrolling monocytes before and after CRT were significantly higher in low responders than in high responders (p=0.0046, p=0.0006). The same trend was observed for classical and intermediate monocytes. The expression of PD-L1 on patrolling monocytes before CRT correlated inversely with the number of T cells and natural killer (NK) cells after CRT. PD-L1(+) ratio in patrolling monocytes was an independent predictor for response to CRT.

Conclusion: PD-L1 expression on patrolling monocytes suppresses cell-mediated immunity in patients receiving CRT which could be related to tumour response, and may be a useful biomarker for decision-making in the management of patients with LARC.
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http://dx.doi.org/10.1111/codi.16167DOI Listing
May 2022

Effect of Systemic or Intraperitoneal Administration of Anti-PD-1 Antibody for Peritoneal Metastases from Gastric Cancer.

In Vivo 2022 May-Jun;36(3):1126-1135

Department of Gastrointestinal Surgery, Jichi Medical University, Simotsuke, Japan

Background/aim: Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) blockade therapy is widely used for the treatment of patients with metastatic gastric cancer (GC). However, it is unclear how PD-1 antibodies affect the local immunity related to the growth of peritoneal metastases (PM). The clinical efficacy of PD-1/PD-L1 inhibitors against PM from GC has not been clearly determined.

Materials And Methods: We established a highly metastatic subclone of murine GC cells to the peritoneum, YTN16P, by in vivo selection and evaluated the effects of intravenous (IV) or intraperitoneal (IP) administration of anti-PD-1 antibody on PM in immunocompetent mice model. Phenotypes of immune cells in the spleen and peritoneal metastatic lesions were determined with flow cytometry and immunohistochemistry.

Results: IP inoculation of YTN16P (1×10) resulted in multiple mesenteric metastases after 3 weeks. IV and IP administration of anti-PD-1mAb reduced the number of metastases to the mesentery by 30~40% compared with isotype controls. However, no differences were observed depending on the route of administration. Although splenocyte phenotypes were not altered, the densities of CD8(+) T cells in peritoneal tumors were significantly increased, whereas those of Gr-1(+) myeloid derived suppressor cells (MDSC) were significantly reduced in mice treated with anti-PD-1 mAb.

Conclusion: PD-1 blockade therapy remodels the cellular immune composition of peritoneal tumors, which can partially suppress the PM from GC regardless of the route of administration. Adding anti-PD-1 antibody to chemotherapeutic regimens may enhance their anti-tumor effects against PM, which can lead to the prolongation of survival of patients with GC with peritoneal involvement.
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http://dx.doi.org/10.21873/invivo.12811DOI Listing
April 2022

Oxaliplatin- versus cisplatin-based regimens for elderly individuals with advanced gastric cancer: a retrospective cohort study.

BMC Cancer 2022 Apr 26;22(1):460. Epub 2022 Apr 26.

Data Science Center, Jichi Medical University, Tochigi, Japan.

Background: Whether an oxaliplatin- or cisplatin-based regimen is more optimal for treating elderly patients with advanced gastric cancer, in terms of survival and adverse events remains unclear.

Methods: In this retrospective cohort study, we used stacked claim data of residents in two Japanese prefectures collected between 2012 and 2017 and between 2014 and 2019, respectively. We included patients with advanced gastric cancer who received oxaliplatin-based and cisplatin-based regimens. Propensity score overlap weighting analysis was conducted to compare overall survival and granulocyte colony-stimulating factor use during chemotherapy between the oxaliplatin- and cisplatin-based treatment groups.

Results: A total of 242 patients were included in the study. After propensity score weighting, Kaplan-Meier analysis showed no significant differences in overall survival between the two groups (hazard ratio: 1.13; 95% confidence interval, 0.60-2.11; p =  0.70). However, the proportion of patients receiving granulocyte colony-stimulating factor was significantly lower in the oxaliplatin group than in the cisplatin group (2.3% vs.22.7%, p = 0.01).

Conclusions: Survival did not differ significantly between elderly patients with advanced gastric cancer treated with oxaliplatin-based versus cisplatin-based regimens; however, the oxaliplatin-based regimen was associated with less granulocyte colony-stimulating factor use.
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http://dx.doi.org/10.1186/s12885-022-09581-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044765PMC
April 2022

The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: an exploratory analysis of JCOG1113.

Sci Rep 2022 01 19;12(1):987. Epub 2022 Jan 19.

Gastrointestinal Medical Oncology, Chiba Cancer Center, Chiba, Chiba, Japan.

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.
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http://dx.doi.org/10.1038/s41598-021-04550-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770671PMC
January 2022

MiR-29b may suppresses peritoneal metastases through inhibition of the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells.

Sci Rep 2022 01 7;12(1):205. Epub 2022 Jan 7.

Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Peritoneal dissemination is a major metastatic pathway for gastrointestinal and ovarian malignancies. The miR-29b family is downregulated in peritoneal fluids in patients with peritoneal metastases (PM). We examined the effect of miR-29b on mesothelial cells (MC) which play critical a role in the development of PM through mesothelial-mesenchymal transition (MMT). Human peritoneal mesothelial cells (HPMCs) were isolated from surgically resected omental tissue and MMT induced by stimulation with 10 ng/ml TGF-β1. MiR-29b mimics and negative control miR were transfected by lipofection using RNAiMAX and the effects on the MMT evaluated in vitro. HPMC produced substantial amounts of miR-29b which was markedly inhibited by TGF-β1. TGF-β1 stimulation of HPMC induced morphological changes with decreased expression of E-cadherin and calretinin, and increased expression of vimentin and fibronectin. TGF-β1 also enhanced proliferation and migration of HPMC as well as adhesion of tumor cells in a fibronectin dependent manner. However, all events were strongly abrogated by simultaneous transfection of miR-29b. MiR-29b inhibits TGF-β1 induced MMT and replacement of miR-29b in the peritoneal cavity might be effective to prevent development of PM partly through the effects on MC.
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http://dx.doi.org/10.1038/s41598-021-04065-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742040PMC
January 2022

Predictors of At-Home Death for Cancer Patients in Rural Clinics in Japan.

Int J Environ Res Public Health 2021 12 2;18(23). Epub 2021 Dec 2.

Division of Community and Family Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan.

Background: The prediction of at-home deaths has become an important topic in rural areas of Japan with an advanced aging society. However, there are no well-established predictors to explain how these factors influence intention. This study aims to investigate the possible predictors of at-home death for cancer patients in rural clinics in Japan.

Methods: This is a nationwide cross-sectional survey. A self-administered questionnaire was sent to 493 rural clinics in Japan. The main outcome was the realization of at-home deaths for cancer patients.

Results: Among the 264 clinics (54%) that responded to the survey, there were 194 clinics with the realization of at-home death. The use of a clinical pathway (adjusted odds ratio 4.19; 95% confidence interval 1.57-11.19) and the provision of organized palliative care (adjusted odds ratio 19.16; 95% confidence interval 7.56-48.52) were associated with the prediction of at-home death, irrespective of island geography or the number of doctors and nurses.

Conclusions: Having a clinical pathway and systematizing palliative care could be important to determine the possibility of at-home deaths for cancer patients in rural clinics in Japan.
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http://dx.doi.org/10.3390/ijerph182312703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656844PMC
December 2021

Intraperitoneal Chemotherapy as Adjuvant or Perioperative Chemotherapy for Patients with Type 4 Scirrhous Gastric Cancer: PHOENIX-GC2 Trial.

J Clin Med 2021 Nov 30;10(23). Epub 2021 Nov 30.

Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.
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http://dx.doi.org/10.3390/jcm10235666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658657PMC
November 2021

Synopsis of a clinical practice guideline for pancreatic ductal adenocarcinoma with peritoneal dissemination in Japan; Japan Peritoneal Malignancy Study Group.

J Hepatobiliary Pancreat Sci 2021 Dec 2. Epub 2021 Dec 2.

Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan.

Patients with pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination have a dismal prognosis because discontinuation of systemic chemotherapy is required for massive ascites or poor performance status. The natural history, diagnosis and treatment of PDAC with peritoneal dissemination have not been fully investigated. We systematically reviewed published information on the clinical diagnosis and treatment of PDAC with peritoneal dissemination using the PubMed database (2000-2020) and provided recommendations in response to clinical questions. This guideline was created according to the "Minds Clinical Practice Guideline Development Guide 2017". The literature quality and body of evidence were evaluated with the GRADE System and classified into four levels ("strong", "medium", "weak", "very weak"). The strength of each final recommendation was decided by a vote of committee members based on the GRADE Grid method. These guidelines address three subjects: diagnostic, chemotherapeutic, and surgical approaches. They include nine clinical questions and statements with recommendation strengths, evidence levels, and agreement rates, in addition to one "column". This is the English synopsis of the 2021 Japanese clinical practice guideline for PDAC with peritoneal dissemination. It summarizes the clinical evidence for the diagnosis and treatment of PDAC with peritoneal dissemination and provides future perspectives.
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http://dx.doi.org/10.1002/jhbp.1085DOI Listing
December 2021

Gap between desired and self-determined roles of general practitioners: a multicentre questionnaire study in Japan.

BMC Fam Pract 2021 07 31;22(1):162. Epub 2021 Jul 31.

Department of Clinical Oncology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi, 329-0498, Japan.

Background: Primary care physicians have diverse responsibilities. To collaborate with cancer specialists efficiently, they should prioritise roles desired by other collaborators rather than roles based on their own beliefs. No previous studies have reported the priority of roles such clinic-based general practitioners are expected to fulfil across the cancer care continuum. This study clarified the desired roles of clinic-based general practitioners to maximise person-centred cancer care.

Methods: A web-based multicentre questionnaire in Japan was distributed to physicians in 2019. Physician roles within the cancer care continuum were divided into 12 categories, including prevention, diagnosis, surgery, follow-up with cancer survivors, chemotherapy, and palliative care. Responses were evaluated by the proportion of three high-priority items to determine the expected roles of clinic-based general practitioners according to responding physicians in similarly designated roles.

Results: Seventy-eight departments (25% of those recruited) from 49 institutions returned questionnaires. Results revealed that some physicians had lower expectations for clinic-based general practitioners to diagnose cancer, and instead expected them to provide palliative care. However, some physicians expected clinic-based general practitioners to be involved in some treatment and survivorship care, though the clinic-based general practitioners did not report the same priority.

Conclusion: Clinic-based general practitioners prioritised involvement in prevention, diagnoses, and palliative care across the cancer continuum, although lower expectations were placed on them than they thought. Some additional expectations of their involvement in cancer treatment and survivorship care were unanticipated by them. These gaps represent issues that should be addressed.
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http://dx.doi.org/10.1186/s12875-021-01512-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325324PMC
July 2021

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113.

Sci Rep 2021 06 18;11(1):12885. Epub 2021 Jun 18.

Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.
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http://dx.doi.org/10.1038/s41598-021-92166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213853PMC
June 2021

Flow cytometry detection of cell type-specific expression of programmed death receptor ligand-1 (PD-L1) in colorectal cancer specimens.

Heliyon 2021 Jan 31;7(1):e05880. Epub 2020 Dec 31.

Department of Gastrointestinal Surgery, Jichi Medical University, Japan.

Aim: PD-1/PD-L1 blockade therapy is now widely used for the treatment of advanced malignancies. Although PD-L1 is known to be expressed by various host cells as well as tumor cells, the role of PD-L1 on non-malignant cells and its clinical significance is unknown. We evaluated cell type-specific expression of PD-L1 in colorectal cancer (CRC) specimens using multicolor flow cytometry.

Methods: Single cell suspensions were made from 21 surgically resected CRC specimens, and immunostained with various mAbs conjugated with different fluorescent dyes. Tumor cells, stromal cells, and immune cells were identified as CD326(+), CD90(+) and CD45(+) phenotype, respectively. CD11b(+) myeloid cells, CD19(+) B cells and CD4(+) or CD8(+) T cells were also stained in different samples, and their frequencies in the total cell population and the ratio of PD-L1(+) cells to each phenotype were determined.

Results: PD-L1 was expressed by all the cell types. The ratio of PD-L1(+) cells to CD326(+) tumor cells was 19.1% ± 14.0%, lower than those for CD90(+) stromal cells (39.6% ± 16.0%) and CD11b(+) myeloid cells (31.9% ± 14.3%). The ratio of PD-L1(+) cells in tumor cells correlated strongly with the ratio in stromal cells, while only weakly with that in myeloid cells. Tumor cells were divided into two populations by CD326 expression levels, and the PD-L1 positive ratios were inversely correlated with the rate of CD326 highly expressing cells as well as mean fluorescein intensity of CD326 in tumor cells, while positively correlated with the frequencies of stromal cells or myeloid cells in CRC.

Conclusion: PD-L1 is differentially expressed on various cell types in CRC. PD-L1 on tumor cells may be upregulated together with CD326 downregulation in the process of epithelial mesenchymal transition. Quantification of cell type-specific expression of PD-L1 using multicolor flow cytometry may provide useful information for the immunotherapy of solid tumors.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797507PMC
January 2021

ASO Author Reflections: Repeated Intraperitoneal Paclitaxel with Systemic Chemotherapy as the First-Line Treatment for Peritoneal Malignancy.

Ann Surg Oncol 2021 Jul 11;28(7):3871-3872. Epub 2021 Jan 11.

Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan.

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http://dx.doi.org/10.1245/s10434-020-09417-2DOI Listing
July 2021

Flow cytometry-based analysis of tumor-leukocyte ratios in peritoneal fluid from patients with advanced gastric cancer.

Cytometry B Clin Cytom 2021 11 4;100(6):666-675. Epub 2020 Dec 4.

Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan.

Background: The frequency of tumor cell dissemination in the peritoneal cavity is critically related to the progression of peritoneal metastases (PM). Recently, flow cytometry (FCM) has been successfully used to detect tumor cells in malignant effusions.

Methods: A total of 143 single cell suspensions derived from ascites or peritoneal lavages from patients with advanced gastric cancer (GC) were stained with monoclonal antibodies to CD45 and to CD326 as well as 4,6-diamidino-2-phenylindole (DAPI) and FVS780. Using FCM, tumor-leukocyte ratio (TLR) were calculated from CD45(-)CD326(+) tumor cell counts/ CD45(+)CD326(+) leukocyte counts in DAPI (+) FVS780(-) gated area. In 54 patients, the ratios of CD11b(+), CD4(+) and CD8(+) cells in CD45(+) leukocytes were evaluated in parallel.

Results: TLR of 69 patients with PM were significantly higher than those of 74 without PM (p < .001) and log(TLR) showed strong correlation with peritoneal cancer index scores in 51 PM (+) patients (r = 0.439). TLR in PM (+) patients also correlated with the ratio of CD11b (+) myeloid cells (r = 0.547), and correlated inversely with those of CD4(+) (r = -0.490) and CD8(+) T cells (r = -0.648). In PM (-) patients who underwent gastrectomy, TLR never exceeded 0.1% in patients with primary GC without serosal involvement (
Conclusion: TLR in peritoneal fluid reflects tumor burden and the immune environment in peritoneal cavity. Multicolor FCM may provide additional information which can be used for the treatment of the patients with PM.
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http://dx.doi.org/10.1002/cyto.b.21978DOI Listing
November 2021

Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Oxaliplatin as Induction Therapy for Patients with Advanced Gastric Cancer with Peritoneal Metastases.

Ann Surg Oncol 2021 Jul 3;28(7):3863-3870. Epub 2020 Dec 3.

Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan.

Background: Intraperitoneal (IP) administration of paclitaxel (PTX) has a great pharmacokinetic advantage to control peritoneal lesions and can be combined with various systemic chemotherapies. In this study, we evaluate the efficacy and tolerability of a combination of IP-PTX and systemic S-1/oxaliplatin (SOX) for induction chemotherapy for patients with peritoneal metastases (PM) from gastric cancer (GC).

Patients And Methods: Patients with GC who were diagnosed as macroscopic PM (P1) or positive peritoneal cytology (CY1) by staging laparoscopy between 2016 and 2019 were enrolled. PTX was IP administered at 40 mg/m on days 1 and 8. Oxaliplatin was IV administered at 100 mg/m on day 1, and S-1 was administered at 80 mg/m/day for 14 consecutive days, repeated every 21 days. Survival time and toxicities were retrospectively explored.

Results: Forty-four patients received SOX + IP-PTX with a median (range) of 16 (1-48) courses, although oxaliplatin was suspended due to the hematotoxicity or intolerable peripheral neuropathy in many patients. The 1-year overall survival (OS) rate was 79.5% (95% CI 64.4-88.8%) with median survival time of 25.8 months. Gastrectomy was performed in 20 (45%) patients who showed macroscopic shrinkage of PM with a 1-year OS rate of 100% (95% CI 69.5-100%). Grade 2 and 3 histological responses was achieved in four (20%) and one (5%) patients. Grade 3/4 toxicities included neutropenia (11%), leukopenia (39%), and anemia (14%). There were no treatment-related deaths.

Conclusions: Combination chemotherapy using SOX + IP-PTX regimen is highly effective and recommended as induction chemotherapy for patients with PM from GC.
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http://dx.doi.org/10.1245/s10434-020-09388-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184712PMC
July 2021

[Assessment of Efficacy and Adverse Effects of Trastuzumab Biosimilar in Gastric Cancer].

Gan To Kagaku Ryoho 2020 Sep;47(9):1341-1344

Dept. of Pharmacy, Jichi Medical University Hospital.

The postmarketing assessment of biosimilars is important because posttranslational modification by glycosylation is altered by the manufacturing process. A retrospective study of 15 patients with gastric cancer receiving a combination anticancer therapy with trastuzumab was performed. The most common concurrent regimen was the S-1 and oxaliplatin combination; efficacy and adverse events were assessed in this group. There was no statistically significant difference in progression-free survival between patients receiving the reference formulation and patients receiving its biosimilar. The adverse events detected were similar in both groups. In the 6 patients who switched from the reference trastuzumab to its biosimilar, adverse events did not differ before and after the switch. This small-scale retrospective study found no differences in efficacy or adverse events between the reference trastuzumab and its biosimilar.
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September 2020

Lactic Acidosis and Hypoglycemia in a Patient with Gastric Diffuse Large B-Cell Lymphoma due to the Warburg Effect.

Case Rep Oncol 2020 May-Aug;13(2):1047-1052. Epub 2020 Sep 1.

Department of Medical Oncology, Jichi Medical University Hospital, Tochigi, Japan.

Lactic acidosis is pathophysiologically classified into type A and type B. The latter is a rare but potentially life-threatening emergency, mainly described in hematological malignancies. The association between Type B lactic acidosis and malignancy is known as the Warburg effect. Patients with the Warburg effect have a very poor prognosis. Herein, we report a case of gastric diffuse large B-cell lymphoma (DLBCL) with severe lactic acidosis and hypoglycemia owing to the Warburg effect that were effectively treated by prompt introduction of chemotherapy. A 73-year-old woman with a 2-month history of abdominal distension was referred to us for suspected peritoneal cancer. Pathological examination revealed gastric DLBCL with peritoneal dissemination. After hospitalization, blood test results revealed prolonged hypoglycemia, with a blood sugar level of 50-70 mg/dL; severe lactic acidosis with pH 7.166; lactate level 12.7 mmol/L; and base excess -21.0 mEq/L, despite continuous administration of glucose and sodium bicarbonate. The cause of lactic acidosis and/or hypoglycemia was considered to be the Warburg effect. We initiated a 50% reduced-dose CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) chemotherapy regimen without rituximab until information on the CD20-positive status was available. During chemotherapy, acidosis, hypoglycemia, and impaired consciousness promptly improved. If lactic acidosis or hypoglycemia is present in patients with malignant tumors, it is important to suspect the possibility of the Warburg effect and to introduce cancer treatment as soon as possible.
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http://dx.doi.org/10.1159/000509510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548916PMC
September 2020

Early Tumor Shrinkage and Depth of Response in the Second-Line Treatment for KRAS exon2 Wild-Type Metastatic Colorectal Cancer: An Exploratory Analysis of the Randomized Phase 2 Trial Comparing Panitumumab and Bevacizumab in Combination with FOLFIRI (WJOG6210G).

Target Oncol 2020 10;15(5):623-633

Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.

Background: Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear.

Objective: This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial.

Patients And Methods: The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman's correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits.

Results: In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P < 0.001; rs = 0.60, P < 0.001) and Bev groups (rs = 0.68, P < 0.001; rs = 0.44, P = 0.002). No significant differences were observed in PFS and OS between the two treatment groups even if in left-sided tumors. No significant interaction between VEGF-D levels and treatment was observed in PFS and OS.

Conclusions: ETS and DpR serve as surrogate markers of PFS and OS in the second-line treatment with FOLFIRI plus targeted agent for mCRC.
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http://dx.doi.org/10.1007/s11523-020-00750-wDOI Listing
October 2020

Ratios of miRNAs in Peritoneal Exosomes are Useful Biomarkers to Predict Tumor Response to Intraperitoneal Chemotherapy in Patients with Peritoneal Metastases from Gastric Cancer.

Ann Surg Oncol 2020 Dec 17;27(13):5057-5064. Epub 2020 Aug 17.

Center for Clinical Research, Jichi Medical University Hospital, Shimotsuke, Tochigi, Japan.

Background: Repeat intraperitoneal (IP) chemotherapy has been successfully used for treatment of peritoneal metastases (PM) from gastric cancer (GC). Exosomes play important roles not only in tumor progression but also in chemoresistance via transfer of microRNAs (miRNAs). However, there is little evidence of an effect of miRNAs in peritoneal exosomes on chemosensitivity of peritoneal lesions.

Methods: In 74 patients with advanced GC who underwent staging laparoscopy, exosomes were isolated from peritoneal fluid and expression levels of miR-21-5p, miR-223-3p, and miR-29b-3p determined using TaqMan Advanced miRNA assays. In 43 patients with PM treated with combination chemotherapy, S-1 plus Oxaliplatin together with IP Paclitaxel, the relationship between their relative expression levels and outcomes was examined.

Results: The ratios of miR-21-5p/miR-29b-3p and miR-223-3p/miR-29b-3p were significantly upregulated in patients with PM, especially in patients with high serum CA125 levels. They showed a mild association with Peritoneal Cancer Index (PCI) score and ascites. More impressively, the ratios were significantly higher in 16 patients with progression of PM within 1 year compared with 27 patients with an excellent tumor response (miR-21-5p/miR-29b-3p: median 17.49, range 1.83-50.90 vs. median 4.64, range 0.40-38.96, p = 0.0015, miR-223-3p/miR-29b-3p: median 1.02, range 0.23-25.85 vs. median 0.21, range 0.01-50.07, p = 0.0006). Overall survival of patients with high miR-21/miR-29b or miR-223/miR-29b ratios was significantly worse than in patients with low ratios (p = 0.0117, p = 0.0021).

Conclusions: The ratios of miRNAs in peritoneal exosome correlate with survival of the patients with PM from GC and suggest the possibility that they modify the chemosensitivity against IP chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-09007-2DOI Listing
December 2020

Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus.

Cancer Sci 2020 Nov 28;111(11):4012-4020. Epub 2020 Sep 28.

Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan.

Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I-III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N-stage was significantly lower in metformin-treated patients (P < .05) with prolonged disease-free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor-infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin-treated patients (P < .001). In those tumors, there were more CD68(+) tumor-associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2-phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM.
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http://dx.doi.org/10.1111/cas.14615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648042PMC
November 2020

Goblet cell carcinoid of the rectum: a case report.

Surg Case Rep 2020 Jul 18;6(1):174. Epub 2020 Jul 18.

Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji Shimotsuke, Tochigi, 329-0498, Japan.

Background: Goblet cell carcinoid (GCC) is a neuroendocrine tumor usually found in the appendix. GCCs exhibit characteristic findings with mixed endocrine-exocrine features such as staining positive for neuroendocrine markers and producing mucin. The primary GCC of the rectum is exceedingly rare.

Case Presentation: A 77-year-old Japanese male presented with hematochezia. Anal tenderness and a hard mass in the anal canal were found on the digital rectal examination, and colonoscopy was performed. Colonoscopy showed an irregularly shaped mass in the anal canal. Biopsy showed mixed features including adenocarcinoma in situ, well-differentiated adenocarcinoma, and mucinous carcinoma with invasive proliferation. No metastatic lesions were found on the computed tomography scan. Pelvic magnetic resonance imaging scan showed extramural growth of a tumor on the ventral side of the rectum without invasion to the prostate. Laparoscopic abdominoperineal resection was performed. The final diagnosis was well-differentiated adenocarcinoma in the mucosa and goblet cell carcinoid from the submucosa to the adventitia of the rectum. The patient was discharged from the hospital on postoperative day 16. Six months after resection, a computed tomography scan revealed multiple metastatic lesions in the liver. Several chemotherapy regimens were given, and the patient has stable disease 27 months after surgery.

Conclusion: We present a patient with rectal GCC with metachronous liver metastases. Since GCC grows intramurally and is biologically aggressive compared to typical carcinoid lesions, the disease is usually diagnosed at an advanced stage. The development of optimal adjuvant chemotherapy is needed for those patients.
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http://dx.doi.org/10.1186/s40792-020-00937-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368876PMC
July 2020

Experimental realization of Lieb-Mattis plateau in a quantum spin chain.

Sci Rep 2020 Jun 8;10(1):9193. Epub 2020 Jun 8.

Center for Advanced High Magnetic Field Science (AHMF), Graduate School of Science, Osaka University, Osaka, 560-0043, Japan.

Topological properties in material science have recently received tremendous attention, as exemplified by topological insulators. As for quantum spin systems, the Haldane chain with integer spins is the best known example. The realization of a topological quantum phase in the Haldane chain is an innovative research development related to the 2016 Nobel Prize in Physics. For mixed spin chains composed of two different spins, the appearance of a topologically quantized magnetization plateau is predicted by the Lieb-Mattis theorem in combination with the Oshikawa-Yamanaka-Affleck criterion. However, the actual magnetization plateau in the mixed spin chain has not yet been observed. Here, we present a model compound forming a mixed spin-(1/2, 5/2) chain. We observe a clear Lieb-Mattis plateau and well explain it quantitatively. The present results demonstrate a quantum many-body effect based on quantum topology and provide a new stage in the search for topological properties in condensed matter physics.
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http://dx.doi.org/10.1038/s41598-020-66336-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280303PMC
June 2020

CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model.

BMC Cancer 2020 May 12;20(1):411. Epub 2020 May 12.

Department of Gastrointestinal Surgery, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan.

Background: Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule.

Method: We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue.

Results: LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. Subcutaneous (sc) transfer of LuM-1 in Balb/c mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (4Gyx3) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 μg × 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-γ production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome.

Conclusion: These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.
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http://dx.doi.org/10.1186/s12885-020-06893-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218548PMC
May 2020

Reduced expression of exosomal miR‑29s in peritoneal fluid is a useful predictor of peritoneal recurrence after curative resection of gastric cancer with serosal involvement.

Oncol Rep 2020 04 17;43(4):1081-1088. Epub 2020 Feb 17.

Center for Clinical Research, Jichi Medical University, Shimotsuke, Tochigi 329‑0498, Japan.

The peritoneal surface is the most frequent site of metastasis disease in patients with gastric cancer. Even after curative surgery and adjuvant chemotherapy, peritoneal recurrences often develop. Exosomes play pivotal roles in tumor metastasis via the transfer of microRNAs (miRNAs). In the present study, exosomes were isolated from peritoneal lavage fluid or ascites in 85 patients with gastric cancer and the relative expression levels of miR‑29s were examined. The expression of miR‑29a‑3p, miR‑29b‑3p and miR‑29c‑3p in peritoneal exosomes were all downregulated in patients with peritoneal metastases (PM) compared to those without PM. In 30 patients who underwent curative gastrectomy with serosa‑involved (T4) gastric cancer, 6 patients exhibited recurrence in the peritoneum within 12 months. The expression levels of miR‑29s at gastrectomy tended to be lower in these 6 patients than in the other 24 patients with significant differences in miR‑29b‑3p (P=0.003). When the patients were divided into two groups based on median levels of miR‑29s, peritoneal recurrence developed more frequently in patients with low expression of miR‑29b‑3p, and lower expression of miR‑29s were related with worse overall survival. miR‑29s are thought to play a suppressive role in the growth of disseminated peritoneal tumor cells. Reduced expression of miR‑29b in peritoneal exosomes is a strong risk factor of developing postoperative peritoneal recurrence.
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http://dx.doi.org/10.3892/or.2020.7505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057811PMC
April 2020

Pathological complete response after intraperitoneal paclitaxel and systemic combined chemotherapy in a patient with peritoneal metastases from gastric cancer: a case report.

Surg Case Rep 2020 Mar 30;6(1):63. Epub 2020 Mar 30.

Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan.

Background: Despite recent progress in systemic chemotherapy, the prognosis of patients with peritoneal metastases from gastric cancer is still poor. Efficacious intraperitoneal and systemic combination chemotherapy regimens to treat patients with peritoneal metastases have recently been developed.

Case Presentation: A 74-year-old man with gastric cancer T4b (transverse mesocolon) N3 M1 (peritoneum) received combination chemotherapy with intraperitoneal administration of paclitaxel, intravenous oxaliplatin, and oral S-1. Eight courses of combined chemotherapy had remarkable anti-tumor effects on the primary lesion, lymph node metastases, and peritoneal metastases. Total gastrectomy with regional lymph node dissection was performed. Pathological examination revealed no viable tumor cells in the resected specimens. After gastrectomy, the patient received 25 courses of the same chemotherapy without oxaliplatin and has no evidence of recurrence 24 months later.

Discussion: Therapeutic approaches including systemic chemotherapy, extended resection, and heated intraperitoneal chemotherapy have been used to treat patients with peritoneal metastases. Repeat therapy with intraperitoneal paclitaxel has been used recently. Intraperitoneal administration of paclitaxel results in prolonged retention in the peritoneal cavity with effects against peritoneal metastases. Repeated administration of paclitaxel does not cause adhesions in the peritoneal cavity. When combination chemotherapy is effective, salvage gastrectomy is a promising option with minimal morbidity and mortality.

Conclusion: Combined chemotherapy with intraperitoneal paclitaxel and systemic chemotherapy followed by gastrectomy is a promising strategy for patients with advanced gastric cancer and peritoneal metastases.
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http://dx.doi.org/10.1186/s40792-020-00818-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105589PMC
March 2020

Exosomal microRNA in peritoneal fluid as a biomarker of peritoneal metastases from gastric cancer.

Ann Gastroenterol Surg 2020 Jan 6;4(1):84-93. Epub 2019 Nov 6.

Center for Clinical Research Jichi Medical University Hospital Shimotsuke Japan.

Aim: Peritoneal metastases (PM) frequently occur in patients with gastric cancer and result in a poor prognosis. Exosomes play pivotal roles in tumor metastasis through the transfer of microRNAs (miRNAs). We examined the exosomal miRNA profile in peritoneal fluids to identify novel biomarkers to reflect tumor burden in the peritoneum.

Methods: Exosomes were isolated from peritoneal fluids of patients of gastric cancer with macroscopic (P1) or microscopic (P0CY1) peritoneal metastasis (PM) and comprehensive miRNA expression analysis was carried out. Expressions of candidate miRNAs were then validated in all 58 samples using TaqMan Advanced miRNA Assays.

Results: In initial screening, we carried out comprehensive analysis of exosomal miRNA using peritoneal fluids from 11 and 14 patients with or without PM, respectively, and identified 11 dysregulated miRNAs in PM (+) samples. Validation analysis showed that four miRNAs (miR-21-5p, miR-92a-3p, miR-223-3p, and miR-342-3p) were significantly upregulated in 12 PM (+) samples, and their expression levels showed positive correlation with peritoneal cancer index. In contrast, miR-29 family were all downregulated in patients with PM (+) samples. Moreover, in 24 patients with pT4 tumor, miR-29 at gastrectomy tended to be lower in six patients with peritoneal recurrence with significant differences in miR-29b-3p ( = .012).

Conclusion: Expression pattern of miRNAs in peritoneal exosomes well reflects the tumor burden in the peritoneal cavity and could be a useful biomarker in the treatment of PM.
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http://dx.doi.org/10.1002/ags3.12296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992685PMC
January 2020

Difference in the Types of Treated Cancer between Clinics and Small-to-Middle-Sized Hospitals in Rural Communities of Japan.

Tohoku J Exp Med 2019 12;249(4):291-294

Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University.

Resolution of regional disparities in cancer mortality is global challenge. Establishing an equal system of cancer treatment throughout the country is required under the Cancer Control Act in Japan. The types of treated cancer may reflect practical experience at the institutions and cooperation to other institutions. This study investigated the types treated at the institutions in rural communities of Japan. A questionnaire survey was conducted for 811 public rural institutions (clinics and small-to-middle-sized hospitals [< 200 beds]) in 2013. The survey's items included the types of treated cancer (14 categories: stomach, colon, breast, liver, biliary tract, pancreatic, prostate, esophageal, lung, renal, urinary tract, testicular, hematopoietic, and others) and the first five types were defined as major cancers. The data were analyzed between hospitals and clinics. The response rate was about 60%, and of 177 hospitals and 281 clinics, 54 hospitals (30%) and 10 clinics (3%) reported the types of cancer. The median number of cancer types in hospitals was significantly greater than that of clinics (4 [interquartile range 3.0-7.8]) vs. 1 [1.0-1.8], P < 0.01). The prevalence of hospitals treating at least one of five major cancers was significantly greater than that of clinics (96% vs. 30%, P < 0.01). The prevalence of clinics treating prostate cancer was significantly greater than that of hospitals (31% vs. 70%, P = 0.03). In conclusion, most types of cancer are treated at small-to-middle-sized hospitals, except for prostate cancer, providing basic information about cancer treatment in rural communities of Japan.
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http://dx.doi.org/10.1620/tjem.249.291DOI Listing
December 2019

Signet ring cell carcinoma and poorly differentiated adenocarcinoma in a gastric hyperplastic polyp with lymphatic invasion: A case report.

Int J Surg Case Rep 2019 17;64:180-183. Epub 2019 Oct 17.

Department of Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

Introduction: Gastric hyperplastic polyps are common stomach lesion and these polyps are generally benign. However, they can undergo malignant transformation. Most reported cases of malignant transformation of gastric hyperplastic polyps have been to well or moderately differentiated adenocarcinoma, and those transformed into poorly differentiated adenocarcinoma are extremely rare. No case has been reported that has changed to diffuse type adenocarcinoma with lymphatic invasion.

Presentation Of Case: A 48-year-old woman presented with worsening anemia. A polyp was seen in the gastric cardia seven years prior to presentation. Helicobacter pylori infection was also found at that time. She underwent upper gastrointestinal endoscopy and biopsy of the polyp revealed signet ring cell carcinoma. Total gastrectomy was performed due to concern about possible invasion into the submucosal layer and there was no evidence of distant metastases. Histologic examination revealed both poorly differentiated adenocarcinoma and signet ring cell carcinoma surrounded by hyperplastic epithelium at the head of the polyp. Lymphatic invasion was also found, and malignant cells were limited to the mucosa.

Discussion: Gastric hyperplastic polyps are commonly associated with chronic gastritis which is related to Helicobacter pylori infections. Gastric hyperplastic polyps are generally benign and rarely undergo malignant transformation to adenocarcinoma with differentiated histology. The gastric hyperplastic polyp in this patient transformed to poorly differentiated adenocarcinoma with lymphatic invasion.

Conclusion: Even small polyps may become poorly differentiated adenocarcinoma with invasion, so close follow-up or endoscopic resection are recommended as well as eradication of Helico Pylori infection when appropriate.
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http://dx.doi.org/10.1016/j.ijscr.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831772PMC
October 2019

Combined subtotal gastrectomy and splenectomy after partial splenic embolization for a patient with gastric cancer and immune thrombocytopenic purpura: A case report.

Int J Surg Case Rep 2019 31;62:140-143. Epub 2019 Aug 31.

Department of Surgery, Jichi Medical University, Tochigi, Japan.

Introduction: Immune thrombocytopenic purpura is an acquired thrombocytopenia. Preoperative management of thrombocytopenia is important in patients with gastric cancer. Partial splenic embolization can be effective for patients with thrombocytopenia, but could lead to ischemic necrosis of the remnant stomach when performing subtotal gastrectomy with splenectomy.

Presentation Of Case: The patient is an 84-year old woman evaluated for anemia. Endoscopy revealed an advanced gastric cancer with bleeding. The patient also had immune thrombocytopenic purpura with a platelet count <50,000/μL. Administration of platelets did not increase the platelet count. Partial splenic embolization was performed followed by administration of high-dose immunoglobulin. The platelet count was over 50,000/μL preoperatively. The patient underwent combined subtotal gastrectomy and splenectomy, followed by an uneventful course.

Discussion: Patients with immune thrombocytopenic purpura and advanced gastric cancer can have anemia. Partial splenic embolization has been used to treat patients with refractory immune thrombocytopenic purpura as an alternative to splenectomy. Preoperative partial splenic embolization and high-dose immunoglobulin therapy resulted an increased platelet count in this patient. Elderly patients with gastric cancer have a high risk of postoperative complications. Patients with gastric cancer undergoing total gastrectomy have an impaired postoperative quality of life compared to those who undergo subtotal gastrectomy. We performed a subtotal gastrectomy and splenectomy as a function-preserving operation, completed safely by maintaining blood flow to the remnant stomach.

Conclusion: Partial splenic embolization is effective for patients with immune thrombocytopenic purpura and gastric cancer. Combined subtotal gastrectomy and splenectomy is achieved by preserving blood flow to the remnant stomach.
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http://dx.doi.org/10.1016/j.ijscr.2019.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737330PMC
August 2019

Phase I Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Cisplatin for Gastric Cancer with Peritoneal Metastasis.

Oncology 2020 5;98(1):48-52. Epub 2019 Sep 5.

Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Introduction: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer (GC) with peritoneal metastasis (PM). Recently, superiority of IP administration of paclitaxel (PTX) combined with S-1 and intravenous PTX over conventional systemic chemotherapy was suggested in a phase III study, although the difference in overall survival did not reach statistical significance in the primary analysis. Thus, attempts to combine IP PTX with other systemic therapies with higher efficacy are warranted. We designed a new regimen combining IP PTX with S-1 plus cisplatin (SP), which is regarded as the standard first-line treatment for metastatic GC in Japan, and subsequently carried out a dose-escalation study.

Methods: The combination was a 5-weekly regimen. IP PTX was to be administered on days 1, 8, and 22 with an initial dose of 15 mg/m2 at level 1 and 20 mg/m2 at level 2. S-1 was to be administered orally at a fixed dose of 80 mg/m2 b.i.d. for 21 days followed by a -14-day rest. Cisplatin was to be administered intravenously at a dose of 60 mg/m2 on day 8. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 (G3) febrile neutropenia, G3 thrombocytopenia, and G3 nonhematological toxicity.

Results: A total of 9 patients with macroscopic PM were enrolled. No DLTs were observed among the 3 patients at level 1 and 6 patients at level 2. No adverse events or technical problems associated with the IP administration were observed. Consequently, the maximum-tolerated dose was not reached, and the dose for further clinical trials of IP PTX was determined as 20 mg/m2. As for efficacy, peritoneal lavage cytology turned negative after the first course in 4 of 7 patients who had positive cytology before treatment.

Conclusion: The present study determined the dose for further clinical trials of IP PTX to be 20 mg/m2, when combined with the 5-weekly SP regimen.
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http://dx.doi.org/10.1159/000502484DOI Listing
January 2020
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