Evaluation of a deuterated triarylmethyl spin probe for in vivo R2 ∗-based EPR oximetric imaging with enhanced dynamic range.

PURPOSE: In this study, we compared two triarylmethyl (TAM) spin probes, Ox071 and Ox063 for their efficacy in measuring tissue oxygen levels under hypoxic and normoxic conditions by R2 *-based EPR oximetry. METHODS: The R2 * dependencies on the spin probe concentration and oxygen level were calibrated using deoxygenated 1, 2, 5, and 10 mM standard solutions and 2 mM solutions saturated at 0%, 2%, 5%, 10%, and 21% of oxygen. For the hypoxic model, in vivo imaging of a MIA PaCa-2 tumor implanted in the hind leg of a mouse was performed on successive days by R2 *-based EPR oximetry using either Ox071 or Ox063. For the normoxic model, renal imaging of healthy athymic mice was performed using both spin probes. The 3D images were reconstructed by single point imaging and multi-gradient technique was used to determine R2 * maps. RESULTS: The signal intensities of Ox071 were approximately three times greater than that of Ox063 in the entire partial pressure of oxygen (pO2 ) range investigated. The histograms of the tumor pO2 images were skewed for both spin probes, and Ox071 showed more frequency counts at pO2 > 32 mm Hg. In the normoxic kidney model, there was a clear delineation between the high pO2 cortex and the low pO2 medulla regions. The histogram of high-resolution kidney oximetry image using Ox071 was nearly symmetrical and frequency counts were seen up to 55 mm Hg, which were missed in Ox063 imaging. CONCLUSION: As an oximetric probe, Ox071 has clear advantages over Ox063 in terms of sensitivity and the pO2 dynamic range.

Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair.

Aims: Pancreatic ductal adenocarcinomas (PDACs) form hypovascular and hypoxic tumors, which are difficult to treat with current chemotherapy regimens. Gemcitabine (GEM) is often used as a first-line treatment for PDACs but has issues with chemoresistance and penetration in the interior of the tumor. Evofosfamide, a hypoxia-activated prodrug, has been shown to be effective in combination with GEM, although the mechanism of each drug on the other has not been established. We used mouse xenografts from two cell lines (MIA Paca-2 and SU.86.86) with different tumor microenvironmental characteristics to probe the action of each drug on the other. Results: GEM treatment enhanced survival times in mice with SU.86.86 leg xenografts (hazard ratio [HR] = 0.35, p = 0.03) but had no effect on MIA Paca-2 mice (HR = 0.91, 95% confidence interval = 0.37-2.25, p = 0.84). Conversely, evofosfamide did not improve survival times in SU.86.86 mice to a statistically significant degree (HR = 0.57, p = 0.22). Electron paramagnetic resonance imaging showed that oxygenation worsened in MIA Paca-2 tumors when treated with GEM, providing a direct mechanism for the activation of the hypoxia-activated prodrug evofosfamide by GEM. Sublethal amounts of either treatment enhanced the toxicity of other treatment in vitro in SU.86.86 but not in MIA Paca-2. By the biomarker γH2AX, combination treatment increased the number of double-stranded DNA lesions in vitro for SU.86.86 but not MIA Paca-2. Innovation and Conclusion: The synergy between GEM and evofosfamide appears to stem from the dual action of GEMs effect on tumor vasculature and inhibition by GEM of the homologous recombination DNA repair process. Antioxid. Redox Signal. 39, 432-444.

PEGPH20, a PEGylated human hyaluronidase, induces radiosensitization by reoxygenation in pancreatic cancer xenografts. A molecular imaging study.

PURPOSE: PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, increasing the delivery of therapeutic molecules. Combinations of chemotherapy and PEGPH20, however, have been unsuccessful in Phase III clinical trials. We hypothesize that by increasing tumor oxygenation by improving vascular patency and perfusion, PEGPH20 will also act as a radiosensitization agent. EXPERIMENTAL DESIGN: The effect of PEGPH20 on radiation treatment was analyzed with respect to tumor growth, survival time, p02, local blood volume, and the perfusion/permeability of blood vessels in a human pancreatic adenocarcinoma BxPC3 mouse model overexpressing hyaluronan synthase 3 (HAS3). RESULTS: Mice overexpressing HAS3 developed fast growing, radiation resistant tumors that became rapidly more hypoxic as time progressed. Treatment with PEGPH20 increased survival times when used in combination with radiation therapy, significantly more than either radiation therapy or PEGPH20 alone. In mice that overexpressed HAS3, EPR imaging showed an increase in local pO2 that could be linked to increases in perfusion/permeability and local blood volume immediately after PEGPH20 treatment. Hyperpolarized [1-13C] pyruvate suggested PEGPH20 caused a metabolic shift towards decreased glycolytic flux. These effects were confined to the mice overexpressing HAS3 - no effect of PEGPH20 on survival, radiation treatment, or pO2 was seen in wild type BxPC3 tumors. CONCLUSIONS: PEGPH20 may be useful for radiosensitization of pancreatic cancer but only in the subset of tumors with substantial hyaluronan accumulation. The response of the treatment may potentially be monitored by non-invasive imaging of the hemodynamic and metabolic changes in the tumor microenvironment.

Distance of Peritoneum to Inferior Mesenteric Artery Predicts the Operation Time During Laparoscopic Colectomy for Sigmoid or Rectosigmoid Colon Cancer.

Background/Aim: Obesity is a major technical limiting factor for laparoscopic surgery because abundant visceral fat is known to extend the operation time. However, special hardware is needed to assess it. We hypothesized that the depth from the peritoneum to the bifurcation of the inferior mesenteric artery (IMA) defined as 'peritoneum to IMA distance (PID)' might be a simple predictive factor for extended operation time during laparoscopic colectomy. Patients and Methods: One hundred twenty-four patients who were diagnosed with sigmoid or rectosigmoid colon cancer and underwent laparoscopic colectomy were included. The patients were divided into two groups based on the operation time (210 min). The vertical distance from the peritoneum to the bifurcation of the inferior mesenteric artery was defined as PID. The factors eliciting an operation time longer than 210 min were investigated. Results: There was significant difference in sex, BMI, cT, cN, and PID between the Early group (<210 min) and Late group (≥210 min). Less blood loss was observed in the Early group than in the Late group. Multivariate analysis showed that PID was the only independent factor that affected operation time (p<0.001). Conclusion: PID predicts the operation time during laparoscopic colectomy for sigmoid or rectosigmoid colon cancer.

Taking antithrombic therapy during emergency laparoscopic cholecystectomy for acute cholecystitis does not affect the postoperative outcomes: a propensity score matched study.

BACKGROUND: Continuing antithrombic therapy (ATT) during surgery increases the risk of bleeding. However, it is difficult to discontinue the ATT in emergency surgery. Therefore, safety of emergency laparoscopic cholecystectomy (LC) for acute cholecystitis (AC) is still unclear. We aimed to clarify the affect of ATT during emergency LC for AC. METHODS: Patients with AC were classified into ATT group (n = 30) and non-ATT group (n = 120). Postoperative outcomes were compared after propensity score matching (n = 22). RESULTS: Higher level of c-reactive protein level and shorter activated partial thromboplastin time (APTT) was observed in ATT group than in non-ATT group after matching. No significant difference was found between other patient characteristics and perioperative results. Blood loss over 100 mL was observed in 8 patients. Multivariate analyze showed that APTT was an independent risk factor for bleeding over 100 mL (P = 0.039), while ACT and APT was not. CONCLUSIONS: Taking ATT does not affect the blood loss or complications during emergency LC for AC. Controlling intraoperative bleeding is essential for a safe postoperative outcome.

Real-Time insight into in vivo redox status utilizing hyperpolarized [1-13C] N-acetyl cysteine.

Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized 13C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-13C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized 13C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.

Purse-string suture after ligating by endoloop for closing of the appendiceal stump is an alternative for endostapler in selected cases: A propensity score-matched study.

INTRODUCTION: The closure of the appendiceal stump is a crucial part of a laparoscopic appendectomy, and an endoloop or endostapler is generally used. The endoloop can be more cost effective than the endostapler. However, reports have shown that the endoloop has a higher postoperative abdominal abscess rate than the endostapler in complicated appendicitis. At our institution, we perform a purse-string suture after ligating by endoloop to reduce postoperative abdominal abscess risk. This study aimed to clarify whether this method could reduce the incidence of postoperative abdominal abscess compared with the endostapler. METHODS: Patients with acute appendicitis were classified into the purse-string suture group (n = 149) and the endostapler group (n = 82). Postoperative outcomes were compared after propensity score matching (n = 47). RESULTS: No significant difference was found between the two groups in terms of the patient characteristics and postoperative complications, including abdominal abscess. However, the purse-string suture group had more drain placement and a shorter hospital stay than the endostapler group (P = .04 and P = .02, respectively). In patients with complicated appendicitis, there was less drain placement and a shorter hospital stay in the purse-string suture group than in the endostapler group (P < .01 and P < .01, respectively). This might have reflected the difficulty of the operation. All postoperative abdominal abscesses occurred in complicated appendicitis cases. CONCLUSIONS: Endoloop with additional purse-string suture had a lower incidence of abscess than previous reports of using endoloop alone. Moreover, the postoperative abdominal abscess rate is similar between the two closure methods.

Feasibility of laparoscopic endoscopic cooperative surgery for non-ampullary superficial duodenal neoplasms: Single-arm confirmatory trial.

OBJECTIVE: Laparoscopic endoscopic cooperative surgery for duodenal tumors (D-LECS) has been developed to prevent duodenal leakage by reinforcing the endoscopic submucosal dissection site. However, there has been no prospective trial showing the feasibility of D-LECS. Herein, we conducted a single-arm confirmatory trial to evaluate the safety of D-LECS for non-ampullary superficial duodenal neoplasms. METHODS: This prospective single-center single-arm confirmatory trial analyzed patients with non-ampullary superficial duodenal neoplasms who underwent D-LECS. The primary endpoint was the incidence of any postoperative leakage occurring on the duodenal wall within 1 month postoperatively. The planned sample size was 20 patients, considering a threshold of 28% and one-sided alpha value of 5%. RESULTS: Between January 2015 and September 2018, 20 eligible patients were enrolled. Sixteen tumors were located in the second portion, three in the first portion, and one in the third portion of the duodenal region. The median operative time was 225 (134-361) min and the median blood loss was 0 (0-150) mL. Curative resection (R0) with negative margins was achieved in 19 cases. One case of postoperative leakage and one case of bleeding of grade 2 according to the Clavien-Dindo classification were observed in this series. The median duration of postoperative hospital stay was 9 (5-12) days. No local recurrence was observed in any patient during the median follow-up of 15.0 (12.0-38.0) months. CONCLUSIONS: This trial confirmed the safety and feasibility of D-LECS for non-ampullary superficial duodenal neoplasms with respect to the low incidence of postoperative duodenal leakage.

[Adjuvant Chemotherapy for High-Risk Stage â ¡ Colon Cancer].

BACKGROUND: This study was designed to clarify effects of postoperative adjuvant chemotherapy for high-risk Stage Ⅱ colorectal cancer. METHOD: The subjects were 99 patients with high-risk Stage Ⅱcolorectal cancer who underwent surgery at our department from October 2013 to March 2018. Patients were classified into adjuvant chemotherapy group and nonadjuvant chemotherapy group. Overall survival(OS)and recurrence-free survival(RFS)were analyzed between the 2 groups. RESULTS: Thirty six patients(36.4%)underwent adjuvant chemotherapy. Adjuvant chemotherapy group were younger(p<0.010), had a better ASA-PS(p<0.010), good preoperative Hb(p<0.010), and preoperative Alb(p<0.010)compared to non-adjuvant chemotherapy group. There was no difference between the 2 groups in the high-risk factors for recurrence. Most patient had an oral medication as for adjuvant chemotherapy. There was no difference in OS and RFS between the 2 groups. CONCLUSION: Postoperative adjuvant chemotherapy for high-risk Stage Ⅱ colorectal cancer did not significantly improve the OS and RFS. Further study is necessary to asses the suitable regimen and patients eligible for chemotherapy.

[Preoperative Chemotherapy with DCF for Advanced Esophageal Cancer].

We conducted a retrospective study to evaluate the efficacy and the problem of the neoadjuvant chemotherapy using DCF for cStage Ⅲ/Ⅳ(squamous cell)esophageal cancer. Eleven patients from January 2017 to December 2018 were enrolled into this study. The median age was 67 years old, male/female ratio was 9:2, performance status was 0 in all patients, and UICC cStage Ⅲ/Ⅳa was 7:4. Cycles of chemotherapy was 2 in 1 patients, 3 in 5 patients and additional 2 courses in 1 patient. Four patients switched to FP therapy after a course of DCF. The efficacy of chemotherapy was evaluated by the clinical response rate, average tumor reduction rate, and histological therapeutic effect rate over Grade 2 which was 63.6%, 48.3%, and 40%, respectively. Neutropenia over Grade 3 was observed in all patients and Grade 4 was observed in 6 patients. In conclusion, preoperative chemotherapy with DCF therapy is useful for the treatment of cStage Ⅲ/Ⅳ(squamous cell) esophageal cancer as long as bone marrow suppression is managed.

Feasibility and Effectiveness of Gastrectomy for Elderly Gastric Cancer Patients.

BACKGROUND/AIM: The benefits of gastrectomy for elderly gastric cancer (GC) patients remain unknown. The aim of this study was to evaluate the validity of gastrectomy. PATIENTS AND METHODS: Patients who had R0 or R1 resection and diagnosed as pathological Stage I-III GC were enrolled in this study. Patients were classified according to age: Elderly group (≥80 years old), non-Elderly group (70-79 years old), Standard group (≤69 years old). RESULTS: As the age raised, the number of comorbidities increased and patients had a worse physical status. Operative procedure and postoperative complications of the Elderly group were similar to that of the non-Elderly group. The overall survival was similar in pathological Stages I and III between the Elderly and non-Elderly groups, while the Stage II Elderly group had shorter overall survival. Also, the Elderly group did not undergo adjuvant chemotherapy compared to other groups. CONCLUSION: Gastrectomy can be performed safely in elderly patients following gastrectomy, survival of elderly patients was similar to non-elderly patients. Therefore, gastrectomy is an acceptable treatment for elderly patients in good condition.

Meaning of C-reactive protein around esophagectomy for cStage III esophageal cancer.

PURPOSE: The prognosis of esophageal cancer is dismal, and the 3-year overall survival of cStage III does not reach 50.0%. C-reactive protein (CRP) is a well-known protein that reflects the short- and long-term operative outcomes of esophageal cancer. However, since elevated CRP levels are often observed in cStage III esophageal cancer, whether or not CRP still reflects the prognosis is unclear. METHODS: Eighty-four patients who were diagnosed with cStage III esophageal cancer and underwent R0/1 operation from January 2007 to December 2014 were retrospectively evaluated. RESULTS: The mean age was 66.8 years, and the majority of patients were male. The median preoperative and postoperative CRP levels were 0.15 and 1.47 mg/dl, respectively. A majority of the patients underwent thoracoscopic surgery, and the median blood loss and operation duration were 456 ml and 11.6 h, respectively. Forty-six patients (54.8%) died during the observation period, and the 3-year overall survival was 52.4%. A multivariate analysis showed that the preoperative CRP level, postoperative albumin level, blood loss, and complications were independent prognostic factors. A multiple linear regression analysis showed that an elevated postoperative CRP level was affected by the operation duration and preoperative CRP levels. CONCLUSIONS: These findings suggest that the preoperative CRP level is a prognostic factor for cStage III esophageal cancer and that postoperative elevation in the CRP level is affected by the operation duration.

PROX1 Is Associated with Cancer Progression and Prognosis in Gastric Cancer.

BACKGROUND: It was recently reported that expression of prospero homeobox protein-1 (PROX1) is correlated with the prognosis of esophageal cancer and colorectal cancer. However, its correlation with gastric cancer is unclear. MATERIALS AND METHODS: Our study analyzed the effect of PROX1 knockdown on the migration, invasion and proliferation of the MKN45 human gastric cancer cell line. The correlation between PROX1 expression levels and clinicopathological factors were also analyzed in tumor samples from 99 patients with gastric cancer. RESULTS: Migration, invasion and proliferation were significantly reduced in MKN45 cells with PROX1 knockdown. PROX1 expression was detected in gastric cancer tissues at various levels. PROX1 expression levels were positively correlated with cancer stage, N factor, lymphatic vascular invasion, and vascular invasion in patients with gastric cancer. Analysis of overall and recurrence-free survival indicated that high PROX1 expression was significantly correlated with poor prognosis. CONCLUSION: PROX1 can be an indicator of poor prognosis and a molecular target for gastric cancer treatment.

Curative Gastrectomy with Perioperative Chemotherapy Improves the Survival for Unresectable Gastric Cancer.

BACKGROUND/AIM: Although there are a few reports recommending gastrectomy for unresectable gastric cancer (UGC) to improve survival, the advantage of gastrectomy remains unclear. The objective of this study was to assess the meanings of the surgical intervention. PATIENTS AND METHODS: Therapeutic outcomes were retrospectively evaluated in 127 patients with UGC. All patients had chemotherapy and 47 patients underwent gastrectomy. Patients were classified to three groups according to the treatment. RESULTS: Multivariate analysis showed that gastrectomy was in independent favorable prognosis factor (p<0.001) as well as performance status 0/1, differentiated type, absence of distant organ metastasis, and second line chemotherapy for UGC. Among the patients with gastrectomy, R0 resection was an independent prognostic factor (p=0.011). R0 resection was mainly achieved when there was a single non-curable factor and no distant organ metastasis (p=0.007 and p=0.024, respectively). CONCLUSION: Gastrectomy has an advantage in improving the survival in selected cases among UGC. If chemotherapy enables to control the non-curable factors, gastrectomy should be considered.

Incarcerated obturator hernia treated using a hybrid laparoscopic and anterior preperitoneal approach: A case report.

Obturator hernia (OH) is a rare cause of bowel obstruction. Although several surgical approaches, including the laparoscopic approach, have been reported to date, a standard approach for treating OH has not been established. A 101-year-old woman who presented with constipation and vomiting was admitted to our hospital. CT revealed an incarcerated small bowel within the left obturator foramen, and a diagnosis of left-sided incarcerated OH with small bowel ileus was made. With the patient under general anesthesia, exploratory laparoscopy was performed; we identified an OH with an incarcerated small bowel, which was judged viable after hernia reduction. We repaired the hernia using an anterior preperitoneal approach under laparoscopic assistance and placed a prosthetic mesh over the obturator foramen. The patient recovered with no postoperative complications and was discharged on postoperative day 4. A hybrid laparoscopic and anterior preperitoneal approach is safe and effective for treating an incarcerated OH in an elderly patient.

Safe management of laparoscopic endoscopic cooperative surgery for superficial non-ampullary duodenal epithelial tumors.

Background and study aims Endoscopic submucosal dissection (ESD) for duodenal tumors results in a high delayed perforation rate due to the thinness of the duodenal wall. In most cases with perforation after duodenal ESD, additional surgery is needed due to severe peritonitis. A newly developed procedure, laparoscopic endoscopic cooperative surgery for duodenal tumors (D-LECS), may help to avoid perforation after ESD. In our institution, patients with superficial non-ampullary duodenal epithelial tumors (SNADET) smaller than 50 mm which could not have en-bloc resection by endoscopic mucosal resection were treated with D-LECS. After a laparoscopic exposure of anterior duodenal wall of second portion, ESD was performed. Laparoscopic suturing from the serosal side of ESD site was performed for reinforcement. There were neither postoperative leakage nor other complications. Therefore, D-LECS can be performed safely and prevent perforation after ESD for SNADET. D-LECS could be selected as a treatment for SNADET which can be cured by ESD.

Successful resection of giant esophageal liposarcoma by endoscopic submucosal dissection combined with surgical retrieval: a case report and literature review.

Liposarcoma of the esophagus is very rare. We experienced a huge (27.5 × 11.6 cm) liposarcoma of the esophagus. A 73-year-old man presented with severe dyspnea requiring emergency tracheal intubation. Computed tomography and esophagogastroduodenoscopy showed a large submucosal tumor arising from the esophageal entrance and extending intraluminally to the lower esophagus. We successfully performed endoscopic submucosal dissection (ESD) and esophagotomy to remove the tumor, which preserved swallowing and phonation. The final diagnosis by histopathologic and immunohistologic examination was well-differentiated liposarcoma of the esophagus. Treatment by the combination of ESD and esophagotomy can be performed even for a very large tumor. This method preserves deglutition with a lower risk of recurrent laryngeal nerve paralysis than that with esophagectomy.

Flt1/VEGFR1 heterozygosity causes transient embryonic edema.

Vascular endothelial growth factor-A is a major player in vascular development and a potent vascular permeability factor under physiological and pathological conditions by binding to a decoy receptor Flt1 and its primary receptor Flk1. In this study, we show that Flt1 heterozygous (Flt1(+/-)) mouse embryos grow up to adult without life-threatening abnormalities but exhibit a transient embryonic edema around the nuchal and back regions, which is reminiscent of increased nuchal translucency in human fetuses. Vascular permeability is enhanced and an intricate infolding of the plasma membrane and huge vesicle-like structures are seen in Flt1(+/-) capillary endothelial cells. Flk1 tyrosine phosphorylation is elevated in Flt1(+/-) embryos, but Flk1 heterozygosity does not suppress embryonic edema caused by Flt1 heterozygosity. When Flt1 mutants are crossed with Aspp1(-/-) mice which exhibit a transient embryonic edema with delayed formation and dysfunction of lymphatic vessels, only 5.7% of Flt1(+/-); Aspp1(-/-) mice survive, compared to expected ratio (25%). Our results demonstrate that Flt1 heterozygosity causes a transient embryonic edema and can be a risk factor for embryonic lethality in combination with other mutations causing non-lethal vascular phenotype.

Changes in modified Glasgow prognostic score after neoadjuvant chemotherapy is a prognostic factor in clinical stage II/III esophageal cancer.

The inflammation-based modified Glasgow prognostic score (mGPS) has been shown to be a prognostic factor for esophageal cancer, but its changes in relation to neoadjuvant chemotherapy (NAC) have never been discussed. The purpose of this study was to evaluate the potential prognostic role of mGPS with regard to NAC. mGPS was evaluated on the basis of admission blood samples taken before chemotherapy and before surgery. Patients with elevated C-reactive protein (CRP) serum levels (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2, patients with elevated CRP serum levels without hypoalbuminemia were allocated a score of 1, and patients with normal CRP serum levels with or without hypoalbuminemia were allocated a score of 0. A total of 100 patients with clinical stage II/III squamous cell esophageal cancer, who underwent NAC and esophagectomy between January 2007 and August 2012, were investigated. From the multivariate analysis, the grade of response to chemotherapy and post-NAC mGPS level was found to be independent prognostic factors. The overall survival rate was significantly higher in the conserved mGPS group than in the worse mGPS group (P = 0.030). Changes in mGPS during chemotherapy affected the prognosis of patients, and post-NAC mGPS is an independent prognostic factor in patients with clinical stage II/III thoracic esophageal squamous cell cancer.