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.

Potential urinary function benefits of initial robotic surgery for rectal cancer in the introductory phase.

We aimed to evaluate the advantages and disadvantages of initial robotic surgery for rectal cancer in the introduction phase. This study retrospectively evaluated patients who underwent initial robotic surgery (n = 36) vs. patients who underwent conventional laparoscopic surgery (n = 95) for rectal cancer. We compared the clinical and pathological characteristics of patients using a propensity score analysis and clarified short-term outcomes, urinary function, and sexual function at the time of robotic surgery introduction. The mean surgical duration was longer in the robot-assisted laparoscopy group compared with the conventional laparoscopy group (288.4 vs. 245.2 min, respectively; p = 0.051). With lateral pelvic lymph node dissection, no significant difference was observed in surgical duration (508.0 min for robot-assisted laparoscopy vs. 480.4 min for conventional laparoscopy; p = 0.595). The length of postoperative hospital stay was significantly shorter in the robot-assisted laparoscopy group compared with the conventional laparoscopy group (15 days vs. 13.0 days, respectively; p = 0.026). Conversion to open surgery was not necessary in either group. The International Prostate Symptom Score was significantly lower in the robot-assisted laparoscopy group compared with the conventional laparoscopy group. Moderate-to-severe symptoms were more frequently observed in the conventional laparoscopy group compared with the robot-assisted laparoscopy group (p = 0.051). Robotic surgery is safe and could improve functional disorder after rectal cancer surgery in the introduction phase. This may depend on the surgeon's experience in performing robotic surgery and strictly confined criteria in Japan.

[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.

Transanal total mesorectal excision and transabdominal robotic surgery for rectal cancer: A retrospective study.

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.

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.

Efficacy of laparoscopic sleeve gastrectomy for patient with morbid obesity and type 1 diabetes mellitus: a case report.

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 ß-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 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.

Tips for operation of inguinal hernia after implantation of artificial urinary sphincter following radical prostatectomy: report of two cases.

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.

Gastric Duplication Cyst With Occult GIST Component.

A 37-year-old man underwent screening examinations, and a pale-colored submucosal tumor was detected on gastric cardia. Endosonography showed a 15-mm cyst with hypoechoic nodules in the muscularis propria, and endoscopic ultrasound-guided fine-needle aspiration obtained mucinous fluid with atypical spindle cells positive for c-kit, indicating a gastrointestinal stromal tumor. Surgical resection was recommended, but he initially agreed to surveillance. After becoming larger for 8 years, partial gastrectomy was performed for the 22 × 22 × 15-mm capsulized lesion. Surprisingly, its histology was gastric duplication cyst without gastrointestinal stromal tumor. Gastric duplication cyst is a rare entity with the possibility of malignant complications, but careful assessment of endoscopic ultrasound-guided fine-needle aspiration might also be required.

[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.

A Catastrophic Case of Idiopathic Cholesterol Crystal Embolism with Multiple Lethal Complications: A Labyrinth Underneath the Diagnosis of Skin Ulcers in Chronic Kidney Disease Patients.

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 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.

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.

[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.

[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 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.