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Purpose We delineated the learning phases of robot-assisted laparoscopic surgery for rectal cancer and compared the surgical and clinical outcomes between robot-assisted laparoscopic surgery and conventional laparoscopic surgery. Methods In total, 210 patients underwent rectal cancer surgery at Sendai Medical Center from 2015 to 2020. Conventional laparoscopic surgery was performed in 110 patients, while robot-assisted laparoscopic surgery was performed in 100 patients. The learning curve was evaluated using the cumulative summation method, risk-adjusted cumulative summation method, and logistic regression analysis. Results The risk-adjusted cumulative summation learning curve was divided into three phases: phase 1 (cases 1–48), phase 2 (cases 49–80), and phase 3 (cases 81–100). The length of hospital stay (13.1 days vs. 18.0 days, respectively; p = 0.016) and the surgical duration (209.1 minutes vs. 249.5 minutes, respectively; p = 0.045) were significantly shorter in the robot-assisted laparoscopic surgery group (phase 3) than in the conventional laparoscopic surgery group. The volume of blood loss was significantly lower in the robot-assisted laparoscopic surgery group (phase 1) than in the conventional laparoscopic surgery group (17.7 ml vs. 79.7 ml, respectively; p = 0.036). The International Prostate Symptom Score was significantly lower (indicating less severe symptoms) in the robot-assisted laparoscopic surgery group (p = 0.0131). Conclusions Robot-assisted laparoscopic surgery for rectal cancer was safe and demonstrated better surgical and clinical outcomes, including a shorter hospital stay, less blood loss, and a shorter surgical duration, than conventional laparoscopic surgery. Tactile familiarity can be acquired from visual information beyond 80 cases.

Background Bariatric surgery is effective for the treatment of patients with morbid obesity and type 2 diabetes mellitus (T2DM), for body weight loss and glycemic control. However, in Japan, there has been no previous report of the effectiveness bariatric surgery in a case of morbid obesity associated with acute onset type 1 diabetes mellitus (T1DM), in which pancreatic β-cells were destroyed and endogenous insulin was depleted. Case presentation A 36-year-old woman with morbid obesity and T1DM, diagnosed when she was 6 years, was admitted for bariatric surgery. At her first consultation, she had a body weight of 106.7 kg and a body mass index of 42.2 kg/m2. Her HbA1c level was 9.0%, with a required daily insulin dose of 75 units. She underwent laparoscopic sleeve gastrectomy. At 1 year after surgery, her body weight had decreased to 81.0 kg and her body mass index to 32.2 kg/m2. In addition, her daily required dose of insulin had decreased to 24 units, with an improvement in her HbA1c level to 7.7%. Conclusions Although further evidence needs to be accumulated, including long-term outcomes, laparoscopic sleeve gastrectomy may provide an effective treatment for patients with morbid obesity and T1DM for body weight loss, improvement in HbA1c level, and insulin dose reduction.

A 64-year-old man with gastric tumor in the antrum had been diagnosed with gastric neuroendocrine carcinoma(NEC) by biopsy and multiple lymph node metastases(#3 and #6)by abdominal computed tomography. After staging laparoscopy showed that there were no non-curative factors, neoadjuvant chemotherapy(S-1/cisplatin[CDDP]: 2 courses)and distal gastrectomy and D2 lymph node dissection were performed. The pathological diagnosis was shown as pathological complete response(pCR). After adjuvant chemotherapy(S-1/CDDP: 2 courses, S-1: 6 courses)was administered, the patient is alive at 8 years without recurrence.

A 75-year-old man with a Type 3 advanced gastric cancer in the middle gastric body and paraaortic lymph node swelling was treated chemotherapy. After treatment, we performed an exploratory laparotomy and curative total gastrectomy. As adjuvant chemotherapy, S-1 treatment was administrated for 4 courses but multiple metastases from left supraclavicular to paraaortic lymph nodes. First, Cape plus CDDP plus T-mab therapy treated. Because of acute renal failure, Cape plus L-OHP plus T-mab was administrated but response evaluation was PD. In the second-line therapy, Ramucirumab plus paclitaxel was performed 4 courses. Third, we administrated Nivolumab. After 6 courses, response evaluation was PR and we continued 24 courses. At the same time, there was acute-onset Nivolumab-induced organizing pneumonia and we treated steroid pulse, azithromycin and introduced home oxygen therapy. At the present, 47 months long-term survival achieved after Nivolumab treatment.

Background Transabdominal robotic surgery and transanal total mesorectal excision (TaTME) are newly introduced strategies for rectal cancer. These procedures might have many advantages in rectal cancer treatment in terms of improving oncological and functional outcomes, especially in cases involving advanced cancer or technical difficulty. In the present study, we aimed to clarify the advantages and disadvantages of transabdominal robotic surgery and laparoscopic TaTME as a hybrid surgery for rectal cancer. Materials and methods We retrospectively evaluated six patients who underwent hybrid surgery for rectal cancer from August 2018 to April 2020. Both clinical and pathological outcomes were assessed. Results Two patients showed circumferential margin involvement both before and after neoadjuvant therapy. Three patients were planned to undergo hybrid surgery with intersphincteric resection because of a narrow pelvis. One patient was planned to undergo hybrid surgery for a giant tumor of >10 cm. The median length of hospitalization was 17 days. No patients required conversion to an open procedure. All patients underwent formation of defunctioning ileostomies. Two patients had a stapled anastomosis and four had a hand-sewn coloanal anastomosis. Complications included one case of anastomotic leakage, which was managed conservatively with ultrasound- and computed tomography-guided drainage and antibiotics. Histological analysis revealed that all specimens had a negative radial margin and distal margin. The median number of lymph nodes harvested was 17.5. Two patients showed extensive lymph node metastases, including lateral node metastasis. Conclusion Hybrid surgery was performed safely and may improve oncological outcomes for rectal cancer. This technique has many potential benefits and would be alternative option in multimodal strategies for rectal cancer., Highlights • No studies to date have focused on treatment of locally advanced rectal cancer in men using intersphincteric resection hybrid technology involving transabdominal robotic surgery with conventional transanal total mesorectal excision. • We found that hybrid surgery is feasible and may improve the quality of total mesorectal excision and the rate of radical resection for advanced rectal cancer. • Hybrid surgery may improve urinary and sexual function. • This technique has many potential benefits and would be an alternative approach for rectal cancer.

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and have been shown to promote cancer aggressiveness. In our previous study, analysis of expression profiles obtained from paired CAFs and normal fibroblasts from colorectal cancer (CRC) tissue revealed that gene sets related to the Wnt signaling pathway were highly enriched in colorectal CAFs. Furthermore, among the components of the β-catenin-independent Wnt pathway, Wnt5a was highly expressed in CAFs. Since Wnt5a is considered to be a regulator of CRC progression in CAFs, we performed immunohistochemical analysis on Wnt5a in 171 patients who underwent surgery for CRC. Positive staining for Wnt5a was often found in cancer stroma, particularly in fibromatous areas, although the immunoreactivity for Wnt5a was weak in cancer cells. Wnt5a status in CAFs was significantly associated with tumor size, depth of invasion, lymphatic and vascular invasion, lymph node metastasis, TNM stage, and recurrence. Subsequent in vitro analyses using human recombinant Wnt5a protein revealed that cancer cell proliferation and migration were significantly increased by stimulation with Wnt5a. Our findings suggest that Wnt5a-derived CAFs play a crucial role in CRC progression and have potential as a target of anti-cancer therapies.

Urinary incontinence is one of the common complications after radical prostatectomy along with inguinal hernia. Artificial urethral sphincter implantation is widely accepted as a treatment option. We report two surgical cases of inguinal hernia after artificial urethral sphincter implantation for urinary incontinence following radical prostatectomy. In Case 1, since the device went through the inguinal canal, adhesion around the pubis was extremely hard. In Case 2, the device was placed on the ventral side of the rectus abdominis muscle, so it was operable almost as normal. In each case, the surgical procedure was considered carefully after confirming the location of the device by preoperative computed tomography and ultrasonography. Hernia repair was successfully performed using the Lichtenstein method. There are few reports regarding surgical repair of inguinal hernia following artificial urinary sphincter implantation. Preoperative image and appropriate choice of approach could facilitate safe and secure surgery.

A 66-year-old man was admitted to our hospital because of multiple refractory skin ulcers. Based on his severe systemic arterial calcification and severe calcium-phosphate imbalance due to severe kidney dysfunction, we initially considered calciphylaxis. However, a skin biopsy provided a diagnosis of cholesterol crystal embolization. Although we initiated hemodialysis, steroid treatment, and low-density lipoprotein-cholesterol apheresis, he died of multiple intestinal perforation. An autopsy showed cholesterol crystals occluding multiple organ arterioles. This case suggests that skin ulcers in patients with chronic kidney disease may be an important diagnostic hallmark and may be associated with several serious diseases.

A 69-year-old man was referred to our institute for the surgical resection of focal resistant peritoneal GIST during imatinib administration. He had been diagnosed with GIST of the small intestine with liver and peritoneal metastases, and imatinib treatment was initiated. Shortly after imatinib administration, the primary lesion perforated, and thus, partial resection of the small intestine was performed. Imatinib treatment was resumed after the first surgery, and he achieved partial response. However, computed tomography scans obtained 7 months after the first surgery showed focal progression, a peritoneal metastasis near the right kidney. Under the diagnosis of focally imatinib-resistant GIST, local resection of the metastatic tumor was performed. In this case, an exon 11 mutation of c-kit was noted initially. After the imatinib treatment, an additional point mutation was observed in exon 18 that caused resistance to imatinib. Therefore, imatinib treatment was reinitiated after the second surgery, and other metastases were well controlled. In case of GIST with multiple metastases, appropriate treatment should be selected based on the resistance of each lesion.

The lymphatic flow along the posterior gastric artery (PGA) is considered of possible clinical importance in terms of lymphatic metastasis; however, little is known about the lymph nodes (LNs) around this artery. The purpose of this study was to establish if LNs exist around the PGA and to evaluate their clinical implications. We examined the tissues surrounding the PGA from 21 cadavers to search for LNs. We also investigated the patterns of lymphatic metastases in patients who underwent surgery for gastric neoplasms at our institute to detect their presence along the PGA. The PGA was identified in 11 cadavers, and LNs around the PGA were detected microscopically in 2 of these. Lymphatic metastasis directly to the LNs at the splenic artery without any metastases was regarded as skip metastasis along the PGA. Skip metastasis was found in two of ten patients who underwent surgery for remnant gastric cancer. The existence of LNs around the PGA was confirmed, and based on our findings, lymphatic metastasis through the PGA is possible in patients with remnant gastric cancer.

A55 -year-old man was diagnosed with rectal cancer invading the urinary bladder and swollen para-aortic lymph nodes. Since distant metastasis was indicated and total pelvic exenteration was required, 6 courses of chemotherapy with mFOLFOX6 plus panitumumab were performed. After the chemotherapy, the rectal cancer and para-aortic lymph nodes significantly decreased in size, and novel distant metastasis was not observed in CT scans. Therefore, the tumor was considered resectable, and operation was performed. Intraoperative frozen section analysis showed that the para-aortic lymph nodes and surgical margin of the urinary bladder were negative. Thus, low anterior resection of the rectum and partial resection of the urinary bladder were performed. R0 resection was pathologically achieved, and adjuvant chemotherapy with S-1 was administered for 6 months. The patient is alive without recurrence for 10 months. Upfront chemotherapy can be a strategy for advanced rectal cancer with urinary bladder invasion to avoid total pelvic exenteration.

A woman in her 40s who presented to a local hospital with bloody stool was referred to our hospital. Colonoscopy showed a rectal tumor, and histological examination showed moderately differentiated adenocarcinoma. CT and MRI revealed that the tumor was 65mm in diameter with no distant metastasis. After the construction of ileostomy, neoadjuvant chemoradiothera- py(NACRT: 45 Gy/25 Fr, S-1 80mg/m2)was performed. The tumor shrank remarkably, and then we performed laparoscopy- assisted low anterior resection. Pathological examination revealed complete disappearance of the cancer cells in the primary site and no appearance of cancer cells in all dissected lymph nodes. NACRT has been recently reported to provide pathological complete response, and these patients are supposed to have a good prognosis. In our case, NACRT enhanced the performance of laparoscopic curative resection while preserving anal function. NACRT should contribute to the curative resection while preserving anal function in patients with locally advanced rectal cancer.

Case 1: A female patient in her 60s underwent laparoscopic intersphincteric resection for rectal cancer. After 42 months, the serum level of carcinoembryonic antigen(CEA)was elevated, and PET-CT showed a locally recurrent rectal cancer that increased FDG-uptake. Carbon ion radiotherapy(CIRT)(73.6 GyE/16 Fr)was performed. Serum CEA level and FDG-uptake were normalized. No regrowth of tumor has been found for 12 months. Case 2: A female patient in her 60s underwent abdominoperineal resection for rectal cancer. After 42 months, the serum level of CEA was elevated, and CT revealed a local recurrence of rectal cancer. Subsequently, the tumor was resected; however, resection margin was microscopically positive. Therefore, chemoradiotherapy(S-1, 60 Gy)was performed. At 31 months after local resection, a re-recurrent tumor was noted in her left ischium. Therefore, CIRT(70.4 GyE/16 Fr)was performed. Serum CEA level and FDG-uptake were normalized. No regrowth of tumor has been found for 24 months. CIRT is an effective therapy for locally recurrent rectal cancer.

According to the treatment guideline for rectal neuroendocrine tumor(NET), tumor with a diameter ofC10mm should be resected endoscopically, while tumor with a diameter of10mm should be resected surgically with lymph node dissection. We experienced a case of a rectal NET with a diameter of 5mm with lymph node metastasis. A 69-year-old man underwent colonoscopy for positive fecal occult blood test. The colonoscopy revealed a submucosal tumor(SMT)with a diameter of 5 mm in the lower rectum. An endoscopic mucosal resection(EMR)was performed after SMT was diagnosed as NET by biopsy. Histopathological findings were NET-G1, 4.5×2.5 mm, v(+), ly(+). Then, laparoscopically assisted rectal resection with D2 lymph node dissection was performed. In histopathological examination, no tumor residue was observed in the specimu; however, a regional lymph node metastasis was detected. Risk factors of lymph node metastasis with rectal NET are a diameter of10 mm, recessed or ulcerated surface, and lymphovascular invasion. However, we have to keep in mind that lymph node metastasis may occur even in small rectal NET with a diameter of ≤10mm.

We here report a case of endoscopy-assisted partial duodenal resection for duodenal adenoma in a patient with familial adenomatous polyposis(FAP). A male underwent total proctocolectomy with ileal pouch anal anastomosis in 1997. Since 2004, duodenal adenomas occurred and the atypical grade of adenoma was gradually aggravated. Therefore, he underwent endoscopy-assisted partial duodenal resection in 2013. The pathological finding of the specimen showed well-differentiated tubular adenocarcinoma(pM, ly0, v0). No recurrence has been observed at 4 years after the operation. Endoscopy-assisted partial duodenal resection was minimum invasive surgery and considered to be useful for the patients with duodenal adenoma.

A52 -year-old woman was diagnosed with ascending colon cancer with ovarian metastasis and peritoneal dissemination. Since the patient did not have symptoms with intestinal obstruction, mFOLFOX6 plus bevacizumab(Bmab)was performed for 12 cycles. After chemotherapy, the tumors of ascending colon and ovary were significantly shrunken and novel distant metastasis was not observed by CT scans. Therefore, the tumors were considered to be resectable and curative resection was performed. In the surgical findings, the peritoneal disseminations were localized, and right colectomy, bilateral oophorectomy and extirpation of the peritoneal disseminations were performed. R0 resection was pathologically achieved and adjuvant chemotherapy with UFT/UZEL was administrated for 6 months. The patient is alive without recurrence for 1 year. Since right sided colon cancer is less likely to have obstruction, upfront chemotherapy can be a strategy for locally advanced right sided colon cancer with distant metastasis.

A 40-year-old man was referred to our hospital because of severe anemia and small intestinal tumor revealed by computed tomography. The enteroscopy exam showed the intraluminal penetration of the tumor, which was considered as a cause of anemia. Although emergency operation was performed laparoscopically, intraoperative findings indicated tumor invasion into peritoneum, and we converted from laparoscopic surgery to open surgery that included concomitant peritoneum resection. Histopathological findings showed spindle-shaped tumor cells with severe atypia. Immunohistochemical study showed tumor cells to be positive for aSMA, but negative for c-kit and CD34, then we diagnosed the tumor as leiomyosarcoma of the ileum. Since leiomyosarcoma of the small intestine is a rare entity, we have reported with literature consideration.

5-Fluorouracil (5-FU), a core anticancer agent for malignancies, induces gastrointestinal (GI) toxicities. Despite recent advances in tumor immunology, it still remains unknown how GI toxicities affect antitumor immunity. S-1 is a tegafur-based oral 5-FU prodrug which has been widely introduced in Japan and other countries. The alternate-day S-1 administration has been proposed to minimize its GI and other toxicities without reducing its anticancer efficacy. In this study, two S-1 administration regimens were compared in mice to evaluate their impact of GI toxicities on immunity. In the daily group as a standard administration model, S-1 was administered for 14 days on and 14 days off, and in the alternate-day group as a non-GI toxicity model, S-1 was administered every other day for 28 days. As well as physical findings, regulatory T cells, Th1 cells and other cells in murine lymphoid tissues were analyzed with flow cytometry. Only the daily group exhibited body weight loss and GI toxicities. In the daily group, a proportion of regulatory T cells in the intestinal lymphoid tissue were demonstrated to be six-fold higher than in the control without S-1, and the proportion of Th1 cells showed a decreasing trend. However, the alternate-day group exhibited almost no change in T-cell subsets. GI toxicities of 5-FU may have a negative influence on antitumor immunity due to increased proportions of regulatory T cells and decreased proportions of Th1 cells. The alternate-day S-1 administration may be a useful regimen with its minimal influence on T-cell subsets.

The aim of this study was to assess the bowel function and quality of life (QOL) in patients with ulcerative colitis (UC) after total proctocolectomy with ileal pouch anal anastomosis (IPAA). Two questionnaires [“Questionnaire sheet on the bowel function” and “Inflammatory bowel disease questionnaire (Japanese IBDQ)”] were sent to 121 patients with UC who underwent IPAA at Tohoku University Hospital. Seventy-nine patients (65%) participated in the study. The median number of daily bowel movements was 6.5, which significantly decreased with postoperative time (≤ 1, 1–5, 5–15 years) and increased with age (

We report a case of a 72-year-old woman who was initially diagnosed with ovarian cancer with peritoneal carcinomatosis. Systemic chemotherapy consisting of paclitaxel and carboplatin(TC)was administered. Although a partial response(PR)was achieved after the 4 courses of TC, this regimen was discontinued due to severe adverse events. Ten months after discontinuation of TC, because abdominal CT and colonoscopy showed an intra-tumoral abscess caused by invasion of the tumor to the sigmoid colon, abdominal total hysterectomy, bilateral salpingo-oophorectomy, and a Hartmann's operation were performed to control the disease symptoms. Pathological examination revealed that the tumor was an undifferentiated carcinoma of the sigmoid colon. This case report suggests that the TC regimen may be effective for treating undifferentiated carcinoma of the colon.

We report a case of a huge gastric gastrointestinal stromal tumor(GIST)that was safely resected followingpreoperative imatinib therapy. A 72-year-old woman was hospitalized with severe abdominal distension. Computed tomography revealed a 27×17 cm tumor in the left upper abdominal cavity. The patient was diagnosed with high risk GIST by EUS-FNA. We initiated preoperative adjuvant chemotherapy with imatinib to achieve a reduction of operative risks and functional preservation. After 6 months of chemotherapy, CT showed a reduction in the tumor size and the patient underwent partial gastrectomy and partial resection of the diaphragm. Histologically, most of the tumor cells were replaced by hyalinized collagen and viable cells were scattered only around the blood vessels. Neoadjuvant chemotherapy with imatinib has the potential to become an important therapeutic option for the treatment of huge GISTs.

A70-year-old man was diagnosed with lower rectal cancer with right inguinal lymph node metastasis. Surgical resection was not suitable for this patient. Chemotherapy(IRIS plus bevacizumab followed by XELOX plus bevacizumab)was administered for 16 months. After the chemotherapy, the rectal tumor and lymph node swelling were significantly reduced and distant metastasis was not observed on CT scans. Therefore, the tumor was considered to be resectable and abdominoperineal resection of the rectum with lymph node dissection was performed. On histopathological examination, cancer cells partially remained in the rectal tumor and lateral lymph nodes, although there were no cancer cells in the inguinal lymph nodes. The patient is alive without recurrence a year later. In cases with a good response to chemotherapy, conversion therapy may become an important therapeutic option.

Background/Aims: The treatment strategy for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤20 mm in diameter has not been established. In this study, we aimed to evaluate the detailed characteristics of NAD-NETs ≤20 mm in diameter to clarify the risk factors of subsequent metastasis. Methods: The patients with NAD-NETs ≤20 mm in diameter who had been treated at 12 institutions between 1992 and 2013 were enrolled. Clinical records were retrieved, and histopathological findings of all cases were centrally reviewed by 2 pathologists. Results: We studied 49 patients with a mean follow-up period of 66.5 months. Thirty-five patients were initially treated with endoscopic resection (ER), and 14 with surgery. A univariate analysis revealed the ORs and 95% CIs of the risk factors for metastasis were lymphovascular invasion (12.5 [2.01-77.9]), multiple tumors (9.75 [1.46-65.4]), a tumor size of 11-20 mm (6.67 [1.21-36.6]), and World Health Organization grade G2 (7.13 [1.16-43.9]). Five-year overall and disease-specific survival rates were 86.1 and 97.2%, respectively. Conclusion: This is the first study to demonstrate the risk factors of metastasis in NAD-NETs ≤20 mm in diameter. These findings may be helpful for determining the appropriate therapeutic approach and the clinical strategy of treatment following ER.

腹腔鏡下鼠径ヘルニア修復術の経腹腔的アプローチ（TAPP）は，前方アプローチのメッシュ手術より利点が多い．しかし，新たな手技習得が必要でラーニングカーブが長いため本邦では必ずしも普及していない．筆者らは，TAPPの手技的難点を軽減する目的に，経皮的に鼠径部腹膜前腔にロピバカインとエピネフリンの膨潤麻酔剤希釈液約150ml注入することを先行する膨潤TAPPを考案し22例を経験した．対象は，男21例，女性1例で平均年齢は58.2歳，24病変，間接ヘルニア19病変，直接ヘルニア5病変であった．手技的に，従来TAPPと比べて，腹膜前腔の膨化によって層確認が容易となり剥離しやすく，出血も少なく，比較的確実な手術が可能となった．合併症は，血腫，水腫各1例でいずれも軽微で，術後疼痛も少ないと考えられた．今後，さらなる症例集積と従来TAPPとの比較試験による検証が必要であるが，膨潤TAPPは従来TAPPを手技的，臨床的に改善すると推察された．

A 49-year-old man had undergone Hartmann's operation for rectal cancer in August 2002. The disease stage (TNM 7th) was T3, N1, M0, Stage ⅢB. He was treated with UFT and Krestin for a year as adjuvant chemotherapy. No recurrence had been detected after the surgery. In July 2014, he presented with symptoms of acute renal failure. A CT scan showed bilateral hydronephrosis and a pelvic tumor between the urinary bladder and rectum. The pathological diagnosis based on biopsy specimens was adenocarcinoma. Because immunostaining studies of the tumor biopsy specimen revealed that CK20, CEA, CA19-9, and p53 were positive and CK7 and PSA were negative, this pelvic tumor was diagnosed as a local recurrence of rectal cancer. Total pelvic exenteration and ileal conduit urinary diversion were carried out for the recurrent tumor with curative intent. The reported recurrence rate of Stage Ⅲ colorectal cancer 5 years after the initial curative operation is 0.67%. Local recurrence of rectal cancer 12 years after the initial operation is quite rare. Immunostaining is helpful to discriminate between rectal cancer and a tumor of the urinary organs. It is important to consider that recurrence of rectal cancer might still occur a long time after the initial operation.

A-39-year-old man presented to a nearby clinic owing to long-term diarrhea and painful defecation. He was diagnosed with a well-differentiated tubular adenocarcinoma of the rectosigmoid and underwent a laparotomy at another hospital. At surgery, the tumor was seen to deeply invade into the urinary bladder with the presence of intra-abdominal abscess. Loop sigmoid colostomy was performed due to possible invasion into the pelvic wall and peritoneal dissemination. The patient was referred to the our hospital for systemic chemotherapy. After 32 courses of FOLFIRI, 10 courses of CapeOX + Bmab, and 34 courses of LV5FU2 + Bmab, radiographic examination revealed complete response (CR) of the rectal tumor, and low anterior resection of the rectum was carried out. Since pathological examination showed no viable cancer cells in any specimen, the patient was considered to have achieved a CR from a pathological standpoint.

We report 2 cases of resectable advanced gastric cancer who achieved pathological complete response by preoperative chemotherapy with S-1 plus weekly low-dose cisplatin (CDDP). S-1 (80 mg/m²)was administered consecutively for 21 days followed by 14 days' rest, with CDDP (25mg/m²) injected on days 1, 8, and 21. Case 1: A man in his 70s diagnosed with cStage III gastric cancer with lymph node metastases received 2 courses of preoperative chemotherapy with S-1 plus weekly low-dose CDDP followed by total gastrectomy with D2 lymph node dissection. Case 2: A man in his 60s diagnosed with cStage III gastric cancer with lymph node metastases received 4 courses of preoperative chemotherapy with S-1 plus weekly low-dose CDDP followed by total gastrectomy with D2 lymph-node dissection. In both cases, postoperative pathological examination revealed no cancer cells in the resected stomach and lymph nodes. The therapeutic effect of preoperative chemotherapy was assessed as Grade 3. With this regimen, we accomplished preoperative chemotherapy successfully without inpatient care. This regimen can be a promising option as preoperative chemotherapy for advanced gastric cancer.

Laparoscopic surgery for this disease is not widely spread due to difficulties in its procedure. We started a laparoscopic procedure for this disease since 2011, and the robotic surgery since 2012. The aim of this study is to assess early results of these procedures. We have operated seven cases from September 2011 through December 2013. First two cases were performed by laparoscopic procedure, and following cases were done by robotically assisted surgery. Of these cases, the perioperative outcome and short-term postoperative morbidity were evaluated. Their average age was 43.6 years old (20-64 years old), and male-female ratio was 2:5. Todani classification was type 1 in all cases. The operation time was 321 min in laparoscopic cases, while 489 min in robotic surgery cases. One case of robotic surgery developed postoperative intestinal obstruction of the biliary limb, requiring laparoscopic adhesiolysis. Pancreatic fistula and anastomotic leakage have not been observed. The robotic surgery for the congenital dilatation of the bile duct is feasible and is a theoretically useful option, especially for hepatico-jejunostomy. On the other hand, the limitation of energy devices, high running cost, and time consumption remain questionable.

The clinicopathological features of neuroendocrine tumor (NET) of the rectum were retrospectively analyzed in 25 patients( 17 men and 8 women; mean age, 57 years[ 30-78 years]) at Tohoku University Hospital from January 1998 to December 2012. The average diameter of 25 tumors was 15 mm (5-70 mm). Local resections and rectal resections with lymph node dissection were performed in 16 and 9 tumors, respectively. Three of the 9 tumors had lymph node metastases (33%), including 2 tumors with a diameter of 10 mm. In a median follow-up of 48 months, tumor recurrence was observed in 3 of 25 patients( 12%); local recurrence was observed in 1 patient; and liver metastasis was observed in 2 patients. Of the 2 patients with liver metastasis, liver metastasis recurred in a patient whose primary tumor, with a diameter of 10 mm, had been locally resected 40 months ago. According to histopathological analysis, 3 primary tumors with local recurrence or liver metastasis were categorized as G2 or G3 according to the World Health Organization (WHO) classification. Tumors with a diameter of ≥10 mm, in principle, may be removed by rectal resection with lymph node dissection. However, histopathological findings such as a proliferation of tumor cells should also be taken into consideration when deciding the treatment strategy for rectal NET.

A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models.Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis.Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP.Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients.

The patient was a 75-year-old woman who had undergone resection of a transverse colon cancer two years before. She had anemia and intestinal obstruction, and a diagnosis of multiple metastases to the small intestine was made by double balloon enteroscopy. Eleven metastatic foci were resected by partial resection of the jejunum and ileum. Adjuvant FOLFOX chemotherapy was given, achieving a 26-month disease-free survival. The double balloon enteroscopy was useful in the definitive diagnosis of this case, and aggressive resection with adjuvant chemotherapy contributed to the good outcome.

Tumor-infiltrating lymphocytes (TIL) play a central role in cellular immunity against tumor. We have revealed the characteristics of TILs in terms of T-cell receptor (TCR) repertoire, T-cell clonality, and cytokine production. TCR repertoire analyses and CDR3 size spectratyping were performed using peripheral blood mononuclear cells (PBMCs) and tissue specimens of gastric or colorectal cancers surgically resected from 11 patients. The cytokine expression was measured by real-time quantitative polymerase chain reaction. TCR repertoires were similar among multiple tissue specimens from different sites of the same tumor. Similar peak patterns of CDR3 size spectratyping were observed among these tumor specimens, but not in normal tissues or PBMCs. In addition, identical peaks were detected in multiple specimens of the same tumor. The ratio of the levels of IFN-gamma to that of IL-4 is significantly higher for tumor lesions compared with PBMCs. These results suggested that a limited number of TILs locally expand in response to tumor antigens exiting within gastric or colorectal cancers and local predominant production of the T helper 1/T cytotoxic 1 type cytokine may affect the anti-tumor immune response of TILs.

[Introduction] 5-fluorouracil (5-FU), a core anticancer agent used for various malignancies, induces gastrointestinal (GI) toxicities. The tegafur-based oral 5-FU prodrug S-1 is recognized to be a key drug for GI and other malignancies in Japan and some Asian countries. S-1 was developed to potentiate antitumor activity of 5-FU and to reduce gastrointestinal toxicities. However, S-1 also causes GI toxicities by the standard daily regimen. On the other hand, the alternate-day administration of S-1 has been proposed to minimize toxicities without reducing the anticancer efficacy of 5-FU. Recently, tumor immunology has greatly advanced, and the role of T cells in antitumor immunity has been well investigated. However, it remains unknown how GI toxicities of 5-FU affect T cell subsets related to antitumor immunity. [Purpose] The purpose of this study is to clarify the influence of 5-FU mediated GI toxicities on T cell subsets related to antitumor immunity. [Methods] Two regimens of S-1 were compared to evaluate the impact of GI toxicities of 5-FU on T cells using Balb/c mice. The first regimen consisted of the daily administration of S-1 (daily group) as a 5-FU GI toxicity model, and the second regimen consisted of the alternate-day administration of S-1 (alternate-day group) as a 5-FU non-GI toxicity model. S-1 was orally administered at a dose of 12 mg/kg as tegafur. We then investigated the degree of GI toxicities and T cell subsets in intra-abdominal lymphoid tissues (spleen, mesenteric lymph node and gut-associated lymphoid tissue). [Results] Only the daily group exhibited body weight loss and GI toxicities. Flow cytometric analyses demonstrated that the proportion of regulatory T cells in the intestinal tissue was 6-fold higher in the daily group than that in the control group, and the proportions of Th1 cells in the daily group showed a decreasing trend. However, the alternate-day group exhibited almost no changes in the proportions of T cell subsets. [Conclusions] GI toxicities of 5-FU increase the proportion of regulatory T cells in intestinal tissue and decrease the proportions of Th1 cells systemically, which suggests that GI toxicities of 5-FU have a negative influence on T cell-dependent antitumor immunity, and the alternate-day administration of S-1 has neither GI toxicities nor the influence on T cell subsets, which suggests that 5-FU regimens without GI toxicities are more useful than those with GI toxicities from the viewpoint of antitumor immunity. Citation Format: Taiki Kajiwara, Koh Miura, Shinobu Ohnuma, Tetsuhiko Shirasaka, Toshihiro Komura, Masahide Toshima, Atsushi Kohyama, Katsuyoshi Kudoh, Sho Haneda, Hiroaki Musha, Fuyuhiko Motoi, Yu Katayose, Takeshi Naitoh, Michiaki Unno. Gastrointestinal toxicities of 5-FU increase the proportion of regulatory T cells in murine intestinal tract: Advantages of alternate-day S-1 administration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 631. doi:10.1158/1538-7445.AM2014-631

[Background] A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. The aim of this study was to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models. [Methods] Mice were treated with S-1/LV either in a daily group (two weeks of administration followed by two weeks of withdrawal) or an alternate-day group (administration on alternate days for four weeks), then the mice of both groups were sacrificed and the xenograft tumors were resected. To assess the adverse reactions, the body weight changes, the condition of feces, mucosal injury of small intestine and myelosuppression were compared between both groups. Furthermore, tumor volume, tumor growth inhibition (TGI) and the expression of Ki67, TUNEL, cIAP2 and XIAP were analyzed to evaluate the antitumor activity and tumor apoptosis. [Results] Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, no adverse reactions were observed in the alternate-day group, except slight myelosuppression. The TGI in the alternate-day group was better than that in the daily group, possibly resulting from apoptosis of tumor cells due to the suppression of cIAP2. [Conclusion] Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve higher antitumor activity without severe adverse reactions. Therefore, we propose that clinical trials with this regimen should be conducted in CRC patients. Citation Format: Toshihiro Komura, Shinobu Ohnuma, Koh Miura, Tetsuhiko Shirasaka, Taiki Kajiwara, Katsuyoshi Kudoh, Sho Haneda, Masahide Toshima, Atsushi Kohyama, Hiroaki Musha, Takeshi Naitoh, Yu Katayose, Michiaki Unno. Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: A shorter drug-free interval leads to more efficient antitumor effects. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 792. doi:10.1158/1538-7445.AM2014-792

Purpose The aim of this study was to investigate the association between 5-fluorouracil (5-FU)-related adverse events (AEs) in Japanese patients with gastrointestinal cancer treated with 5-FU and the patient genotypes DPYD, MTHFR, OPRT, and TYMS. Methods Sequence analyses of 33 gene polymorphisms in four genes were performed using genomic DNA extracted from peripheral blood mononuclear cells of 103 patients with gastric (n = 34) or colorectal (n = 69) cancer. The 5-FU-related AEs of 157 regimens in these 103 patients were evaluated based on the medical records of patients in each of three groups: the intravenous administration group (i.v. group, n = 51), oral administration group (p.o. group, n = 106), and all-regimens group (both i.v. and p.o. group, n = 157). The associations between the incidence of AEs and each genotype were statistically analyzed. Results Six single-nucleotide polymorphisms (SNPs) were identified (three SNPs in DPYD: c.496A>G, c.1905+1G>A, and c.2303C>A; two SNPs in MTHFR: c.677C>T and c.1298A>C; and one SNP in OPRT: c.638G>C). Among them, the patients in the all-regimens group carrying any one of three DPYD SNPs showed statistically significant associations with the incidence of AEs of any type and fatigue. Furthermore, the MTHFR SNP c.1298A>C was significantly associated with the incidence of neutropenia. A similar trend was observed in the p.o. group, but not in the i.v. group. Conclusion These findings suggest that the DPYD SNPs c.496A>G, c.1905+1G>A, and c.2303C>A and the MTHFR SNP c.1298A>C may be predictive factors for the occurrence of severe 5-FU-related AEs. Citation Format: Masahide Toshima, Shinobu Ohnuma, Michiiro Tanaka, Koh Miura, Wataru Fujibuchi, Taiki Kajiwara, Toshihiro Komura, Hiroaki Musha, Sho Haneda, Katsuyoshi Kudoh, Atsushi Kohyama, Takeshi Naitoh, Michiaki Unno. Single nucleotide polymorphisms of DPYD and MTHFR predict adverse events associated with 5-fluorouracil in patients with gastrointestinal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2832. doi:10.1158/1538-7445.AM2014-2832

625 Background: The synchronous liver metastases (SLM) from colorectal cancer (CRC) have a poor prognosis. Therefore, we conducted a phase II study of neoadjuvant mFOLFOX6 + bevacizumab for SLM to explore the appropriate initial treatment (BeFORE study). Here, assess the impact of histological tumor response (HR) on the relapse-free survival (RFS) and the overall survival (OS). Methods: The main inclusion criteria of BeFORE study were SLM within 10 nodules and with measurable disease. The primary endpoint was the response rate (RR). The secondary endpoints included R0-liver resection rate, HR, RFS and OS. Patients (pts) were enrolled after R0-resection of the primary CRC and received 8 courses of mFOLFOX6 + BV (the first and last courses were mFOLFOX6 alone). After this neoadjuvant chemotherapy, pts underwent resection of liver metastases within 4-8 weeks. HR was re-assessed on the basis of the tumor regression grade (TRG) which evaluates the extent of fibrosis of tumor cells, and the modified TRG which evaluates the extent of fibrosis and therapeutic-associated necrosis, using resected tumor samples. Results: Between June 2008 and November 2010, 47 pts were enrolled and 44 pts were treated per protocol. The median number of metastases was 2 nodules, and the maximum diameter of tumors was 12.9 cm. The overall RR was 72.7%. Forty pts underwent liver resection and 39 pts had the R0-liver resection. Five pts (12.5%) of resected 40 pts achieved TRG 1-2 (major HR), 5 pts (12.5%) had TRG 3 (partial HR) and 30 pts (75.0%) had TRG 4-5 (no HR). 8 pts (20.0%) achieved mTRG 1-2, 8 pts (20.0%) had mTRG 3, and 24 pts (60.0%) had mTRG 4-5. With a median follow-up of 35 months, the 2-year RFS rate was 27.3% (the median RFS was 10.5 months), and the 2-year OS rate was 88.4%. Here, we perform sub-group analyses of RFS and OS by TRG, mTRG, respectively. Conclusions: The impact of HR (TRG, mTRG) on survival could help us with considering about the appropriateness of neo-adjuvant mFOLFOX6 + BV as the initial treatment for SLM. (This trial is on University hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR); UMIN000001568.) Clinical trial information: UMIN000001568.

322 Background: Therapeutic strategies for colorectal cancer (CRC) patients with synchronous liver metastases are still indeterminate; therefore, we conducted a phase II multicenter trial of neoadjuvant chemotherapy mFOLFOX6 combined with bevacizumab for resectable synchronous liver metastases after R0-resections of primary CRCs. This study was started in June 2008. This is the interim report. Purpose: The aim of this interim analysis is to evaluate the response rate (RR) and adverse events (AEs) of the enrolled patients. Methods: Eligibility criteria included CRC patients with 10 or less synchronous liver metastases that were preoperatively diagnosed as surgically resectable. 20 of the enrolled patients received 8 courses of mFOLFOX6 with bevacizumab, but bevacizumab was omitted at the initial and the final courses, to avoid the AEs at the operations. The primary endpoint was the RR. Results: Among the 20 patients, one patient was excluded from the study because the assumed metastasis was diagnosed to be hemangioma later with the MRI imaging. RR was analyzed for the 19 patients, and AEs were analyzed for the 20 patients. Complete response and partial response were achieved in 2 (10.5%) and 11 (57.9%), respectively (RR: 68.4%); 4 (21.1%) were stable disease, and 2 (10.5%) were progressive disease. The RR was higher than the prespecified boundary; therefore, this study was scheduled to be continued. AEs were the following: neutropenia, hypertension, anemia, leucopenia, nausea, appetite loss, stomatitis, bleeding and proteinuria. Grade 3 neutropenia occurred in 4 cases (20.0%), and sensory neuropathy, stomatitis, diarrhea, and cerebral infarctions occurred in each one (5.0%) of the patients. There was no AE of grade 4 or 5. Liver resections were performed in 17 cases, and R0-resection was achieved in all of the operable cases (R0 rate was 85%). Conclusions: Neoadjuvant chemotherapy mFOLFOX6 combined with bevacizumab appears to be effective and well tolerated. The study is continued as scheduled, to further evaluate the benefit of this regimen. No significant financial relationships to disclose.