[A Case of Synchronous-Metachronous Cancer of the Rectum, Stomach, Pharynx, Esophagus and Small Intestine].

A 71-year-old man presented with the chief complaint of fecal occult blood. Based on imaging studies, the patient was diagnosed advanced rectal cancer. He received laparoscopic low anterior resection. Three months after the rectal cancer operation, upper gastrointestinal endoscopy revealed gastric cancer. The patient had a diagnosis of synchronous cancer of the rectum and stomach, and received laparoscopic distal gastrectomy. Two years after the rectal cancer operation, liver metastasis(S4)was detected and resected. Three years after the rectal cancer operation, esophageal cancer and laryngeal cancer were detected synchronously and chemoradiotherapy was performed. Five years after the rectal cancer operation, small intestinal cancer with infiltration of descending colon and esophagus cancer were detected synchronously. Small intestinal resection and Hartmann procedure were performed for small intestinal cancer. ESD was performed for esophageal cancer. Six years after the rectal cancer operation, FDG-PET showed the peritracheal lymph node metastasis, lumbar spine metastasis and local recurrence in the pelvis. Currently, systemic chemotherapy is undergoing. We report a rare case of synchronous- metachronous cancer of the rectum, stomach, pharynx, esophagus and small intestine.

[A Case of Sigmoid Colon Cancer with Intussusception Prolapsing through the Anus].

A 76-year-old woman presented to the hospital with the colon prolapsing through the anus. The enhanced abdominal computed tomography(CT)showed intussusception of the sigmoid colon due to sigmoid colon cancer. It was difficult to reduce the intussusception, and we did not recognize the ileus and ischemic change of the colon. Therefore, we performed an elective surgery. Hartmann's procedure and lymph node dissection were performed 8 days after the hospitalization. The postoperative course was uneventful. We report a case of sigmoid colon cancer with intussusception prolapsing through the anus.

Vaccine Based on Dendritic Cells Electroporated with an Exogenous Ovalbumin Protein and Pulsed with Invariant Natural Killer T Cell Ligands Effectively Induces Antigen-Specific Antitumor Immunity.

(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells.

Risk Factors and Outcome of Portal Vein Thrombosis After Laparoscopic and Open Hepatectomy for Primary Liver Cancer: A Single-Center Experience.

BACKGROUND: Post-hepatectomy portal vein thrombosis (PH-PVT) is a severe complication. The risk factors of PH-PVT after laparoscopic and open hepatectomy have not been clarified yet. We aimed to retrospectively investigate the risk factors and outcome of PH-PVT in patients with primary liver cancer. METHODS: We enrolled 622 consecutive patients who underwent hepatectomy in our hospital between January 2006 and August 2016. RESULTS: Of 21 patients (3.4%) with PH-PVT, 7 had grade I; 13, grade II; and 1, grade III. The patients with PH-PVT were significantly older than those without PH-PVT. Of the 413 patients who underwent open hepatectomy, those who underwent a major right hepatectomy (4.1%) had a slightly higher incidence of PH-PVT. Of the 209 patients who underwent laparoscopic hepatectomy, those who underwent a left lateral sectionectomy (21.2%) and major right hepatectomy (16.7%) had high incidence rates of PH-PVT. The treatment was only observation in five patients, medication with an antithrombotic drug in 15 patients, and reoperation in one patient. PH-PVT diminished in 17 patients. Cavernous transformation and/or stenosis of the portal vein developed in three patients. The patient with grade III PH-PVT after open right hemihepatectomy underwent reoperation but died of hepatic failure. CONCLUSION: This study demonstrated that patient age, left lateral sectionectomy were risk factors of PH-PVT. Laparoscopic left lateral sectionectomy and major right hepatectomy might bring about relatively higher risk of PH-PVT. Major right hepatectomy tends to lead to severe PH-PVT. Careful handling of the PV during hepatectomy and early treatment of PH-PVT are necessary.

Does anastomotic leakage after rectal cancer resection worsen long-term oncologic outcome?

PURPOSE: The influence of anastomotic leakage on long-term survival in patients with rectal cancer is debatable. The aim of this study was to evaluate relationships between anastomotic leakage and long-term survival. METHODS: In this multicenter retrospective cohort study, 395 consecutive stage I to III rectal cancer patients underwent anterior resection between 2007 and 2012. Five-year overall survival, 5-year disease-free survival, and 5-year local recurrence-free survival were compared between patients with leakage (Leakage (+)) and patients without leakage (Leakage (-)). RESULTS: Of 395 patients, 50 (12.7%) had anastomotic leakage. Of these 50, 34 (68.0%) required urgent surgery and 16 (32.0%) could be managed by watchful waiting or with percutaneous drainage. The median follow-up period was 62.6 months. Five-year overall survival did not differ between the two groups (Leakage (+) 93.8% vs. Leakage (-) 89.0%, P = 0.121). Five-year disease-free survival also did not differ between the two groups (81.6% vs. 80.3%, P = 0.731), and neither did 5-year local recurrence-free survival (91.9% vs. 86.1%, P = 0.206). In a multivariable Cox regression model, BMI > 25, preoperative CA19-9 > 37, pathological T stage, pathological N stage, and circumferential resection margin (CRM) positive were independent predictors of disease-free survival. Moreover, pathological T stage, pathological N stage, and CRM positive were the only independent predictors of overall survival and local recurrence-free survival. Anastomotic leakage was not a risk factor for overall survival, disease-free survival, or local recurrence-free survival. CONCLUSION: Anastomotic leakage is not associated with a significant decrease in long-term survival in rectal cancer patients.

Laparoscopic vs open surgery for colorectal cancer patients with high American Society of Anesthesiologists classes.

INTRODUCTION: Laparoscopic surgery has become popular for colorectal cancer treatment in recent years. However, its success rate even among high-risk patients remains debatable. The present study aims to compare the short- and long-term outcomes between laparoscopic and open surgeries in the American Society of Anesthesiologists (ASA) classes 3 and 4 patients with colorectal cancer. METHODS: This was a single-center, retrospective, cohort study performed at a university hospital, with 78 patients suffering from colorectal cancer who underwent surgery in ASA classes 3 and 4 as respondents. Patient and tumor characteristics, operative outcomes, and prognoses were factors compared between the open and laparoscopic groups. RESULTS: Compared with the open group, laparoscopic group had longer operation time (median 287.5 vs 204.5 minutes, P = .001), less operative blood loss (median 40 vs 240 mL, P = .020), and fewer postoperative complications (24% vs 55%, P = .011). In addition, operative approach (open vs laparoscopic) served as an independent factor for the occurrence of postoperative complications [HR = 3.963 (1.344-12.269), P = .013]. In terms of overall survival and recurrence-free survival (P = .171 and .087, respectively), no significant difference was found between the two groups. CONCLUSION: Laparoscopic surgery is thus associated with more favorable short-time outcomes and could be adopted as treatment even for colorectal cancer ASA class 3 and 4 patients.

Neoadjuvant Chemotherapy Increases PD-L1 Expression and CD8+ Tumor-infiltrating Lymphocytes in Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.

Recent advances of neoadjuvant chemoradiotherapy in rectal cancer: Future treatment perspectives.

Neoadjuvant chemoradiotherapy (nCRT) has been widely used as a multidisciplinary approach for stage II/III rectal cancer. However, its safety and efficacy are controversial because previous studies have shown conflicting outcomes. The present review aimed to elucidate the benefits and limitations of nCRT for patients with rectal cancer. Future perspectives of nCRT are also described. No recent randomized trials have been able to show a survival benefit, although many studies have demonstrated good local control with the use of fluoropyrimidine (e.g. 5-fluorouracil [FU] or capecitabine)-based nCRT. Addition of oxaliplatin (OX) to FU-based nCRT might improve overall survival by preventing distant metastasis, as shown in recent meta-analyses. However, control of adverse effects is an important concern with this treatment. New treatment strategies such as nonoperative management (watch and wait policy) and total neoadjuvant therapy (TNT) are promising, but the establishment of reliable diagnostic methods of metastasis is essential. Development of new biomarkers is also necessary to select patients who are more likely to benefit from nCRT.

Evaluation of the venous drainage pattern of the splenic flexure by preoperative three-dimensional computed tomography.

INTRODUCTION: Anatomical evaluation of the splenic flexure vein is essential for complete mesocolic excision with central vascular ligation when treating patients with splenic flexure cancer. Although there have been several studies relating to the arterial branches of the splenic flexure, very limited data are available regarding the variation in venous anatomy in this region. METHODS: Sixty-six patients with colorectal cancer who underwent preoperative 3-D CT between April 2016 and April 2017 were included in this retrospective study. The pattern of the venous drainage of the splenic flexure and its association with the inferior border of the pancreas were evaluated. RESULTS: The inferior mesenteric vein flowed into the splenic vein in 32 patients (48.5%), into the superior mesenteric vein in 27 patients (40.9%), and into the confluence of splenic vein and superior mesenteric vein in 7 patients (10.6%). The splenic flexure vein joined the inferior mesenteric vein in 62 patients (93.9%), the splenic vein in 2 patients (3.0%), and the middle colic vein in 2 patients (3.0%). The splenic flexure vein flowed into the inferior mesenteric vein below the level of the inferior border of the pancreas in 58 patients (90.6%) and above it in 4 patients (6.3%). CONCLUSION: Preoperative evaluation of the venous pattern of the splenic flexure on 3-D CT is useful before complete mesocolic excision with central vascular ligation to avoid intraoperative bleeding during splenic flexure cancer surgery.

Application of iNKT Cell-targeted Active Immunotherapy in Cancer Treatment.

In tumor immunity, invariant natural killer T (iNKT) cells play a pivotal role as a link between the innate and adaptive immune systems. With a precisely regulated activation mechanism, iNKT cells have the ability to respond quickly to antigenic stimulation and rapidly produce cytokines and chemokines, and subsequently an effective antitumor immune response. The development of iNKT cell-targeted active immunotherapy enables, not only an antitumor immune response through innate and acquired immunity, but also the conversion of an immunosuppressive into an immunogenic microenvironment. This review is focused on the activation mechanism and the role of iNKT cells after therapeutic active immunization. The therapeutic strategy targeting iNKT cells is expected to be applied to clinical practice in combination with surgery and chemotherapy.

Immunosuppression Induced by Perioperative Peritonitis Promotes Lung Metastasis.

BACKGROUND/AIM: Perioperative intra-abdominal infection has been reported as a risk factor for metastasis. The aim of this study was to investigate the mechanism by which peritonitis induces immunosuppression in the lung, which in turn promotes lung metastasis. MATERIALS AND METHODS: C57BL/6 mice were intravenously administered B16F10 melanoma cells to induce lung metastasis and subsequently subjected to cecal ligation and puncture (CLP) to induce peritonitis or sham surgery. The number of lung metastatic nodules was evaluated. Cell fractions in lungs and serum cytokines after CLP were investigated. RESULTS: CLP mice showed an increased number of lung metastases compared to sham-treated mice. The fraction and number of natural killer (NK) cells in lungs of CLP mice were significantly reduced in early post-CLP phase. Myeloid-derived suppressor cells (MDSCs) in lungs were significantly decreased in CLP mice. Serum IL-6 and TNF levels were significantly elevated in CLP mice. CONCLUSION: Peritonitis promoted lung metastasis in a murine model, which may be attributable to the impact of NK cells and MDSCs in the lungs.

The Clinical Significance of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography in Patients with Occupational Cholangiocarcinoma

Objective: The present study aimed to identify the clinical significance of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in patients with occupational cholangiocarcinoma. Methods: This study included 10 men with occupational cholangiocarcinoma who were former or current workers at a printing company in Osaka, Japan. Of the 10 patients, 2 had 2 main tumors and 1 had 3 main tumors. Twelve FDG-PET imaging findings in the 10 patients could be analyzed. We evaluated the relationships between FDG-PET imaging parameters and clinicopathological findings of occupational cholangiocarcinoma. Results: Abnormal FDG uptake was observed in 8 of the 14 main tumors, with maximum standardized uptake values ranging from 2.9 to 11.0, and the sensitivity was 57.1%. Four patients had lymph node metastases, and abnormal marrow uptake was detected in all these patients. Although precancerous lesions, such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB) without any invasion, were not detected, abnormal FDG uptake was demonstrated in 2 of 4 patients with IPNB having an associated invasive carcinoma.Conclusions: Although FDG-PET may be useful for assessing tumor progression factors, such as lymph node metastasis, it cannot accurately detect precancerous lesions, such as BilIN and IPNB without invasive carcinoma.

Esophagojejunostomy With Linear Staplers in Laparoscopic Total Gastrectomy: Experience With 168 Cases in 5 Consecutive Years.

PURPOSE: We evaluate surgical outcomes of intracorporeal esophagojejunostomy in laparoscopic total gastrectomy using 2 linear stapler methods. MATERIALS AND METHODS: The functional end-to-end anastomosis (FEEA) method was chosen as a first choice. The overlap method was chosen in cases with esophageal invasion. We retrospectively analyzed the early and late surgical outcomes of consecutive 168 laparoscopic total gastrectomy cases from April 2011 to December 2016. RESULTS AND CONCLUSIONS: The FEEA method was selected in 120 cases, and the overlap method was selected in 48 cases. The mean time of esophagojejunostomy for the FEEA and overlap method was 13.2 and 36.5 minutes, respectively. Two cases with FEEA method and 3 cases with overlap method experienced complications due to esophagojejunostomy leakage. These cases were treated without performing a reoperation. One case with FEEA method was complicated due to esophagojejunostomy stenosis. This case was endoscopically treated. Our procedures are safe and feasible.

Safety and Effectiveness of Laparoscopic Colorectal Resection in Elderly Patients with Colorectal Cancer: A Propensity Score Matching Study.

BACKGROUND/AIM: The aim of this study was to evaluate the safety and effectiveness of laparoscopic surgery in elderly patients with colorectal cancer. PATIENTS AND METHODS: In total, 223 patients aged <75 years and 66 patients aged ≥75 years who underwent laparoscopic colorectal resection were included. Short- and long-term outcomes were compared between the younger and elderly patients after propensity score matching. RESULTS: Post-operative complications were similar in both groups (younger vs. elderly: 24.7% vs. 19.3%, p=0.479). There were no significant differences in disease-free survival (DFS) (5-year DFS: 96.3% vs. 86.9%, p=0.079) and overall survival (OS) (5-year OS: 92.9% vs. 78.1%, p=0.106) between the two groups. CONCLUSION: Laparoscopic surgery for colorectal cancer is as safe and effective for elderly patients as for younger patients.

Frequency of Myeloid-derived Suppressor Cells in the Peripheral Blood Reflects the Status of Tumor Recurrence.

BACKGROUND: Malignant tumors inhibit antitumor immune responses, which are driven by T-regulatory cells or myeloid-derived suppressor cells (MDSCs). Since MDSCs are involved in invasion, migration, and metastasis of tumor cells, we hypothesized that MDSCs are also involved in tumor recurrence after surgical resection. MATERIALS AND METHODS: C57BL/6 mice were subcutaneously inoculated with B16F10 melanoma cells in the right flank. In some experiments, established tumors were surgically resected. Peripheral blood was drawn over time, and immune cells and cytokines were evaluated using flow cytometry. RESULTS: MDSCs and relevant pro-inflammatory cytokines increased in the peripheral blood of tumor-bearing mice. Moreover, the frequency of MDSCs rapidly increased in mice with tumor recurrence. CONCLUSION: The frequency of MDSCs in the peripheral blood of tumor-bearing mice reflects the status of tumor progression as well as tumor recurrence. Continuous monitoring of MDSCs in the peripheral blood might be a useful indicator of tumor recurrence.

The PD-1/PD-L1 axis may be aberrantly activated in occupational cholangiocarcinoma.

An outbreak of cholangiocarcinoma in a printing company was reported in Japan, and these cases were regarded as an occupational disease (occupational cholangiocarcinoma). This study examined the expression status of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in occupational cholangiocarcinoma. Immunostaining of PD-1, PD-L1, CD3, CD8, and CD163 was performed using tissue sections of occupational cholangiocarcinoma (n = 10), and the results were compared with those of control cases consisting of intrahepatic (n = 23) and extrahepatic (n = 45) cholangiocarcinoma. Carcinoma cells expressed PD-L1 in all cases of occupational cholangiocarcinoma, whereas the detection of PD-L1 expression in cholangiocarcinoma cells was limited to a low number of cases (less than 10%) in the control subjects. In cases of occupational cholangiocarcinoma, occasional PD-L1 expression was also noted in precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. Additionally, tumor-associated macrophages and tumor-infiltrating T cells expressed PD-L1 and PD-1, respectively. The number of PD-L1-positive mononuclear cells, PD-1-positive lymphocytes, and CD8-positive lymphocytes infiltrating within the tumor was significantly higher in occupational cholangiocarcinoma compared with that in control cases. These results indicate that immune escape via the PD-1/PD-L1 axis may be occurring in occupational cholangiocarcinoma.

Prospective registry for laparoscopic liver resection.

INTRODUCTION: Laparoscopic liver resection (LLR) has been widely performed throughout the world. Although prospective registry studies to clarify the safety of LLR have been feasible, no prior multicenter prospective study has addressed this issue. We have conducted a multicenter prospective cohort study to reveal the current status of LLR in Japan. METHODS: From April 2015 to March 2016, candidates for LLR were preoperatively enrolled at 12 institutions. The primary end-point was surgical safety, which was evaluated based on surgical factors and on short-term and midterm outcomes. RESULTS: A total of 102 patients were enrolled. Planned laparoscopic procedures included 96 pure laparoscopies, 1 hand-assisted laparoscopy, and 5 hybrid techniques. Non-anatomical partial resection or left lateral sectionectomy were performed in almost all cases. The median duration of surgery was 221 min. The median blood loss was 80.5 mL. Conversion was required for four patients (3.9%). The 90-day postoperative morbidities with grades more severe than II in the Clavien-Dindo classification were observed in six patients (5.9%). The median postoperative hospital stay was 9.5 days. No cases involved reoperation or mortality. CONCLUSION: Minor resection of LLR has been performed safely. To ensure the safe dissemination of LLR, including for major resection, a larger multicenter prospective study is required.

Our experience with laparoscopic partial gastrectomy by the 'lift-and-cut method' for gastric gastrointestinal stromal tumor with maximal preservation of the remnant stomach.

BACKGROUND: Wedge resection is the most commonly used method in laparoscopic partial gastrectomy for gastric gastrointestinal stromal tumor (GIST). However, this method can involve inadvertent resection of additional gastric tissue and cause gastric deformation. To minimize the volume of resected gastric tissue, we have developed a laparoscopic partial gastrectomy with seromyotomy which we call the 'lift-and-cut method' for gastric GIST. Here, we report a case series of this surgery. METHOD: First, the seromuscular layer around the tumor is cut. Because the mucosa and submucosa are extensible, the tumor is lifted toward the abdominal cavity. After sufficient lifting, the gastric tissue under the tumor is cut at the submucosal layer with a linear stapler (thus 'lift-and-cut method'). Finally, the defect in the seromuscular layer is closed with a hand-sewn suture. RESULTS: From April 2011 to December 2015, 28 patients underwent laparoscopic partial gastrectomy by this method at Osaka Red Cross Hospital. Average operation time was 126 min (range 65-302 min) and average blood loss was 10 ml (range 0-200 ml). No intraoperative complications including tumor rupture or postoperative complications regarded as Clavien-Dindo Grade II or higher occurred. All patients took sufficient solid diet at discharge. Median postoperative hospital stay was 7 days (range 5-21 days). On median follow-up of 26.6 months (range 6-54 months), no recurrence was reported. CONCLUSION: Laparoscopic partial gastrectomy by the lift-and-cut method is safe and simple, and widely applicable for gastric GIST.