Publications by authors named "Kengo Kanetaka"

82 Publications

Functional changes of cocultured hepatocyte sheets subjected to continuous liver regeneration stimulation in cDNA-uPA/SCID mouse: Differences in transplantation sites.

Regen Ther 2021 Dec 18;18:7-11. Epub 2021 Mar 18.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

Aim: The formation of a secondary liver is expected in ectopic transplants in liver therapy. It is reported that the transplantation of hepatocyte sheets constitutes one of the techniques used to form a secondary liver. Accordingly, we established a subcutaneous transplant for hepatocyte/fibroblast sheets in previous studies. In this development study with hepatocyte/fibroblast sheets, we evaluated the differences in transplantation sites to promote the maturation of transplanted tissue in a liver injury model.

Methods: A cocultured hepatocyte sheet of fibroblasts (TIG-118 cells) and human hepatocytes (PXB cells) was prepared on a temperature-responsive culture dish. The prepared cocultured hepatocyte sheet was either transplanted subcutaneously or on the liver surface of a persistent liver injury model (cDNA-uPA/SCID mouse: uPA mouse), and was evaluated by the human albumin concentration in mouse blood. As a control group, hepatocyte cell sheets were used that were transplanted to both areas and compared.

Results: Although the cocultured hepatocyte sheet led to functional improvements in the early stages of culture in subcutaneous transplantation, these did not last in the long-term after transplantation. Although coculture effects were not observed in the liver surface transplantation case, long-term functional expressions in mono- and cocultured sheets in the case of liver surface transplantation were exhibited compared with subcutaneous administration.

Conclusion: These results suggest that sustained stimulation of liver regenerationvaries depending on the transplant site and is largely involved in the maturation of hepatocyte tissue.
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http://dx.doi.org/10.1016/j.reth.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010356PMC
December 2021

Bioengineering of a CLiP-derived tubular biliary-duct-like structure for bile transport in vitro.

Biotechnol Bioeng 2021 Apr 3. Epub 2021 Apr 3.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The integration of a bile drainage structure into engineered liver tissues is an important issue in the advancement of liver regenerative medicine. Primary biliary cells, which play a vital role in bile metabolite accumulation, are challenging to obtain in vitro because of their low density in the liver. In contrast, large amounts of purified hepatocytes can be easily acquired from rodents. The in vitro chemically induced liver progenitors (CLiPs) from primary mature hepatocytes offer a platform to produce biliary cells abundantly. Here, we generated a functional CLiP-derived tubular bile duct-like structure using the chemical conversion technology. We obtained an integrated tubule-hepatocyte tissue via the direct coculture of hepatocytes on the established tubular biliary-duct-like structure. This integrated tubule-hepatocyte tissue was able to transport the bile, as quantified by the cholyl-lysyl-fluorescein assay, which was not observed in the un-cocultured structure or in the biliary cell monolayer. Furthermore, this in vitro integrated tubule-hepatocyte tissue exhibited an upregulation of hepatic marker genes. Together, these findings demonstrated the efficiency of the CLiP-derived tubular biliary-duct-like structures regarding the accumulation and transport of bile.
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http://dx.doi.org/10.1002/bit.27773DOI Listing
April 2021

Prevention of delayed gastric emptying after living donor left hepatectomy.

Asian J Surg 2021 Mar 6. Epub 2021 Mar 6.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Background: Delayed gastric emptying (DGE) is uncomfortable complication after left hepatectomy. The aim of this study is to show our strategy to prevent DGE after living donor left hepatectomy.

Methods: The cases were divided into 3 groups as without any prevention (control group), prevented DGE with putting omentum between the liver and pylorus (O group), and with putting a Seprafilm (S group). The incidence of DGE and the CT finding 1 month after surgery were retrospectively compared between the groups.

Results: The incidence of DGE was significantly decreased in O and S group than control group (P < 0.05, Fisher's test). In S group, fluid collection along the cutting surface of the liver was observed on CT significantly more than other groups, but the incidence of bile leakage was adversely less in S groups than other groups, meaning that collected fluid in S group were presumed as the ascites without bile.

Conclusion: Omentum patching and Seprafilm were equally effective to prevent DGE after living donor left hepatectomy, and Seprafilm might be better because it is more physiologic.
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http://dx.doi.org/10.1016/j.asjsur.2021.02.006DOI Listing
March 2021

Protocol for studying the efficiency of ChemoCalc software in helping patients to understand drug treatment costs for breast cancer: A multicenter, open-label, randomized phase 2 study.

Contemp Clin Trials Commun 2021 Mar 11;21:100739. Epub 2021 Feb 11.

Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.

Survival of patients with breast cancer can be prolonged by treatment with drugs, particularly new molecular-targeted drugs. However, these agents can be expensive and such treatments can be "an economic burden." In this ongoing trial, we aim to assess the usefulness of ChemoCalc, a software package for calculating drug costs, to help patients understand the financial outlays. In this multicenter, randomized controlled phase 2 trial, 106 patients with advanced breast cancer will be assigned to either the "ChemoCalc" or "Usual Explanation" group. Treatment using ChemoCalc will be discussed with patients in the ChemoCalc group, whereas standard treatments, without using ChemoCalc, will be discussed with patients in the Usual Explanation group. Subsequently, the participants will decide the treatment and complete a five-grade evaluation questionnaire; those in the Usual Explanation group will receive information about ChemoCalc. Investigators will report if patients subsequently decide to change treatments. The primary endpoint will be the scores of two key questions compared between the groups: "Did you understand the cost of treatment in today's discussion?" and "Do you think the cost of treatment is important in choosing a treatment?". The secondary endpoints will be to compare discrepancies between treatments recommended by physicians and those selected by patients, the time required for discussion, other questionnaire factors, and the relationship between Comprehensive Score for Financial Toxicity tool and treatment selection. This will be the first randomized controlled trial to assess the efficacy of software to help patients understand drug cost estimates and whether it subsequently affects treatment choice. This study will be conducted according to the CONSORT statement. All participants will sign a written consent form. The study protocol was reviewed and approved by the Clinical Research Review Board of Nagasaki University (19070801). The protocol (version 1) was designed and will be conducted in accordance with the Declaration of Helsinki (1964) and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (2017). The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals.

Trial Registration: UMIN Clinical Trials Registry, UMIN000039904. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041968.
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http://dx.doi.org/10.1016/j.conctc.2021.100739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921475PMC
March 2021

Subcutaneous transplantation of engineered islet/adipose-derived mesenchymal stem cell sheets in diabetic pigs with total pancreatectomy.

Regen Ther 2021 Mar 13;16:42-52. Epub 2021 Jan 13.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki city, Nagasaki, 852-8501, Japan.

Introduction: Intraportal islet transplantation is a promising therapeutic approach for patients with type 1 diabetes mellitus (T1DM). However, despite being minimally invasive, the method has some limitations, such as short-term graft loss, portal venous thrombosis, and difficulty in collecting adequate amounts of islets. Subcutaneous islet transplantation on adipose-derived mesenchymal stem cell (ADSC) sheets has been suggested to overcome these limitations, and in this study, we have examined its feasibility in T1DM pigs.

Methods: Inguinal subcutaneous fat was harvested from young pigs and then isolated and cultured adequate ADSCs to prepare sheets. Islets were isolated from the pancreases of mature pigs and seeded on the ADSC sheets. T1DM pigs were generated by total pancreatectomy, and ADSC sheets with transplanted islets were administered subcutaneously to the waist ( = 2). The effects of the islets on the ADSC sheets and on blood glucose levels were evaluated. Insulin secretion was measured by insulin stimulation index.

Results: Islet viability was higher on ADSCs compared to islets alone (91.8 ± 4.3 vs. 81.7 ± 4.1%). The insulin stimulation index revealed higher glucose sensitivity of islets on ADSC sheets compared to islets alone (2.8 ± 2.0 vs. 0.8 ± 0.3). After transplantation, the blood glucose levels of two pigs were within the normal range, and sensitive insulin secretion was confirmed by intravenous glucose tolerance tests. After graftectomy, decreased insulin secretion and hyperglycemia were observed.

Conclusions: Subcutaneous islet transplantation using ADSC sheets can regulate the blood glucose levels of T1DM pigs.
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http://dx.doi.org/10.1016/j.reth.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810917PMC
March 2021

Changes in the Role and Mode of Liver Resection for Hepatocellular Carcinoma Over 20 Years: A Single-Center Analysis.

World J Surg 2021 Apr 25;45(4):1152-1158. Epub 2021 Jan 25.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Introduction: The aim of this study was to analyze changes in characteristics of HCC and the modes of LR over 20 years in order to show the impact of those changes in the outcome of LR. In addition, BCLC staging was used to assess the limitations of this classification system and changes over the decade.

Patients And Methods: In our department, 500 liver resections (LR) were performed for hepatocellular carcinoma (HCC) over the 20 years between January 2000 and February 2020. The 208 cases performed through 2009 were designated as Era 1, and the 292 cases between 2010 and February 2020 were termed Era 2. We analyzed changes in the characteristics of HCC and mode of LR (Study 1), and final outcomes of LR are shown according to the BCLC staging classifications and eras using data from the 5 years after LR (Study 2).

Results: In Era 1, the mean age of the patients was 68, while in Era 2 the mean age was 71, which was significantly older than the patients in Era 1. HCC that developed from non-B, non-C liver cirrhosis was significantly increased in Era 2 (45%) as compared to that in Era 1 (34%). Laboratory data were all comparable between the eras in patients undergoing LR for HCC. The size and numbers of the HCC as well as tumor markers were similar between the eras. As to the mode of LR, although the extent of LR was similar between the eras, the laparoscopic method was significantly increased in Era 2. Blood loss was significantly lower in Era 2 (mean 519 g) than in Era 1 (1,085 g). Patient survival and recurrence-free survival (RFS) were similar between the two eras, while RFS at 5 years after LR was better in Era 2. Even in the BCLC A category, only patients with a single HCC less than 5 cm showed best results, while patients with HCC within the rest of BCLC A and BCLC B showed a dismal outcome. There was no difference in OS and RFS between the eras after stratification by BCLC.

Conclusion: There are conspicuous changes in the baseline characteristics and mode of LR over 20 years, which should be taken into account for patient care and informed consent for patients undergoing LR going forward.
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http://dx.doi.org/10.1007/s00268-020-05914-3DOI Listing
April 2021

Regenerative medicine for the upper gastrointestinal tract.

Regen Ther 2020 Dec 4;15:129-137. Epub 2020 Aug 4.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan.

The main surgical strategy for gastrointestinal tract malignancy is resection, which consists of not only resection of the involved organs but also simultaneous resection of the surrounding or adjacent mesenteries that contain lymph vessels and nodes. After resection of the diseased organs, the defect of the gastrointestinal conduit is replaced with organs located downstream, such as the stomach and jejunum. However, esophageal and gastric reconstruction using these natural substitutes is associated with a diminished quality of life due to the loss of the reserve function, damage to the antireflux barrier, and dumping syndrome. Thus, replacement of the deficit after resection with the patient's own regenerated tissue to compensate for the lost function and tissue using regenerative medicine will be an ideal treatment. Many researchers have been trying to construct artificial organs through tissue engineering techniques; however, none have yet succeeded in growing a whole organ because of the complicated functions these organs perform, such as the processing and absorption of nutrients. While exciting results have been reported with regard to tissue engineering techniques concerning the upper gastrointestinal tract, such as the esophagus and stomach, most of these achievements have been observed in animal models, and few successful approaches in the clinical setting have been reported for the replacement of mucosal defects. We review the recent progress in regenerative medicine in relation to the upper gastrointestinal tract, such as the esophagus and stomach. We also focus on the functional capacity of regenerated tissue and its role as a culture system to recapitulate the mechanisms underlying infectious disease. With the emergence of technology such as the fabrication of decellularized constructs, organoids and cell sheet medicine, collaboration between gastrointestinal surgery and regenerative medicine is expected to help establish novel therapeutic modalities in the future.
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http://dx.doi.org/10.1016/j.reth.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770370PMC
December 2020

The efficacy of intraoperative indocyanine green fluorescence angiography in gastric cancer operation after living donor liver transplantation: A case report.

Int J Surg Case Rep 2020 24;77:614-617. Epub 2020 Nov 24.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

Introduction: The incidence of de novo malignancies after organ transplantation is increasing. We herein report a patient who developed gastric cancer after living donor liver transplantation (LDLT) and splenectomy. Intraoperative indocyanine green (ICG) fluorescence angiography immediately after gastrectomy was useful for evaluating the blood supply into the remnant stomach in this patient.

Presentation Of Case: A 69-year-old woman underwent LDLT and splenectomy for end-stage liver disease. Gastric cancer was found by an endoscopic examination eight years after LDLT. Although total gastrectomy was considered due to previous splenectomy, we decided to intraoperatively evaluate the flow of the remnant stomach using ICG fluorescence. After ligation of the left gastric artery and transection of the stomach with a sufficient proximal margin from the tumor, intraoperative ICG fluorescence angiography showed abundant intramural blood flow of the remnant stomach. We were able to preserve the proximal stomach with confidence and she recovered smoothly after the operation without any signs of acute rejection.

Conclusion: Intraoperative ICG fluorescence angiography may be helpful for evaluating the blood flow in the remnant stomach during surgery for de novo gastric cancer after LDLT.
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http://dx.doi.org/10.1016/j.ijscr.2020.11.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708749PMC
November 2020

Limited resection vs. pancreaticoduodenectomy for primary duodenal adenocarcinoma: a systematic review and meta-analysis.

Int J Clin Oncol 2021 Mar 1;26(3):450-460. Epub 2021 Jan 1.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.

It is well known that surgery is the mainstay treatment for duodenal adenocarcinoma. However, the optimal extent of surgery is still under debate. We aimed to systematically review and perform a meta-analysis of limited resection (LR) and pancreatoduodenectomy for patients with duodenal adenocarcinoma. A systematic electronic database search of the literature was performed using PubMed and the Cochrane Library. All studies comparing LR and pancreatoduodenectomy for patients with duodenal adenocarcinoma were selected. Long-term overall survival was considered as the primary outcome, and perioperative morbidity and mortality as the secondary outcomes. Fifteen studies with a total of 3166 patients were analyzed; 995 and 1498 patients were treated with limited resection and pancreatoduodenectomy, respectively. Eight and 7 studies scored a low and intermediate risk of publication bias, respectively. The LR group had a more favorable result than the pancreatoduodenectomy group in overall morbidity (odd ratio [OR]: 0.33, 95% confidence interval [CI] 0.17-0.65) and postoperative pancreatic fistula (OR: 0.13, 95% CI 0.04-0.43). Mortality (OR: 0.96, 95% CI 0.70-1.33) and overall survival (OR: 0.61, 95% CI 0.33-1.13) were not significantly different between the two groups, although comparison of the two groups stratified by prognostic factors, such as T categories, was not possible due to a lack of detailed data. LR showed long-term outcomes equivalent to those of pancreatoduodenectomy, while the perioperative morbidity rates were lower. LR could be an option for selected duodenal adenocarcinoma patients with appropriate location or depth of invasion, although further studies are required.
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http://dx.doi.org/10.1007/s10147-020-01840-5DOI Listing
March 2021

Chemical conversion of aged hepatocytes into bipotent liver progenitor cells.

Hepatol Res 2021 Mar 22;51(3):323-335. Epub 2021 Feb 22.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Aim: In the aging society, understanding the influence of hepatocyte age on hepatocyte donation may inform efforts to expand alternative cell sources to mitigate liver donor shortage. A combination of the molecules Y27632, A-83-01, and CHIR99021 has been used to reprogram rodent young hepatocytes into chemically induced liver progenitor (CLiP) cells; however, whether it could also reprogram aged hepatocytes has not yet been elucidated.

Methods: Primary hepatocytes were isolated from aged and young donor rats, respectively. Hepatic histological changes were evaluated. Differences in gene expression in hepatocytes were identified. The in vitro reprogramming plasticity of hepatocytes as evidenced by CLiP conversion and the hepatocyte and cholangiocyte maturation capacity of reprogrammed CLIPs were analyzed. The effect of hepatocyte growth factor (HGF) on cell propagation was also investigated.

Results: The histological findings revealed ongoing liver damage with inflammation, fibrosis, senescence, and ductular reaction in aged livers. Microarray analysis showed altered gene expression profiles in hepatocytes from aged donors, especially with regard to metabolic pathways. Aged hepatocytes could be converted into CLiPs (Aged-CLiPs) expressing progenitor cell markers, but with a relatively low proliferative rate compared with young hepatocytes. Aged-CLiPs possessed both hepatocyte and cholangiocyte maturation capacity. HGF facilitated CLiP conversion in aged hepatocytes, which was partly related to the activation of Erk1 and Akt1 signaling.

Conclusions: Aged rat hepatocytes have retained reprogramming plasticity as evidenced by CLiP conversion in culture. HGF promoted proliferation and CLiP conversion in aged hepatocytes. Hepatocytes from aged donors may be used as an alternative cell source to mitigate donor shortage.
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http://dx.doi.org/10.1111/hepr.13609DOI Listing
March 2021

Thoracoscopy-thoracotomy approach for an aortoesophageal fistula: a case report.

Gen Thorac Cardiovasc Surg 2021 Jan 25;69(1):168-171. Epub 2020 Nov 25.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-7-1, Nagasaki, 8528501, Japan.

An aortoesophageal fistula is often fatal, and standard radical surgery is highly invasive because both bilateral thoracotomy and laparotomy are required. We successfully incorporated thoracoscopic esophagectomy into this procedure for a 43-year-old man with an aortoesophageal fistula. After detaching the esophagus from the adjacent tissue, and leaving just the fistula in the right thoracoscopic procedure, we performed an open aortic graft replacement. Subsequently, we created an omental pedicle graft and wrapped it over the graft. Through this thoracoscopy-thoracostomy approach, minimal destruction of the right thoracic wall was achieved and the successful dissection of the diseased esophagus could be carried out while reducing the amount of bleeding during anticoagulation for cardiopulmonary bypass, and the field of view for the aortic replacement was not disturbed during left thoracotomy. Four months later, we reconstructed the esophagus by a pedunculated small intestinal graft through the ante-thoracic route. A thoracoscopy-thoracotomy approach is therefore considered to be effective and useful for treating a patient with an aortoesophageal fistula.
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http://dx.doi.org/10.1007/s11748-020-01553-6DOI Listing
January 2021

A rare case of meningeal carcinomatosis and internal auditory canal metastasis presenting with the deafness for gastric cancer.

Surg Case Rep 2020 Nov 23;6(1):295. Epub 2020 Nov 23.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Zip code, 852-8501, Nagasaki, Nagasaki, Japan.

Background: Meningeal carcinomatosis is a very rare metastatic site of gastric cancer and meningeal carcinomatosis without other metastatic sites is much extremely rare. Herein, we report our experience with a very rare case of meningeal carcinomatosis which was difficult to diagnose the recurrence by general systemic examination and was found due to the deafness despite the sustained high tumor markers.

Case Presentation: A 68-year-old man consulted a hospital with vomiting and hematemesis. Laboratory tests revealed severe anemia. He was referred to our hospital and underwent an emergency gastroscopy, which revealed Borrman type 3 tumor and oozing of blood. Biopsy specimen showed gastric cancer. After several examinations, total gastrectomy was performed and tegafur-gimeracil-oteracil potassium (S-1) was initiated as adjuvant chemotherapy one month after surgery. Tumor marker levels (CEA and CA19-9) remained high for three months after surgery. S-1 was continued while shortening the imaging study follow-up period. Nine months after surgery, he noticed difficulty in hearing with facial paralysis, dizziness, tinnitus, and appetite loss. He was diagnosed with meningeal carcinomatosis and bilateral internal auditory canal metastasis. He died approximately two months later.

Conclusion: Meningeal carcinomatosis should be considered if bilateral deafness and vestibulopathy develop after gastrectomy, even if no recurrence is apparent in the abdominal cavity.
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http://dx.doi.org/10.1186/s40792-020-01018-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683756PMC
November 2020

The Efficacy of Autologous Myoblast Sheet Transplantation to Prevent Perforation After Duodenal Endoscopic Submucosal Dissection in Porcine Model.

Cell Transplant 2020 Jan-Dec;29:963689720963882

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The recent advent of endoscopy has enabled the endoscopic submucosal dissection (ESD) of superficial nonampullary duodenal epithelial tumors. However, the substantially thin wall and presence of bile and pancreatic juice make it technically difficult to perform duodenal ESD without perforation, which leads to lethal complications. The present study evaluated the efficacy of autologous myoblast sheet transplantation for the prevention of late perforation after duodenal ESD in a porcine model. Two weeks before ESD, skeletal muscle was surgically excised from the femur of pigs, and myoblasts were isolated and seeded in temperature-responsive culture dishes to prepare sheets. Immediately after ESD, the autologous myoblast sheets were attached to the serosal surface at the ESD site with omentopexy. The pigs were divided into two groups: the autologous myoblast sheet group ( = 5), where the myoblast cell sheet was attached to the ESD ulcer part from the duodenal serous side, and the Omentum group ( = 5), where only the omentum was used. The pigs were sacrificed and analyzed macroscopically and histologically on postoperative day 3. The macroscopic examination of the abdominal cavity revealed perforation in the ESD ulcer area and leakage of bile in the Omentum group but no perforation in the Sheet group. A histopathological examination revealed that continuity of the duodenal wall at the ESD site was maintained with dense connective tissue in the Sheet group. In conclusion, autologous myoblast sheets were useful for preventing perforation after duodenal ESD.
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http://dx.doi.org/10.1177/0963689720963882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784576PMC
October 2020

Study Protocol for Assessing the Efficacy of Compression Therapy Using Stockings and Sleeves to Prevent Docetaxel-Induced Peripheral Neuropathy in Breast Cancer Patients.

Acta Med Okayama 2020 Oct;74(5):455-459

Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan.

Taxanes are key drugs for patients with breast cancer. A major adverse effect associated with the administration of the taxane docetaxel is chemotherapy-induced peripheral neuropathy (CIPN). We are conducting a singlecenter, single-arm, open-label historical control trial to evaluate the ability of compression therapy using stockings or sleeves to prevent CIPN due to docetaxel treatment. The primary endpoint is the incidence of all-grade CIPN according to patients' records until 3 weeks after the fourth docetaxel administration. This study's results will clarify whether compression therapy using stockings or sleeves can prevent CIPN in breast cancer patients.
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http://dx.doi.org/10.18926/AMO/60808DOI Listing
October 2020

The incidence of non-ampullary duodenal cancer in Japan: The first analysis of a national cancer registry.

J Gastroenterol Hepatol 2021 May 9;36(5):1216-1221. Epub 2020 Oct 9.

Department of Surgery, Nara Medical University, Nara, Japan.

Background And Aim: Although duodenal cancer is rare, no epidemiological research on this disease has been conducted in Asian countries. We aimed to elucidate the incidence and clinical features of duodenal cancer in Japan using a large-scale national database.

Methods: Data of patients with primary duodenal cancer diagnosed from January 1, 2016, to December 31, 2016, were extracted from the Japanese national cancer registry. Excluding malignant neoplasm of the Vater's ampulla, we calculated the incidence among the population as a crude number of patients with duodenal cancer divided by the total Japanese population in 2016. We performed multivariate analyses using logistic regression models to identify risk factors for advanced cancer, defined as metastatic cancer or local invasion to adjacent organs.

Results: Data on 3005 patients were included. The incidence of duodenal cancer was 23.7 per 1 000 000 person-years. In total, 56.4% of cases were detected at the localized stage. In the localized cancer group, endoscopic resection was more frequently performed (48.0%), whereas in the advanced cancer group, surgery and chemotherapy were the major treatment options (39.3% and 41.5%, respectively). Multivariate analyses identified age ≥80 years (odds ratio [OR], 1.489; 95% confidence interval [CI], 1.113-1.992; P = 0.007), incidental detection (OR, 2.325; CI, 1.623-3.331; P < 0.0001), and precise examination for symptomatic patients (OR, 10.561; CI, 7.416-15.042; P < 0.0001) as independent risk factors for advanced cancer.

Conclusions: Our study revealed the incidence of duodenal cancer in Japan. However, localized cancer was the major tumor stage at detection, resulting in a high rate of endoscopic resection.
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http://dx.doi.org/10.1111/jgh.15285DOI Listing
May 2021

Efficacy of endoscopic preventive procedures to reduce delayed adverse events after endoscopic resection of superficial nonampullary duodenal epithelial tumors: a meta-analysis of observational comparative trials.

Gastrointest Endosc 2021 Feb 22;93(2):367-374.e3. Epub 2020 Aug 22.

Department of Surgery, Nara Medical University, Nara, Japan.

Background And Aims: Although various procedures have been used to prevent serious adverse events after endoscopic resection of the duodenum, their effectiveness has not been determined. In this study, we conducted a systematic review and meta-analysis to determine whether endoscopic preventive procedures reduce delayed adverse events.

Methods: Studies on endoscopic treatment for superficial nonampullary duodenal tumors were selected. We compared the following 2 groups: the closure group, which underwent mucosal sutures and coverage of mucosal defects after resection, and the unclosed group, which did not. The primary outcome was the rate of delayed adverse events, including perforation and bleeding. The pooled risk ratios (RRs) of all outcomes investigated, the 95% confidence intervals (CIs), and P values were calculated.

Results: A total of 438 patients from 4 studies were included in the meta-analysis. The pooled overall adverse event rates in the closure group and unclosed group were 3.6% and 21.1%, respectively. This rate was significantly lower in the closure group (RR, 0.19; 95% CI, 0.10-0.38; P < .01; I = 0%), and the rate of delayed bleeding was significantly lower in the closure group (RR, 0.14; 95% CI, 0.06-0.33; P < .01; I = 0%). Regarding delayed perforation, the RR in the closure group was 0.39 (95% CI, 0.12-1.32; P = .13; I = 0%).

Conclusions: Preventive procedures significantly reduced the risk of delayed adverse events by more than 80%. After endoscopic resection of the duodenum, the implementation of preventive procedures, including mucosal sutures and coverage of mucosal defects, to delay adverse events is strongly recommended.
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http://dx.doi.org/10.1016/j.gie.2020.08.017DOI Listing
February 2021

Differentiation of chemically induced liver progenitor cells to cholangiocytes: Investigation of the optimal conditions.

J Biosci Bioeng 2020 Nov 9;130(5):545-552. Epub 2020 Aug 9.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Electronic address:

Chemically induced liver progenitor (CLiP) cells, converted in vitro from mature hepatocytes, possess the bipotentiality to differentiate into both hepatocytes and cholangiocytes. Here, we aimed to investigate the optimal conditions for bile duct (BD) induction from rat CLiPs. A two-step induction protocol was used for the differentiation of cholangiocytes. We investigated the effects of passage number, preincubation times, Matrigel, and mouse embryonic fibroblast (MEF) feeder cells on the induction of cholangiocytes. Earlier passages of CLiPs were better for BD induction compared with stable CLiPs. Extending the preincubation time of CLiPs before induction delayed the formation of the BD. Matrigel provided cells with space to form three-dimensional (3D) structures, but the long-term use of Matrigel from the induction step did not benefit the differentiation of CLiPs to cholangiocytes. MEF feeder cells, through the Jag/Notch pathway, affected BD formation and function, as well as gene and protein expression. CLiPs were a good cell source for cholangiocyte differentiation under appropriate conditions and may offer a key vehicle for the study of cholangiopathies in vitro.
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http://dx.doi.org/10.1016/j.jbiosc.2020.07.009DOI Listing
November 2020

Living donor liver transplantation for congenital absence of portal vein in portal venous reconstruction with a great saphenous vein graft.

Surg Case Rep 2020 Jun 29;6(1):153. Epub 2020 Jun 29.

Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto, Nagasaki, 852-8102, Japan.

Background: Congenital absence of portal vein (CAPV) is a rare structural anomaly in which the portal vein (PV) blood that normally flow into the liver directly drains into the systemic venous system through other collateral circulation. Congenital portal vein shunts (CPSs) is classified into types I and II according to the absence or presence of the intrahepatic portal vein, respectively. The CPS type I is also known as CAPV. The liver transplantation may be the only treatment option for CAPV. The key point of liver transplantation for CAPV is the reconstruction of the PV.

Case Presentation: A 29-year-old man was diagnosed with CAPV with splenomegaly and gastroesophageal varix when being treated for pancytopenia and liver dysfunction. A living donor liver transplantation was performed for him using the right lobe which had been donated by his mother. The PV was reconstructed using his own great saphenous vein (GSV) as a graft vein. The end of the GSV graft was anastomosed to the inferior mesenteric vein while the other end was anastomosed to the vein graft of the right hepatic vein from the explanted liver.

Conclusion: Using the patient's own GSV for PV reconstruction during living donor transplantation in the patient with CAPV seems to be an effective method.
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http://dx.doi.org/10.1186/s40792-020-00916-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324451PMC
June 2020

Packing procedure effective for liver transplantation in hemophilic patients with HIV/HCV coinfection.

Surg Today 2020 Oct 22;50(10):1314-1317. Epub 2020 Jun 22.

Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan.

We herein report an effective procedure for liver transplantation (LT) for severe cirrhotic patients with hemophilia. Three hemophilic patients suffering from liver cirrhosis due to human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection underwent deceased donor LT in our institute. Basic clotting parameters were measured and evaluated during LT to determine the optimal packing procedure. All patients were treated with a gauze packing procedure to ensure stable hemostasis in relation to hemophilia during the peri-transplant period. The graft function of all patients recovered well upon gauze removal (depacking) procedure and the patients were finally discharged to home. The administration of clotting factor was discontinued on day 3 after deceased donor LT. No infectious complications occurred in any of the 3 patients. This technique could be an option for achieving successful LT in these patients. Cooperation between transplant surgeons and anesthesiologists can make this challenging operation possible.
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http://dx.doi.org/10.1007/s00595-020-02051-1DOI Listing
October 2020

Downstaging and Histological Effects Might Be Reliable Predictors of the Efficacy of DOC+CDDP+5-FU (DCF) as Neoadjuvant Therapy for Stage III or Borderline Resectable Esophageal Cancer: a Single Institute Experience.

J Gastrointest Cancer 2020 Jun 10. Epub 2020 Jun 10.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki City, Nagasaki, 852-8501, Japan.

Purpose: In Japan, two courses of CDDP+5-FU (CF) therapy followed by surgery are accepted as a standard treatment for stage II/III esophageal cancer (EC) based on the results of the JCOG9907 trial. To gain a better survival, benefit especially for stage III patients in comparison with CF therapy, a three-arm phase III trial (neoadjuvant setting: CF vs. CF + radiation vs. DOC+CF [DCF]) is ongoing. We have aggressively performed DCF therapy for stage III or IV patients since October 2014. We herein review the outcomes of DCF therapy.

Methods: We retrospectively reviewed the cases of 27 patients with stage III or IV EC (male, n = 24; female, n = 3; median age, 70.0 years) who received DCF therapy.

Results: The response rate was 48.1%. Downstaging was achieved over the course of treatment in 14 patients (51.9%). Twenty-six patients transitioned to surgery, with 25 receiving R0 resection. DCF-treated patients who achieved downstaging showed significantly longer relapse-free survival (RFS) than those without downstaging (p = 0.0002). DCF-treated patients with a grade ≥ 1b histological effect showed significantly longer RFS than those with a grade < 1b effect (p = 0.0282). The multivariate analysis showed that downstaging was the only factor significantly associated with RFS in DCF-treated patients.

Conclusions: DCF therapy for stage ≥ III esophageal carcinoma is both feasible and effective. These findings suggest that downstaging and the histological effect might predict the effects of DCF therapy for EC.
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http://dx.doi.org/10.1007/s12029-020-00431-xDOI Listing
June 2020

Simultaneous Deceased Donor Liver and Kidney Transplantation in a Human Immunodeficiency Virus/Hepatitis C Virus -Coinfected Patient With Hemophilia in Japan: A Case Report.

Transplant Proc 2020 Nov 14;52(9):2786-2789. Epub 2020 May 14.

Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The authors describe the first case of simultaneous liver and kidney transplantation (SLK) in a human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patient with severe hemophilia in Japan, and it could be second case in the world. The patient was a 61-year-old Japanese man with HCV cirrhosis complicated with HIV coinfection through contaminated blood product for hemophilia B at age 1 year. The patient's liver disease was classified as Child-Pugh C, Model for End-Stage Liver Disease score 38. He had been on hemodialysis for 6 years, but HIV RNA and HCV RNA had been undetectable after appropriate antiviral therapies. In September 2019, the patient underwent successful deceased donor (DD) SLK. The donor was a man in his 60s deceased due to cerebral hemorrhage. Regular DD liver transplantation was performed using the piggyback technique with a full-sized liver graft. Cold ischemia time was 566 min, and the graft liver weighed 1154 g. The graft kidney was transplanted extraperitoneally in the right iliac fossa. The administration of clotting factor IX was discontinued on day 3. The immunosuppressive regimen was based on intravenous induction with 2 mg/kg of basiliximab and 1 g methylprednisolone and subsequent oral administration of mycophenolate mofetil and prednisolone, followed by low-dose tacrolimus after 1 week for kidney-sparing purpose. Steroid therapy was gradually discontinued at 3 months after SLK. The same pretransplantation antiretroviral therapy (ART; tenofovir and dolutegravir) was introduced after 3 days when the CD4 cell count was more than 300/μL and HIV RNA was within an undetectable range. The postoperative course was uneventful without infectious complication, and the patient was transferred to a referral hospital on day 90 and discharged home on day 111. Strategic surgical planning and meticulous pre- and post-transplant management of ART and clotting factors could lead to the success of SLK.
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http://dx.doi.org/10.1016/j.transproceed.2020.05.005DOI Listing
November 2020

Difference in driver gene expression patterns between perihilar and peripheral intrahepatic cholangiocarcinoma in an experimental mouse model.

J Hepatobiliary Pancreat Sci 2020 Aug 13;27(8):477-486. Epub 2020 Jul 13.

Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Background: The prognosis of intrahepatic cholangiocarcinoma (ICC) is based on tumor localization; however, the mechanism remains unknown. Therefore, we investigated the biological characteristics of perihilar and peripheral ICC in a mouse model.

Methods: The model was established by the administration of three oncogenic plasmids harboring myristoylated AKT, mutated human YAP, and pCMV-Sleeping Beauty into the mice. The perihilar and peripheral ICC tumors that developed in the same mouse were assessed for the expression of cell adhesion factors and driver genes with immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR).

Results: The perihilar ICC tumors were irregularly shaped, whereas the peripheral tumors were mostly circular, similar to the differences found in patients. Alpha-smooth muscle actin was strongly expressed in the perihilar tumors at 10 weeks, and vimentin expression was significantly up-regulated in the perihilar ICC at 14 weeks. Fgfr2 level significantly increased in peripheral ICC at 10 weeks, whereas Idh2 expression was up-regulated in perihilar ICC.

Conclusions: Despite diffuse injection of oncogenic plasmid, expression of driver genes and oncogenes in ICC tumor cells differs depending on the tumor localization, resulting in changes in epithelial-mesenchymal transition, which may explain the different outcomes of patients with peripheral and perihilar ICC.
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http://dx.doi.org/10.1002/jhbp.772DOI Listing
August 2020

[Locally Advanced Rectal Cancer Curatively Resected after Modified FOLFOXIRI plus Bevacizumab Chemotherapy-A Case Report].

Gan To Kagaku Ryoho 2020 Mar;47(3):453-455

Dept. of Surgery, Nagasaki University Graduate School of Biomedical Sciences.

A 69-year-old man with dyschezia was diagnosed with locally advanced colorectal cancer invading the urinary bladder and pelvis. We performed ileostomy to avoid passage disturbance because curative resection was difficult. The patient received 2 courses of modified FOLFOXIRI plus bevacizumab. The size of the primary tumor and lymph nodes decreased after chemotherapy. High anterior resection with D3 lymph node dissection was performed. Histopathological analysis revealed that the tumor stage was pT3, N0, M0, StageⅡ. The patient has been receiving adjuvant chemotherapy with oral UFT/UZEL for 6months. No recurrence has been observed for the past 4 months.
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March 2020

S-1 and CPT-11 Plus Ramucirumab (IRIS+Rmab) as Second-Line Chemotherapy for Patients with Oxaliplatin-Refractory Metastatic Colorectal Cancer (mCRC): A Multicenter Phase II Study in Japan (N-DOCC-F-C-1701).

Kurume Med J 2020 Jul 1;66(1):43-47. Epub 2020 May 1.

Department of Surgery, Nagasaki Rosai Hospital.

This multicenter phase II N-DOCC-F-C-1701 trial is being planned in order to investigate the efficacy and safety of CPT-11+S-1 +Ramucirumab (IRIS+Rmab), which is anticipated to have a stronger anti-tumor effect than IRIS+Bmab in patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin (L-OHP) containing regimen, in consideration of the result of RAISE, FIRIS and some phase II trials of IRIS+Bevacicizumab (Bmab). The number of patients is set at 38 for the statistical analysis, assuming an expected median PFS of 5.0 months (threshold: 3.0 months). The primary endpoint of the study is the progression free survival (PFS), and the secondary endpoints are the overall response rate (ORR), overall survival (OS), adverse events (AE), quality of life (QOL) and review of nausea and vomiting. This trial is registered in the UMIN Clinical Trials Registry as UMIN000028170. We intend to start conducting the trial in September 1, 2017. If this trial meets the endpoint, IRIS+Rmab might be supported as a new optional standard regimen for mCRC.
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http://dx.doi.org/10.2739/kurumemedj.MS661007DOI Listing
July 2020

Establishment of an in-vivo porcine delayed perforation model after duodenal endoscopic submucosal dissection.

Dig Endosc 2021 Mar 22;33(3):381-389. Epub 2020 Jun 22.

Departments of, Department of, Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Objectives: Duodenal endoscopic submucosal dissection (ESD) for superficial non-ampullary duodenal epithelial tumors has a significant incidence rate of delayed perforation. Although several methods have been proposed to prevent delayed perforation, the most appropriate methods remain unclear. Currently, there is no appropriate animal model to validate methods for preventing duodenal delayed perforation. This study aimed to establish an in-vivo porcine delayed perforation model after duodenal submucosal dissection.

Methods: Two porcine models underwent either ESD or surgical submucosal dissection. In the surgical dissection model, an inverted duodenal mucosa was resected with electrosurgical energy. In the ESD model, a gauze was placed behind the duodenum with grasped transverse part to improve endoscopic maneuverability. The mucosal defects after dissection were treated with omental coverage without suture in both models. All models were euthanized 0-5 days after procedure. Body weight; resection size; procedure dissection time; presence of intraoperative perforation and delayed perforation; and adhesion score were assessed.

Results: There were no significant differences in body weight and adhesion score between the two models. Resection size was significantly larger in the surgical dissection models than in the ESD models (19 mm vs 14.3 mm, P < 0.01). Procedure time was significantly longer in the ESD models than in the surgical models (45.2 minutes vs 4.5 minutes, P < 0.01). Delayed perforation rates in the surgical dissection models and the ESD models were 0% (0/5) and 100% (5/5), respectively (P < 0.01).

Conclusions: This study indicated that our in-vivo porcine duodenal ESD model is beneficial to evaluate a prevention strategy for delayed perforation.
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http://dx.doi.org/10.1111/den.13710DOI Listing
March 2021

The Efficacy of Software to Help Patients Understand Drug for Adjuvant Treatment for Breast Cancer: A Pilot Randomized Controlled Trial.

Acta Med Okayama 2020 Apr;74(2):95-101

Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan.

We assessed the usefulness of ChemoCalc, a software package for calculating drug costs, in helping patients understand these costs. We randomly assigned, in a 1 : 1 ratio, 20 women who had undergone surgery for early breast cancer to a group that discussed adjuvant treatment with their physicians using the ChemoCalc software (ChemoCalc group) or a group that discussed adjuvant treatment without ChemoCalc (Usual Explanation group). The participants completed a five-grade evaluation questionnaire after these discussions. The primary endpoint was the intergroup comparison of the questionnaire scores regarding participants' understanding of their treatment-associated drug costs. Median age was not significantly different between the ChemoCalc group and Usual Explanation group (57 vs. 50, respectively; p=0.27). Patients in the ChemoCalc group had a significantly higher perceived level of understanding of the drug cost than those in the Usual Explanation group (5 [4-5] vs. 2.5 [1-5], respectively; p=0.002). Scores related to the patients' perception that understanding drug costs is an important part of breast cancer treatment were also higher in the ChemoCalc group than the Usual Explanation group (5 [2-5] vs. 3 [1-5], respectively; p=0.049). ChemoCalc was found to be useful for understanding drug costs.
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http://dx.doi.org/10.18926/AMO/58266DOI Listing
April 2020

Optimal Tumor Reduction Rate and Modalities for Predicting pCR in Women With Breast Cancer.

Anticancer Res 2020 Apr;40(4):2303-2309

Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.

Background/aim: To predict pCR during neoadjuvant chemotherapy is still difficult. The aim of this study was to evaluate the optimal tumor reduction rate and modalities for predicting pCR after two cycles of docetaxel.

Patients And Methods: We analyzed 52 patients with HER2-positive or triple-negative breast cancer. The tumor reduction rate was evaluated after two 3-week cycles of docetaxel (plus trastuzumab for HER2-positive cancer patients). Patients without progression completed two additional cycles of docetaxel and four cycles of an anthracycline-containing regimen.

Results: Twenty-eight patients achieved pCR. The optimal tumor reduction rates for predicting pCR were 23, 39, 32, and 40% for US, caliper, MMG, and MRI measurements, respectively. The AUC was highest for caliper measurements. The optimal modality for predicting pCR differed among subtypes.

Conclusion: Although tumor reduction rate after two cycles of chemotherapy is highly predictive of pCR, the optimal cutoff value differed among the modalities and breast cancer subtype.
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http://dx.doi.org/10.21873/anticanres.14196DOI Listing
April 2020

Daikenchuto improved perioperative nutritional status of the patients with colorectal cancer: A prospective open-labeled randomized exploratory study.

Interv Med Appl Sci 2019 Jun;11(2):84-88

Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Background And Aims: The aim of this study is to exploratively evaluate the effect of Tsumura Daikenchuto Extract Granules (DKT, TJ-100) on abdominal symptoms, body weight, and nutritional function following colorectal cancer surgery.

Methods: The subjects included 20 patients for curative resection of colorectal cancer. A TJ-100 administration group ( = 10) and non-administration group ( = 10) were randomized and compared. In the administration group, TJ-100 was administered from 2 days prior to surgery up to 12 weeks following surgery. The endpoints included body weight gain, Gastrointestinal Symptom Rating Scale (GSRS), and blood biochemical factors. For the purpose of observing safety, drug adverse events were evaluated including liver function tests.

Results: Excluding one patient, we compared 9 cases in the administration group and 10 cases in the non-administration group. No obvious adverse events were observed in any of the cases. In the comparison of body weight gain, the TJ-100 administration group showed significantly higher values at 2, 4, and 12 weeks following the surgery. There was a tendency for lower stable GSRS scores in the administration group overall, with no statistically significant difference.

Conclusion: It is suggested that TJ-100 can be safely administered in the perioperative period for cases undergoing colorectal cancer surgery, potentially preventing weight loss during the early postoperative period.
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http://dx.doi.org/10.1556/1646.11.2019.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044534PMC
June 2019

Efficacy and Safety of Modified FOLFOXIRI+α in the Treatment of Advanced and Recurrent Colorectal Cancer: A Single-center Experience.

Intern Med 2020 May 19;59(10):1239-1245. Epub 2020 Feb 19.

Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan.

Objective In the treatment of advanced and recurrent colorectal cancer (ARCC), FOLFOXIRI regimens have been proven to be significantly superior to FOLFIRI in terms of the progression-free survival (PFS), response rate (RR), and overall survival (OS). Furthermore, the Tribe trial showed that the RR and PFS rates in patients who received bevacizumab (Bmab) +FOLFOXIRI were superior to those in patients treated with Bmab+FOLFIRI. A phase III trial of panitumumab (Pmab) +FOLFOXIRI is currently ongoing. A modified FOLFOXIRI regimen is also widely used to reduce adverse events. In our department, we introduced modified FOLFOXIRI+α (mFOLFOXIRI+α) in 2015. The present study reviewed the efficacy and safety of mFOLFOXIRI+α. Methods Eligible patients were retrospectively reviewed, and their results were compared to those of patients treated with other regimens (OTHERS) (n=134) to demonstrate the efficacy of this treatment. Patients: Between February 2015 and November 2018, 12 patients with ARCC (male/female=6/6; average age, 60.7 years old) received mFOLFOXIRI+α (Bmab: 10, Pmab: 1, alone: 1). Results The median PFS in the mFOLFOXIRI+α and OTHERS groups was 565 and 322 days, respectively (p=0.0544). The RR in the mFOLFOXIRI+α and OTHERS groups was 66.7% and 31.3%, respectively (p=0.0135). The conversion rate (Conv R) in the mFOLFOXIRI+α and OTHERS groups was 50.0% and 12.7%, respectively (p=0.0007). While 58% of patients treated with FOLFOXIRI+α developed grade ≥3 leukopenia, the incidence of febrile neutropenia (FN) was only 17%. In all patients with symptoms due to the tumor burden, the symptoms subsided with mFOLFOXIRI+α treatment. Conclusion Based on the RR, Conv R, and symptom palliation ability, mFOLFOXIRI+α was suggested to be a viable candidate for first-line treatment for patients with ARCC, especially those with a high tumor burden.
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http://dx.doi.org/10.2169/internalmedicine.3274-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303458PMC
May 2020

Study protocol for efficacy and safety of steroid-containing mouthwash to prevent chemotherapy-induced stomatitis in women with breast cancer: a multicentre, open-label, randomised phase 2 study.

BMJ Open 2020 02 13;10(2):e033446. Epub 2020 Feb 13.

Surgery, Nagasaki University School of Medicine Graduate School of Biomedical Sciences, Nagasaki, Japan.

Introduction: Stomatitis is a frequent adverse event in patients undergoing chemotherapy for breast cancer. Stomatitis can hamper oral nutrition resulting in malnutrition, reduce quality of life and introduce the need for dose reductions and interruption of chemotherapy; however, there is currently no standard approach for preventing chemotherapy-induced stomatitis. We aimed to assess the safety and efficacy of a dexamethasone-based elixir mouthwash for preventing chemotherapy-induced stomatitis in patients with early breast cancer.

Methods And Analysis: In this multicenter, randomised, controlled phase 2 trial, we will randomly assign 120 women with early breast cancer undergoing chemotherapy to use of a dexamethasone-based elixir or standard oral care, to compare their preventive effects on chemotherapy-induced stomatitis. Patients will be assigned in a 1:1 ratio. Patients in the intervention group will receive chemotherapy, oral care and a dexamethasone-based elixir (10 mL 0.1 mg/mL; swish for 2 min and spit, four times daily for 9 weeks), and patients in the control group will receive chemotherapy and oral care. The primary endpoint is the difference in incidence of stomatitis between the two groups. The sample size allows for the detection of a minimum difference of 20% in the incidence of stomatitis between the two groups. Secondary endpoints are severity of stomatitis, duration of stomatitis, completion rate of chemotherapy and adverse events.

Ethics And Dissemination: All participants signed a written consent form, and the study protocol has been reviewed and approved by the Clinical Research Review Board of Nagasaki University (CRB7180001).

Trial Registration Number: UMIN Clinical Trials Registry (UMIN000030489).
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http://dx.doi.org/10.1136/bmjopen-2019-033446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045258PMC
February 2020