Vascular endothelial growth factor inhibitors promote antitumor responses via tumor microenvironment immunosuppression in advanced colorectal cancer.

PURPOSE: This study aims to investigate changes in the tumor immune environment of patients who underwent therapy with a vascular endothelial growth factor (VEGF) inhibitor for advanced colorectal cancer. METHODS: Patients (n = 135) with T3 or T4 colorectal cancer were included in this retrospective study. They were classified as follows: patients who had not received preoperative treatment (UPFRONT group, n = 54), who had received FOLFOX as preoperative chemotherapy (FOLFOX group, n = 55), and who had undergone resection after combination FOLFOX and bevacizumab as unresectable colorectal cancer (B-MAB group, n = 26). The number of cytotoxic T lymphocytes (CTLs), FOXP3+ lymphocytes (including regulatory T cells (Tregs)), CD163+ monocytes (including M2-type tumor-associated macrophages (TAM-M2 type)), and programmed cell death 1 (PD-1)+ lymphocytes was evaluated immunohistochemically in the cancer cell area (CC) and stromal cell area (ST) of surgical specimens, and compared among the three groups. RESULTS: The CTL population did not differ among the three groups in both areas. In the B-MAB group, the numbers of PD-1+ cells in the ST, FOXP3+ lymphocytes in both areas, and CD163+monocytes in the ST was lower than that in the other two groups, and a correlation with the histological therapeutic effect was observed. CONCLUSIONS: In advanced colorectal cancer, VEGF inhibitors may decrease the number of PD-1+ cells and inhibit the infiltration of FOXP3+ lymphocytes and CD163+monocytes into the tumor environment.

Mucosectomy of the anal canal via transanal minimally invasive surgery combined with transanal total mesorectal excision for familial adenomatous polyposis: A technical note.

AIM: Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment modality for familial adenomatous polyposis (FAP). It is challenging to perform proctectomy and preserve anal sphincter function. In this video, precise mucosectomy of the anal canal via transanal minimally invasive surgery (MAC-TAMIS) is reported. METHODS: An asymptomatic 35-year-old man was found to have a positive faecal occult blood test in routine screening examination and was diagnosed with FAP on colonoscopic examination. The patient was scheduled for total proctocolectomy with IPAA using the TAMIS approach combined with transanal total mesorectal excision. MAC-TAMIS was performed to preserve the internal anal sphincter during laparoscopy. RESULTS: The total duration of surgery was 543 min, blood loss was minimal, and the postoperative course was uneventful. The postoperative hospital stay was 12 days. The pathological findings demonstrated no evidence of malignancy. Gastrographic imaging from the ileostomy showed sufficient size of the J pouch and good tonus of the anus at 6 months after surgery. The Wexner scores at 1, 3 and 6 months after ileostomy closure were 5, 3 and 0, respectively. CONCLUSION: The MAC-TAMIS technique is safe and feasible during total proctocolectomy with IPAA in patients with FAP. This technique allows us to precisely preserve the internal anal sphincter using a laparoscopic approach.

[A Case of Curative Resection Following TNT for Locally Advanced Rectal Cancer with Liver Metastasis].

The standard treatment of locally advanced rectal cancer is preoperative chemoradiotherapy(CRT)in Europe and the United States, while that is surgical excision and lateral pelvic lymph node dissection followed by adjuvant chemotherapy in Japan. Recently, total neoadjuvant therapy(TNT), which combines neoadjuvant chemotherapy and preoperative CRT, have been popular. We performed curative excision for initially locally advanced rectal cancer with liver metastasis after TNT. A 61- year-old woman was diagnosed as having rectal cancer with liver metastasis and invasion of the uterus, vagina, bladder, and left ureter. The patient underwent 8 courses of FOLFOX plus bevacizumab, followed by radiotherapy, and totally pelvic excision for the primary tumor. Because of liver metastasis progression, hepatectomy was performed after 6 courses of FOLFIRI plus panitumumab. The patient has been cancer free for 20 months to date. TNT is considered to be an effective strategy for the treatment of large locally advanced rectal cancer.

A new overlapped delta-shaped anastomosis technique using linear staplers with reinforced bioabsorbable material for intracorporeal anastomosis during laparoscopic colectomy.

AIM: Totally laparoscopic colectomy with intracorporeal anastomosis (IA) is associated with less surgical trauma and wound related complications compared to laparoscopy-assisted colectomy with extracorporeal anastomosis. Delta shaped anastomosis is a widely popular IA technique. In this study, we discuss a construction technique for an overlapped delta-shaped anastomosis using a linear stapler with a reinforced bioabsorbable material. METHODS: We excised the bowel at a point 10 cm from the tumour on either sides and laid them in an overlapped fashion. The entry hole was created at a point 3 cm proximal to the right stump and 7 cm distal to the left stump on the antimesenteric side. Then, a 60-mm linear stapler with reinforced bioabsorbable material was inserted inside each lumen and fired. Finally, the common entry hole was fixed with a suture in the middle, the bowel was elevated holding the bioabsorbable material, and closed using the linear stapler in a delta-shaped manner. RESULTS: The technique was applied in five patients with tumours in the ascending, transverse, and descending colon. The median surgery time, anastomosis construction time and postoperative stay was 329 min (range 285-682 min), 19 min (range 14-29 min), and 12 days (range 9-15 days), respectively. There were no perioperative complications and only one postoperative complication. CONCLUSION: The overlapped delta-shaped anastomosis technique using linear staplers with reinforced bioabsorbable material appears to be both safe and feasible.

Radiomics Texture Analysis for the Identification of Colorectal Liver Metastases Sensitive to First-Line Oxaliplatin-Based Chemotherapy.

OBJECTIVE: The aim of this study was to develop a radiomics-based prediction model for the response of colorectal liver metastases to oxaliplatin-based chemotherapy. METHODS: Forty-two consecutive patients treated with oxaliplatin-based first-line chemotherapy for colorectal liver metastasis at our institution from August 2013 to October 2019 were enrolled in this retrospective study. Overall, 126 liver metastases were chronologically divided into the training (n = 94) and validation (n = 32) cohorts. Regions of interest were manually segmented, and the best response to chemotherapy was decided based on Response Evaluation Criteria in Solid Tumors (RECIST). Patients who achieved clinical complete and partial response according to RECIST were defined as good responders. Radiomics features were extracted from the pretreatment enhanced computed tomography scans, and a radiomics score was calculated using the least absolute shrinkage and selection operator regression model in a trial cohort. RESULTS: The radiomics score significantly discriminated good responders in both the trial (area under the curve [AUC] 0.8512, 95% confidence interval [CI] 0.7719-0.9305; p < 0.0001) and validation (AUC 0.7792, 95% CI 0.6176-0.9407; p < 0.0001) cohorts. Multivariate analysis revealed that high radiomics scores greater than - 0.06 (odds ratio [OR] 23.803, 95% CI 8.432-80.432; p < 0.0001), clinical non-T4 (OR 6.054, 95% CI 2.164-18.394; p = 0.0005), and metachronous disease (OR 11.787, 95% CI 2.333-70.833; p = 0.0025) were independently associated with good response. CONCLUSIONS: Radiomics signatures may be a potential biomarker for the early prediction of chemosensitivity in colorectal liver metastases. This approach may support the treatment strategy for colorectal liver metastasis.

Indications for laparoscopic surgery for older rectal cancer patients with comorbidities.

PURPOSE: Given the lack of safety studies concerning laparoscopic surgery for rectal cancer in patients ≥ 80 years old with comorbidities, we sought to investigate this in the current study. METHODS: Between 2012 and 2019, 24 patients ≥ 80 years old underwent laparoscopic surgery for rectal cancer without preoperative treatment. These patients were divided into those with [comorbidity(+) group, n = 13] and without [comorbidity(-) group, n = 11] comorbidities. The preoperative nutritional status and ASA classification, postoperative complications, time to oral diet, and length of hospital stay were evaluated in each group. RESULTS: In the comorbidity(+)/comorbidity(-) groups, the average age was 85.9/84.1 years old, respectively. The major comorbidities were heart disease including atrial fibrillation and valvular disorder. The average PNI and CONUT scores in the comorbidity(+)/comorbidity(-) groups were 44.7/44.2 an 3.1/2.2, respectively. Planned surgical procedures were completed in all patients. Postoperative complications occurred in 2/3 cases in the comorbidity(+)/comorbidity(-) groups, respectively, and the average time to oral diet was 3.8/3.7 days, while the average length of hospitalization after surgery was 15.2/16.5 days, respectively. In the comorbidity(+) group, there was no exacerbation of comorbidities in any cases. CONCLUSION: The safety of laparoscopic surgery is acceptable among older rectal cancer patients with comorbidities.

[A case report of advanced gastric cancer with bulky lymph node metastases successfully treated with induction chemotherapy followed by curative resection].

The patient was a 74-year-old woman with advanced gastric cancer in the greater curvature of the antrum and lesser curvature of the angle.Abdominal computed tomography revealed bulky lymph node metastases of No. 3, 8a, and 11p.She was diagnosed with clinical Stage IIIA gastric cancer (cT3N2M0) and underwent surgery.Laparotomy findings revealed invasion of bulky lymph nodes to the common hepatic artery and pancreas.Since radical resection was not feasible, exploratory laparotomy was performed.After the surgery, she received 1 course of S-1 monotherapy and 3 courses of S-1/cisplatin (CDDP) therapy.The therapeutic response, as assessed by imaging studies, was partial for the primary lesions and complete for the enlarged lymph nodes.Distal gastrectomy and D2 lymph node dissection were performed.Histopathological findings showed no evidence of lymph node involvement, allowing the patient to undergo radical surgery.The patient received postoperative adjuvant chemotherapy with S-1.She is alive 11 months after the surgery, with no evidence of recurrence.Induction chemotherapy appears to be a promising option for advanced gastric cancer with significant lymph node involvement.

[A case report of neuroendocrine carcinoma of the stomach with liver metastases curatively resected after neoadjuvant chemotherapy].

The patient was a 73-year-old male with advanced gastric cancer in the lesser curvature of the antrum.Abdominal computed tomography revealed multiple liver metastases(S5, S8).He was diagnosed with clinical Stage IV gastric cancer (cT3N0M1H1).He received 3 courses of combined neoadjuvant chemotherapy with capecitabine, cisplatin, and trastuzumab because immunostaining indicated the tumor was human epidermal growth factor receptor 2(HER2)-positive.The therapeutic response, as assessed by imaging studies, was partial for the primary lesions and stable for liver metastases.Distal gastrectomy, D2 lymph node dissection, and S5 extended subsegmentectomy of the liver were performed.Histopathological findings indicated that both the primary tumor and liver metastases were neuroendocrine carcinoma.The patient declined post-operative adjuvant chemotherapy and he is alive 6 months after the surgery with no evidence of recurrence.Surgery with neoadjuvant chemotherapy appears to be a promising option for advanced gastric cancer with liver metastases.

Influence of Robotic Rectal Resection Versus Laparoscopic Rectal Resection on Postoperative Ileus: A Single-center Experience.

AIM: This study was performed to clarify the relationship between robotic rectal resection and postoperative ileus (POI) by comparing robotic surgery with laparoscopic surgery. MATERIALS AND METHODS: We retrospectively reviewed 238 patients who underwent robotic (n=41) or laparoscopic (n=197) rectal resection for rectal cancer in our institution from January 2013 to June 2020. First, we compared the background factors and short-term surgical outcomes between robotic and laparoscopic surgery. Next, we investigated the postoperative complications of robotic and laparoscopic rectal resection. Finally, we identified the risk factors for POI following rectal cancer resection. RESULTS: The percentages of patients with an Rb tumor location, treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection, a temporary diverting ileostomy, and a long operation time were significantly higher in robotic than laparoscopic surgery ( P <0.0001, P =0.0002, P =0.0078, and P =0.0001, respectively). There was no significant difference in any individual postoperative complication between robotic and laparoscopic surgery. Risk factors for POI were male sex ( P =0.0078), neoadjuvant chemoradiotherapy ( P =0.0007), an Rb tumor location ( P =0.0005), treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection ( P =0.0044), a temporary diverting ileostomy ( P <0.0001), and operation time of ≥240 minutes ( P =0.0024). Notably, robotic surgery was not a risk factor for POI following rectal resection relative to laparoscopic surgery. CONCLUSION: Although patients who underwent robotic surgery had more risk factors for POI, the risk of POI was similar between robotic and laparoscopic rectal resection.

Impact of a Long Linear Staplers on the Incidence of Stricture after Triangulating Esophagogastric Anastomosis.

BACKGROUND: Various techniques have been reported for esophagogastric anastomosis to prevent anastomotic leakage. Recently, not only postoperative anastomotic leakage but also anastomotic stricture is considered important because stricture contributes to the patient's postoperative quality of life. However, the best procedure for anastomosis has not been established. MATERIALS AND METHODS: The authors divided 101 patients with thoracic or abdominal esophageal cancer who underwent cervical triangulating esophagogastric anastomosis using a linear stapler between May 2017 and May 2020 into 2 groups: surgery with a short (45 mm) linear stapler (SS group, n=59) or a long (60 mm) stapler (LS group, n=42). The frequencies of anastomotic leakage and stricture were compared between the 2 groups. RESULTS: The incidence of anastomotic leakage and stricture without leakage were significantly lower in the LS versus SS group (respectively: leakage: 15% vs. 0%, P=0.01; stricture: 36% vs. 7%, P=0.01). A short linear stapler and anastomotic leakage were independent risk factors for anastomotic stricture in the multivariate analysis (short stapler: odds ratio, 3.27; 95% confidence interval, 1.08-9.9; P=0.03; anastomotic leakage: odds ratio, 2.78; 95% confidence interval, 1.02-8.5; P=0.04). CONCLUSION: A long linear stapler is preferable for cervical triangulating esophagogastric anastomosis.

Cytolytic activity score as a biomarker for antitumor immunity and clinical outcome in patients with gastric cancer.

BACKGROUND: A simple measure of immune cytolytic activity (CYT) base on mRNA expression levels of two genes, GZMA and PRF1, was recently reported. Here, we aimed to evaluate the CYT score's potential as a measure of antitumor immunity and predictor of clinical outcome in gastric cancer (GC) patients. MATERIALS AND METHODS: We evaluated the correlations between tumor-infiltrating immune cells and the CYT score in 238 GC samples from The Cancer Genome Atlas (TCGA). Next, we investigated CYT score associations with molecular subtypes, somatic mutation load, and immune checkpoint molecules in GC samples from TCGA and Asian Cancer Research Group (ACRG). Moreover, we evaluated the clinical significance of the CYT score calculated by reverse transcription (RT)-quantitative PCR (qPCR) data in 123 GC samples and the association of the CYT score with the response to anti-PD-1 therapy in 7 GC samples from Kyushu University Hospital. RESULTS: The CYT score positively correlated with the proportions of tumor-infiltrating CD8+ T cells and macrophages and negatively correlated with the proportion of regulatory T cells in GC tissues. A high CYT score was associated with common immune checkpoint molecules, a high mutation, the Epstein-Barr virus subtype, and the microsatellite instability subtype in GC. Moreover, a low CYT score was a poor prognosis factor in patients with GC. Finally, the CYT score was higher in a responder to anti-PD-1 therapy compared to nonresponders. CONCLUSION: The CYT score reflects antitumor immunity and predicts clinical outcome in GC patients.

Quadruple gastrointestinal cancer with discordance of mismatch repair protein deficiency and microsatellite instability suggesting Lynch syndrome.

A 65-year-old woman with prior personal and family histories of cancer was admitted to our hospital for quadruple cancer. Preoperative endoscopy revealed a type 0-II gastric cancer (GC; gastric body), advanced type-II colon cancer (ascending colon), and early-stage recto-sigmoid colon cancers. We diagnosed her with Lynch syndrome (LS) per Amsterdam criteria, and performed distal gastrectomy, ileocecal resection and high anterior resection. Her pathological diagnoses were GC: well-to-poorly differentiated adenocarcinoma (AD, por2 > tub2) with signet-ring cells, ypT1b SM2; ascending colon cancer: AD with focal mucin products (tub2 > muc), SS; sigmoid colon cancer: AD (tub1), M; recto-sigmoid cancer: AD (tub1 > tub2), SM. Immunohistochemical tests revealed that all cancers lacked the MLH1/PMS2 protein. However, the three colon cancers were found to have high microsatellite instability (MSI); the GC was microsatellite stable (MSS). No recurrence or other cancers were observed for 30 months after surgery without adjuvant chemotherapy. As patients with LS may also develop MSS cancers, we should check for MSI in all LS cancers for proper treatment.

New Anastomosis Technique to Prevent Anastomotic Leakage in Laparoscopic Anterior Resection for Rectal Cancer, Especially Upper Rectal Cancer.

BACKGROUND/AIM: Anastomotic leakage (AL) is a major problem in rectal cancer surgery. To prevent AL, we developed a side-to-side anastomosis technique using a circular stapler and termed it the circular side stapling technique (CST). We herein report the method and outcome of the CST. PATIENTS AND METHODS: In this study, we analyzed 154 patients with stage 0 to III rectal cancer who underwent curative laparoscopic low anterior resection. Perioperative factors and complications were compared between the CST and usual double stapling technique (DST). RESULTS: The CST was performed in 110 of the 154 patients. When comparing the outcomes of patients with upper rectal cancer. AL occurred in no patients in the CST group and in three patients in the DST group (p=0.011). The CST prevented AL in all patients with upper rectal cancer. CONCLUSION: The CST is a safe and useful procedure in laparoscopic anterior resection. This technique can prevent AL, especially in patients with upper rectal cancer.

A rare case of esophageal adenocarcinoma with urinary bladder metastasis.

A 75-year-old man was admitted to our hospital for treatment of esophageal cancer (EC) in March 2017. Esophagogastroduodenoscopy revealed Barrett's esophagus and superficial, distal EC (type 0-IIc). Tumor biopsy showed esophageal adenocarcinoma. Computed tomography revealed no lymph node metastasis but did reveal a 19-mm tumor on the right side of the urinary bladder. Bladder cancer (BC) was also suspected, and the patient underwent endoscopic submucosal dissection for EC and transurethral resection of the bladder tumor. The pathological diagnosis of EC was moderately to poorly differentiated adenocarcinoma (tub2), pT1b (SM), ly0, v0. The pathological horizontal margin was negative and the vertical margin was positive. Additional esophagectomy and lymph node dissection were indicated for curability. Esophagectomy was difficult because the patient had severe cardiovascular disease, so follow-up observation was adopted. BC was classified as urothelial carcinoma Ta, ly0, v0. After 32 months, multiple tumors were found in the bladder, and BC recurrence was suspected. Transurethral resection of the bladder was performed again for seven tumors, and pathological diagnosis was poorly differentiated adenocarcinoma (tub2). The immunohistochemical features matched those of EC. We diagnosed EC metastasis in the urinary bladder. Bladder adenocarcinoma is difficult to distinguish from metastasis from other organs, especially the upper gastrointestinal tract, and cytomorphological features and appropriate clinical history are required.

Obstructive rectal endometriosis treated by robot-assisted laparoscopic surgery: a case report.

BACKGROUND: Rectal endometriosis is a rare disease. A definitive diagnosis prior to surgery is often difficult. We encountered a patient with rectal sub-obstructive endometriosis that was treated by robot-assisted laparoscopic low anterior resection. CASE PRESENTATION: A 43-year-old woman visited our hospital with suspected stenosis caused by upper rectal cancer. She had a 2-year history of constipation. We were unable to confirm the diagnosis through detailed examinations, including laparoscopy. Robot-assisted laparoscopic low anterior resection with D3 lymph node dissection was performed for both diagnosis and treatment. The postoperative specimen showed a submucosal tumor. The pathological examination confirmed rectal endometriosis. CONCLUSIONS: We herein describe a rare case of obstructive rectal endometriosis that we were unable to diagnose preoperatively. Robotic surgery was useful in this case, which involved extensive pelvic adhesion.

Involvement of MAF1 homolog, negative regulator of RNA polymerase III in colorectal cancer progression.

Polymerase (Pol) III­dependent transcription controls the abundance of transfer RNAs, 5S ribosomal RNA and small non­coding RNAs within cells, and is known to serve an essential role in the maintenance of intracellular homeostasis. However, its contribution to cancer progression has not been extensively explored. The present study demonstrated that the evolutionarily conserved MAF1 homolog, negative regulator of RNA Pol III (MAF1) may be closely associated with malignant potential and poor prognosis in colorectal cancer (CRC). Notably, immunohistochemical analysis of 146 CRC surgical specimens revealed that high expression levels of MAF1 were associated with advanced tumor depth, lymph node metastasis, distant metastasis and poor prognosis. In vitro loss­of­function assays revealed that MAF1 knockdown suppressed chemoresistance and migration of CRC cancer cells. Furthermore, detailed analysis of an independent CRC dataset (n=615) demonstrated that the prognostic impact of MAF1 gene expression was particularly marked in microsatellite instability (MSI)­positive patients, who benefit from immune checkpoint blockade. High expression levels of MAF1 were revealed to be an independent prognostic indicator in MSI­positive CRC. These findings suggested that MAF1 may have an essential role in CRC progression, particularly in MSI­positive cases.

Tubular adenoma of the common bile duct with uptake in 18F-FDG PET: A case report.

A 64-year-old man presented with epigastric discomfort and nausea. Laboratory analyses revealed increased levels of total and direct bilirubin, and increased levels of aminotransferases. Computed tomography revealed the presence of a mass in the distal common bile duct. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography revealed a 25 mm filling defect in the distal common bile duct, and biopsy of the lesion disclosed the presence of tubular adenoma. Using fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed an increased accumulation of the tracer in the lesion, with a maximum standard uptake value (SUVmax) of 3.3. The patient received a pylorus-preserving pancreatoduodenectomy. The histopathological examination revealed a tubular adenoma with low-grade atypia. The patient remains alive 15 months following the surgery, with no evidence of recurrence of the adenoma. 18F-FDG PET has been successfully applied in clinical practice to detect a wide variety of tumor types, including lymphoma, lung, colon and bile duct cancer. In the present study, a case of bile duct adenoma with low-grade atypia was reported, revealing the uptake of 18F-FDG. 18F-FDG PET may be able to detect premalignant tumors of the bile duct, although whether 18F-FDG PET is able to differentially discriminate between diagnoses of adenoma and carcinoma of the bile duct remains to be fully elucidated, and the assessment of further case studies is required.