Contrast-enhanced abdominal computed tomography to evaluate anastomotic integrity before ileostomy closure in postoperative colorectal cancer patients.

PURPOSE: To investigate the usefulness of contrast-enhanced abdominal computed tomography (CECT) to predict clinically significant anastomotic leakage (CSAL) in patients who received colorectal cancer surgery with diverting ileostomy. METHODS: In this retrospective cohort study, patients who underwent colorectal cancer surgery with diverting ileostomy from January 2014 to May 2018 and postoperative CECT were included. The performance of significant CECT features, identified using multivariable logistic regression, to predict CSAL was calculated. In subgroup analysis, the areas under the receiver operating characteristic curve (AUROCs) were compared between CECT and water-soluble contrast enema (WSCE) using DeLong's method. RESULTS: Of 325 patients (median age, 58 years; 213 men), CECT was routinely performed to evaluate cancer status in 307 (94.5%), and CSAL was observed in 28 (8.6%). After multivariable adjustment, anastomotic mural defect (odds ratio [OR] 5.24; 95% confidence interval [CI] 1.77-15.51; p = 0.003), perianastomotic air (OR 7.28; 95% CI 1.82-29.17; p = 0.007) and ischemic colitis (OR 3.30; 95% CI 1.13-9.61; p = 0.029) were significantly associated with CSAL. The sensitivity, specificity, accuracy, and positive and negative predictive values of significant CECT features were 60.7%, 88.2%, 85.9%, 32.7%, and 96.0%, respectively. In subgroup analysis of 144 patients, the AUROC using significant CECT features (optimal sensitivity/specificity, 50.0%/90.4%) was comparable to that using WSCE (optimal sensitivity/specificity, 12.5%/97.8%) to predict CSAL (0.704 vs. 0.552, p = 0.085). CONCLUSION: CECT performed after colorectal cancer surgery may be useful to assess anastomotic integrity before ileostomy closure, especially to negatively predict CSAL. In the presence of anastomotic mural defect, perianastomotic air, or ischemic colitis, WSCE may be recommended to exclude CSAL.

Upfront radical surgery with total mesorectal excision followed by adjuvant FOLFOX chemotherapy for locally advanced rectal cancer (TME-FOLFOX): an open-label, multicenter, phase II randomized controlled trial.

BACKGROUND: Preoperative chemoradiotherapy (PCRT) followed by surgery and adjuvant chemotherapy is the current standard treatment for stage II/III rectal cancer. However, radiotherapy in the pelvic area is commonly associated with complications such as anastomotic leakage, sexual dysfunction, and fecal incontinence. Recently, the MERCURY study showed that preoperative high-resolution magnetic resonance imaging (MRI) helped to selectively avoid PCRT. It remains unclear whether PCRT is necessary in patients who can achieve a negative circumferential resection margin (CRM) with surgery alone and in patients with cT1-2N1 or cT3N0 without CRM involvement and lateral lymph node metastasis. This study aims to evaluate the efficacy of upfront radical surgery with total mesorectal excision (TME) followed by adjuvant chemotherapy with folinic acid (or leucovorin), fluorouracil, and oxaliplatin (FOLFOX) versus the current standard treatment in patients with surgically resectable, locally advanced rectal cancer. METHODS: This study, named TME-FOLFOX, is a prospective, open-label, multicenter, phase II randomized trial. Patients with locally advanced rectal cancer will be randomized to receive PCRT followed by TME and adjuvant chemotherapy (arm A) or upfront radical surgery with TME followed by adjuvant FOLFOX chemotherapy (arm B). Clinical stage II/III rectal cancer without CRM involvement and lateral lymph node metastasis will be defined using preoperative MRI. The primary endpoint is 3-year disease-free survival (DFS). Secondary endpoints include 5-year DFS, local recurrence rate, systemic recurrence rate, cost-effectiveness, and overall survival. We hypothesized that our experimental group (arm B) will have a 3-year DFS of 75% and a non-inferiority margin of 15%. DISCUSSION: Identifying whether patients require PCRT is one of the critical issues in locally advanced rectal cancer. This study aims to elucidate whether PCRT may not be required for all patients with stage II/III rectal cancer, especially for the MRI-based intermediate-risk group (with cT1-2N1 or cT3N0) without CRM involvement and lateral lymph node metastasis. If the findings indicate that our proposed treatment, which omits PCRT, is non-inferior to the standard treatment, then patients may avoid unnecessary radiation-related toxicity, have a shorter treatment duration, and save on medical costs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02167321. Registered on 19 June 2014.

Gadolinium retention in rat abdominal organs after administration of gadoxetic acid disodium compared to gadodiamide and gadobutrol.

PURPOSE: To compare gadolinium retention in the abdominal organs after administration of gadoxetic acid disodium, a liver-specific contrast agent, compared to gadodiamide and gadobutrol. METHODS: Three types of gadolinium-based contrast agents (GBCAs) were administered to rats. A single (gadodiamide and gadobutrol, 0.1 mmol/kg; gadoxetic acid disodium, 0.025 mmol/kg) or double label-recommended dose was intravenously administered once (Group 1), a single dose was administered 4 times (Group 2) and a single dose with or without a chelating agent (intraperitoneal injection immediately after each GBCA administration) was administered (Group 3). Rats were sacrificed after 1, 4, and 12 weeks and gadolinium concentrations in the liver, spleen, kidney, muscle, and bone were measured by inductively coupled plasma mass spectrometry. P values less than 0.05 were considered statistically significant. RESULTS: More gadolinium was retained with a double dose compared to a single dose, but there was no observed significant difference in gadolinium retention after a double dose compared to a single dose (P > .05). Gadodiamide was retained the most in all tissues followed by gadobutrol and gadoxetic acid disodium. Residual gadolinium was significantly less at 4 weeks compared to 1 week (P < .05), but no further decrease was observed after 4 weeks (P > .05). The presence of the chelating agent did not significantly decrease the concentration of residual gadolinium (P > .05). CONCLUSION: Gadolinium was retained the least in abdominal organs after gadoxetic acid disodium was administered and most of the residual gadolinium was excreted 4 weeks after GBCA administration when a label-recommended dose was administered. A commercially available chelation therapy agent could not reduce gadolinium retention.

Complementary utility of targeted next-generation sequencing and immunohistochemistry panels as a screening platform to select targeted therapy for advanced gastric cancer.

We tested the clinical utility of combined profiling of Ion Torrent PGM based next-generation sequencing (NGS) and immunohistochemistry (IHC) for assignment to molecularly targeted therapies. A consecutive cohort of 93 patients with advanced/metastatic GC who underwent palliative chemotherapy between March and December 2015 were prospectively enrolled. Formalin fixed paraffin embedded tumor biopsy specimens were subjected to a 10 GC panels [Epstein Barr virus encoding RNA in-situ hybridization, IHC for mismatch repair proteins (MMR; MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (HER2, EGFR, and MET), PTEN, and p53 protein], and a commercial targeted NGS panel of 52 genes (Oncomine Focus Assay). Treatment was based on availability of targeted agents at the time of molecular diagnosis. Among the 81 cases with available tumor samples, complete NGS and IHC profiles were successfully achieved in 66 cases (81.5%); only IHC results were available for 15 cases. Eight cases received matched therapy based on sequencing results; ERBB2 amplification, trastuzumab (n = 4); PIK3CA mutation, Akt inhibitor (n = 2); and FGFR2 amplification, FGFR2b inhibitor (n = 2). Eleven cases received matched therapy based on IHC; ERBB2 positivity, trastuzumab (n = 5); PTEN loss (n = 2), PI3Kß inhibitor; MMR deficiency (n = 2), PD-1 inhibitor; and EGFR positivity (n = 2), pan-ERBB inhibitor. A total of 19 (23.5%) and 62 (76.5%) cases were treated with matched and non-matched therapy, respectively. Matched therapy had significantly higher overall response rate than non-matched therapy (55.6% vs 13.1%, P = 0.001). NGS and IHC markers provide complementary utility in identifying patients who may benefit from targeted therapies.

A Randomized Phase 2 Study of Neoadjuvant Chemoradiaton Therapy With 5-Fluorouracil/Leucovorin or Irinotecan/S-1 in Patients With Locally Advanced Rectal Cancer.

PURPOSE: The purpose of this study was to evaluate the rate of pathologic complete response (pCR) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation therapy (CRT) with leucovorin (FL) versus irinotecan/S-1 (IS). METHODS AND MATERIALS: Patients with resectable LARC (clinical stage T3/4, lymph node positive, or both) were randomly assigned to receive preoperative radiation (45-50.4 Gy in 25 to 28 daily fractions) and concomitant chemotherapy either with a bolus injection of FL (400 mg/m(2)/day 5-fluorouracil and 20 mg/m(2)/day leucovorin) for 3 consecutive days every 4 weeks for 2 cycles (FL group) or with 40 mg/m(2) irinotecan on days 1, 8, 15, 22, and 29, and 35 mg/m(2) S-1 twice on the day of irradiation (IS group). Curative surgery was performed approximately 4 to 8 weeks after the completion of CRT. The postoperative chemotherapy regimen was FL with a primary endpoint of a pCR rate evaluation. RESULTS: One hundred forty-two eligible patients were randomly assigned, and the median follow-up duration was 43.8 months (95% confidence interval, 40.8-46.8 months). One hundred thirty-three patients (93.7%) of 142 underwent total mesorectal excision; pCR was achieved in 11 (16.7%) of 66 patients in the FL group and 17 (25.8%) of 67 patients in the IS group (P=.246). When good responders were defined as patients with Mandard grades 1 and 2, the rate of good responders was significantly higher in the IS group than in the FL group (54.6% vs 36.4%, respectively, P=.036). The preoperative rates of grade 3 and 4 toxicities were higher in the IS group (7.0%) than in the FL group (1.4%, P=.095). The 3-year disease-free survival was not significantly different between the 2 groups (79.7% vs 76.6%, respectively, P=.896). CONCLUSIONS: IS-based preoperative CRT did not increase pCR rate, but it did increase acute toxicities compared with standard 5-FU treatment. Therefore, further investigation is needed.

Fluorescent iodized emulsion for pre- and intraoperative sentinel lymph node imaging: validation in a preclinical model.

PURPOSE: To validate the usefulness of a newly developed tracer for preoperative gastric sentinel lymph node (LN) (SLN) mapping and intraoperative navigation after a single preoperative submucosal injection in rat and beagle models. MATERIALS AND METHODS: This study was approved by the Experimental Animal Ethical Committee of Yonsei University College of Medicine according to the eighth edition of the Guide for the Care and Use of Laboratory Animals published in 2011. An emulsion was developed that contained indocyanine green in iodized oil, which can be visualized with both computed tomography (CT) and near-infrared (NIR) optical imaging and has the property of delayed washout. This emulsion was injected into the footpad of rats (n = 6) and the gastric submucosa of beagles (n = 8). CT lymphography was performed. The degree of enhancement of popliteal LNs was measured in rats, and the enhancing LNs were identified and the degree of enhancement of the enhancing LNs was measured in beagles. Next, NIR imaging was performed in beagles during open, laparoscopic, and robotic surgery to identify LNs containing the fluorescent signals of indocyanine green. The enhanced LNs detected with CT lymphography and NIR imaging were matched to see if they corresponded. RESULTS: Preoperative CT lymphography facilitated SLN mapping, and 26 SLNs were identified in eight beagles. NIR imaging enabled high-spatial-resolution visualization of both SLNs and the intervening lymphatic vessels and was useful for intraoperative SLN navigation. CONCLUSION: SLN mapping with fluorescent iodized oil emulsion is effective and feasible for both CT and NIR imaging.

Nanoscale iodized oil emulsion: a useful tracer for pretreatment sentinel node detection using CT lymphography in a normal canine gastric model.

BACKGROUND: Pretreatment identification of the sentinel lymph nodes (SLNs) in gastric cancer patients may have great advantages for minimally invasive treatment. No reliable method for the detection of SLNs during the pretreatment period in gastric cancer has been established. The aim of this study was to determine whether computed tomographic (CT) lymphography using nanoscale iodized oil emulsion via endoscopic submucosal injection can visualize LNs. METHODS: Five dogs underwent CT lymphography after endoscopic submucosal injection of 2 ml of a nanoscale iodized oil emulsion. CT images were taken before and 30, 90, and 210 min after contrast injection. Intraoperative SLN detection was performed using endoscopically injected indocyanine green lymphography for comparison. RESULTS: Computed tomographic lymphography with nanoscale iodized oil emulsion enabled the visualization of 19 enhanced LNs (mean = 3.8/dog, range = 3-6) with a 100% SLN detection rate. The locations of the SLNs were the lesser curvature (n = 7), greater curvature (n = 1), infrapyloric (n = 3), and left gastric (n = 8) areas. Contrast enhancement of SLNs continuously increased and peaked after 210 min at 142.4 ± 42.3 HU. No green LNs were visualized in the three locations that were detected by CT lymphography. However, no additional LNs were visualized using the dye method. The concordance rate based on the LNs between the SLNs on CT lymphography and the green LNs using the ICG method was 84% (16/19), whereas the concordance rate of the stations identified by CT lymphography and the dye method was 78.6% (11/14). CONCLUSIONS: Computed tomographic lymphography using nanoscale iodized oil emulsion is a promising tool for preoperative SLN detection for early gastric cancer if the biological safety of the nanoscale iodized oil emulsion can be established.

Nanoscaled iodized oil emulsion as a CT contrast agent for the detection of experimental liver tumors in a rat model.

RATIONALE AND OBJECTIVES: To characterize an iodized oil emulsion for computed tomography (CT) imaging of experimental hepatic tumors in rat models. MATERIALS AND METHODS: For characterizing the agents in normal rats, three rats were intravenously infused and imaged with clinical CT up to 1 week. Iopamidol solution was also used as controls (n = 3). For evaluating the feasibility of diagnosis of hepatic tumors, 12 rats were injected with C6 glial tumor cells into the liver 11, 9, 7, and 5 days before CT (n = 3 per day). After CT imaging, gross and histopathologic correlation of liver tumors with CT images were performed. RESULTS: CT numbers of aorta and inferior vena cava (IVC) increased immediately after injection of the emulsion and remained above 200 Hounsfield units for 1 hour (maximum: 295.67 +/- 27.65 in aorta and 347.07 +/- 10.58 in IVC). The mean attenuation in liver and spleen was relatively stable between 30 and 180 minutes (maximum: 188.84 +/- 18.70 in liver and 210.97 +/- 15.83 in spleen). All 20 tumors later confirmed by pathology were detected as hypodense lesions on CT (sensitivity: 100%; range, 2.0-16.4 mm). The mean enhancement ratios of liver at all time points were significantly higher than those of tumors (P < .05). CONCLUSION: The hepatic enhancement achieved by the iodized oil emulsion is reticuloendothelial system-specific with the property of blood pool enhancement and longer lasting than that achievable with the current water soluble agents. Thus, this agent may offer significant advantages for diagnosis of hepatic metastases.

Liposomes coloaded with iopamidol/lipiodol as a RES-targeted contrast agent for computed tomography imaging.

PURPOSE: The need for computed tomography (CT) of reticuloendothelial system (RES)-rich organs such as the liver is increasing, particularly in patients with suspected hepatic metastasis. CT images of the liver have been improved by encapsulating currently used, water-soluble iodine contrast agent in liposomes. The present study was performed to investigate a possibility to overcome the limitations of entrapped iodine in liposomes by preparing liposomes co-loaded with iopamidol, a water-soluble iodinated compound, and lipiodol, an iodized oil. METHODS: Iopamidol and lipiodol were simultaneously loaded in liposomes by modified reverse-phase evaporation method. The entrapped iodine concentration, mean particle size and polydispersity index of resulting liposomes were evaluated. Following intravenous injection of these liposomes into rats, CT scanning was performed. RESULTS: Simultaneous loading of iopamidol and lipiodol into liposomes resulted in entrapped iodine concentrations as high as 49.2 iodine mg/ml. The mean particle size was 280 nm, and the mean polydispersity index was 0.230. CT scanning with these iopamidol/lipiodol (I/L) liposomes into rats resulted in more pronounced and more persistent increases in RES-rich organs, liver and spleen, compared with free liposomes or liposomes loaded with iopamidol alone. CONCLUSIONS: These findings indicate that I/L liposomes have the potential to allow thorough CT examination of RES-rich organs.

Feasibility of interstitial CT lymphography using optimized iodized oil emulsion in rats.

OBJECTIVES: To formulate an iodine-based contrast agent with an oil-in-water emulsion and to evaluate the feasibility of the agent for use as an interstitial computed tomographic (CT) lymphographic agent in a normal rat model. MATERIALS AND METHODS: The effect of iodized oil (lipiodol) content and the type of surfactant/cosurfactant on the resultant emulsion size and polydispersity was investigated to obtain an optimized lipiodol emulsion for CT lymphography. Optimized emulsions (144 mg/mL) were injected in the hind paws of 6 rats, using 0.5 mL per paw. As control groups, iopamidol solution and lipiodol diluted with squalene to adjust the injection volume with iodine concentration equivalent to the emulsions were used. Precontrast and postcontrast CT images up to 1 week after contrast agent injection were obtained. Time-enhancement curves of the popliteal lymph nodes were obtained. Analysis of variance and post hoc analysis with the Dunn procedure were used for comparing mean peak enhancement, time to peak enhancement, and sustained duration of contrast enhancement. RESULTS: Optimized emulsion formulations composed of 30% lipiodol and 282 mg/mL of 9:1 surfactant mixture (Tween 80:TPGS [alpha-tocopheryl polyethylene glycol succinate], Tween 80:Kollidon 12 PF, or Tween 80:Span 85) exhibited mean particle size less than 120 nm, and they were stable without significant particle size change up to 1 month. Targeted lymph nodes in all emulsion groups showed continuously increasing enhancement until 4 or 8 hours after injection, followed by continuous washout. Peak enhancement (time to peak enhancement) was 172.4 +/- 54.5 HU (Hounsfield unit) (384.0 +/- 131.5 minutes) for Tween 80:TPGS; 172.8 +/- 28.0 HU (432.0 +/- 107.3 minutes) for Tween 80:Kollidon 12 PF, and 177.2 +/- 68.9 HU (294.0 +/- 190.2 minutes) for Tween 80:Span 85. For iopamidol, peak enhancement of 153.0 +/- 46.1 HU (0.5 +/- 0.5 minutes) occurred early with rapid washout. For lipiodol as a reference agent, contrast enhancement continuously increased even 1 week after injection without washout (peak enhancement, 486.0 +/- 97.4 HU). Peak enhancement among the emulsion groups and the iopamidol group was not statistically different (P = 0.95). All emulsion groups showed more prolonged enhancement than the iopamidol group; enhancement duration for the emulsion groups was 534.0 +/- 481.1 minutes for Tween 80:TPGS; 957.0 +/- 524.8 minutes for Tween 80:Kollidon 12 PF; and 750.0 +/- 566.0 minutes for Tween 80:Span 85, and enhancement duration for iopamidol was 8.2 +/- 12.3 minutes (all P < 0.05 in multiple comparisons). However, there was no significant difference in enhancement duration among the 3 emulsion groups (P > 0.05). CONCLUSIONS: Iodized oil emulsion made with a surfactant mixture (Tween 80 as the main surfactant and TPGS, Kollidon 12 PF, or Span 85 as the cosurfactant) provided sufficient and sustained contrast enhancement on CT of targeted lymph nodes with washout on delayed phase.