[Two Cases of the Significant Liver Damage by Regorafenib].

There is a liver damage in a serious side effect of regorafenib. Case 1 was a 54-year-old woman, and she had an operation of rectal cancer and metastasized to multiple organs afterwards and started regorafenib as third-line. Erythema exudativum multiform developed on the 8th day after a start and regorafenib was canceled once and reduced on the 21st day when a skin symptom was relieved and restarted. However, because a significant rise of AST, ALT, T -Bil was recognized afterwards, regorafenib was canceled on the 27th day and enforced steroid pulse therapy and was relieved afterwards. Case 2 was a 61-year-old woman, and she had an operation of ascending colon cancer, ovarian metastasis and peritoneum dissemination. Regorafenib was started by frequent occurrence lung metastasis, cancerous pleurisy afterwards as fifth-line. Dissemination erythema developed on the 16th day and a liver damage developed on the 22nd day. Because a rise of AST, ALT went and was prolonged, liver biopsy was enforced in a cause close inspection purpose on the 45th day. A medicamentosus liver damage was diagnosed. The liver enzyme decreased afterwards. It may be easy to make the liver damage by regorafenib serious, and attention is necessary.

[A Case of Myeloid Sarcoma in the Small Intestine Presenting with Intussusception].

A sixty-something man presented with lower abdominal pain in early Y month 20XX, and was examined at the hospital's internal medicine outpatient clinic. An abdominal CT showed a soft tissue mass around the left hip joint, and multiple enlarged lymph nodes from inside the pelvis to the mesentery of the abdomen. We noted a small-intestinal intussusception in the lower right abdomen, and suspected malignant lymphoma. We did a CT-guided biopsy on the left hip joint soft tissue mass, and performed surgery on the small-intestinal intussusception. During surgery, we noted an approximately 30 cm ileal intussusception located about 60 cm from the terminal ileum, and enlarged lymph nodes in the nearby mesentery. We removed the ileal intussusception. The pathological diagnosis was myeloid sarcoma, and the soft tissue mass in the left hip joint was also diagnosed as myeloid sarcoma. We performed a bone-marrow biopsy at the hematology department, and diagnosed acute myeloid leukemia M2. We then started remission-induction therapy and consolidation therapy, and the patient was diagnosed as in remission in Y+5 month 20XX. We also need to keep in mind myeloid sarcoma in the intestine as a subtype of acute myeloid leukemia, as malignant tumor in the small intestine presenting with intussusception.

[A Case of Rectal Cancer Presenting with Perianal Abscess].

An 81-year old man with a perirectal abscess was referred in May 2017 by another hospital. We observed swelling in the anal region at the 4 o'clock position and performed incisional drainage. Although this alleviated the pain and inflammation in the anal region, the irritation recurred in early June. The patient presented with bloody stools and a low-grade fever since late June. Pelvic magnetic resonance imaging(MRI)confirmed a solid tumor in the center of the lower rectum(Rb), outside of the anal fistula. We surmised this was rectal cancer. Colonoscopy revealed an ulcerative invasive(Grade 3)tumor extending more than halfway around the Rb; a biopsy confirmed a diagnosis of differentiated adenocarcinoma. Surgery was the preferred treatment option; however, as the patient also had the complication of anal fistula, there were concerns that the cancerous cells would contaminate the intraperitoneal area during surgery. We subsequently we decided to construct a colostomy and then start chemoradiotherapy. The patient began radiotherapy in the beginning of August, and received S-1 as a sensitizer. Contrast computed tomography(CT)and MRI at the completion of chemoradiotherapy confirmed that the rectal cancer had reduced in size. We scheduled later surgery, but the patient declined and preferred to continue with S-1. The tumor has continued to decrease in size, with good local control.

[A Case of SIADH in an Elderly Patient with Advanced Gastric Cancer].

An 82-year-old woman underwent surgery for gastric cancer at another hospital in May 2007. The pathological diagnosis was pT4a, pN2, M1, CY1, pStage Ⅳ. Although postoperative chemotherapy was administered, recurrence was observed on the abdominal wall in March 2014, and she was treated usingchemotherapy and resection. Intestinal obstruction due to peritoneal metastasis occurred in December 2017 and mid-July 2018 but symptoms improved with conservative treatment. In late August 2018, she was unable to eat and was readmitted to the hospital. Serum Na level at admission was low at 120 mEq/L, and Na correction was performed. Hyponatremia did not improve, and the serum Na level continued to decrease to 115mEq/L on the 14th day of hospitalization. Plasma osmolality was 229mOsm/kg, urine osmolality was 323mOsm/kg, and urine sodium concentration was 56mEq/L. Diagnosis of SIADH was made according to diagnosis standards. Hyponatremia improved by fluid restriction and Na correction. Subsequently, her peritoneal metastasis exacerbated, and she died in mid- October. We would like to report a case of SIADH in an elderly patient with advanced gastric cancer.

[A Case of Duodenum Dissemination after Surgery for Transverse Colon Carcinoma Which Was Unresponsive to Chemotherapy, but Immunotherapy Was Significantly Effective].

The patient was a 73-year-old woman who received surgery for transverse colon cancer(laparoscopic right hemicolectomy) in December 2014. Histopathologic examination findings were tub2, pT4b, pN1, sH0, sM0, ly2, v0, Stage III a. XELOX 2 courses→FOLFIRI plus panitumumab(Pmab)12 courses was performed after surgery. Stenosis due to duodenum dissemination was observed in the follow-up period(December 2015), and a laparoscopic gastrojejunostomy was performed. Later, the patient's tumor marker value significantly increased, and enlargement of duodenum dissemination was observed by abdominalCT. From April 2016, treatment was switched to mFOLFOX6 plus Pmab and 5 courses were subsequently performed. Still, metastasis to the abdominal wall was observed. According to results of the microsatellite instability test of MSIH, the patient was registered into a clinicaltrialfor pembrolizumab, which is anti-PD-1, and administration began from June. The tumor marker value significantly decreased, and a reduction in the size of the duodenum dissemination over time could also be observed by abdominal CT. Significant tumor reduction was observed, indicating that immune therapy may be significantly effective in some cases.

[A Case Where Rectal Cancer Ileus Caused Perforation in the Ascending Colon].

The patient was a 65-year-old man. He had not defecated for a week in early December 2015, and had noticed abdominal pain and abdominaldistension from 4 days prior. The pain and distension worsened, and the patient was rush transported to our hospital. Via abdominal CT we found free air in the upper abdomen, expansion of the small and large intestines, and notably, significant intestinal tract expansion and a gas reservoir in the ascending colon. We found significant narrowing as well as hypertrophy along the entire circumference of the rectum and suspected gastrointestinal perforation due to rectal cancer ileus. Inflammation findings were abnormally high and we performed emergency surgery. We found a laceration on the ascending colon, which had expanded markedly. We elevated that location and installed a colostomy. Following surgery the patient developed mild SSI and ileus, which were alleviated through conservative treatment. A month after the operation we performed a colonoscopy and found a tumor along the entire circumference of the rectum Rs. It was diagnosed as group V tub1-2 via biopsy. We performed surgery in late January 2016(colostomy closure, laparotomy rectal low anterior resection). We are reporting a rare case where rectal cancer ileus caused perforation in the ascending colon.

[A Case of Colorectal Cancer with Anaphylactic Shock to Oxaliplatin].

We present the case of a 61-year-old woman with cecum cancer, ileal and multiple hepatic metastases, and peritoneal dissemination. Surgery (right hemicolectomy) was performed on December 2013. After surgery, 7 courses of mFOLFOX6 plus bevacizumab were administered. In May 2014, 4 minutes after starting the 8th course of oxaliplatin, dyspnea, nausea, vomiting, and general malaise were observed. Oxaliplatin administration was immediately discontinued and an injection of an antiemetic drug was administered, but the patient's blood pressure dropped to 87/53 mmHg and the SpO2 decreased to 87% (room air). The patient showed facial pallor; oxygen administration was initiated. Although blood pressure recovered to 124/69 mmHg 3 minutes after oxygen administration, reddening of the palms, pruritus, and headache were observed. The dyspnea eased 8 minutes after oxygen administration, the SpO2 recovered 18 minutes after oxygen administration, and the headache ceased. The patient subsequently was admitted to the hospital for observation, but no significant change was observed, and she was discharged the following day. Anaphylaxis due to oxaliplatin occurring after the 6th course is commonly reported, and the symptoms in this case were comparable to those described in the literature.

[A case in which metachronous ovarian metastasis developed 9 months after surgery for cecal carcinoma perforation and peritonitis].

The patient was a 78-year-old woman who underwent surgery for cecal carcinoma perforation and peritonitis (ileocecal resection and ileostomy)in January 2012. Liver metastasis was observed on the postoperative computed tomography (CT) scan and chemotherapy was performed. However, in October, a CT scan revealed a tumor, 9 cm in diameter, in the right ovary. Based on the results of a positron emission tomography (PET)-CT scan, this was suspected to be primary or metastatic ovarian cancer, and bilateral salpingo-oophorectomy was performed the following January. Histopathology and immunostaining indicated that this was a cytokeratin (CK) 20-positive and CK7-negative adenocarcinoma, and the patient was diagnosed with metastatic cecal carcinoma.

[A case of ascending colon signet-ring cell careinoma discovered after treatment for acute cholecystitis].

A 81-year-old woman confined to full bed rest due to the effects of a stroke 7 years prior, was brought to our hospital with acute cholecystitis in late April 2013. After PTGBD, her condition improved and she was discharged in early June. However, she was urgently hospitalized at the beginning of August with melena and a fever. A detailed examination revealed aspiration pneumonia, which was resolved with a course of antibiotics. A colonoscopy, conducted to find the cause of the melena, revealed a circumferential type 2 tumor in the ascending colon, and a fiberscope was unable to pass through the stenosis. A biopsy confirmed a diagnosis of signet-ring cell carcinoma. Using abdominal computed tomography, thickening of the ascending colon wall, suggesting infiltration to the periphery, was visible. The adjacent lymph nodes were enlarged, but there were no clear signs of liver metastasis. Cancerous peritonitis was suspected due to the presence of ascitic fluid. Considering the overall condition of the patient, surgery was not performed, and colonic stent was not placed due to the proximity of the stenosis to the ileocecal valve. The patient's family chose best supportive care. The patient's condition worsened and she died 3 months after leaving the hospital.

Significant improvement in islet yield and survival with modified ET-Kyoto solution: ET-Kyoto/Neutrophil elastase inhibitor.

Although islet transplantation can achieve insulin independence in patients with type 1 diabetes, sufficient number of islets derived from two or more donors is usually required to achieve normoglycemia. Activated neutrophils and neutrophil elastase (NE), which is released from these neutrophils, can directly cause injury in islet grafts. We hypothesized that inhibition of NE improves islet isolation and islet allograft survival. We tested our hypothesis by examining the effects of modified ET-Kyoto solution supplemented with sivelestat, a NE inhibitor (S-Kyoto solution), on islet yield and viability in islet isolation and the effect of intraperitoneally injected sivelestat on islet graft survival in a mouse allotransplant model. NE and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increased markedly at the end of warm digestion during islet isolation and exhibited direct cytotoxic activity against the islets causing their apoptosis. The use of S-Kyoto solution significantly improved islet yield and viability. Furthermore, treatment with sivelestat resulted in significant prolongation of islet allograft survival in recipient mice. Furthermore, serum levels of IL-6 and TNF-α at 1 and 2 weeks posttransplantation were significantly higher in islet recipients than before transplantation. Our results indicated that NE released from activated neutrophils negatively affects islet survival and that its suppression both in vitro and in vivo improved islet yield and prolonged islet graft survival. The results suggest that inhibition of NE activity could be potentially useful in islet transplantation for patients with type 1 diabetes mellitus.

[Surgical treatment for gall bladder cancer with a confluence stone-a case report].

The patient was a 71-year-old man. In September 2011, he experienced abdominal pain with high fever. Abdominal computed tomography (CT) diagnosed acute cholecystitis with a confluence stone (corlette classification type II). He underwent total cholecystectomy and placement of a T-tube in the main bile duct through the gall bladder duct. However, pathological investigations revealed gall bladder cancer in the neck and body part of the gall bladder, leading to a diagnosis of gall bladder adenocarcinoma(Gbn, Flat type, tub2, INF ß,pSS, pHinf0, pBinf1, pPV0, pA0, pT3) with a confluence stone. We suspected that the tumor was present in the common bile duct. Therefore, in October 2011, he underwent choledochectomy, resection of the liver bed, lymph node dissection, and choledocho-jejunostomy. Pathological findings revealed that the tumor was present in the common bile duct. He died 8 months after the last surgery because of recurrence of peritoneal metastasis.

Combined transplantation of pancreatic islets and adipose tissue-derived stem cells enhances the survival and insulin function of islet grafts in diabetic mice.

BACKGROUND: Overcoming significant loss of transplanted islet mass is important for successful islet transplantation. Adipose tissue-derived stem cells (ADSCs) seem to have angiogenic potential and antiinflammatory properties. We hypothesized that the inclusion of ADSCs with islet transplantation should enhance the survival and insulin function of the islet graft. METHODS: Syngeneic ADSCs and allogeneic islets were transplanted simultaneously under the kidney capsules of diabetic C57BL/6J mice. Rejection of the graft was examined by measurement of blood glucose level. Revascularization and inflammatory cell infiltration were examined by immunohistochemistry. RESULTS: Transplantation of 400 islets only achieved normoglycemia with graft survival of 13.6±1.67 days (mean±standard deviation), whereas that of 100 or 200 allogeneic islets never reversed diabetes. Transplantation of 200 islets with 2×10(5) ADSCs reversed diabetes and significantly prolonged graft survival (13.0±5.48 days). Results of glucose tolerance tests performed on day 7 were significantly better in islets-ADSCs than islets-alone recipients. Immunohistochemical analysis confirmed the presence of insulin-stained islet grafts with well-preserved structure in islets-ADSCs transplant group. Significant revascularization (larger number of von Willebrand factor-positive cells) and marked inhibition of inflammatory cell infiltration, including CD4+ and CD8+ T cells and macrophages, were noted in the islets-ADSCs transplant group than islets-alone transplant group. CONCLUSIONS: Our results indicated that cotransplantation of ADSCs with islet graft promoted survival and insulin function of the graft and reduced the islet mass required for reversal of diabetes. This innovative protocol may allow "one donor to one recipient" islet transplantation.

Increased immunogenicity of tumor-associated antigen, mucin 1, engineered to express alpha-gal epitopes: a novel approach to immunotherapy in pancreatic cancer.

Mucin 1 (MUC1), a bound mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic carcinoma. Evidence suggests that MUC1 can be used as a tumor marker and is a potential target for immunotherapy of pancreatic cancer. However, vaccination with MUC1 peptides fails to stimulate the immune response against cancer cells because immunity toward tumor-associated antigens (TAA), including MUC1, in cancer patients is relatively weak, and the presentation of these TAAs to the immune system is poor due to their low immunogenicity. We investigated whether vaccination with immunogenetically enhanced MUC1 (by expressing alpha-gal epitopes; Galalpha1-3Galbeta1-4GlcNAc-R) can elicit effective antibody production for MUC1 itself as well as certain TAAs derived from pancreatic cancer cells and induced tumor-specific T-cell responses. We also used alpha1,3galactosyltransferase (alpha1,3GT) knockout mice that were preimmunized with pig kidney and transplanted with B16F10 melanoma cells transfected with MUC1 expression vector. Vaccination of these mice with alpha-gal MUC1 resulted in marked inhibition of tumor growth and significant improvement of overall survival time compared with mice vaccinated with MUC1 alone (P = 0.003). Furthermore, vaccination with pancreatic cancer cells expressing alpha-gal epitopes induced immune responses against not only differentiated cancer cells but also cancer stem cells. The results suggested that vaccination using cells engineered to express alpha-gal epitopes is a novel strategy for treatment of pancreatic cancer.

Prolonged survival of pig islets xenograft by adenovirus-mediated expression of either the membrane-bound human FasL or the human decoy Fas antigen gene.

BACKGROUND: Pig islets are considered an attractive alternative treatment for patients with Type 1 diabetes. However, pig islet xenografts, transplanted into non-human primates, are directly rejected by cell-mediated processes. We have previously reported that cell-mediated xenograft-rejections, and especially human CD8(+) cytotoxic T lymphocytes (CTL)-mediated cytotoxicity, are highly detrimental to pig xenograft cells. Moreover, we have explored novel strategies for the prevention of CTL killing by overexpression of either human decoy Fas antigen or membrane-bound human FasL in pig endothelial cells. In this study, we assessed the cytoprotective effects of these molecules for pig islets both in vitro and in vivo. MATERIALS AND METHODS: Pig islets were freshly isolated by modified Ricordi's methods. Subsequently, these islets were transfected with an adenoviral expression vector containing the DNA fragments of either membrane-bound human FasL or human decoy Fas. Transfected islets were transplanted into preimmunized diabetic rats under the kidney capsule. Control pig islets (i.e., MOCK), which were transfected with an adenoviral expression vector containing only the enhanced green fluorescent protein gene, were also transplanted. RESULTS: Efficiency of adenoviral expressions of these molecules in pig islets was approximately 80% at a multiplicity of infection of 100. In an in vitro assay, approximately 80% suppression of cytotoxicity was observed in membrane-bound human FasL-expressing pig islets and 60% inhibition of CTL killing was displayed in decoy Fas expression pig islets. In an in vivo transplant model, prolonged survival of pig islets xenografts, expressing either membrane-bound human FasL or human decoy Fas genes, was elicited in comparison with that of control islets xenografts. CONCLUSION: The extracellular remodeling of either death receptor or death ligand genes by adenoviral expression was effective for the prevention of CTL-mediated xenocytotoxicity in pig islets.