Preoperative risk factors for 90-day postoperative mortality outcome in patients with non-occlusive mesenteric ischemia.

PURPOSE: The mortality rate for non-occlusive mesenteric ischemia remains high even after patients survive the acute postoperative period with tremendous treatment efforts, including emergency surgery, which is challenging. The aim of this study was to explore the preoperative risk factors for 90-day postoperative mortality in patients with non-occlusive mesenteric ischemia. METHODS: This single-center, retrospective cohort study included patients diagnosed with non-occlusive mesenteric ischemia who underwent emergency surgery between August 2014 and January 2023. All patients were divided into survival-to-discharge and mortality outcome groups at the 90-day postoperative follow-up. Preoperative factors, including comorbidities, preoperative status of vital signs and consciousness, blood gas analysis, blood test results, and computed tomography, were compared between the two groups. RESULTS: Twenty patients were eligible, and 90-day mortality was observed in 10 patients (50%). The mortality outcome group had significantly lower HCO3- (20.9 vs. 14.6, p = 0.006) and higher lactate (4.4 vs. 9.4, p = 0.023) levels than did the survival outcome group. The median postoperative time to death was 19 [2-69] days, and five patients (50%) died after postoperative day 30, mainly because hemodialysis was discontinued because of hemodynamic instability in patients requiring hemodialysis. CONCLUSION: Low preoperative HCO3- and high lactate levels may be preoperative risk factors for 90-day postoperative mortality in patients with non-occlusive mesenteric ischemia. However, patients on hemodialysis die from discontinuing hemodialysis even after surviving the acute postoperative phase. Therefore, indications for emergency surgery in patients with risk factors for postoperative mortality should be carefully determined.

Lectin-based phototherapy targeting cell surface glycans for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to current treatments but lectin-based therapy targeting cell surface glycans could be a promising new horizon. Here, we report a novel lectin-based phototherapy (Lec-PT) that combines the PDAC targeting ability of rBC2LCN lectin to a photoabsorber, IRDye700DX (rBC2-IR700), resulting in a novel and highly specific near-infrared, light-activated, anti-PDAC therapy. Lec-PT cytotoxicity was first verified in vitro with a human PDAC cell line, Capan-1, indicating that rBC2-IR700 is only cytotoxic upon cellular binding and exposure to near-infrared light. The therapeutic efficacy of Lec-PT was subsequently verified in vivo using cell lines and patient-derived, subcutaneous xenografting into nude mice. Significant accumulation of rBC2-IR700 occurs as early as 2 hours postintravenous administration while cytotoxicity is only achieved upon exposure to near-infrared light. Repeated treatments further slowed tumor growth. Lec-PT was also assessed for off-target toxicity in the orthotopic xenograft model. Shielding of intraperitoneal organs from near-infrared light minimized off-target toxicity. Using readily available components, Lec-PT specifically targeted pancreatic cancer with high reproducibility and on-target, inducible toxicity. Rapid clinical development of this method is promising as a new modality for treatment of pancreatic cancer.

Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial).

BACKGROUND: Locally advanced pancreatic ductal adenocarcinoma (PDAC), accounting for about 30% of PDAC patients, is difficult to cure by radical resection or systemic chemotherapy alone. A multidisciplinary strategy is required and our TT-LAP trial aims to evaluate whether triple-modal treatment with proton beam therapy (PBT), hyperthermia, and gemcitabine plus nab-paclitaxel is a safe and synergistically effective treatment for patients with locally advanced PDAC. METHODS: This trial is an interventional, open-label, non-randomized, single-center, single-arm phase I/II clinical trial organized and sponsored by the University of Tsukuba. Eligible patients who are diagnosed with locally advanced pancreatic cancer, including both borderline resectable (BR) and unresectable locally advanced (UR-LA) patients, and selected according to the inclusion and exclusion criteria will receive triple-modal treatment consisting of chemotherapy, hyperthermia, and proton beam radiation. Treatment induction will include 2 cycles of chemotherapy (gemcitabine plus nab-paclitaxel), proton beam therapy, and 6 total sessions of hyperthermia therapy. The initial 5 patients will move to phase II after adverse events are verified by a monitoring committee and safety is ensured. The primary endpoint is 2-year survival rate while secondary endpoints include adverse event rate, treatment completion rate, response rate, progression-free survival, overall survival, resection rate, pathologic response rate, and R0 (no pathologic cancer remnants) rate. The target sample size is set at 30 cases. DISCUSSION: The TT-LAP trial is the first to evaluate the safety and effectiveness (phases1/2) of triple-modal treatment comprised of proton beam therapy, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer. ETHICS AND DISSEMINATION: This protocol was approved by the Tsukuba University Clinical Research Review Board (reference number TCRB22-007). Results will be analyzed after study recruitment and follow-up are completed. Results will be presented at international meetings of interest in pancreatic cancer plus gastrointestinal, hepatobiliary, and pancreatic surgeries and published in peer-reviewed journals. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031220160. Registered 24 th June 2022, https://jrct.niph.go.jp/en-latest-detail/jRCTs031220160 .

Total Superior Mesenteric Artery Nerve Plexus Preservation During Pancreaticoduodenectomy for Pancreatic Cancer.

BACKGROUND: Superior mesenteric artery (SMA) nerve plexus (PLsma) dissection has been performed to achieve R0 resection in pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) in high-volume centers. However, full-extent PLsma preservation in PD is employed in our institution. The feasibility of the PLsma preservation strategy was investigated. METHODS: Between January 2010 and December 2020, 156 patients underwent PLsma preservation PD for PDAC at our institution. Of these, 118 patients had resectable PDAC (R group) and 38 patients had borderline resectable artery (BR-A group). Clinical and oncological outcomes focusing on local recurrence, patient prognoses, and morbidities (including postoperative refractory diarrhea) were retrospectively analyzed and our postoperative outcomes were compared with those of other institutions. RESULTS: Pathological R0 resection by PLsma preservation PD was achieved in 96 R group patients (81.4%) and 27 BR-A group patients (71.1%). The median postoperative hospital stay was 15.0 days in both groups. Local site-only recurrence was observed in 10.2% (12/118) of R-group and 10.5% (4/38) of BR-A-group patients, whereas distant site-only recurrence occurred in 21.2% (25/118) of R-group and 28.9% (11/38) of BR-A-group patients. Median survival times were 64.3 months (R group) and 35.4 months (BR-A group, p = 0.07). Median disease-free survival (DFS) times were 31.0 months (R group) and 12.0 months (BR-A group). No diarrhea requiring opioids was observed in either group. These results were equal or superior to those of PLsma dissection PD in other institutions. CONCLUSIONS: PLsma preservation in PD was feasible compared to PLsma dissection in recurrence and overall survival.

The Impact of Tunneled Central Venous Hemodialysis Catheter on Mortality of Elderly Hemodialysis Patients Hospitalized in a Long-Term Care Hospital.

INTRODUCTION: The association between tunneled central venous hemodialysis catheters (TCVCs) and mortality in hospitalized elderly hemodialysis (HD) patients remains unclear. METHODS: This retrospective observational study was conducted in a long-term care hospital. We evaluated the association between TCVC and mortality in HD patients hospitalized between 2015 and 2020. RESULTS: A total of 463 patients were compared: TCVC group (n = 53) and non-TCVC group (n = 410) including arteriovenous fistula (AVF, n = 369), arteriovenous graft (AVG, n = 30), and superficialized brachial artery (SBA, n = 11). The mean ages were 80 and 78 years in the TCVC and non-TCVC groups, respectively. Overall mortality rates for all-cause and cardiovascular diseases (CVDs) were higher in the TCVC group than in the non-TCVC group (log-rank, p = 0.01, and p = 0.009). Overall mortality was higher in the TCVC group than in the AVF group (p = 0.04), but there were no significant differences between the TCVC, AVG, and SBA groups. In Cox proportional hazards regression models, age, dialysis vintage, male sex, Charlson Comorbidity Index (CCI), and serum albumin level were associated with all-cause, CVD, and infectious disease (ID) mortalities, but TCVC was not associated with all-cause (hazard ratio, 1.31; 95% confidence interval, 0.95-1.80; p = 0.1), CVD (1.54; 0.99-2.39; p = 0.051), and ID (0.91; 0.48-1.70; p = 0.8) mortalities. Among patients aged ≥80 years, with dialysis vintage ≥7 years and CCI ≥10, the overall mortality rates were comparable between the two groups. CONCLUSIONS: Among elderly HD patients in the long-term care hospital, TCVC was not associated with mortality.

Clinical advantage of transmediastinal esophagectomy in terms of postoperative respiratory complications.

BACKGROUND: Although the transmediastinal approach as a radical esophagectomy for esophageal carcinoma patients has attracted attention, its advantages over the transthoracic approach remain unclear. This study aimed to evaluate the efficacy of transmediastinal esophagectomy (TME) in terms of postoperative respiratory complications compared to that of open transthoracic esophagectomy (TTE). METHODS: We reviewed patients with thoracic and abdominal esophageal carcinoma who underwent TME or TTE between February 2014 and November 2021. We compared postoperative respiratory complications as the primary outcome. The secondary outcomes included perioperative operation time, blood loss, postoperative complications, and the number of harvested mediastinal lymph nodes. RESULTS: Overall, 60 and 54 patients underwent TME and TTE, respectively. The baseline characteristics were similar between the two groups, except for age and histological type. There were no intraoperative lethal complications in either group. The incidence of respiratory complications was significantly lower in the TME group than in the TTE group (6.7 vs. 22.2%, p = 0.03). The TME group had a shorter operation time (403 vs. 451 min, p < 0.01), less blood loss (107 vs. 253 mL, p < 0.01), and slightly higher anastomotic leakage (11.7 vs. 5.6%, p = 0.33). The number of harvested lymph nodes was similar in both groups (24 vs. 26, p = 0.10). Multivariate analysis revealed that TME is an independent factor in reducing respiratory complications (odds ratio = 0.27, p = 0.04). CONCLUSIONS: TME for esophageal carcinoma was performed safely. TME was superior to TTE in terms of postoperative respiratory complications; however, the relatively higher frequency of anastomotic leakage should be considered and requires further evaluation.

Usefulness of Human Jejunal Spheroid-Derived Differentiated Intestinal Epithelial Cells for the Prediction of Intestinal Drug Absorption in Humans.

This study aimed to demonstrate the usefulness of human jejunal spheroid-derived differentiated intestinal epithelial cells as a novel in vitro model for clarifying the impact of intestinal drug-metabolizing enzymes and transporters on the intestinal absorption of substrate drugs in humans. Three-dimensional human intestinal spheroids were successfully established from surgical human jejunal specimens and expanded for a long period using L-WRN-conditioned medium, which contains Wnt3a, R-spondin 3, and noggin. The mRNA expression levels of intestinal pharmacokinetics-related genes in the human jejunal spheroid-derived differentiated intestinal epithelial cells were drastically increased over a 5-day period after seeding compared with those in human jejunal spheroids and were approximately the same as those in human jejunal tissue over a culture period of at least 13 days. Activities of typical drug-metabolizing enzymes [cytochrome P450 (CYP) 3A, CYP2C9, uridine 5'-diphospho-glucuronosyltransferase 1A, and carboxylesterase 2] and uptake/efflux transporters [peptide transporter 1/solute carrier 15A1], P-glycoprotein, and breast cancer resistance protein) in the differentiated cells were confirmed. Furthermore, intestinal availability (Fg) values estimated from the apical-to-basolateral permeation clearance across cell monolayer showed a good correlation with the in vivo Fg values in humans for five CYP3A substrate drugs (Fg range, 0.35-0.98). In conclusion, the functions of major intestinal drug-metabolizing enzymes and transporters could be maintained in human jejunal spheroid-derived differentiated intestinal epithelial cells. This model would be useful for the quantitative evaluation of the impact of intestinal drug-metabolizing enzymes and transporters on the intestinal absorption of substrate drugs in humans. SIGNIFICANCE STATEMENT: Limited information is available regarding the quantitative prediction of the impact of drug-metabolizing enzymes and transporters on the human intestinal absorption of substrates using in vitro assays with differentiated cells derived from human intestinal spheroids/organoids. This study confirmed the functions of typical drug-metabolizing enzymes and transporters in human jejunal spheroid-derived differentiated intestinal epithelial cells and demonstrated that intestinal availability (Fg) estimated from apical-to-basolateral permeation clearance across cell monolayers showed a good correlation with in vivo human Fg for CYP3A substrates.

Prevalence of work-related musculoskeletal disorders among general surgeons in Japan.

PURPOSE: General surgeons are at high risk for work-related musculoskeletal disorders (WRMSDs), especially in their neck and back. The prevalence and risk factors for surgeons' WRMSDs in Japan have not been well surveyed. METHODS: A cross-sectional questionnaire survey on WRMSDs was conducted among general surgeons in Japan. Surgeons were asked about the presence and degree of neck, shoulder, and back disability in relation to open and laparoscopic surgery. RESULTS: The questionnaire was sent to 174 general surgeons in 21 hospitals and 106 (60.9%) responded. The prevalence of WRMSDs in the last month was 65.1%, and the prevalence at least once in a lifetime was 79.2%. The rate of WRMSDs of the neck and back was higher after open surgery (44.3%, 42.5%) than after laparoscopic surgery (28.2%, 31.1%), but there was no marked difference in shoulder pain. Age was the strongest risk factor for WRMSDs, and the pain scores, prevalence of chronic pain, and rate of WRMSD-related absence from work tended to increase with age. CONCLUSION: A questionnaire survey of surgeons in Japan showed that about 80% of surgeons suffer from WRMSDs. Countermeasures for WRMSDs among surgeons are urgently desired to ensure that limited numbers of surgeons work in the operating theatre throughout their career. CLINICAL TRIAL REGISTRATION: Registry name: a survey of surgeons' musculoskeletal pain associated with performing surgery. University of Tsukuba Institutional Review Board registration number: 1519.

Pancreatic juice outflow in pancreatojejunostomy monitoring with the inter-anastomosis drainage tube; a retrospective observational study.

BACKGROUND: Pancreatic fistula remains the biggest problem in pancreatic surgery. We have previously reported a new pancreatojejunostomy method using an inter-anastomosis drainage (IAD) suction tube with Blumgart anastomosis for drainage of the pancreatic juice leaking from the branched pancreatic ducts. This study aimed to evaluate the postoperative outcomes of our novel method, in pancreatojejunostomy and investigate the nature of the inter-anastomosis space between jejunal wall and pancreas parenchyma. METHODS: This retrospectively study consist of 282 pancreatoduodenectomy cases, including 86 reconstructions via the Blumgart method plus IAD (B + IAD group) and 196 cases reconstructed using the Blumgart method alone (B group). Postoperative outcomes and the amylase value and the volume of the drainage fluids were compared between the two groups. The IAD tube was placed to collect amylase-rich fluid from the inter-anastomosis space during operative procedure between the jejunal wall and pancreatic stump. RESULTS: The daily IAD drainage volume and the amylase level was significantly higher in patients with a soft pancreas (vs hard pancreas; 16.5 vs. 10.0 mL/day, p = 0.012; 90,900 vs. 1634 IU/L, p < 0.001, respectively). The mean amylase value of IAD collection in 86 cases of B + IAD group was 63,100 IU/L. The incidence of clinically relevant pancreatic fistula grade B and C (23.2% vs. 23.0%, p = 0.55) and the hospital stay was similar between the groups (median 17 vs. 18 days, p = 0.55). In 176 patients with soft pancreas, the incidence of pancreatic fistula grade B and C (33.3% vs. 35.3%, p = 0.67) and the hospital stay was also similar between the groups (median 22.5 vs. 21 days, p = 0.81). CONCLUSIONS: Positive effect of the IAD method observed in the pilot cases was not reproduced in the current study. IAD tube objectively demonstrated the existence of amylase-rich discharge at the anastomosis site, and countermeasures to eliminate this liquid are highly desired for preventing pancreatic fistula, especially in patients with soft pancreatic texture. Trial registration Retrospectively registered.

Postoperative Portal Hypertension Enhances Alloimmune Responses after Living-Donor Liver Transplantation in Patients and in a Mouse Model.

Controlling portal vein pressure in living-donor liver transplantation has received increased attention owing to its potential importance for graft survival. Portal hypertension may lead to the activation of liver-resident APCs, including liver sinusoidal endothelial cells (LSECs), which have immunological tolerogenic capacity. We investigated the effects of portal hypertension on graft survival and the antidonor immune response using clinical data and a mouse model. We categorized patients (n = 136) according to their portal vein pressure values at the end of surgery. Using propensity score-matching analyses, we found that portal hypertension was significantly associated with a higher antidonor immune response and incidence of acute rejection. To investigate the mechanism, we performed an allogeneic coculture assay using a 70% hepatectomized (HTx) mouse model with or without a portosystemic shunt. Liver cells from HTx mice without a shunt exhibited a significantly greater anti-BALB/c B6 T cell response than those from sham-operated mice or HTx mice with a shunt. LSECs from sham-operated mice, but not from HTx mice, suppressed the B6 T cell alloresponse in a dose-dependent manner. Furthermore, LSECs from HTx mice without a shunt showed significantly downregulated MHC class I/II and programmed death-ligand 1 expression, and those from mice with a shunt showed recovered expression of these molecules. Postoperative portal hypertension enhances alloimmune responses in recipients after living-donor liver transplantation, likely due, in part, to the impaired immune-suppression capacity of LSECs.

Retrospective analysis of neoadjuvant chemotherapy followed by surgery versus definitive chemoradiotherapy with proton beam for locally advanced esophageal squamous cell carcinoma.

BACKGROUND: This is the first study to compare the long-term outcomes between neoadjuvant chemotherapy + surgery and definitive chemoradiotherapy with proton beam therapy for locally advanced esophageal squamous cell carcinoma. METHODS: We reviewed patients with clinical stage IB-III esophageal squamous cell carcinoma (UICC 7th edition) who underwent neoadjuvant chemotherapy + surgery or definitive chemoradiotherapy with proton beam therapy (2009-2017). Overall survival, progression-free survival, and recurrence or regrowth rates were compared between the two treatment groups. Subgroup analyses of overall survival according to baseline characteristics were also performed. RESULTS: Forty-three patients received neoadjuvant chemotherapy + surgery (median follow-up 47.4 months) and 60 received definitive chemoradiotherapy with proton beam therapy (median follow-up 51.5 months). Baseline characteristics were similar between the groups except for sex, tumor location, and cT classification. The neoadjuvant chemotherapy + surgery and definitive chemoradiotherapy with proton beam therapy groups had similar 3-year overall survival rates (73.1% and 61.7%, respectively, hazard ratio: 0.88, 95% confidence interval 0.49-1.58, p = 0.66), 3-year progression-free survival rates (46.5% and 45%, respectively, hazard ratio: 1.03, 95% confidence interval 0.62-1.70, p = 0.92), and recurrence or regrowth rates (53.5% vs. 50.0%, p = 0.84). In the subgroup analysis, favorable survival was observed after definitive chemoradiotherapy with proton beam therapy for cT1-2 disease (hazard ratio 2.58, 95% confidence interval 0.84-7.99) and after neoadjuvant chemotherapy + surgery for cT3 or higher disease (hazard ratio 0.32, 95% confidence interval 0.15-0.67, p-for-interaction = 0.002). CONCLUSIONS: Long-term outcomes were comparable between the treatments. The choice of the treatment according to cT classification might affect survival.

Delayed primary fascia closure of Björck grade 4 open abdomen with enteroatmospheric fistulas after repeated surgery for adhesive small bowel obstruction: a case report.

BACKGROUND: An open abdomen with frozen adherent bowels is classified as grade 4 in Björck's open abdomen classification, and skin grafting after wound granulation is a typical closure option. We achieved delayed primary fascia closure for a patient who developed open abdomen with enteroatmospheric fistulas due to severe adherent small bowel obstruction. We present here the details of his management. CASE PRESENTATION: A 52-year-old man suffered acute abdominal pain during a flight and received an emergency laparotomy due to adhesive small bowel obstruction. Repeated laparotomies were required, and later open abdomen and proximal site jejunostomy were selected. After negative pressure wound therapy, he was transferred to our institution. Two enteroatmospheric fistulas emerged on the exposed intestine, and we diagnosed the condition as a Björck grade 4 open abdomen. After 8 months of wound care and parenteral nutrition, we decided to attempt primary wound closure because the patient required permanent oral restriction and total parenteral nutrition due to short bowel syndrome. A circular incision along the circumference of the exposed bowel allowed us to take a safe approach into the abdominal cavity. We removed the intestinal adhesions completely and resected the bowels, including the fistulas and anastomosed parts. Finally, the abdominal wall defect was reconstructed using the component separation technique, and the patient was discharged without an ostomy. CONCLUSIONS: Primary fascia closure for grade 4 open abdomen is hard, but leaving a long interval before radical surgery and applying pertinent wound management may help solve this adverse situation.

Intentional internal drainage tube method for nonlocalized persistent pancreatic leakage: a case report.

BACKGROUND: Persistent pancreatic leakage (PL) due to disconnected pancreatic duct syndrome (DPDS) is associated with severe morbidity and mortality and it usually treated with internal drainage. However, in cases without localized fistula formation, internal drainage is challenging to perform. We report an original one-stage surgical approach for nonlocalized persistent PL, namely, the "intentional internal drainage tube method". CASE PRESENTATION: A 49-year-old woman whose main pancreatic duct was penetrated during endoscopic retrograde cholangiopancreatography experienced severe PL. Peritoneal lavage and a second operation involving central pancreatectomy failed to relieve the symptoms, and nonlocalized PL persisted due to DPDS. Although we attempted a radical resection of the pancreatic remnants as a third strategy, the highly inflamed tissue and massive bleeding prevented the completion of the procedure. We sutured the pancreatic head margin and performed a pancreaticojejunostomy to the distal margin. Because these two cut margins could possibly be the source of the persistent PL, we created a hole at the Roux-en-Y jejunal limb, and a silicone drainage tube was inserted into the peritoneal space via this hole. Postoperatively, we continuously suctioned the intentional internal drainage tube, and the residual PL cavity gradually diminished. Even after removal of the tube, the residual PL drained internally into the jejunum through this hole. CONCLUSIONS: We present this intentional internal drainage tube method as a novel alternative approach for the management of nonlocalized PL consequential of DPDS. Due to the simplicity and minimally invasive nature of this method, we propose this technique may also be used to treat various types of nonlocalized persistent PL or be used prophylactically for central pancreatectomy.

[A Case of Non-Resectable Advanced Gastric Cancer for Which Nivolumab Was Markedly Effective].

A 74-year-old man presented to our hospital because of anorexia. Upper gastrointestinal endoscopy revealed type 3 gastric cancer. Further examination disclosed metastasis to the perigastric lymph nodes and to the liver, and a diagnosis of non- resectable advanced gastric cancer(cT4N2H1P0M0)in cStage Ⅳ was made. A total of 4 courses of S-1 plus oxaliplatin therapy(80 mg/body/day and 100 mg/m2/cycle, respectively, for 2 weeks followed by a 1-week rest)were administered as the primary chemotherapy. Then, another metastasis to the abdominal lymph nodes and increased liver metastasis were found; thus, the patient's condition was rated as progressive disease(PD). Secondary chemotherapy comprising 10 courses of weekly nab-paclitaxel(nab-PTX)plus ramucirumab(RAM)therapy(100 mg/m2 on days 1, 8, and 15 and 8 mg/kg on days 1 and 15, respectively, every 4 weeks)were administered. Although temporary reductions in the perigastric lymph node metastasis and liver metastasis as compared with the baseline were observed, another metastasis to the abdominal lymph nodes occurred subsequently, resulting in PD. As tertiary chemotherapy, nivolumab therapy(240 mg/body, every 3 weeks) was repeated up to a total of 30 courses over 13 months. This therapy was markedly effective, achieving a near complete response. The patient is currently being followed up as an outpatient.

Novel Pancreatic Cancer Therapy Targeting Cell Surface Glycans by Liposomes Modified with rBC2LCN Lectin.

INTRODUCTION: Since the outermost layer of cancer cells is covered with various glycans, targeting these groups may serve as an effective strategy in cancer therapy. We previously reported that fucosylated glycans are specifically expressed on pancreatic cancer cells, and that a protein specifically binding to these glycans, namely rBC2LCN lectin, is a potential guiding drug carrier. In the present study, a novel type of glycan-targeting nanoparticle was developed by modifying the surface of doxorubicin-containing liposomes with rBC2LCN lectin. The efficiency and specificity of this formulation, termed Lec-Doxosome, were examined in vitro and in vivo in human pancreatic cancer models. METHODS: Lec-Doxosome was prepared by a post-insertion method based on the insertion of rBC2LCN lectin into the liposomal surface via a lipid linker. The in vitro cellular binding, uptake, and cytotoxicity of Lec-Doxosome were compared with the corresponding parameters in the unmodified liposomes by applying to human pancreatic cancer cell line (Capan-1) with affinity for rBC2LCN lectin. For the in vivo assay, Lec-Doxosome was intravenously injected once per week for a total of 3 weeks into mice bearing subcutaneous tumors. RESULTS: The in vitro application of Lec-Doxosome resulted in a 1.2- to 1.6-fold higher intracellular doxorubicin accumulation and a 1.5-fold stronger cytotoxicity compared with the respective rates of accumulation and cytotoxicity in the unmodified liposomes. In vivo, Lec-Doxosome reduced the mean tumor weight (368 mg) compared with that in mice treated with unmodified liposomes (456 mg), without causing any additional adverse events. CONCLUSION: It was demonstrated from the results obtained herein that rBC2LCN lectin is a potent modifier, as a means for boosting the efficiency of nanoparticles in the targeting of cancer cell surface glycans.

Three-dimensional simulation of pancreatic surgery showing the size and location of the main pancreatic duct.

PURPOSE: We performed three-dimensional (3D) surgical simulation of pancreatic surgery, including the size and location of the main pancreatic duct on the resected pancreatic surface. METHODS: The subjects of this retrospective analysis were 162 patients who underwent pancreatic surgery. This cohort was sequentially divided into a "without-3D" group (n = 81) and a "with-3D" group (n = 81). We compared the pancreatic duct diameter and its location, using nine sections in a grid pattern, with the intraoperative findings. The perioperative outcomes were also compared between patients who underwent pancreaticoduodenectomy (PD) and those who underwent distal pancreatectomy (DP). RESULTS: There were no significant differences in the main pancreatic duct diameter between the 3D-simulated values and the operative findings. The 3D-simulated main pancreatic duct location was consistent with its actual location in 80 % of patients (65/81). In comparing the PD and DP groups, the intraoperative blood loss was 1174 ± 867 and 817 ± 925 ml in the without-3D group, and 828 ± 739 and 307 ± 192 ml in the with-3D group, respectively (p = 0.024, 0.026). CONCLUSION: The 3D surgical simulation provided useful information to promote our understanding of the pancreatic anatomy, including details on the size and location of the main pancreatic duct.

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer.

Even with current promising antitumor antibodies, their antitumor effects on stroma-rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa-2; moderate, BxPC-3; and abundant, Capan-1 and Ope-xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra-abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa-2 model, moderate (1063) in the BxPC-3 model, and negative in the Capan-1 and Ope-xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8-fold (2980, 3015) in the BxPC-3 model, 2.5- or 4.8-fold (1881, 3615) in the Capan-1 model, and 3.2- or 4.2-fold (1469, 1922) in the Ope-xeno model, respectively. Cetuximab was effective in treating even stroma-rich and k-ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.

The effects of AP521, a novel anxiolytic drug, in three anxiety models and on serotonergic neural transmission in rats.

We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic-like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action.

The Tight Adaptation at Pancreatic Anastomosis Without Parenchymal Laceration: An Institutional Experience in Introducing and Modifying the New Procedure.

BACKGROUND: Among the types of pancreatic anastomosis used after pancreatoduodenectomy (PD), Blumgart type reconstruction has rapidly been distributed for its theoretical reasonableness, including secure tight adaptation of jejunal wall and pancreatic parenchyma without cause of parenchymal laceration. The clinical appropriateness of our modified Blumgart method was demonstrated by comparing to that of Kakita method. METHODS: Retrospective analysis of 156 patients underwent elective open PD, reconstructed former 78 patients with the Kakita method, utilizing a full-thickness penetrating suture for tight stump adhesion. The later 78 patients were treated with the modified Blumgart method, which involved clamping the pancreatic parenchymal stump by the jejunal seromuscular layers with horizontal mattress-type penetration sutures. Evaluated variables were the rate of pancreatic fistula (PF) and the length of postoperative hospital stay (POHS). RESULTS: The rate of ISGPF grade B+C PF was 29/78 (37.2%) in the Kakita group and 16/78 (20.5%) in the Blumgart group (P=0.033). The median POHS for the Kakita group was 23 days, whereas that for the Blumgart group was 16 days (P<0.001), one of the shortest value among Japanese high-volume centers. There was no perioperative intensive hemorrhage or deaths in either group. CONCLUSION: A unique concept of Blumgart pancreatic anastomosis, i.e., utilizing the jejunum as an interstitial cushion to prevent pancreatic laceration at the knot site, has become realistic through a simple "one step" modification. This technique, also providing flexible handling space at main pancreatic duct anastomosis, should contribute to the improved PF prevention and shortening the POHS.

TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass.

AIMS/HYPOTHESIS: Common genetic variations of the transcription factor 7-like 2 gene (encoded by TCF7L2), one of the T cell factor/lymphoid enhancer-binding factor transcription factors for the converging wingless-type MMTV integration site family (Wnt)/ß-catenin signalling pathway, are known to be associated with type 2 diabetes. Individuals with at-risk alleles of TCF7L2 exhibit impaired insulin secretion. Although previous studies using animal models have revealed the existence of a relationship between the Wnt/ß-catenin signalling pathway and glucose homeostasis, it remains unclear whether TCF7L2 in the pancreatic beta cells might be causally involved in insulin secretion in vivo. In this study, we investigated the role of TCF7L2 expressed in the pancreatic beta cells in glucose homeostasis. METHODS: Three independent groups of genetically engineered mice (DN mice) were generated, in which expression of the dominant-negative form of Tcf7l2 was driven under a rat insulin promoter. Phenotypes of both adult and newborn mice were evaluated. The levels of genes and proteins expressed in isolated islets were determined by reverse transcription-quantitative PCR and western blot analysis, respectively. RESULTS: Adult DN mice showed impaired glucose tolerance and decreased insulin secretion in both oral and intraperitoneal glucose tolerance tests. Marked reduction of the beta cell area and whole-pancreas insulin content was observed in both the adult and newborn DN mice. Islets from the DN mice showed decreased gene expressions of Ccnd1, Ccnd2, Irs1, Irs2, Ins1, Ins2 and Mafa, consistent with the deleterious effects of the dominant-negative form of Tcf7l2 on beta cell proliferation and insulin production. CONCLUSIONS/INTERPRETATION: TCF7L2 expressed in the pancreatic beta cells plays a crucial role in glucose metabolism through regulation of the beta cell mass.