Double Negativity of MRI-Detected and Pathologically-Diagnosed Extramural Venous Invasion is a Favorable Prognostic Factor for Rectal Cancer.

BACKGROUND: Extramural venous invasion (EMVI) is a prognostic factor in rectal cancer. There are two types: EMVI detected by magnetic resonance imaging (MRI) (mr-EMVI) and EMVI detected by pathology (p-EMVI). They have been separately evaluated, but they have not yet been concurrently evaluated. We therefore evaluate both mr-EMVI and p-EMVI in rectal cancer at the same time and clarify their association with prognosis. PATIENTS AND METHODS: Included were the 186 consecutive patients who underwent complete radical resection of tumors ≤ stage III at Wakayama Medical University Hospital, Japan, between 2010 and 2018. All underwent preoperative MRI examination, and were reassessed for EMVI by a radiologist. Surgically resected specimens were then reassessed for EMVI by a pathologist. We assessed the correlation between positivity of mr-EMVI and p-EMVI and prognosis, and the clinicopathological background behind them. RESULTS: Patients with double negativity for mr-EMVI and p-EMVI had better prognosis than patients with mr-EMVI or p-EMVI positivity (p < 0.0001). Positivity for mr-EMVI or p-EMVI was a poor independent prognostic factor in multivariate analysis. CONCLUSIONS: Combined analysis of mr-EMVI and p-EMVI may enable prediction of postoperative prognosis of rectal cancer. Patients with double negativity of mr-EMVI and p-EMVI had better prognosis than patients with some form of positivity. Stated differently, patients with positivity of mr-EMVI, p-EMVI, or both had a poorer prognosis than those with double negativity. Postoperative adjuvant chemotherapy may improve poor prognosis. Combined evaluation of mr-EMVI and p-EMVI may be used to predict clinical outcomes and may be an effective prognostic predictor of rectal cancer.

Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system.

We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.

Randomized controlled trial comparing cosmetic results of midline incision versus off-midline incision for specimen extraction in laparoscopic colectomy.

PURPOSE: A notable advantage of laparoscopic colorectal surgery is that only a small incision at the extraction site is necessary, which is considered to be cosmetically beneficial. Meanwhile, the optimal extraction site for the resected specimen in laparoscopic colectomy is controversial in terms of cosmetic benefit. This randomized controlled trial compares midline and off-midline extraction sites in laparoscopic colectomy in patients with colon cancer, with consideration of cosmetic benefits as the primary endpoint. METHODS: Included were patients that underwent elective laparoscopic colectomy at WMUH between October 2014 and February 2017. Patients were randomly assigned to either midline incision group or off-midline incision group. Prospectively collected data included cosmetic results (patients and observer assessment scale) and complications including incidence of incisional hernia, SSI, and pain. This trial was registered with UMIN Clinical Trials (UMIN000028943). RESULTS: Finally, 98 patients with colorectal cancer were analyzed. No significant differences were found between the two groups in patient and observer assessment scales of cosmetic results (midline 8 ± 1.1 vs off-midline 11 ± 5.9 p = 0.16, midline 13.5 ± 6.6 vs off-midline 15 ± 11 p = 0.58, respectively) or in postoperative pain. However, incisional hernia occurred in four cases in the midline group (8%), which was significantly higher than that in the off-midline group (no cases, 0%). CONCLUSION: There was no significant difference in terms of cosmetic benefit, the primary endpoint, between the two groups. In this study, only the extraction site location was compared; future studies will examine differences depending on the incisional direction, including the incidence of incisional hernia.

New diagnostic strategy using narrow-band imaging (NBI) during laparoscopic surgery for patients with colorectal cancer.

BACKGROUND: Accurate tumor stage diagnosis during laparoscopic surgery remains difficult. We clarify the impact of new diagnostic strategy using narrow-band imaging (NBI) during laparoscopic surgery for colorectal cancer compared with other strategies. METHODS: We defined angiogenesis (Ag) and fibrosis (Fib) grades using NBI laparoscopy (lap-NBI), and assessed the clinicopathological features associated with these grades for 67 patients with colorectal cancer who underwent surgery. We assessed vessel density and gray scale with computer software. RESULTS: NBI-Ag-grade and NBI-Fib-grade of the serosal surface of cancer lesions and peritoneal nodules correlated with vessel density and gray scale of those assessed by Image J computer software. NBI-Fib-grades of liver nodules also correlated with gray scale. NBI-Ag- grade and Fib-grade of the serosal surface of cancer lesions correlated with pathological depth of invasion. These NBI grades of pathological metastatic peritoneal nodules were higher than those of pathologically benign peritoneal nodules. NBI- Fib grades of pathological metastatic liver nodules were higher than those of pathologically benign liver nodules. In multivariate analysis, lap-NBI was associated with different diagnosis for T3, T4 and non-T3, and non-T4. Moreover, lap-NBI was associated with different diagnosis for T4 and non-T4. Predictive value for T4 by lap-NBI showed high sensitivity (85%) specificity (87%), positive predictive value (74%), negative predictive value (93%), and overall accuracy (87%). Sensitivity and overall accuracy of lap-NBI was superior to that of other diagnostic modalities. CONCLUSION: We clarified the usefulness of the new diagnostic strategy using lap-NBI during laparoscopic surgery for colorectal cancer in comparison with other strategies.

High visceral to subcutaneous fat area ratio predicts early postoperative small bowel obstruction after surgery for colorectal cancer.

PURPOSE: Risks for postoperative small bowel obstruction have been demonstrated in several reports, most of which indicated male sex was a risk factor, but with the reason remaining unknown. We tested the hypothesis that it could be because males have more visceral fat than females. This prospective observational study aims to examine risks of early postoperative small bowel obstruction (EPSBO) after colorectal cancer surgery and the association between visceral to subcutaneous fat area ratio (V/S ratio) and EPSBO. METHODS: Four hundred and seventy-four patients who underwent colectomy for colorectal cancer in our hospital were enrolled in this study. The influence of several factors including V/S ratio on the development of EPSBO was analyzed. RESULTS: Thirty-one of the 474 patients (6.5%) developed EPSBO. EPSBO occurred more frequently in males (p = 0.03) and cases who developed postoperative anastomotic leakage (p < 0.001) or wound infection (p = 0.02). Higher V/S ratio was strongly related to male sex (p < 0.001). Multivariate analysis revealed higher V/S ratio (OR 2.25; p = 0.049) and anastomotic leakage (OR 5.86; p < 0.001) were independent risk factors for EPSBO. CONCLUSION: Higher V/S ratio was significantly related to EPSBO, suggesting that one of the reasons EPSBO was more likely to occur in males because they have more visceral fat than females. Preoperative identification of this risk factor could help us watch out for this potential complication.

Optimal Assessment of Frailty Predicts Postoperative Complications in Older Patients with Colorectal Cancer Surgery.

OBJECTIVES: The increasingly elderly worldwide population has affected the incidence of colorectal cancer. Establishment of reliable assessment of frailty and proposals for multi-disciplinary interventions are urgently required in oncology practices. Kihon Checklist (KCL) was published by the Japanese Ministry of Health, Labor and Welfare originally to identify individuals ≥ 65 years old at probable risk for requiring care or social support. We investigate the validity of KCL for frailty assessment to predict postoperative complication in older patients with colorectal cancer. METHODS: Consecutive colorectal cancer patients aged ≥ 65 (n = 500) were prospectively examined between May 2017 and December 2018. Preoperative frailty assessment was conducted by the G8 questionnaire and KCL. The main outcome measures were correlation between frailty, other clinical variables, and postoperative complications within 30 days after elective surgery. RESULTS: Of the 500 patients, 278 (55.6%) and 164 (32.8%) patients were classified as 'frail' by G8 and KCL, respectively. Overall complications counted among 97 patients (19.4%), and they were significantly associated with KCL ≥ 8-frail (46/164, p = 0.001), as opposed to G8 ≤ 14-frail (56/278, p = 0.531). Multivariate analysis showed that KCL ≥ 8 (hazard ratio 1.88, 95% confidence interval 1.16-3.04, p = 0.011) was an independent risk factor for these complications. CONCLUSIONS: KCL assessment can identify frail older patients likely to suffer from postoperative complications after colorectal cancer surgery. Preoperative screening of frailty, particularly by KCL, would help older patients prevent their worse outcomes in colorectal cancer. TRIAL REGISTRATION: UMIN000026689.

Tumor Sidedness Is Associated with Survival in Patients with Synchronous Colorectal Peritoneal Carcinomatosis.

BACKGROUND: Synchronous colorectal peritoneal carcinomatosis (SCPC) is not a rare entity, and the prognosis is extremely poor compared to other metastatic sites such as the liver and lung. Therefore, optimal treatment based on tumor characteristics is needed. Recently, the tumor sidedness of colorectal cancer has been reported as one of the prognostic factors and also as a key factor for the treatment strategy. The purpose of this study was to assess the clinical impact of tumor sidedness in patients with SCPC. METHODS: A total of 189 cases of SCPC were identified in a retrospective database at Wakayama Medical University Hospital (WMUH) between 1998 and 2014, and were analyzed with a special focus on tumor location. RESULTS: In multivariate analysis, a right-sided location (p = 0.02) and the presence of liver metastases (p < 0.001) were found to be the worst prognostic factors. The median survival time (MST) with right-sided and with left-sided SCPC was 10 and 16 months, respectively. The right-sided SCPC group included more aged patients (p = 0.045) and fewer patients who received postoperative chemotherapy (p = 0.034). When we focused on patients with macroscopically complete resection (n = 39), the MST and disease-free survival in the right-sided SCPC group was significantly shorter than in the left-sided SCPC group (p = 0.030 and p = 0.043, respectively). The MST of the right-sided and the left-sided SCPC patients among the completely resected patients was 24 and 73 months, respectively. CONCLUSION: Tumor sidedness may be a potent prognostic indicator for patients with SCPC. The survival time with right-sided SCPC is dramatically reduced compared to that with left-sided SCPC, especially among completely resected cases. We should change the treatment strategy according to the location of SCPC.

Defunctioning loop ileostomy for rectal anastomoses: predictors of stoma outlet obstruction.

PURPOSE: Creation of defunctioning loop ileostomy is a standard procedure in laparoscopic lower rectal surgery. Stoma-related obstruction sometimes occurs, but its cause has not been fully analyzed. This study aims to assess stoma obstructive complications and clarify the risk factors of stoma-related obstructions. METHODS: Two hundred and thirty consecutive patients who underwent laparoscopic rectal cancer surgery with defunctioning loop ileostomy between April 2007 and December 2017 were recruited, numbering 230. We statistically examined the frequency and risk factor of stoma outlet obstruction. RESULTS: Postoperative stoma-related complications developed in 41 patients (17.8%) overall, and there was no 30-day mortality. Stoma outlet obstructions occurred in 16 patients (7.0%) during postoperative course. Thick subcutaneous fat at the stoma-marking site (vertical distance ≥ 20 mm) and body mass index (≥ 22.2) were significantly associated with the risk of stoma outlet obstruction in univariate analysis. Thick subcutaneous fat was a significant predictive factor of stoma outlet obstruction according to multivariate analysis (odds ratio 3.80). CONCLUSIONS: This report investigates significant predictors of stoma outlet obstruction in laparoscopic rectal cancer surgery for the first time. In laparoscopic procedure, stoma outlet obstruction should be particularly considered in obese patients who have especially thick subcutaneous fat of the abdominal wall.

[A Case of Recurrent Small Bowel Cancer That Successfully Responded to Chemoradiation Therapy].

Primary small bowel cancer is a rare entity; thus, it is often found in progress. Therefore, the prognosis is often poor. Because of its low frequency, there are few reports concerning the treatment for small bowel cancer; hence, it is important to examine individual cases in detail. In this study, we present a case of recurrent small bowel cancer that successfully responded to chemoradiation therapy. Case: A 48-year-old woman had anemia. Colonoscopy showed a tumor in the terminal ileum. Because of invasion in the ovaries and uterus, ileocecal resection, hysterectomy, and bilateral adnexectomy were performed. The pathological diagnosis was small bowel cancer with lymph node metastasis, and CapeOX therapy was administered as postoperative adjuvant chemotherapy. Since local recurrence was detected in the right lower quadrant 6 months after the surgery, IRIS plus BV was initiated. Radiation therapy(2Gy×25 times, total 50 Gy)was also administered within the same period(only S-1 administration during radiation). After radiation therapy, the tumor decreased significantly in size and showed CR. Currently, the patient is under observation without treatment, but she has had no recurrence for 6 years after the confirmation of recurrence(6 years and 6 months after surgery). It is extremely rare for chemoradiation therapy to be effective for recurrent small bowel cancer; we report such a case with literatures.

Perineural Invasion Is Associated with Poor Survival after Preoperative Chemoradiation Therapy for Advanced Lower Rectal Cancer.

BACKGROUND: Preoperative chemoradiation therapy (pCRT) is a standard procedure for patients with advanced lower rectal cancer. It has been reported that pCRT cannot prolong the survival of patients with advanced lower rectal cancer. The aim of this study is to address the controllable and uncontrollable pathological factors of pCRT in predicting local and distant recurrences. METHODS: One hundred two patients with stages 2 and 3 cancer were consecutively enrolled to the study. The first 51 patients (October 2008-August 2010) underwent curative resection without pCRT. The latter 51 patients (September 2010-May 2015) underwent curative resection after pCRT. Pathological factors of patients were evaluated to assess the association between local and distant recurrences. RESULTS: Multivariate analyses for local and distant recurrences of patients without pCRT revealed that the independent risk factors were tumor deposit and perineural invasion respectively. pCRT was able to diminish circumferential resection margin, tumor deposit, venous invasion, and lymphatic permeation but not neural invasion and lymph node involvement. Kaplan-Meier curve of local and distant recurrence-free survival of patients with pCRT illustrated that tumor deposit is controllable, whereas perineural invasion is uncontrollable by pCRT. CONCLUSION: pCRT-uncontrollable perineural invasion may be a factor for distant recurrence of advanced rectal cancer patients, leading to poor survival.

[Cancer Immunotherapy Using Human Induced Pluripotent Stem Cell-Derived Dendritic Cells(iPSDCs)Expressing Carcinoembryonic Antigen].

The difficulty in obtaining a sufficient number of functional dendritic cells(DCs)is a well-known serious problem in DCbased immunotherapy. Therefore, we used induced pluripotent stem cell-derived DCs(iPSDCs). We have reported that mouse iPSDCs are equivalent to BMDCs, in terms of maturation and antigen presentation. In this study, the antitumor immune response of human iPSDCs expressing the carcinoembryonic antigen was examined, to determine its clinical application in gastrointestinal cancer. Human iPS cells were established from healthy human fibroblasts using a Sendai virus vector, and human iPSDCs were differentiated under a feeder-free culture. Additionally, the surface marker expression, cytokine production, and migratory capacity of human iPSDCs were equivalent to those of monocyte-derived DCs(MoDCs). After 3 cycles of stimulation of autologous PBMCs by genetically modified DCs, the 51Cr-release assay was performed. The lymphocytes stimulated by iPSDCs-CEA showed cytotoxic activity against LCL-CEA and CEA652-pulsed LCL, but showed no cytotoxicity against LCL-LacZ. In addition, they showed cytotoxic activity against CEA-positive human cancer cell lines, MKN45 and HT29, but showed no cytotoxicity against CEA-negative human cancer cell line MKN1. In conclusion, CEA-specific CTLs responses could be induced by iPSDCs-CEA. This vaccination strategy may be useful in future clinical applications of cancer vaccines.

Clinical characteristics of anastomotic leakage after an anterior resection for rectal cancer by assessing of the international classification on anastomotic leakage.

PURPOSE: The International Study Group of Rectal Cancer (ISREC) has proposed a new definition of anastomotic leakage (AL) which was simply classified into three grades; however, these criteria have not been assessed well. The aims of this study are to assess the new definition and to show the clinical features of AL after an anterior resection for rectal cancer. METHODS: Fifty consecutive patients developed AL after an anterior resection for rectal cancer was retrospectively assessed. AL was defined by the ISREC criteria. RESULTS: Twenty-seven (54 %) patients with AL were diagnosed by drain contents. The postoperative day of diagnosis for AL was later in grade A versus grades B and C (p = 0.038 vs p = 0.006, respectively). Permanent stoma (PS) was significantly more frequent in patients with grade C but not grade B compared to the patients with no AL (p < 0.001 and p = 0.171, respectively). In patients without diverting stoma, there was more serious grade of AL (p < 0.001). CONCLUSIONS: Differences were observed in the postoperative day of diagnosis, the creation rate of PS, and impact on diverting stoma after AL between each grade of leakage. The new classification was easy and reasonable to evaluate AL. As a result, it should be widely used in future studies.

Antitumor immune response of dendritic cells (DCs) expressing tumor-associated antigens derived from induced pluripotent stem cells: in comparison to bone marrow-derived DCs.

It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) is a serious problem in DC-based immunotherapy. Therefore, we used the induced pluripotent stem (iPS) cell-derived DCs (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow-derived DCs (BMDCs), then the aforementioned problems may be solved. In our study, we induced iPSDCs from iPS cells and examined the capacity for maturation of iPSDCs compared to that of BMDCs in addition to the capacity for migration of iPSDCs to regional lymph nodes. We adenovirally transduced the hgp100 gene, natural tumor antigens, into DCs and immunized mice once with the genetically modified DCs. The cytotoxic activity of CD8 (+) cytotoxic T lymphocytes (CTLs) was assayed using a (51) Cr-release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results showed that iPSDCs have an equal capacity to BMDCs in terms of maturation and migration. Furthermore, hgp100-specific CTLs were generated in mice immunized with genetically modified iPSDCs. These CTLs exhibited as high a level of cytotoxicity against B16 cells as BMDCs. Moreover, vaccination with the genetically modified iPSDCs achieved as high a level of therapeutic efficacy as vaccination with BMDCs. Our study clarified experimentally that genetically modified iPSDCs have an equal capacity to BMDCs in terms of tumor-associated antigen-specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine.

Perineal approach for a gastrointestinal stromal tumor on the anterior wall of the lower rectum.

BACKGROUND: Wide margins of resection and regional lymphadenectomy for GIST are not necessary. Several procedures for rectal GIST have been designed according to the location and size of the tumor to preserve the anal function and decrease the morbidity rate. CASE PRESENTATION: We report a 61-year-old-man with rectal bleeding. Proctologic examination revealed a small mass of approximately 2 cm in diameter on the anterior wall of the rectum at a distance of 4 cm from the anal verge. Histological examination of the biopsy sample via the rectum led to a diagnosis of GIST due to immunohistochemical positivity for C117 and CD34. Perineal resection was planned because abdominoperineal resection with sacrificing the sphincter function was excessive for this small tumor, and low anterior resection with the double stapling technique was difficult due to the lower position. A hemispheric incision was made from one mid-ischial tuberosity to the other with an apex of approximately 2 cm above the anus. The fascia band and muscles were successively transected in order to expose the anterior wall of the rectum, and excision of the tumor was performed. The postoperative course was uneventful, and the patient remained free from incontinence and recurrence. CONCLUSIONS: This perineal approach for a GIST on the anterior wall of the rectum is one option for preserving the anal function and decreasing the morbidity rate.

Impact of the post/preoperative serum CEA ratio on the survival of patients with rectal cancer.

PURPOSE: This study demonstrated the usefulness of the post/preoperative serum carcinoembryonic antigen (CEA) ratio as a predictor of survival after surgery for stage III rectal cancer patients. METHODS: One hundred and four patients with stage III rectal cancer who underwent surgery between 1991 and 2000 were enrolled. The ratio of the postoperative serum CEA value divided by the preoperative serum CEA value was defined as post/preoperative serum CEA ratio, and the patients were separated into two groups: post/preoperative serum CEA ratio ≤ 1 (n = 86) and >1 (n = 18). RESULTS: The multivariate analyses demonstrated that the intraoperative blood loss, lack of a sphincter-saving procedure and a post/preoperative serum CEA ratio >1 were independent factors predicting a poor prognosis for the overall and disease-free survival. The overall and disease-free survival rates among patients with a high preoperative serum CEA level (>5 ng/ml) or patients with a high postoperative serum CEA (>5 ng/ml) were longer in patients with a post/preoperative serum CEA ratio ≤ 1, in comparison to those with a post/preoperative serum CEA ratio >1. Liver metastasis was observed more frequently in patients with a post/preoperative serum CEA ratio >1. CONCLUSIONS: The post/preoperative serum CEA ratio may be a predictor of the prognosis after surgery for stage III rectal cancer patients.

Clinical outcome of up-front surgery in patients with asymptomatic, incurable synchronous peritoneal carcinomatosis.

PURPOSES: The purpose of this study was to show the clinical features of up-front surgery of the primary tumor in asymptomatic patients with incurable colorectal PC. METHODS: Forty-six patients that were diagnosed between 1998 and 2007 with asymptomatic colorectal PC who could not be successfully cured by surgery were assessed retrospectively. RESULTS: A univariate analysis revealed the presence of liver metastases, without the use of oxaliplatin (OX)/irinotecan (IRI) and without a primary tumor resection to be poor prognostic factors for survival (p = 0.044, p = 0.030, p < 0.001, respectively). According to a multivariate analysis, no use of OX/IRI and no primary tumor resection, were found to be independent poor prognostic factors for survival (HR 2.57; p = 0.047, HR 6.62; p = 0.003, respectively). The median survival time of patients treated with and without OX/IRI was 18 and 7 months, respectively. The median survival time of patients with and without primary tumor resection was 10 and 2 months, respectively. The number of patients needing surgical intervention for intestinal obstruction after surgery significantly increased in patients treated with OX/IRI (p = 0.001). CONCLUSION: Improvement of survival may be related to widespread use of modern systemic chemotherapy and primary tumor resection. However, an increased number of patients that needed surgery for an intestinal obstruction were observed, even after up-front surgery, when patients were treated with modern systemic chemotherapy.

[Cancer vaccine therapy using genetically modified induced pluripotent stem cell-derived dendritic cells expressing the TAA gene].

It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) poses a serious problem in DC-based immunotherapy. Therefore, we used induced pluripotent stem (iPS) cell-derived DCs (iPSDCs) instead. If the therapeutic efficacy of iPSDCs was equivalent to that of bone marrow-derived DCs( BMDCs), then the above-mentioned problems may be solved. In this study, we generated iPSDCs from iPS cells and compared their capacity to mature and migrate to the regional lymph nodes with that of BMDCs. We adenovirally transduced the hgp100 gene, which codes for a natural tumor antigen, into the DCs and immunized the mice with these genetically modified DCs. The cytotoxic activity of CD8( +) cytotoxic T lymphocytes( CTLs) was assayed using a 51Cr-release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results demonstrated that iPSDCs equaled BMDCs in terms of their maturation and migration capacity. Furthermore, hgp100-specific CTLs were generated in mice that were immunized with the genetically modified iPSDCs. These CTLs exhibited a high level of cytotoxicity against B16 cells, which is similar to that exhibited by CTLs generated in BMDCs immunized mice. Moreover, vaccination with genetically modified iPSDCs elicited a high level of therapeutic efficacy equaling that of vaccination with BMDCs. This study clarified experimentally that genetically modified iPSDCs are equivalent to BMDCs in terms of tumor-associated antigen-specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine.

What is related to postoperative outcome of frail status in elective colorectal cancer surgery?

Background: The population affected by colorectal cancer is growing, and there is an increasing need for prevention of functional decline following treatment. We proposed that the Kihon Checklist published by the Japanese Ministry of Health, Labor, and Welfare would be an appropriate means of frailty assessment for prediction of postoperative complications in older patients with colorectal cancer. This prospective cohort study aims to identify the factors influencing postoperative frailty. Methods: We prospectively enrolled consecutive patients with colorectal cancer and aged ≥ 65 year (N = 500) between May 2017 and December 2018. Eligible patients were assessed with the Kihon Checklist prior to surgery and 30 days after surgery. The main measures were variables related to postoperative change in view of frail status. Results: According to the Kihon Checklist questionnaire, 164 patients were frail preoperatively and 172 patients were frail postoperatively, whereas 38 patients changed from "nonfrail" before surgery to postoperative "frail." Overall complications were counted in 97 patients (19.4%), and 5 patients died. Performance status ≥ 2, history of laparotomy, open surgery, complication, ostomy creation, and delirium were significantly associated with changing postoperative "frail" (P = .014, P = .023, P = .006, P < .001, P = .023, and P = .024, respectively). In multivariate analysis, independent related factors of changing postoperative "frail" were complication (odds ratio 2.69, 95% confidence interval 1.19-6.09, P = .018) and ostomy creation (odds ratio 2.32, 95% confidence interval 1.01-5.33, P = .047). Conclusion: The Kihon Checklist questionnaire could identify the factors related to postoperative change of frailty status in older patients with colorectal cancer. This cohort concluded that whether postoperative complication occurred or not was closely associated with perioperative change of frailty status.

Appendiceal goblet cell adenocarcinoma with peritoneal recurrence 9 years after surgery.

Goblet cell adenocarcinoma is extremely rare tumor in which the same cells have both exocrine and neuroendocrine properties. It is considered to be more aggressive than conventional carcinoids and more likely to cause metastasis. We report a case of goblet cell adenocarcinoma that developed late peritoneal recurrence, and we review pertinent literature. A 63-year-old male underwent appendectomy for acute appendicitis. Histopathological findings of appendectomy specimen showed mixed adenoneuroendocrine carcinoma, and positive resection margin. He also underwent laparoscopic ileocecal resection and apical lymph node dissection. After 9 years, he presented with ileus and abdominal CT examination indicated possible peritoneal dissemination. Laparoscopic observation revealed disseminated nodules throughout the entire abdominal cavity, and the patient underwent resection of the omental nodule and gastrointestinal bypass surgery. Previous appendectomy specimens showed goblet cell adenocarcinoma (GCA) according to the 5th edition of the WHO classification. Omental specimens confirmed the histopathological findings, and we diagnosed peritoneal recurrence of appendiceal goblet cell adenocarcinoma. Goblet cell adenocarcinoma may develop and cause late recurrence, and long-term follow-up may be required.

Tumor RNA transfected DCs derived from iPS cells elicit cytotoxicity against cancer cells induced from colorectal cancer patients in vitro.

Significant efficacy of induced pluripotent stem cells (iPSCs) in generating DCs for cancer vaccine therapy was suggested in our previous studies. In clinical application of DC vaccine therapy, however, few DC vaccine systems have shown strong clinical response. To enhance immunogenicity in the DC vaccine, we transfected patient-derived iPSDCs with in vitro transcriptional RNA (ivtRNA), which was obtained from tumors of three patients with colorectal cancer. We investigated iPSDCs-ivtRNA which were induced by transfecting ivtRNA obtained from tumors of three colorectal cancer patients, and examined its antitumor effect. Moreover, we analyzed neoantigens expressed in colorectal cancer cells and examined whether iPSDCs-ivtRNA induced cytotoxic T lymphocytes (CTLs) against the predicted neoantigens. CTLs activated by iPSDCs-ivtRNA exhibited cytotoxic activity against the tumor spheroids in all three patients with colorectal cancer. Whole-exome sequencing revealed 1251 nonsynonymous mutations and 2155 neoantigens (IC50 < 500 nM) were predicted. For IFN-γ ELISPOT assay, these candidate neoantigens were further prioritised and 12 candidates were synthesized. IFN-γ ELISPOT assay revealed that the CTLs induced by iPSDCs-ivtRNA responded to one of the candidate neoantigens. In vitro CTLs obtained by transfecting tumor-derived RNA into iPSDCs derived from three patients with colorectal cancer showed potent tumor-specific killing effect.