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Mini-abstract We developed a novel technique for valvuloplastic esophagogastrostomy, named tri double-flap hybrid method (TDF). TDF is shown to be simple and useful for Siewert type II esophagogastric junction carcinoma. Background Research has found valvuloplastic esophagogastrostomy using the conventional hand-sutured double-flap (CDF) technique to be a useful anti-reflux procedure after proximal gastrectomy. However, no study has focused on this reconstruction procedure after laparoscopic transhiatal lower esophagectomy and proximal gastrectomy (LEPG) for esophagogastric junction carcinoma primarily because of its profound difficulty. Thus, we devised a novel technique for valvuloplastic esophagogastrostomy comprising triangular linear-stapled esophagogastrostomy and hand-sutured flap closure, which we term the tri double-flap hybrid (TDF) method. Methods After reviewing our institution’s prospective gastric cancer database, 59 consecutive patients with Siewert type II esophagogastric junction carcinoma who underwent LEPG with valvuloplastic esophagogastrostomy from January 2014 to August 2018 were analyzed. Short- and mid-term surgical outcomes were then compared between the LEPG-TDF and LEPG-CDF groups to evaluate the efficacy of the TDF method. Results The median operative time was 316 min (184–613 min) and blood loss was 22.5 ml (0–180 ml). In comparison between the two groups, the LEPG-TDF group had a significantly shorter operative time (298 vs. 336 min, p  = 0.041) and significantly lower postoperative anastomotic leak/stenosis rates (0 vs. 14.2%, p  = 0.045), compared to the LEPG-CDF group. No patient suffered from severe gastroesophageal reflux symptoms (Visick score ≥ III). Conclusions This study showed that double-flap valvuloplastic esophagogastrostomy is safe and feasible for reconstruction after LEPG for Siewert type II esophagogastric junction carcinoma. Moreover, the TDF method is a simple and useful technique that offers a shorter operative time and lower morbidity compared to the CDF technique.

ObjectiveThis prospective randomized trial compared the invasiveness of laparoscopic gastrectomy using a single-port approach with that of a conventional multi-port approach in the treatment of gastric cancer.Summary Background DataThe benefit of single-port laparoscopic gastrectomy (SLG) over multi-port laparoscopic gastrectomy (MLG) has yet to be confirmed in a well-designed study.MethodsOne hundred and one patients who were scheduled to undergo laparoscopic distal gastrectomy for histologically confirmed clinical stage I gastric cancer between April 2016 and September 2018 were randomly allocated to SLG (n = 50) or MLG (n = 51). The primary endpoints were the postoperative visual analog scale pain scores. Secondary endpoints were frequency of use of analgesia, short-term outcomes, such as operating time, intraoperative blood loss, inflammatory reactions, postoperative morbidity, and 90-day mortality.ResultsThe postoperative pain score was significantly lower in the SLG group than in the MLG group (p < 0.001) on the operative day and the postoperative day 1–7. Analgesics were administered significantly less often in the SLG group than in the MLG group (1 vs. 3 days, p = 0.0078) and the duration of use of analgesics was significantly shorter in the SLG group (2 vs. 3 days, p = 0.0171). The operating time was significantly shorter in the SLG group than in the MLG group (169 vs. 182 min, p = 0.0399). Other surgical outcomes were comparable between the study groups.ConclusionsSLG was shown to be safe and feasible in the treatment of gastric cancer with better short-term results in terms of less severe pain and may be suitable for treatment of cStage I gastric cancer.Clinical trial registration:UMIN000022218

BackgroundPreoperative weight loss in esophageal cancer is reported to be associated with a poor prognosis. However, the impact of postoperative weight loss on the prognosis of patients with esophageal cancer remains unclear.MethodsThis study included 186 patients with esophageal squamous cell carcinoma who underwent surgery between January 2012 and January 2015. The relationship between weight loss 6 months after esophagectomy as well as the clinical factors and prognosis of patients was investigated.ResultsThe mean weight loss rate for all the patients was 9.3% at 3 months, 10.8% at 6 months, 11.1% at 12 months, and 11.4% at 24 months after surgery. The patients with severe weight loss 6 months after surgery (≥ 12%) exhibited lower serum albumin levels and a lower prognostic nutrition index 6 months after esophagectomy than the patients with moderate weight loss (< 12%; p = 0.011 and 0.009, respectively). Although overall survival did not differ significantly between the two groups, for all the patients, severe weight loss was significantly associated with shortened overall survival for the cStages 3 and 4 patients (3-year overall survival rate, 76.6% in the moderate group vs 54.5% in the severe group; p = 0.042). The multivariate analyses identified only severe weight loss as an independent factor associated with worse overall survival for the cStages 3 and 4 patients (p = 0.034).ConclusionThis study showed that postoperative weight loss negatively affected the prognosis for patients with advanced esophageal cancer, indicating the necessity of administering nutritional interventions to these patients to prevent postoperative weight loss.

Primary culture of the cancer cells from patients' tumors can provide crucial information of individual tumors, yet the technology has not been optimized until now. We developed an innovative culture method for primary colorectal cancer cells, based on the principle that cell-cell contact of cancer cells was maintained throughout the process. When tumor tissue was dissociated into cell clusters, in which cell-cell contact was retained, they rapidly formed spheroids that we termed cancer tissue-originated spheroids (CTOSs). CTOSs of colorectal cancer consisted of highly purified and viable cancer cells, and they were prepared with high efficiency. In immunodeficient mice, CTOSs formed xenograft tumors that retained the features of the parental tumors. Moreover, CTOSs were able to be cultured and expanded in vitro using a 3D culture system and stem cell culture medium. This method allowed evaluation of chemosensitivity and signal pathway activation in cancer cells from individual patients. Easy preparation and culture of pure primary cancer cells provides an innovative platform for studying cancer biology and developing personalized medicine.

POU5F1-expressing cells can self-renew and differentiate, contributing to metastasis formation in colorectal cancer (CRC), but it plays an important role in normal pluripotent stem cells. Here, we identified the CRC-specific gene, HNF1A, which is the downstream of POU5F1. HNF1A associates with fatty acid and glucose metabolism, and CRC cells highly expressed it. In 198 CRC patients, high HNF1A expression was an independent predictor of disease-free ( P  = 0.031) and overall ( P  = 0.007) survival. HNF1A-knockdown showed significantly reduced cell growth, increased apoptosis, and improved anticancer drug sensitivity. We revealed that HNF1A regulated controlled GLUT1 expression via HIF1A and multidrug resistance protein function to suppress SRI. HNF1A expression was elevated in persister cells after exposure to anticancer drugs, and anticancer drug sensitivity was also improved in persister cells via the inhibition of HNF1A. In conclusion, HNF1A expression can reflect resistance to anticancer drug treatment, and its suppression improves anticancer drug sensitivity as a new therapeutic target.

A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

Patient‐derived cancer organoid culture is an important live material that reflects clinical heterogeneity. However, the limited amount of organoids available for each case as well as the considerable amount of time and cost to expand in vitro makes it impractical to perform high‐throughput drug screening using organoid cultures from multiple patients. Here, we report an advanced system for the high‐throughput screening of 2427 drugs using the cancer tissue‐originated spheroid (CTOS) method. In this system, we apply the CTOS method in an ex vivo platform from xenograft tumors, using machines to handle CTOS and reagents, and testing a CTOS reference panel of multiple CTOS lines for the hit drugs. CTOS passages in xenograft tumors resulted in minimal changes of morphological and genomic status, and xenograft tumor generation efficiently expanded the number of CTOS to evaluate multiple drugs. Our panel of colorectal cancer CTOS lines exhibited diverse sensitivities to the hit compounds, demonstrating the usefulness of this system for investigating highly heterogeneous disease. We report an advanced system for the high‐throughput screening of 2427 drugs using organoids. In this system, we apply the cancer‐tissue originated spheroid (CTOS) method in an ex vivo platform from xenograft tumors, using machines to handle organoids and reagents, and testing a CTOS reference panel of multiple CTOS lines for the hit drugs. Our panel of colorectal cancer CTOS lines exhibited diverse sensitivities to the hit compounds, demonstrating the usefulness of this system for investigating highly heterogeneous disease.

BackgroundThe benefits of robotic gastrectomy (RG) over laparoscopic gastrectomy (LG) remain controversial. This single-center, propensity score-matched study aimed to compare the outcomes of RG with those of LG for treating gastric cancer.MethodsWe searched the prospective gastric cancer database of our institute for patients with gastric cancer who underwent RG or LG between January 2014 and December 2019, excluding patients with remnant stomach cancer and those who underwent concurrent surgery for comorbid malignancies. One-to-one propensity score matching was performed to reduce bias from confounding patient-related variables, and short- and long-term outcomes were compared between the groups.ResultsWe identified 1189 patients who underwent LG (n = 979) or RG (n = 210). After propensity score matching, we selected 210 pairs of patients who underwent LG (distal gastrectomy, 138; total or proximal gastrectomy, 72) or RG (distal gastrectomy, 143; total or proximal gastrectomy, 67). RG was associated with a significantly shorter operative time (RG = 201 min vs. LG = 231 min, p = 0.0051), less blood loss (RG = 13 mL vs. LG = 42 mL, p < 0.0001), lower postoperative morbidity (RG = 1.0% vs. LG = 4.8%, p = 0.0066), and a shorter postoperative hospital stay (p = 0.0002) than LG. Drain amylase levels on postoperative Days 1 and 3 in the RG group were significantly lower than those in the LG group (p < 0.0001).ConclusionsRG is a safe and feasible treatment for gastric cancer, with a shorter operative time, less blood loss, and lower postoperative morbidity than LG. The application of robotics in minimally invasive gastric cancer surgery may offer an alternative to conventional surgery. Multicenter, prospective, randomized controlled trials comparing RG with conventional LG are needed to establish the feasibility and efficacy of minimally invasive gastric cancer surgery.

Urinary free-glycans are promising markers of disease. In this study, we attempted to identify novel tumor markers by focusing on neutral free-glycans in urine. Free-glycans extracted from the urine of normal subjects and cancer patients with gastric, colorectal, pancreatic and bile duct were fluorescently labeled with 2-aminopyridine. Profiles of these neutral free-glycans constructed using multidimensional high performance liquid chromatography separation were compared between normal controls and cancer patients. The analysis identified one glycan in the urine of cancer patients with a unique structure, which included a pentose residue. To reveal the glycan structure, the linkage fashion, monosaccharide species and enantiomer of the pentose were analyzed by high performance liquid chromatography and mass spectrometry combined with several chemical treatments. The backbone of the glycan was a monoantennary complex-type free- N -glycan containing β1,4-branch. The pentose residue was attached to the antennal GlcNAc and released by α1,3/4- l -fucosidase. Intriguingly, the pentose residue was consistent with d -arabinose. Collectively, this glycan structure was determined to be Galβ1-4( d -Araβ1-3)GlcNAcβ1-4Manα1-3Manβ1-4GlcNAc-PA. Elevation of d -arabinose-containing free-glycans in the urine of cancer patients was confirmed by selected reaction monitoring. This is the first study to unequivocally show the occurrence of a d -arabinose-containing oligosaccharide in human together with its detailed structure.

Mesorectal excision is the international standard surgical procedure for lower rectal cancer. However, lateral pelvic lymph node metastasis occasionally occurs in patients with clinical stage II or stage III rectal cancer, and therefore mesorectal excision with lateral lymph node dissection is the standard procedure in Japan. We did a randomised controlled trial to confirm that the results of mesorectal excision alone are not inferior to those of mesorectal excision with lateral lymph node dissection. This study was undertaken at 33 major hospitals in Japan. Eligibility criteria included histologically proven rectal cancer of clinical stage II or stage III, with the main lesion located in the rectum with the lower margin below the peritoneal reflection, and no lateral pelvic lymph node enlargement. After surgeons had confirmed macroscopic R0 resection by mesorectal excision, patients were intraoperatively randomised to mesorectal excision alone or with lateral lymph node dissection. The groups were balanced by a minimisation method according to clinical N staging (N0 or N1, 2), sex, and institution. Allocated procedure was not masked to investigators or patients. This study is now in the follow-up stage. The primary endpoint is relapse-free survival and will be reported after the primary analysis planned for 2015. Here, we compare operation time, blood loss, postoperative morbidity (grade 3 or 4), and hospital mortality between the two groups. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00190541. 351 patients were randomly assigned to mesoretcal excision with lateral lymph node dissection and 350 to mesorectal excision alone, between June 11, 2003, and Aug 6, 2010. One patient in the mesorectal excision alone group underwent lateral lymph node dissection, but was analysed in their assigned group. Operation time was significantly longer in the mesorectal excision with lateral lymph node dissection group (median 360 min, IQR 296–429) than in the mesorectal excision alone group (254 min, 210–307, p<0·0001). Blood loss was significantly higher in the mesorectal excision with lateral lymph node dissection group (576 mL, IQR 352–900) than in the mesorectal excision alone group (337 mL, 170–566; p<0·0001). 26 (7%) patients in the mesorectal excision with lateral lymph node dissection group had lateral pelvic lymph node metastasis. Grade 3–4 postoperative complications occurred in 76 (22%) patients in the mesorectal excision with lateral lymph node dissection group and 56 (16%) patients in the mesorectal excision alone group. The most common grade 3 or 4 postoperative complication was anastomotic leakage (18 [6%] patients in the mesorectal excision with lateral lymph node dissection group vs 13 [5%] in the mesorectal excision alone group; p=0·46). One patient in the mesorectal excision with lateral lymph node dissection group died of anastomotic leakage followed by sepsis. Mesorectal excision with lateral lymph node dissection required a significantly longer operation time and resulted in significantly greater blood loss than mesorectal excision alone. The primary analysis will help to show whether or not mesorectal excision alone is non-inferior to mesorectal excision with lateral lymph node dissection. National Cancer Center, Ministry of Health, Labour and Welfare of Japan.