Neighboring macrophage-induced alteration in the phenotype of colorectal cancer cells in the tumor budding area.

BACKGROUND: A higher number of tumor buds in the invasive front of colorectal cancer (CRC) specimens has been shown to contribute to a poor prognosis in CRC patients. Because macrophages (Mφs) have been demonstrated to alter the phenotype of cancer cells, we hypothesized that the phenotype of CRC cells in the tumor budding (TB) area might be changed by the interaction between CRC cells and Mφs. METHODS: We assessed the expression of topoisomerase 1 in CRC cells to estimate the acquisition of chemoresistance in CRC. To demonstrate the tumor-stromal interaction between CRC cells and Mφs, we assessed two histological findings, the number of Mφs per single CRC cell and the proximity between CRC cells and Mφs by histological spatial analysis using HALO software. RESULTS: The expression levels of topoisomerase 1 in CRC cells were decreased in deeper areas, especially in the TB area, compared to the surface area. Our histological spatial analysis revealed that 2.6 Mφs located within 60 µm of a single CRC cell were required to alter the phenotype of the CRC cell. Double-immunofluorescence staining revealed that higher Mφs were positive for interleukin-6 (IL-6) in the TB area and that AE1/AE3-positive CRC cells were also positive for phospho-STAT3 (pSTAT3) in the TB area; thus, the IL-6 receptor (IL-6R)/STAT3 signaling pathway in CRC cells was upregulated by IL-6 derived from neighboring Mφs. CONCLUSION: IL-6 secreted from the neighboring Mφs would alter the phenotype of CRC cells via IL-6R/STAT3 signaling pathway.

Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation.

Inflammatory bowel diseases (IBDs), such as Crohn's disease or ulcerative colitis, can be treated with anti TNF-alpha (TNF-α) antibodies (Abs), but they also put patients with IBDs at risk of cancer. We aimed to determine whether the anti TNF-α Ab induces colon cancer development in vitro and in vivo, and to identify the genes involved in colitis-associated cancer. We found that TNF-α (50 ng/mL) inhibited the proliferation, migration, and invasion of HCT8 and COLO205 colon cancer cell lines and that anti TNF-α Ab neutralized TNF-α inhibition in vitro. The effects of anti TNF-α Ab, infliximab (10 mg/kg) were investigated in mouse models of colitis-associated cancer induced by intraperitoneally injected azoxymethane (AOM: 10 mg/kg)/orally administered dextran sodium sulfate (DSS: 2.5%) (AOM/DSS) in vivo. Infliximab significantly attenuated the development of colon cancer in these mice. Microarray analyses and RT-qPCR revealed that mast cell protease 1, mast cell protease 2, and chymase 1 were up-regulated in cancer tissue of AOM/DSS mice; however, those mast cell related genes were downregulated in cancer tissue of AOM/DSS mice with infliximab. These results suggested that mast cells play a pivotal role in the development of cancer associated with colitis in AOM/DSS mice.

Learning curve of robotic rectal surgery using risk-adjusted cumulative summation: a 5-year institutional experience.

PURPOSE: Outline learning phases of robot-assisted laparoscopic surgery for rectal cancer and compare surgical and clinical outcomes between each phase of robot-assisted laparoscopic surgery and the mastery phase of conventional laparoscopic surgery. METHODS: From 2015 to 2020, 210 patients underwent rectal cancer surgery at Sendai Medical Center. We performed conventional laparoscopic surgery in 110 patients and, laparoscopic surgery 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). Duration of hospital stay (13.1 days vs. 18.0 days, respectively; p = 0.016) and surgery (209.1 min vs. 249.5 min, respectively; p = 0.045) were significantly shorter in phase 3 of the robot-assisted laparoscopic surgery group than in the conventional laparoscopic surgery group. Blood loss volume was significantly lower in phase 1 of the robot-assisted laparoscopic surgery group 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 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. After experience with at least 80 cases, tactile familiarity can be acquired from visual information only (visual haptic feedback). CLINICAL TRIAL REGISTRATION: UMIN reference no. UMIN000019857.

[Pathological Complete Response and Long-Term Survival of a Gastric Neuroendocrine Carcinoma Patient Treated by Neoadjuvant Chemotherapy].

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 Case of Long-Term Survival by Multidisciplinary Surgical Treatment for Metastatic Multi-Organ Metastasis after Radical Resection of Esophageal Cancer].

A 78-year-old man with advanced thoracic esophageal cancer underwent radical esophagectomy after neoadjuvant chemotherapy with cisplatin plus 5-FU. He had left adrenal metastasis 10 months after surgery and removed it, but 3 months later he had liver metastases. After 2 courses of chemotherapy with nedaplatin plus 5-FU, resection was performed. One course of nedaplatin plus 5-FU for adjuvant chemotherapy was added, but the patient was followed up without another chemotherapy after surgery because of intestinal obstruction due to infection and increase of the lymphatic cyst in the abdominal cavity. Six months after the liver resection, nodules appeared in the right lung, and 4 months later, multiple nodules extending to both lungs were observed. Therefore, it was judged that there were multiple lung metastases, and administration of nivolumab was started. He has been 3 years since the recurrence of esophageal cancer and 17 months after the start of nivolumab administration, but the recurrence lesion is only progressing to lung metastasis.

Wnt5a in cancer-associated fibroblasts promotes colorectal cancer progression.

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 ß-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.

[A Case of Long-Term Survival Achieved after Nivolumab Treatment for Recurrence of Postoperative Advanced Gastric Cancer].

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.

[A Case of Peritoneal Metastasis Resection from GIST of the Small Intestine with Focal Resistance Against Imatinib Mesylate].

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.

[A Case of Curatively Resected Rectal Cancer with Preservation of Urinary Function after Chemotherapy].

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.

The functional outcome and factors influencing the quality of life after ileal pouch anal anastomosis in patients with ulcerative colitis.

PURPOSE: 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). METHODS: 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. RESULTS: 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 (< 45, ≥ 45 years at colectomy). The ratio of patients who usually had bowel movements at night also significantly decreased with postoperative time and increased with age. The median total IBDQ score was 180. A multivariate analysis showed that "trip activity", "care about where the restroom is", and "bowel movements in the day" were significant independent risk factors for the daily life satisfaction score. CONCLUSIONS: The bowel function and QOL were acceptable in patients with UC after IPAA; however, patients with a short postoperative time or older age had a lower functional outcome than others.

Lymph nodes around the posterior gastric artery: their existence, frequency, and clinical implications.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Endoscopy-Assisted Partial Duodenal Resection for Duodenal Adenoma in a Patient with Familial Adenomatous Polyposis].

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.

[Two Cases of Locally Recurrent Rectal Cancer Successfully Treated by Carbon Ion Radiotherapy].

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.

[A Case of Laparoscopically Resected Giant Rectal Cancer Following Neoadjuvant Chemoradiotherapy].

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.

[A Small Rectal Neuroendocrine Tumor of Less Than 5mm with Lymph Node Metastasis].

According to the treatment guideline for rectal neuroendocrine tumor(NET), tumor with a diameter ofC10mm should be resected endoscopically, while tumor with a diameter of>10mm 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 of>10 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.

The Risk Factors for Metastasis in Non-Ampullary Duodenal Neuroendocrine Tumors Measuring 20 mm or Less in Diameter.

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.

[A Case of Leiomyosarcoma of the Small Intestine with Intestinal Hemorrhage Due to Intraluminal Penetration].

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.

[A Case of Curatively Resected Ascending Colon Cancer with Ovarian Metastasis and Peritoneal Dissemination after Chemotherapy].

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.

[Multidisciplinary Treatment for Squamous Cell Carcinoma of the Anal Canal].

Chemoradiotherapy(CRT)has been recognized as a standard treatment for locoregional squamous cell carcinoma of the anal canal in Western countries. However, surgery had historically been considered as a standard treatment and there are only a few reports on CRT for anal canal cancer in Japan. In this study, we analyzed medical records of 5 anal canal cancer patients treated with CRT in our hospital between 2005 and 2015. Patients' characteristics were as follows: median age, 70 years (range 42-80 years); male/female, 1/4; and clinical Stage I / III a/ III b, 3/1/1. The regimens of chemotherapy were MMC plus 5-FU in 4 patients and CDDP in 1 patient. The median follow-up period was 30 months(range, 6 to 100 months). After CRT, 4 patients achieved complete response. The other patient with partial response underwent salvage surgery. All patients were alive without recurrence. In conclusion, our retrospective study showed that CRT is considered to be a standard treat- ment for anal canal cancer.

[A Successful Case of Conversion Therapy after Chemotherapy for Advanced Rectal Cancer with Inguinal Lymph Node Metastasis].

CASE: 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.