Publications by authors named "Eri Munekage"

38 Publications

A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma.

Neoplasia 2021 Sep 28;23(9):939-950. Epub 2021 Jul 28.

Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan; Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, Japan; Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan. Electronic address:

An antibody-drug conjugate (ADC) is a promising therapeutic modality because selective and effective delivery of an anti-cancer drug is achieved by drug-conjugated antibody-targeting cancer antigen. Glypican 1 (GPC1) is highly expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC). Herein, we describe the usefulness of GPC1-targeting ADC. Humanized anti-GPC1 antibody (clone T2) was developed and conjugated with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC) linkers (humanized GPC1-ADC[MMAE]). Humanized GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC and ESCC cell lines via inducing cycle arrest in the G2/M phase and apoptosis in vitro. The binding activity of humanized GPC1-ADC(MMAE) with GPC1 was comparable with that of the unconjugated anti-GPC1 antibody. The humanized GPC1-ADC(MMAE) was effective in GPC1-positive BxPC-3 subcutaneously xenografted mice but not in GPC1-negative BxPC-3-GPC1-KO xenografted mice. To assess the bystander killing activity of the humanized GPC1-ADC(MMAE), a mixture of GPC1-positive BxPC-3 and GPC1-negative BxPC-3-GPC1-KO-Luc cells were subcutaneously inoculated, and a heterogenous GPC1-expressing tumor model was developed. The humanized GPC1-ADC(MMAE) inhibited the tumor growth and decreased the luciferase signal, measured with an in vivo imaging system (IVIS), which suggests that the suppression of the BxPC-3-GPC1-KO-Luc population. The humanized GPC1-ADC(MMAE) also inhibited the established liver metastases of BxPC-3 cells and significantly improved the overall survival of the mice. It exhibited a potent antitumor effect on the GPC1-positive PDAC and ESCC patient-derived xenograft (PDX) models. Our preclinical data demonstrate that GPC1 is a promising therapeutic target for ADC.
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http://dx.doi.org/10.1016/j.neo.2021.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340053PMC
September 2021

Intrahepatic bile duct adenoma in a patient with gastric cancer.

Int Cancer Conf J 2019 Jan 12;8(1):7-11. Epub 2018 Sep 12.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505 Japan.

We report a case of intrahepatic bile duct adenoma (BDA) detected during laparoscopic distal gastrectomy for gastric cancer. A 70-year-old man was referred to our hospital for the treatment of gastric cancer. Esophagogastroduodenoscopy revealed an irregular, nodular, and elevated lesion on the greater curvature side of the middle third of the stomach. Abdominal contrast-enhanced computed tomography showed wall thickening with homogeneous enhancement in the middle part of the stomach, and no lesions in the liver. The patient underwent laparoscopic distal gastrectomy with regional lymphadenectomy, and during the operation a small whitish nodule was observed on the lateral segment of the liver surface. The lesion was excised by partial resection of the liver for the purpose of both histological diagnosis and treatment. Pathological examination of the liver lesion revealed no structural or cellular atypia, no stromal invasion, and immunohistochemical positivity for CK7 and CK19, but negativity for p53. The final diagnosis was well-differentiated adenocarcinoma invading the gastric serosal layer without lymph node metastasis, and intrahepatic BDA measuring 0.4 × 0.3 cm. Following surgery, the patient remained symptom-free without evidence of recurrence for 5 months. To the best of our knowledge, this is the first case of BDA with gastric cancer. Because it is difficult to distinguish BDA from other liver tumors including metastatic cancer due to its characteristically small size and lack of specific morphological features on standard imaging, surgical resection should be considered as the most suitable approach for both accurate diagnosis and treatment.
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http://dx.doi.org/10.1007/s13691-018-0345-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498292PMC
January 2019

Early gastric cancer with multiple submucosal heterotopic gastric gland: A case report.

Mol Clin Oncol 2019 Jun 18;10(6):583-586. Epub 2019 Apr 18.

Department of Surgery, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.

A case of early gastric cancer involving multiple submucosal gastric glands that was treated by distal gastrectomy was described in the present case report. An 85-year-old man was referred to our hospital for the treatment of gastric cancer. Esophagogastroduodenoscopy revealed an irregular, nodular, elevated lesion on the posterior wall of the middle third of the stomach, and biopsy specimens indicated well-differentiated tubular adenocarcinoma. Submucosal tumor (SMT)-like lesions were detected in the area adjacent to the nodular lesion, in the anterior wall side of the middle third of the stomach. Abdominal contrast-enhanced computed tomography showed cystic lesions in the middle part of the stomach, and no mass lesions in the liver. The patient underwent distal gastrectomy with regional lymphadenectomy. Macroscopic examination of the resected specimen showed an SMT-like lesion measuring 2.8×2.6 cm in contact with a superficial, depressed lesion measuring 1.7×0.9 mm in the middle third of the stomach, and another SMT-like lesion measuring 1.5×1.4 cm in diameter, which was also in the middle third of the stomach. The pathological diagnosis was well-differentiated tubular adenocarcinoma invading the gastric submucosal layer without lymph node metastasis, but with nearby submucosal heterotopic gastric gland (SHGG) detected. Following surgery, the patient remained symptom-free without evidence of recurrence for 3 months. The finding of SHGG remains a rare entity, and further studies are warranted to clarify the association between these submucosal lesions and the development of cancer.
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http://dx.doi.org/10.3892/mco.2019.1846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488944PMC
June 2019

[A Case of Long-Term Survival in a Patient with Lung Metastasis of Gastric Cancer Treated Using Curative Surgery].

Gan To Kagaku Ryoho 2018 Dec;45(13):1827-1829

Dept. of Surgery, Kochi Medical School.

A 50-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy(EGD)revealed an irregular nodular lesion with an ulcer in the esophagogastric junction, the biopsy specimens of which showed moderately differentiated adenocarcinoma. Abdominal computed tomography(CT)showed a lymph node measuring 1.2 cm in the perigastric area. A clinical diagnosis of advanced gastric cancer was made, and the patient underwent total gastrectomy with D2 lymphadenectomy followed by Roux-en-Y reconstruction. Microscopic examination confirmed that the moderately differentiated adenocarcinoma invaded the muscularis propria with 1 lymph node metastasis and lymphovascular invasion. The final diagnosis according to the Japanese classification of gastric carcinoma was UE, Less, Type 2, 3.8×1.7 cm, T2(MP), M0, H0, P0, N1(1/15), tub2, ly1, v2, StageⅡ. The postoperative course was uneventful, and he received postoperative adjuvant chemotherapy with S-1. The patient underwent periodic follow-up physical examinations, and 1 year after the surgery, CT showed a well-defined mass measuring 1.0 cm in diameter located in the middle lobe of the right lung. Because there was no evidence of further metastatic lesions in any other organs, he underwent surgical resection of the solitary pulmonary lesion by video-assisted thoracic surgery. Pathological examination confirmed the presence of moderately differentiated adenocarcinoma, and the proliferating tumor cells were positive for cytokeratin(CK)7 and CK20, and negative for thyroid transcription factor 1, which confirmed metastasis from gastric cancer. After the surgery, the patient received combination chemotherapy with S-1 plus cisplatin, followed by S-1 monotherapy. Five years after pulmonary metastasectomy, we discontinued chemotherapy because of no evidence of recurrence and the patient's wishes. The patient has remained in good health without evidence of recurrence for 7 years following the second surgery. Resection of the metastatic lesion might be a promising treatment for solitary pulmonary metastasis of gastric cancer; however, further investigations involving the accumulation of a large number of cases and prospective cohort studies are required to verify the above issue, and future development of multidisciplinary therapy is expected.
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December 2018

Prognostic significance of serum alkaline phosphatase and lactate dehydrogenase levels in patients with unresectable advanced gastric cancer.

Gastric Cancer 2019 07 11;22(4):684-691. Epub 2018 Nov 11.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.

Background: This study evaluated the prognostic value of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) together with host-related factors in patients with unresectable advanced gastric cancer.

Methods: The study enrolled 262 patients who received chemotherapy for unresectable advanced gastric cancer at Kochi Medical School from 2007 to 2015. Clinicopathological information and systemic inflammatory response data were analyzed for associations between baseline cancer-related prognostic variables and survival outcomes.

Results: The median survival time was significantly lower for patients with high ALP, high LDH, high total bilirubin, high aspartate aminotransferase, high alanine transaminase, high gamma-glutamyltransferase, high creatinine, a Glasgow prognostic score (GPS) of 1 or 2 score compared to GPS 0, higher compared to lower neutrophil to lymphocyte ratio (NLR) 3.9, lower compared to higher prognostic nutrition index 36.1, T3-4 compared to T1-2 tumor and diffuse-type compared to intestinal-type histology. Multivariate survival analysis identified high ALP 322 (HR 1.808; 95% CI 1.015-3.220; P = 0.044), T2-3 (HR 2.622; 95% CI 1.224-5.618; P = 0.013), and diffuse-type gastric cancer (HR 2.325; 95% CI 1.341-4.032; P = 0.003) as significant independent predictors of worse prognosis in the studied group of cancer patients.

Conclusions: High level of ALP is an independent, worse prognosis factor for patients receiving chemotherapy for unresectable and recurrent gastric cancer.
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http://dx.doi.org/10.1007/s10120-018-0897-8DOI Listing
July 2019

Pathological Complete Response by S-1 Chemotherapy in Advanced Gastric Cancer.

In Vivo 2018 Sep-Oct;32(5):1211-1216

Department of Surgery, Kochi Medical School, Kochi, Japan.

A pathological complete response (pCR) to treatment for gastric cancer is a rare event, even when powerful treatment regimens are used. Herein, a case of 61-year-old male referred to our hospital with advanced gastric cancer who achieved a pCR following chemotherapy using S-1, and subsequently underwent total gastrectomy is reported. His initial esophagogastroduodenoscopy (EGD) revealed an irregular, nodular, ulcerated lesion in the upper third of the stomach that was analyzed by biopsy to be a moderately differentiated adenocarcinoma. Abdominal contrast-enhanced computed tomography (CT) showed gastric wall thickening and lymph node swelling in the perigastric area. The patient was clinically diagnosed with cT3N1M0, stage IIB advanced gastric cancer. The patient decided against curative surgery due to his work circumstances and was started on S-1 (80 mg/m) chemotherapy administered orally twice a day for 4 weeks, followed by 2 weeks of no chemotherapy. After four such courses of systemic S-1 chemotherapy, EGD showed a small, reddened lesion with aggregated, whitish lines. The gastric wall thickening and lymphadenopathy in the perigastric area were also reduced remarkably. The patient subsequently agreed to surgery, undergoing total gastrectomy with D2 lymphadenectomy. Gross examination of the surgically resected specimen showed a slightly erythrogenic, flat lesion measuring 1.5×1.0 cm. Pathological examination of the resected specimen and harvested lymph nodes detected no malignant cells. The postoperative course was uneventful. The patient has continued to receive S-1 chemotherapy, with no evidence of recurrence at 4 months post-surgery. To the best of our knowledge, this is only the second case of a gastric cancer patient achieving a pCR by S-1 monotherapy reported in the English literature and indicates the potential adoption of curative resection after S-1 chemotherapy as a treatment strategy for advanced gastric cancer.
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http://dx.doi.org/10.21873/invivo.11366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199615PMC
December 2018

Successful treatment of liver metastases arising from early gastric cancer achieved clinical complete response by nivolumab.

Surg Case Rep 2018 Jul 5;4(1):71. Epub 2018 Jul 5.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.

Background: Although a recent randomized clinical trial has demonstrated that the objective response rate to nivolumab for metastatic gastric cancer was 11.2%, there was no patients confirmed complete response. Herein, we report on a case of liver metastasis arising from early gastric cancer in which a complete clinical response was achieved to nivolumab as third-line therapy.

Case Presentation: A 77-year-old man was referred to Kochi Medical School Hospital for the treatment of liver metastases from gastric cancer. The patient had undergone laparoscopic total gastrectomy with regional lymph node dissection 30 months prior for early gastric cancer, with a final diagnosis of T1N0M0, stage IA. The patient developed solitary splenic metastasis measuring 42 mm 28 months later and underwent splenectomy because there was no evidence of further metastatic lesions in any other organ. The patient was treated with S-1 plus oxaliplatin based on negative immunohistochemical staining of the resected specimens for human epidermal growth factor receptor 2 (HER2). Four months after the splenectomy, the patient developed multiple liver metastases and was treated with ramucirumab plus paclitaxel. Because of disease progression, the patient was administered 3 mg/kg, i.v., nivolumab every 2 weeks. After 4 cycles of systemic treatment using nivolumab, abdominal computed tomography revealed marked shrinkage of the liver metastases. After 12 cycles of nivolumab, the liver metastases had disappeared completely. The patient did not develop any adverse reactions, including immune-reactive adverse events, during treatment. The patient continues to receive nivolumab, and there is no evidence of disease recurrence in the 8-month period since starting nivolumab.

Conclusions: To the best of our knowledge, this is the first case report in the English literature of a gastric cancer patient achieving a complete clinical response to nivolumab, and highlights the potential for successful treatment of metastatic gastric cancer using nivolumab.
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http://dx.doi.org/10.1186/s40792-018-0479-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033840PMC
July 2018

Clinical application of photodynamic medicine technology using light-emitting fluorescence imaging based on a specialized luminous source.

Med Mol Morphol 2018 Dec 4;51(4):187-193. Epub 2018 Apr 4.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.

The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials.
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http://dx.doi.org/10.1007/s00795-018-0190-2DOI Listing
December 2018

Epstein-Barr virus-associated early gastric carcinoma with lymphoid stroma, accompanied with lymph node metastasis.

Mol Clin Oncol 2018 04 5;8(4):557-560. Epub 2018 Feb 5.

Department of Surgery, Kochi Medical School, Kochi 783-8505, Japan.

The present case report presents a rare case of Epstein-Barr virus (EBV)-associated early gastric carcinoma with lymphoid stroma, accompanied by lymph node metastasis. A 61-year-old woman was referred to our hospital following observation of a gastric mass lesion that was initially diagnosed at a medical check-up. Esophagogastroduodenoscopy revealed a slightly elevated lesion with a central irregular depression in the middle third of the stomach. Endoscopic ultrasonography revealed a well-circumscribed hypoechoic mass located predominantly within the submucosa and the mucosa. Biopsy specimens of the lesion indicated the possibility of carcinoma with lymphoid stroma with a lymphoepithelial lesion. Abdominal contrast-enhanced computed tomography (CT) revealed a well-defined mass with homogeneous enhancement approximately 1.2 cm in diameter in the middle part of the stomach, demonstrating lymphadenopathy in the perigastric area at a maximum size of 1.4 cm in diameter. The patient underwent laparoscopic distal gastrectomy with regional lymphadenectomy due to suspicion of a gastric carcinoma with lymphoid stroma. Histopathological and immunohistochemical findings verified the diagnosis of carcinoma with lymphoid stroma, which were positive for EBV-encoded RNA (EBER-ISH) by hybridization. There was one lymph node metastasis, which was in line with the CT imaging. Marked infiltration of lymphoid cells was observed in the tumor stroma, which were negative for EBER-ISH. The present case is informative of the pathological characteristics of this condition, and clinicians should recognize the features of this disease to make an accurate diagnosis and select the appropriate treatment.
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http://dx.doi.org/10.3892/mco.2018.1567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838299PMC
April 2018

[A Case of Advanced Gastric Cancer with Liver Metastasis Treated by Curative Surgery after Chemotherapy Using S-1 plus Oxaliplatin].

Gan To Kagaku Ryoho 2017 Nov;44(12):1446-1448

Dept. of Surgery, Kochi Medical School.

A 76-year-old man was referred to our hospital with gastric cancer.Esophagogastroduodenoscopy (EGD)revealed an irregular, nodulated lesion with ulcers in the lower part of the stomach, for which biopsy specimens indicated poorly differentiated adenocarcinoma.Abdominal computed tomography(CT)showed a well-defined mass lesion measuring 5.3 cm in the posterior segment of the liver.Under the clinical diagnosis of advanced gastric cancer with liver metastasis, the patient received chemotherapy using S-1 and oxaliplatin.After 8 courses of chemotherapy, abdominal CT and EGD revealed that the size of liver metastasis was reduced to 2.3 cm. He underwent distal gastrectomy with D2 lymphadenectomy and resection of the liver metastases because there was no evidence of further metastatic lesions in any other organs after 10 courses of chemotherapy.The gross appearance of the surgically resected specimen showed a shrunk gastric tumor measuring 3.5×3.0 cm and a well-circumscribed, solid liver mass.Pathological examination confirmed the diagnosis of solid-type, poorly differentiated adenocarcinoma in the stomach that had invaded the submucosal layer with no lymph node metastasis, and necrotic change of the liver mass.The postoperative course was uneventful, and the patient has been well, receiving maintenance chemotherapy using S-1, without evidence of recurrence for 9 months following the operation.Conversion surgery following chemotherapy might be a proposed treatment for patients with advanced gastric cancer; however, further studies and assessments are needed to establish this treatment strategy.
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November 2017

Serum carbohydrate antigen 125 is a significant prognostic marker in patients with unresectable advanced or recurrent gastric cancer.

Surg Today 2018 Apr 17;48(4):388-394. Epub 2017 Oct 17.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.

Purpose: We evaluated the diagnostic and prognostic value of three tumor markers: carcino-embryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125), in the pretreatment serum of patients with unresectable advanced or recurrent gastric cancer.

Methods: The subjects of this retrospective analysis were 245 patients with unresectable advanced or recurrent gastric cancer diagnosed at Kochi Medical School between 2007 and 2015. We ascertained the sensitivity of CEA, CA19-9, and CA125 to identify a certain survival time and then evaluated the relative prognosis of the patients.

Results: The overall positive rates for each tumor marker in the study group were as follows: 57.6% (141/245) for CEA, 38.4% (94/245) for CA19-9, and 34.3% (84/245) for CA125; the sensitivity of these three biomarkers in combination was 73.1% (179/245). The median survival time of the CA125-positive patients was 4.5 months, which was significantly shorter than that of a normal range group (18.3 months, P < 0.001). Multivariate survival analysis identified that high CA125 was independently associated with a worse prognosis (HR 3.941; 95% CI 2.544-6.106; P < 0.001).

Conclusions: Pretreatment serum CA125 is a useful prognostic biomarker in patients with unresectable advanced or recurrent gastric cancer. Evaluating a panel of serum tumor biomarkers is a useful diagnostic tool as elevated values might be associated with poor survival.
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http://dx.doi.org/10.1007/s00595-017-1598-3DOI Listing
April 2018

Metachronous solitary splenic metastasis arising from early gastric cancer: a case report and literature review.

BMC Surg 2017 Aug 29;17(1):96. Epub 2017 Aug 29.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.

Background: The metastasis of malignant tumors to the spleen is rare, and only a small percentage of cases can be treated surgically, as splenic metastases generally occur in the context of multivisceral metastatic cancer at a terminal stage. We report a rare case of metachronous solitary splenic metastasis arising from early gastric cancer.

Case Presentation: A 75-year-old man was initially referred to our hospital for examination of gastric cancer, diagnosed at a medical check-up. Esophagogastroduodenoscopy showed a slightly elevated lesion with a central irregular depression in the upper-third of the stomach. Biopsy specimens of the lesion showed a moderately-differentiated adenocarcinoma, and abdominal computed tomography showed no evidence of distant metastases. Endoscopic submucosal dissection was performed, with histological confirmation of a moderately-differentiated adenocarcinoma invading the submucosal layer. The patient subsequently underwent laparoscopic total gastrectomy with regional lymph node dissection, resulting in no residual carcinoma and no lymph node metastasis. Computed tomography, 28 months later, showed a well-defined mass measuring 4.2 cm in diameter in the spleen, and the patient underwent a splenectomy, since there was no evidence of further metastatic lesions in any other organs. Histological examination confirmed the diagnosis of a poorly-differentiated adenocarcinoma originating from the previous gastric cancer. The patient was alive 2 months after surgical resection of the splenic metastasis without any recurrence.

Conclusion: To the best of our knowledge, this is only the second case of a solitary splenic metastasis from early gastric cancer to be reported in the English literature. The present case suggests surgical resection may be the preferred treatment of choice for patients with a solitary splenic metastasis from gastric cancer.
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http://dx.doi.org/10.1186/s12893-017-0292-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576276PMC
August 2017

Clinical presentation and treatment of gastric metastasis from other malignancies of solid organs.

Biomed Rep 2017 Aug 6;7(2):159-162. Epub 2017 Jul 6.

Department of Surgery, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.

The aim of the present study was to analyze the clinicopathologic features and treatment outcomes of gastric metastasis from other malignancies of solid organs. A review was conducted of patients with metastatic tumors in the stomach from other malignancies of solid organs detected endoscopically at the Department of Surgery, Kochi Medical School, from January 1991 to December 2015. Seven patients (four men and three women), with a median age of 64 years (range, 42-71 years), had metastatic gastric tumors. Median tumor size was 7.3 cm (range, 2.5-12.0 cm). The primary malignancy leading to metastatic tumors in the stomach was esophageal cancer in three patients, breast cancer in two patients, renal cell carcinoma in one patient, and ovarian cancer in one patient. Gastric metastasis presented as solitary lesions in six patients and as multiple lesions in one patient. Four patients had solitary gastric metastasis, whereas three had multiple metastases in other organs. The median tumor size was significantly smaller in patients with solitary rather than multiple metastases (4.6 vs. 12.0 cm, respectively; P=0.038). Three patients received systemic therapy and four underwent surgical resection of the metastatic tumor, and of these, only one was alive 58 months after surgery. Clinicians should be aware of the possible existence of metastatic gastric cancer, especially in breast carcinoma and esophageal cancer. Surgical resection may considerably improve patients' quality of life, and could be of benefit when there is a risk of bleeding and/or a solitary metastasis.
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http://dx.doi.org/10.3892/br.2017.943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526074PMC
August 2017

Gastric adenocarcinoma at the anastomotic site 50 years after gastrojejunostomy: A case report.

Mol Clin Oncol 2017 Aug 29;7(2):249-251. Epub 2017 Jun 29.

Department of Surgery, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.

We herein report a rare case of superficially spreading early gastric cancer occurring 50 years after gastrojejunostomy. An 83-year-old woman was diagnosed with gastric cancer after complaining of epigastric discomfort. The patient had undergone gastrojejunostomy with Braun jejunojejunostomy for benign chronic peptic ulcer 50 years prior. Esophagogastroduodenoscopy revealed an irregular nodular lesion on the gastric side of the anastomosis of the gastrojejunostomy. No abnormal lesions were identified by abdominal contrast-enhanced computed tomography. The patient underwent distal gastrectomy with regional lymphadenectomy. The final diagnosis was signet ring cell carcinoma invading the gastric submucosal layer, without lymph node metastasis, located in the area surrounding the original gastrojejunostomy and measuring 9.5×4.5 cm. In addition, dilated cystic glands were found in the submucosal layer, indicating gastritis cystica profunda. Following surgery, the patient remained symptom-free without evidence of recurrence for 46 months. Although it is not clear whether the adenocarcinoma at the stomal site was associated with the superficial spreading-type tumor in the present case, the observations may provide clues as to the pathogenic process of this entity.
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http://dx.doi.org/10.3892/mco.2017.1309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532684PMC
August 2017

Subcutaneous metastasis arising from gastric cancer: A case report.

Mol Clin Oncol 2017 Apr 24;6(4):515-516. Epub 2017 Feb 24.

Department of Surgery, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.

A 59-year-old man was referred to the Kochi Medical School Hospital due to left shoulder pain. Physical examination revealed a nodular, painful mass lesion in the subcutaneous tissue of the right chest wall, with a diameter of ~2 cm. Esophagogastroduodenoscopy revealed a large ulcerated tumor in the lower gastric body near the lesser curvature, and biopsy specimens of the gastric and humeral lesions revealed poorly differentiated adenocarcinoma. Abdominal computed tomography revealed multiple low-density lesions in the liver and a well-defined, 2.2-cm mass in the subcutaneous tissue of the right chest wall. The diagnosis was advanced gastric cancer with metastases to the liver, bone and skin, and systemic chemotherapy with radiotherapy for the bone metastasis was recommended. The patient also underwent distal gastrectomy to control bleeding from the primary gastric cancer lesion due to unresolved anemia, not improving by blood transfusion, and a low hemoglobin level. The subcutaneous tumor in the right chest wall was resected at the same time, to alleviate the pain caused by the mass. Macroscopic examination of the resected specimen revealed a well-circumscribed, solid tumor, measuring 2.2×2.1 cm, with a firm consistency. Microscopic examination showed infiltration of poorly differentiated adenocarcinoma cells into the subcutaneous tissue. Subcutaneous metastasis from gastric cancer is a rare manifestation, with a reported incidence of 0.8-1.0%. Cutaneous metastasis of cancer generally appears late in the course of the disease. Surgical resection of metastatic skin tumors is occasionally undertaken as palliative treatment to improve the patient's quality of life by controlling severe symptoms, including pain and hemorrhage.
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http://dx.doi.org/10.3892/mco.2017.1175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374947PMC
April 2017

[Two Cases of Krukenberg Tumors That Metastasized from Gastric Cancer Treated with Multidisciplinary Therapy].

Gan To Kagaku Ryoho 2016 Nov;43(12):2211-2212

Dept. of Surgery, Kochi Medical School.

A 34-year-old woman underwent total gastrectomy with D2 lymphadenectomy for gastric cancer, and the final diagnosis was T4N3M0, Stage III C, R0. Bilateral ovarian metastases were identified 51 months later, which were removed, and the patient received S-1 plus CDDP chemotherapy. Because the patient developed pubic bone metastasis 16 months after the second operation, we continued chemotherapy using paclitaxel with bisphosphonate. The patient was alive 70 months after the initial operation. The second patient was a 55-year-old woman who underwent total gastrectomy with D2 lymphadenectomy and was diagnosed with T2N2M0, Stage III A gastric cancer. Bilateral ovarian metastases were identified 72 months later, which were removed, and the patient received S-1 plus CDDP chemotherapy. The patient is alive with no signs of disease recurrence 96 months after the initial operation. For patients with ovarian metastases from gastric cancer, surgical resection in addition to chemotherapy might be an effective treatment. However, further studies and assessments of additional cases are needed to confirm the ideal treatment for this condition.
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November 2016

Neurofibroma of the Gallbladder Not Associated with Neurofibromatosis.

Surg Technol Int 2016 Dec;30:89-92

Kochi Medical School, Kochi, Japan.

An 82-year-old woman had visited her local clinic with a history of abdominal discomfort and dyspepsia related to meals over a period of several months. Esophagogastroduodenoscopy revealed a superficial spreading tumor that, on biopsy, was proven to be an adenocarcinoma, and colonoscopy revealed an ascending mass that was found to be an adenocarcinoma on biopsy, so the patient was referred to our hospital. Abdominal computed tomography revealed a mass in the ascending colon with regional lymph node swelling and a gallbladder stone measuring 1.5 cm in diameter. The patient underwent laparoscopy-assisted distal gastrectomy with cholecystectomy and right colectomy with regional lymph node dissection, resulting in a diagnosis of poorly differentiated adenocarcinoma invading the gastric submucosal layer and moderately differentiated tubular adenocarcinoma invading the colonic serosa with lymph node metastasis. Macroscopic examination of the gallbladder revealed a well-circumscribed, solid tumor measuring 0.3 x 0.3 cm with a firm consistency in the neck portion associated with lithiasis. Microscopic examination of the gallbladder tumor revealed infiltration of spindle-shaped neoplastic cells that were arranged in a fasciculated and woven pattern in abundant intersecting bundles. Immunohistochemical analyses were positive for S-100 protein and neurofilament. Although neurofibromas commonly occur in the superficial skin or subcutaneous region, isolated neurofibroma of the gallbladder is quite rare. To the best of our knowledge, this is only the 11th case of a neurofibroma of the gallbladder to be reported in English literature. In the present case, as in most previously reported cases, the tumor was found incidentally in the resected gallbladder following cholecystectomy for cholecystolithiasis.
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December 2016

Analysis of Factors Associated with Weight Loss After Esophagectomy for Esophageal Cancer.

Anticancer Res 2016 10;36(10):5409-5412

Department of Surgery, Kochi Medical School, Nankoku, Japan.

Aim: To investigate the factors associated with weight loss (WL) after esophagectomy for esophageal cancer.

Patients And Methods: We retrospectively reviewed 136 patients who underwent esophagectomy for esophageal cancer. Preoperative characteristics, surgical methods, postoperative outcomes and weight changes at 6 months after surgery were analyzed.

Results: Seventy-eight patients had more than 10% WL compared to their weight at surgery. On univariate analysis, higher body mass index [(BMI): ≥20.8; p=0.012] and shorter length of hospitalization [(LOH); p=0.041] demonstrated an association with more than 10% WL. On multivariate analysis, higher BMI [odds ratio (OR)=2.821; 95% confidence interval (CI)=1.238-6.426; p=0.014] and shorter LOH (OR=2.953; 95% CI=1.009-8.646; p=0.048) were independently associated with more than 10% WL.

Conclusion: Higher BMI and shorter LOH were unfavorable risk factors for WL after esophagectomy for esophageal cancer.
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http://dx.doi.org/10.21873/anticanres.11117DOI Listing
October 2016

Antitumor Effects of Eribulin Mesylate in Gemcitabine-resistant Pancreatic Cancer Cell Lines.

Anticancer Res 2016 11;36(11):6077-6082

Department of Surgery, Kochi Medical School Hospital, Kochi, Japan.

Background/aim: One reason of poor survival rate of patients with pancreatic cancer is the development of chemoresistance. The aim of the present study was to investigate the effects of eribulin mesylate in gemcitabine-refractory advanced pancreatic cancer cell lines.

Materials And Methods: Three human pancreatic cancer cell lines (AsPC-1, Panc-1, and SUIT-2) and human pancreatic endoderm (hPE) cells were used to evaluate the antitumor effects of gemcitabine and eribulin mesylate. Cell viability after treatment of cells with different concentrations of gemcitabine and eribulin mesylate was evaluated using water-soluble tetrazolium salts (WST) assays; cytotoxic effects were evaluated on the basis of morphological changes to cells.

Results: Gemcitabine had no effect on cell viability of AsPC-1 nor Panc-1 cells, whereas gemcitabine reduced cell viability of SUIT-2 cells in a dose-dependent manner. Eribulin mesylate significantly reduced cell viability of both AsPC-1 and Panc-1 cells (p<0.001 and p=0.002, respectively), but had no effect on hPE cells. Microscopic examination of AsPC-1 and Panc-1 cells after treatment with eribulin mesylate revealed morphological changes that included cell shrinkage, membrane blebbing, and fragmentation of the cells after drug exposure, and these were concentration-dependent effects.

Conclusion: The findings of the present study suggest that eribulin mesylate may be a promising potential anticancer drug for gemcitabine-refractory advanced pancreatic cancer.
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http://dx.doi.org/10.21873/anticanres.11197DOI Listing
November 2016

Juxtapapillary Duodenal Diverticulum Impacted with Enterolith.

J Gastrointest Surg 2017 May 21;21(5):920-922. Epub 2016 Sep 21.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.

A 64-year-old man underwent abdominal computed tomography (CT) as periodic follow-up following a distal gastrectomy with lymphadenectomy for gastric cancer and mucosal-associated lymphoid tissue (MALT) lymphoma conducted 31 months earlier. Contrast-enhanced CT demonstrated a well-circumscribed mass lesion with heterogeneous density measuring 2.2 cm in diameter located between the second segment of the duodenum and uncinate process of the pancreas. Esophagogastroduodenoscopy revealed no remarkable findings in the remnant stomach; however, the scope could not reach the duodenum due to altered anatomy by Roux-en-Y reconstruction after the distal gastrectomy. The patient underwent surgical resection of the mass lesion under the clinical diagnosis of MALT lymphoma relapse. An orange calculus was apparent in the thinly extended duodenal wall on stretching, and the hall was closed by meticulous primary suture after the duodenal resection. Macroscopically, the extracted calculus was solid and quite hard, measured 2.2 × 2.1 × 2.1 cm, and the cut surface revealed a layered structure in the outer areas with granulated contents in the center. Although duodenal diverticula are relatively common, an enterolith developing within a juxtapapillary duodenal diverticulum is rare, and to the best of our knowledge, this is the first such case due to altered anatomy after gastrectomy reported in the English literature.
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http://dx.doi.org/10.1007/s11605-016-3271-3DOI Listing
May 2017

Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer.

Mol Clin Oncol 2016 Jul 10;5(1):74-78. Epub 2016 May 10.

Department of Surgery, Kochi Medical School, Kochi 783-8505, Japan.

The present study aimed to evaluate the efficacy and safety of trastuzumab plus chemotherapy for patients with unresectable advanced or recurrent gastric cancer. A retrospective analysis of 213 patients with unresectable advanced or recurrent gastric cancer who received systemic chemotherapy, including 15 patients who were also administered trastuzumab, at Kochi Medical School between 2007 and 2013 was performed. The overall survival was compared between patients who received trastuzumab plus chemotherapy and patients who received chemotherapy alone, and the safety and efficacy of the trastuzumab-containing regimen was evaluated. Human epidermal growth factor receptor (HER)2 status was examined in 86 patients, of whom 15 (17.4%) exhibited strong positive HER2 expression. The rate of strong positive HER2 expression was significantly higher for intestinal type tumors compared with diffuse type tumors [23.6 (13/55) vs. 6.5% (2/31); P=0.044]. The median overall survival of the patients treated with trastuzumab was significantly longer compared with that for patients who were not treated with trastuzumab (22.9 vs. 11.6 months; P=0.014). The objective response rate and disease control rate for trastuzumab plus chemotherapy were 46.7 and 86.7%, respectively. Frequently encountered grade 3-4 toxicities included neutropenia (26.7%; 4/15), anemia (13.3%; 2/15) and fatigue (13.3%; 2/15). Trastuzumab plus chemotherapy is effective for patients with HER2-positive advanced or recurrent gastric cancer, and the frequencies of hematological and non-hematological toxicities experienced by patients in the present study indicated that it can be safely administered clinically.
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http://dx.doi.org/10.3892/mco.2016.892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907018PMC
July 2016

Reconstruction with Jejunal Pouch after Gastrectomy for Gastric Cancer.

Am Surg 2016 Jun;82(6):510-7

Department of Surgery, Kochi Medical School, Nankoku, Japan.

The construction of a gastric substitute pouch after gastrectomy for gastric cancer has been proposed to help ameliorate postprandial symptoms and nutritional performance. Adequate reconstruction after gastrectomy is an important issue, because postoperative patient quality of life (QOL) primarily depends on the reconstruction method. To this end, jejunal pouch (JP) reconstructions were developed to improve the patient's eating capacity and QOL by creating large reservoirs with improved reflux barriers to prevent esophagitis and residual gastritis. It is important that such reconstructions also preserve blood and extrinsic neural integrity for maintaining pouch function, because JP motility is associated directly with QOL. Some problems remain to be resolved with the JP reconstructions method including gastrointestinal motility, which plays a major role in food transfer, digestion, and absorption of nutrients. Further studies including basic research and larger prospective randomized control trials are also needed to obtain definitive results. With persistent innovations in surgical techniques, JP after gastrectomy could become a safe and preferable reconstructive modality to improve patient QOL after gastrectomy.
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June 2016

Evaluation of Systemic Inflammatory Response Biomarkers in Patients Receiving Chemotherapy for Unresectable and Recurrent Advanced Gastric Cancer.

Oncology 2016 26;90(6):321-6. Epub 2016 May 26.

Department of Surgery, Kochi Medical School, Kochi, Japan.

Background: The present study sought to evaluate an inflammation-based prognostic score (Glasgow prognostic score, GPS) and the neutrophil to lymphocyte ratio (NLR) as prognostic factors in patients receiving chemotherapy for advanced gastric cancer.

Methods: The study enrolled 224 patients who received chemotherapy for advanced gastric cancer at the Kochi Medical School from 2007 to 2014. Clinicopathological information and systemic inflammatory response data were obtained to investigate associations between baseline cancer-related prognostic variables and survival outcomes.

Results: The median survival time was significantly higher for patients with intestinal-type compared to diffuse-type histology (p = 0.039), a GPS 0 score compared to GPS 1 or 2 score (p = 0.004), and lower compared to higher NLR 4 (p = 0.002). Multivariate survival analysis identified high NLR 4 (HR 1.651; 95% CI 1.187-2.297; p = 0.003) and diffuse-type histology (HR 1.645; 95% CI 1.025-2.639; p = 0.039) as significant independent predictors associated with worse prognosis in the studied group of cancer patients.

Conclusions: NLR and histological type are independent prognostic factors for patients receiving chemotherapy for unresectable and recurrent gastric cancer.
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http://dx.doi.org/10.1159/000446373DOI Listing
December 2016

Current topics in glycemic control by wearable artificial pancreas or bedside artificial pancreas with closed-loop system.

J Artif Organs 2016 Sep 3;19(3):209-18. Epub 2016 May 3.

Department of Surgery, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku, Kochi, 783-8505, Japan.

The incidence of diabetes is increasing at an unprecedented pace and has become a serious health concern worldwide during the last two decades. Despite this, adequate glycemic control using an artificial pancreas has not been established, although the 21st century has seen rapid developments in this area. Herein, we review current topics in glycemic control for both the wearable artificial pancreas for type 1 and type 2 diabetic patients and the bedside artificial pancreas for surgical diabetic patients. In type 1 diabetic patients, nocturnal hypoglycemia associated with insulin therapy remains a serious problem that could be addressed by the recent development of a wearable artificial pancreas. This smart phone-like device, comprising a real-time, continuous glucose monitoring system and insulin pump system, could potentially significantly reduce nocturnal hypoglycemia compared with conventional glycemic control. Of particular interest in this space are the recent inventions of a low-glucose suspend feature in the portable systems that automatically stops insulin delivery 2 h following a glucose sensor value <70 mg/dL and a bio-hormonal pump system consisting of insulin and glucagon pumps. Perioperative tight glycemic control using a bedside artificial pancreas with the closed-loop system has also proved safe and effective for not only avoiding hypoglycemia, but also for reducing blood glucose level variability resulting in good surgical outcomes. We hope that a more sophisticated artificial pancreas with closed-loop system will now be taken up for routine use worldwide, providing enormous relief for patients suffering from uncontrolled hyperglycemia, hypoglycemia, and/or variability in blood glucose concentrations.
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http://dx.doi.org/10.1007/s10047-016-0904-yDOI Listing
September 2016

[MANAGEMENT OF PERIOPERATIVE HYPERGLYCEMIA USING AN ARTIFICIAL PANCREAS].

Nihon Geka Gakkai Zasshi 2016 May;117(3):194-8

During the perioperative period, hyperglycemia is induced by surgical stress, which is the main risk factor for the development of postoperative infection associated with failure of neutrophil function, resulting in glucose toxicity. In elderly people with weakened immune systems, it is important to control perioperative hyperglycemia by maintaining sufficient nutrition administration. The artificial endocrine pancreas system allows strict glycemic control, which is beneficial in reducing glucose toxicity including postoperative infection not only in patients with diabetes mellitus or glucose intolerance but also in those who develop surgical diabetes during the perioperative period. Furthermore, it can contribute to the prevention of hypoglycemia and medical staff workload reduction. Therefore, the artificial pancreas is expected to come into widespread use in various fields involving glycemic control in patients.
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May 2016

Synchronous Large Gastrointestinal Stromal Tumor and Adenocarcinoma in the Stomach Treated with Imatinib Mesylate Followed by Total Gastrectomy.

Anticancer Res 2016 Apr;36(4):1855-9

Department of Surgery, Kochi Medical School, Kochi, Japan.

Herein we report on a case of synchronous large gastrointestinal stromal tumor (GIST) and adenocarcinoma of the stomach treated with radical surgery following neoadjuvant therapy with imatinib mesylate. A 58-year-old man was referred to our hospital with a large mass in the peritoneal cavity. Abdominal computed tomography showed a large mass measuring 21×20×14 cm in the left upper peritoneal cavity. Esophagogastroduodenoscopy revealed a large elevated lesion in the upper body and a depressed lesion in the lower gastric body near the lesser curvature. Biopsy specimens revealed GIST in the large elevated lesion and signet-ring cell carcinoma in the depressed lesion. Because of the large size of the GIST, the patient was treated with neoadjuvant therapy with imatinib mesylate (400 mg/day) for 5 months. After confirmation of a marked decrease in tumor size following imatinib mesylate therapy, the patient underwent total gastrectomy and regional lymph-node dissection with distal pancreatectomy and splenectomy. Pathological examination confirmed the diagnosis of high-risk GIST and signet-ring cell carcinoma invading the muscularis propria with one lymph-node metastasis. At the time of writing, the patient was receiving postoperative chemotherapy using oral fluoropyrimidine (S-1) without evidence of disease recurrence for 4 months after surgery. In addition to the present case, we provide a retrospective review of another 15 patients who were diagnosed with synchronous GIST in the stomach and primary gastric adenocarcinoma.
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April 2016

[The Clinical Role of the Neutrophil/Lymphocyte Ratio in Patients with Advanced Gastric Cancer Treated with Protein-Bound Polysaccharide K and Chemotherapy].

Gan To Kagaku Ryoho 2015 Nov;42(12):2081-3

Dept. of Surgery, Kochi Medical School.

This study aimed to evaluate the efficacy of protein-bound polysaccharide K (PSK)-containing chemotherapy in patients with unresectable advanced or recurrent gastric cancer (AGC). We retrospectively analyzed 190 patients with AGC who received systemic chemotherapy including 69 patients who were treated with a PSK-containing regimen. Using propensity score matching, we obtained 62 matched patients in the S-1 and S-1 plus PSK groups for outcomes analysis. There was a tendency for overall survival to be higher in the S-1 plus PSK group than in the S-1 alone group. In particular, there was a tendency for overall survival in the S-1 plus PSK group to be higher in patients with a neutrophil/lymphocyte ratio (NLR)<2.2 than in patients with a NLR<2.2. There was a tendency for fewer changes in the NLR after the beginning of treatment in the S-1 plus PSK group than in the S-1 alone group. PSK-containing chemotherapy may contribute to improved treatment outcomes of AGC patients. In particular, it may be effective in patients with a high NLR. Further investigations, including a prospective randomized controlled trial, are expected to verify the mechanisms of interaction between cancer cells and the immunoreaction.
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November 2015

Laparoscopy-assisted distal gastrectomy for multiple adenocarcinomas in intrathoracic upside-down stomach.

Asian J Endosc Surg 2016 Feb;9(1):57-60

Department of Surgery, Kochi Medical School, Nankoku, Japan.

Herein we report on a case of two adenocarcinomas arising from an upside-down stomach in an elderly patient. An 83-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy showed two superficial depressed lesions in the stomach that were confirmed on biopsy as constituting a moderately differentiated tubular adenocarcinoma. CT and an upper gastrointestinal barium study revealed that the entire stomach and parts of the duodenum were located in the mediastinum. The patient underwent laparoscopy-assisted distal gastrectomy and regional lymph node dissection with Billroth I reconstruction, followed by reduction of the migrated stomach. The hiatal defect was closed by primary suturing of the right and left crura at the anterior space of the esophagus. The patient's postoperative course was good, and follow-up after discharge was uneventful. To the best of our knowledge, this is the first case report of multiple adenocarcinomas in an upside-down stomach treated by laparoscopy-assisted distal gastrectomy.
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http://dx.doi.org/10.1111/ases.12217DOI Listing
February 2016

Pharmacokinetics of Active Components of Yokukansan, a Traditional Japanese Herbal Medicine after a Single Oral Administration to Healthy Japanese Volunteers: A Cross-Over, Randomized Study.

PLoS One 2015 7;10(7):e0131165. Epub 2015 Jul 7.

Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan.

Context: Yokukansan (YKS) is a traditional Japanese herbal medicine called kampo medicine in Japan. Its extract comprises seven crude drugs: Atractylodis lanceae rhizoma, Poria, Cnidii rhizoma, Uncariae uncis cum ramulus, Angelicae radix, Bupleuri radix, and Glycyrrhizae radix. YKS is used to treat neurosis, insomnia, as well as behavioral and psychological symptoms of dementia.

Objective: To confirm the exposure and pharmacokinetics of the active components of YKS in healthy volunteers.

Design, Setting, And Participants: A randomized, open-label, 3-arm, 3-period, crossover trial was conducted on 21 healthy Japanese volunteers at the Kochi Medical University between May 2012 and November 2012.

Interventions: Single oral administration of YKS (2.5 g, 5.0 g, or 7.5 g/day) during each period.

Main Outcome Measure: Plasma concentrations of three active compounds in YKS, namely 18β-glycyrrhetinic acid (GA), geissoschizine methyl ether (GM), and hirsuteine (HTE).

Results: The mean maximum plasma concentrations (Cmax) of GM and HTE increased dose-dependently (ranges: 0.650-1.98 ng/mL and 0.138-0.450 ng/mL, respectively). The times to maximum plasma concentration after drug administration (tmax) were 0.500 h for GM and 0.975-1.00 h for HTE. The apparent elimination half-lives (t1/2) were 1.72-1.95 h for GM and 2.47-3.03 h for HTE. These data indicate the rapid absorption and elimination of GM and HTE. On the other hand, the Cmax, tmax, and t1/2 of GA were 57.7-108 ng/mL, 8.00-8.01 h, and 9.39-12.3 h, respectively.

Conclusion: We demonstrated that pharmacologically active components of YKS are detected in humans. Further, we determined the pharmacokinetics of GM, HTE, and GA. This information will be useful to elucidate the pharmacological effects of YKS.

Trial Registration: Japan Pharmaceutical Information Center JAPIC CTI-121811.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131165PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495062PMC
April 2016
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