Investigation of Expanded Human Adipose-derived Stem Cell Dosage and Timing for Improved Defecation Function.

BACKGROUND/AIM: Although certain treatment options exist for intestinal incontinence, none are curative. Adipose-derived stem cells (ADSCs) have emerged as promising therapeutic agents, but most preclinical studies of their effectiveness for anal function have used autologous or allogeneic ADSCs. In this study, the effectiveness, timing of administration, and required dosage of human ADSCs were investigated for clinical application. MATERIALS AND METHODS: A 10-mm balloon catheter was used to induce anal sphincter injury in immunodeficient mice in the following experimental groups (n=4 per group): ADSC (injected ADSCs after injury), PBS (injected phosphate-buffered saline after injury), and control (uninjured). The effects of different timing (immediately after injection and 30 days following injury) and number of human ADSCs administered was compared among groups based on defecation status and pathological evaluation. RESULTS: In terms of defecation status, groups receiving ≥1×104 human ADSCs after injection showed improvement. Pathological images showed that compared to the PBS group, the thinnest part of the sphincter was thicker for animals that received ≥1×104 human ADSCs, and fibrosis of the sphincter was notable in those treated with 1×103 human ADSCs or PBS. Furthermore, defecation status was improved by administration of human ADSCs, not only immediately after injury, but also at 30 days following injury. CONCLUSION: Human ADSC administration in a mouse model of anal sphincter injury was effective. Injection of ≥1×104 human ADSCs was the amount necessary to improve defecation status, an effect detected in both the acute and chronic phases.

[A Case of Laparoscopic Uterine and Vaginal Resection for Local Recurrence after Abdominoperineal Resection for Anal Canal Cancer].

The patient was an 80s woman. She visited our hospital with chief complaint of melena, and further evaluation revealed anal canal cancer. We performed robot-assisted abdominoperineal resection(D3 lymphadenectomy)and lateral lymph node dissection. The pathological diagnosis was anal canal cancer, muc>por1>tub2, T3N1bM0, pStage Ⅲb. One year after the surgery, she had a mass in the soft tissue of perineum on CT scan and PET-CT showed abnormal accumulation, which was diagnosed as local recurrence. At the same time, she also had a mass with abnormal accumulation in ascending colon, and it was diagnosed as ascending colon cancer. In both cases, we judged radical resection was possible, and the policy of surgery was decided. First, laparoscopic ileocecal resection was performed. The local recurrence lesion became a mass, invading the soft tissue of the perineum, the posterior wall of the vagina, and the cervix. So, we performed laparoscopic excision of local recurrent region together with the uterus and the posterior wall of the vagina. Based on the result of pathological examination, the patient was diagnosed with ascending colon cancer(tub1, pT1bN1aM0, pStage Ⅲa), and recurrence of anal canal cancer. The postoperative course is good and there are no signs of recurrence for 6 months after the operation.

Efficacy of PET/CT in diagnosis of regional lymph node metastases in patients with colorectal cancer: retrospective cohort study.

BACKGROUND: Endoscopic and transanal local resection without lymph node dissection are treatment options for patients with a low risk of lymph node metastasis; however, some patients might have undiagnosed lymph node metastases before surgery. This retrospective study aimed to evaluate the efficacy of preoperative PET/CT for diagnosing regional lymph node metastasis. METHODS: Patients who underwent curative resection with lymph node dissection for colorectal cancer at Osaka University between January 2012 and December 2015 were included. The cut-off values appropriate for diagnosing lymph node metastasis were calculated by way of a receiver operating characteristic (ROC) curves from maximum standard unit value (SUVmax) of main tumour, and lymph node short axis, and SUVmax of lymph node. The cut-off values of primary tumour SUVmax: 7, short-axis diameter of the lymph node at 7 mm, and lymph node SUVmax at 1.5 were set. RESULT: A total of 541 patients were included. Regional lymph node metastases were confirmed in resected specimens from 187 patients (35 per cent). With a primary tumour SUVmax of 7 used as a cut-off value, the sensitivity and specificity of regional lymph node metastasis were 70.1 per cent and 45.5 per cent respectively. With a cut-off short-axis diameter of the regional lymph node of 7 mm, the sensitivity and specificity of regional lymph node metastasis were 75.2 per cent and 82.6 per cent respectively, and with a cut-off regional lymph node SUVmax of 1.5, the sensitivity and specificity of regional lymph node metastasis were 78.6 per cent and 96.8 per cent respectively. When the diagnostic criteria were defined by a lymph node short-axis diameter of 7 mm or SUVmax of 1.5, the sensitivity and specificity were 87.4 per cent and 81.8 per cent respectively. CONCLUSION: Preoperative PET/CT is a useful modality for evaluating regional lymph node metastasis in patients with colorectal cancer.

Usefulness of An Anal Sphincter Injury Mouse Model by Means of a Balloon Catheter and a New Method of Evaluating Anal Sphincter Function.

Background: The incidence of fecal incontinence is ~2%, and the associated symptoms significantly impact daily life. New treatment methods including electrical stimulation and regenerative therapy using stem cells for fecal incontinence have been reported. We explored the usefulness of an anal sphincter injury mouse model by means of a balloon catheter and focused on the defecation status of mice as a novel method for evaluating anal function. We examined the utility of the mouse model of anal sphincter injury and the efficacy of electrical stimulation as a treatment modality using this model. Methods: A 10-mm balloon catheter was used to create an anal sphincter injury model in mice. Sphincter function was evaluated in the noninjured (n = 4), injured (n = 4), noninjured electrical stimulation (n = 4), and injured electrical stimulation (n = 4) groups. Defecation status (defecation frequency in 24 h and fecal weight per stool) and pathological evaluation were used for comparison. Results: The defecation frequency increased and the fecal weight per stool decreased significantly in the anal sphincter injury model. Pathological evaluation revealed that anal sphincter tears occurred the day after the injury. Meanwhile, the defecation frequency improved on d 7, and the fecal weight per stool gradually normalized to that of the control group and exhibited significant sphincter muscle hypertrophy in the electrical stimulation group. Conclusion: Anal sphincter injury using a balloon catheter in mice allowed us to create a uniform model. The evaluation of defecation status in mice is a useful method for comparatively evaluating anal function.

[A Case of Early Appendiceal Adenocarcinoma Coexisting with High-Grade Appendiceal Mucinous Neoplasm].

We report a case of a female in her fifties with early appendiceal adenocarcinoma coexisting with high-grade appendiceal mucinous neoplasm(HAMN)with a review of the literature. The patient presented to our hospital because of an enlarged appendix noted by contrast-enhanced CT performed for hematuria. Contrast-enhanced CT showed that the appendix had swollen to 10 mm and mucus had accumulated inside, which had no evidence of obvious malignancy. She was followed up on CT once a year. Four years after her first visit, she underwent laparoscopic appendectomy for a definitive diagnosis. There were no adhesions or inflammation in her abdominal cavity, and the appendix root was dissected with an automatic anastomosis device. Her resected specimen macroscopically showed mild wall thickening, but no obvious neoplastic lesion. Pathological examination revealed that in many areas centered on the tip of the appendix, highly columnar atypical epithelium with enhanced mucus production was densely proliferated in the form of glandular tubular and papillary. The nuclei of the proliferating epithelium were large and the fission image was conspicuous, but they remained in the mucosa. Pathological examination diagnosed as HAMN according to the WHO classification. The atypical epithelium in a small area at the tip was particularly strong in nuclear atypia, and showed a strong positive diffusely in p53, which was an image of well-differentiated tubular adenocarcinoma. The pathological diagnosis was V, Type 0-Ⅱb, 2 mm, tub1 in HAMN, pTis, Ly0, V0, Pn0, pPM0, pDM0, pRM0, R0. Six months have passed since the operation, but no recurrence has been observed.

[A Case of Jejunal Cancer Treated by Laparoscopic Partial Jejunectomy].

The patient was a 30s male visited our hospital with the complaints of abdominal pain and melena. The internal medicine physician could not detect the cause of the melena by upper and lower gastrointestinal endoscopy. Although the patient resolved with a fast as conservative management so he left our hospital once, he relapsed nausea and abdominal pain. He visited our department. We performed surgery under a preoperative diagnosis of intestinal obstruction. The histopathological diagnosis was moderate differentiated jejunal adenocarcinoma(Stage ⅡA). At present, 1 year 7 months since surgery, the patient survives although with lymphnode recurrence.

Efficacy of positron emission tomography in diagnosis of lateral lymph node metastases in patients with rectal Cancer: a retrospective study.

BACKGROUND: The presence of lateral pelvic lymph node (LLN) metastasis is an essential prognostic factor in rectal cancer patients. Thus, preoperative diagnosis of LLN metastasis is clinically important to determine the therapeutic strategy. The aim of this study was to evaluate the efficacy of preoperative positron emission tomography/computed tomography (PET/CT) in the diagnosis of LLN metastasis. METHODS: Eighty-four patients with rectal cancer who underwent LLN dissection at Osaka University were included in this study. The maximum standardized uptake value (SUVmax) of the primary tumor and LLN were preoperatively calculated using PET/CT. Simultaneously, the short axis of the lymph node was measured using multi-detector row computed tomography (MDCT). The presence of metastases was evaluated by postoperative pathological examination. RESULTS: Of the 84 patients, LLN metastases developed in the left, right, and both LLN regions in 6, 7, and 2 patients, respectively. The diagnosis of the metastases was predicted with a sensitivity of 82%, specificity of 93%, positive predictive value of 58%, negative predictive value of 98%, false positive value of 7%, and false negative value of 18% when the cutoff value of the LLN SUVmax was set at 1.5. The cutoff value of the short axis set at 7 mm on MDCT was most useful in diagnosing LLN metastases, but SUVmax was even more useful in terms of specificity. CONCLUSIONS: The cutoff value of 1.5 for lymph node SUVmax in PET is a reasonable measure to predict the risk of preoperative LLN metastases in rectal cancer patients.

Specific activation of glycolytic enzyme enolase 2 in BRAF V600E-mutated colorectal cancer.

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E-mutated tumors via in silico analysis using a large-scale clinical database. We found that BRAF V600E-mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E-mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E-mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild-type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E-mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP-1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E-mutated CRC and indicate the therapeutic implications of targeting this gene.

A case report of anal canal cancer with pagetoid spread requiring differential diagnosis.

INTRODUCTION: Paget's disease is an intraepithelial invasion by a malignant tumour and is characterised by erythema and inflammation. It can manifest as mammary or extramammary Paget's disease (EMPD), with the latter often developing in the perianal area. Anorectal cancer can cause transepithelial invasion into the epidermis, resulting in an appearance similar to that of EMPD. This is called pagetoid spread (PS), which is completely different from EMPD. These two conditions are difficult to differentiate because of the nature of intricacy and requirements of histopathology. PRESENTATION OF CASE: We present a case in which differential diagnosis between these two conditions was not possible during the preoperative examination, resulting in difficulties in treatment. The patient was a 70-year-old woman who experienced pain in the anus since the previous month and presented with red, flat and elevated lesions. DISCUSSION: Treatment for dermatitis was ineffective, and endoscopic examination did not indicate rectal or anal cancer. However, immunohistochemical examination of the biopsy specimen suggested PS. Thus, two-stage operation was planned. Transanal surgery was performed to confirm the diagnosis of PS and intersphincteric resection was allowed as a radical surgery. CONCLUSION: Thus, when differentiation between EMPD and PS is intricacy, two-stage operation is useful in selecting an appropriate radical surgery method, leading to preservation of anal function.

[XELIRI plus Bmab Therapy as a Secondary Treatment for Recurrent Colorectal Cancer with Long-Term Survival].

A 71-year-old woman complained of melena, and laparoscopic right hemicolectomy was performed for advanced colorec- tal cancer. Pathological examination revealed pStage Ⅲa(RAS-positive)disease. After the operation, UFT/LV was administered. However, peritoneal recurrence was confirmed. We changed the chemotherapeutic regimen to CapeOX plus Bmab and capecitabine plus Bmab. After 5 years and 9 months, pulmonary metastasis was observed. Therefore, we again changed the chemotherapeutic regimen to biweekly XELIRI plus Bmab. After 43 courses, the patient had stable disease. During biweekly XELIRI plus Bmab therapy, Grade 4 neutropenia occurred, so we reduced the CPT-11 dose by 20%. After dose reduction the patient experienced no more Grade 3/4 adverse events. We experienced a case of colorectal cancer wherein biweekly XELIRI plus Bmab therapy contributed to disease control as second-line treatment.

[A Case of Hyperammonemia Induced by Chemotherapy with 5-Fluorouracil for Metastatic Colon Cancer].

Systemic chemotherapy based on 5-fluorouracil(5-FU)is a standard treatment for unresectable or recurrent colon cancers. Here, we report a case of hyperammonemia induced by chemotherapy using 5-FU for metastatic colon cancer. An 84-yearold male patient with past histories of liver cirrhosis related to hepatitis C virus and renal dysfunction underwent an operation for the rectosigmoid colon cancer 8 years ago. Three years after that operation, a local recurrence of the colon cancer was diagnosed, and chemotherapy using sLV5FU2 was initiated. The recurrence lesion reduced markedly by this chemotherapy, which was ceased 2 years ago. Two years after the cessation the recurrent tumor had been enlarged, and the chemotherapy using the same drugs at the same dose was performed. On the treatment day 3, he was emergently transported to our hospital due to the disturbance of consciousness. Since laboratory tests showed the high concentration of plasma ammonia and the progressed renal dysfunction with no other definite cause of obnubilation, he was diagnosed as the hyperammonemia induced by 5-FU. He was treated by administrating the branched-chain amino acids solutions combined with fluid therapy, which quickly recovered him from the encephalopathy. He is followed up without any chemotherapy because of his high age. When a patient treated with the chemotherapy using 5-FU is sent with the disturbance of consciousness, we should take hyperammonemia into consideration, especially when he or she has the hepatic or renal dysfunction.

[A Case of Chemotherapy with FOLFOXIRI plus Cetuximab for Liver Metastasis of Sigmoid Colon Cancer].

We report a case of chemotherapy with FOLFOXIRI plus cetuximab for liver metastasis of sigmoid colon cancer. The patient was a 40's man who was diagnosed with sigmoid colon cancer with liver metastasis. Colonoscopy revealed a type 2 tumor with stenosis in the sigmoid colon. He underwent sigmoidectomy under laparotomy, and after the operation, received 7 courses of chemotherapy with FOLFOXIRI plus cetuximab. The liver tumor was sufficiently reduced, and laparotomy and liver right lobectomy were performed. Histopathology revealed a modified, Grade 2 tumor regression. He has been followed for 1 year 4months after the operation.

[A Case of Primary Duodenal Cancer with Duodenocolic Fistula Treated with Pancreatoduodenectomy and Right Hemicolectomy].

A patient was 59-year-old female. She presented our hospital with weight loss, anorexia and lower abdominal bloating. Abdominal computed tomography(CT), gastrointestinal endoscopy, colonoscopy and duodenal fistulagram showed duodenal cancer or colon cancer with duodenocolic fistula and ovary metastasis. She underwent subtotal stomach preserving pancreatoduodenectomy and right hemicolectomy. In these pathological findings, tumor was diagnosed as a duodenal cancer with duodenocolic fistula. She was surviving 12 months after the last surgery. In cases of cancer with duodenocolic fistula, pancreatoduodenectomy with right hemicolectomy would be necessary for nutrition improvement and cancer treatment.

[Continued Chemotherapy for Advanced Gastric Cancer and Seven Year Survival after Operation].

The patient was a 66-year-old man. Total abdominal gastrectomy and D2 dissection were performed for gastric cancer (cT3N0M0P0CYXH0, cStage II A). Pathological examination confirmed a diagnosis of Stage III C mucinous adenocarcinoma (pT4pN3pM0, pStage III C). He underwent adjuvant chemotherapy with TS-1(120mg/body). One year after adjuvant chemotherapy, anastomotic stricture was caused. Although it was not possible to point out recurrent lesions on the CT image, we strongly suspected that extrinsic compression around the anastomotic portion was due to peritoneal dissemination recurrence because of symptoms and marked tumor elevation. Therefore, TS-1(120mg/body)plus cisplatin(CDDP 60mg/m2)were administered as first-line therapy for advanced gastric cancer. TS-1 plus CDDP(SP)chemotherapy resulted in marked tumor reduction and improved symptoms. However, after 33 courses of SP chemotherapy, renal function was worse due to cisplatin; thus, docetaxel(DTX 70mg/m2)was administered as second line therapy. After 8 courses of DTX, peritoneal dissemination recurrence was diagnosed, and the patient was treated with irinotecan(CPT-11 150mg/m / 2), ramucirumab(RAM 8 mg/kg) plus paclitaxel(PTX 80mg/m2 day 1, 8, 15). However, the disease worsened. The side effect of SP therapy was renal dysfunction. Nonetheless, we experienced that long-term disease control could be achieved by administering chemotherapy under strict follow-up.

[A Case of a Single Incisional Laparoscopic Assisted Partial Jejunectomy Performed to Treat a Primary Small Intestine Cancer in a Young Woman].

A 35-year-old woman was followed by epilepsy therapy. She was admitted to our hospital because of a 15 kg decrease in weight, bilious vomit, and frequent epileptic seizures because she could not take oral antiepileptic drugs. A primary small intestinal cancer was suspected in the jejunum about 100 cm from the incisor by single-balloon enteroscopy. A single incisional laparoscopic assisted partial jejunectomy that was minimally invasive was performed to improve the symptoms of intestinal obstruction. The histopathological diagnosis was moderately differentiated adenocarcinoma, ly0, v1, pT4(SE), pN0, pM0, pStage II B. A primary small intestinal cancer is a relatively rare disease, accounting for 0.3-1.0%ofall cancers ofthe digestive tract. The primary method oftreatment is surgery, and understanding the positional relationship ofthe tumor is important when performing surgery because most primary small intestinal cancers are located in the vicinity ofthe ligaments ofTreitz. We present a case in which safe and minimally invasive surgery was performed to treat a primary small intestinal cancer in a young woman with intractable epilepsy and a significant decrease in ADL for intestinal obstruction, along with a review of the literature.

[A Patient with Colon Cancer Local Site Recurrence Who Experienced Difficulty Tolerating Intensive Chemotherapy Was Treated Effectively with sLV5FU2 Therapy].

An 82-year-old man underwent anterior resection for rectal cancer in 2006. Local recurrence was diagnosed 5 years and 4 months after the operation. He could not undergo intensive chemotherapy because of his age and health status(a history of tubercular and pancytopenia due to chronic hepatitis C). sLV5FU2 chemotherapy was initiated. The CEA level decreased immediately after chemotherapy, and a complete response was observed on CT. After 18 courses, chemotherapy was discontinued. A complete response was detected for 1 year after the chemotherapy holiday began. For patients who experience difficulty tolerating intensive chemotherapy, good outcomes have been achieved even if relatively light regimens are used. For elderly patients or those with several complications, we suggest selecting a regimen based on the QOL.

[A Case of Long-Term Survival of Resected Pancreatic Metastasis from Colon Cancer].

Pancreatic metastasis of colorectal cancer is uncommon and is often identified in later stages of cancer, thereby making resection more uncommon. We report a case oflong -term survival after resection of metachronous metastasis to the pancreas from primary sigmoid colon cancer. A 50-year-old female patient underwent a sigmoid colon resection and bilateral salpingo-oophorectomy for sigmoid colon cancer and metastatic ovarian cancer in 2007. She underwent partial lung resection for metastatic lung cancer twice. Four years and 11 months after the first operation, an isolated mass was identified in the pancreatic tail, and a distal pancreatectomy, splenectomy, left adrenal gland removal, and regional lymph node dissection were performed. The tumor stained negatively for cytokeratin 7 and positively for cytokeratin 20, resulting in a diagnosis of pancreatic metastatic cancer from sigmoid colon cancer. The patient is alive 3 years and 4 months after distal pancreatectomy. This suggests that curative resection is effective for metastasis of colorectal cancer to the pancreas, similarly to metastases to the liver and lung.

[Laparoscopic Resection in a Case of Local Recurrence of Rectal Cancer].

A 65-year-old man had undergone high anterior resection for rectal cancer. Seven years after the surgery, a liver metastasis was identified, and the metastasis was surgically resected. A year after the liver surgery, blood testing showed high carcinoembryonic antigen(CEA). A fluorodeoxyglucose(FDG) / -positron emission tomography(PET)/CT examination showed a high FDG accumulation at the rectal anastomosis site, and we diagnosed local recurrence of rectal cancer and prostate invasion. Because there were no distant metastases, he underwent laparoscopic lower anterior resection, radical prostatectomy, and ileostomy. Histopathological examination of the tumor revealed adenocarcinoma and invasion to the right seminal vesicle, suggesting local recurrence of the primary rectal adenocarcinoma. The surgical margin was free of cancer. Operations for local recurrence of rectal cancer are difficult because of tumor invasion and tissue adhesions. In spite of the extended operation, the patient showed good postoperative recovery. Laparoscopic resection for local recurrence of rectal cancer is less invasive than open abdominal operations, and it may be the treatment of choice for local recurrences of rectal cancer.

[Examination of the Usefulness of Laparoscopic Resection for Primary Lesions of Stage â £ Colorectal Cancer].

For patients with Stage Ⅳ colorectal cancer, primary site resection improves survival and relieves symptoms of bleeding and obstruction by the primary lesion. Laparoscopic surgery is thought to be useful for Stage Ⅳ colorectal cancer because of its low aggressiveness and the short recovery time. We examined the usefulness of laparoscopic resection of primary lesions for Stage Ⅳ colon cancer patients. Forty-one cases of Stage Ⅳ colorectal cancer treated by resection of the primary lesion were investigated, and we compared the group of patients with laparoscopic surgery (LAC) to the group of patients with open laparotomy (OP). The LAC Group was superior to the OP Group from the viewpoint of blood loss, days of hospitalization, and length of time from operation to start of chemotherapy. For Stage Ⅳ colorectal cancer, laparoscopic resection of the primary lesion is thought to be a useful method to reduce the invasiveness of treatment.

[Two Effective Cases of Re-Insertion of Self-Expanding Metallic Stent(SEMS)for Re-Obstruction of Colon Cancer after SEMS Treatment].

Recently, self-expanding metallic stent (SEMS) have been found to be useful for treatment of intestinal obstruction by colorectal cancer, either as a bridge to surgery or terminal treatment. When SEMS are used for patients in the terminal stage with obstruction due to colorectal cancer, re-obstruction is a severe problem. We report 2 cases of re-insertion of SEMS for obstruction of colon cancer after the first insertion of SEMS. No major problems occurred in either the 2 cases. In the first case, the patient suffered from re-obstruction of colon cancer 6 months after the first SEMS treatment and died 9 months after the second SEMS treatment. In the second case, the patient suffered from re-obstruction of colon cancer 5 months after the first SEMS treatment and died 7 months after the second SEMS treatment. Re-insertion of SEMS for a second obstruction due to colorectal cancer after SEMS treatment is useful for terminal treatment for maintaining QOL.