Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in MRI-Defined Locally Advanced T3 Resectable Rectal Cancer: Final Results of a Randomized, Noncomparative Phase 2 INOVA Study.

BACKGROUND: Recurrence and distant metastases remain a significant issue in locally advanced rectal cancer (LARC). Several multimodal strategies are assessed in clinical trials. PATIENTS AND METHODS: Patients with mid/low magnetic resonance imaging-defined high-risk LARC were randomized to arm A (12-week bevacizumab + FOLFOX-4 then bevacizumab-5-fluorouracil [5-FU]-radiotherapy [RT] before total mesorectal excision [TME]) or arm B (bevacizumab-5-FU-RT then TME). Long-term efficacy and safety up to 5 years' follow-up are reported. No comparison between arms was planned. RESULTS: Overall, 91 patients (46 in arm A and 45 in arm B) were included. Main results have been presented previously. During the late follow-up period (> 4 weeks after surgery), 4 patients (8.7%) in arm A and 4 (8.9%) in arm B experienced grade 3/4 adverse events related to bevacizumab; the most frequent were 2 anastomotic fistulas (both in arm A) and abscesses (1 in arm A and 2 in arm B). At 5 years' follow-up, 9 (19.6%) and 11 (24.4%) patients in arms A and B developed a fistula in the year after surgery, and 2 (4.3%) in arm A at > 1 year after surgery. Most resolved before study end. Five-year disease-free survival was 70% and 64.3% in arms A and B, respectively. Five-year overall survival was 90.5% (95% confidence interval, 76.7, 96.3) in arm A and 72.7% (95% confidence interval, 56.0, 83.9) in arm B. CONCLUSION: Neoadjuvant bevacizumab + FOLFOX-4 may have the potential to increase survival outcomes when followed by bevacizumab-5-FU-RT and TME in LARC. Bevacizumab-5-FU-RT then TME was associated with a higher-than-projected rate of anastomotic fistulas. Further research of neoadjuvant strategies in LARC is encouraged.

Diffusion-Weighted Magnetic Resonance Imaging: A New Tool for the Diagnosis of Bladder Pain Syndrome/Interstitial Cystitis.

OBJECTIVES: To determine whether diffusion-weighted magnetic resonance imaging (DWMRI), a noninvasive procedure, can contribute to the diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC). METHODS: The pelvic DWMRI of patients with chronic pelvic pain syndrome was selected between January 2012 and June 2017. A radiologist analyzed the bladder wall signal; he was blinded to the patients' clinical data. According to the 2008 European Society for the Study of Bladder Pain Syndrome/Interstitial Cystitis criteria, 2 groups of patients were determined: BPS/IC and no BPS/IC. The association between BPS/IC and the wall signal intensity was compared. RESULTS: In the 106 patients included, 82 had criteria for BPS/IC and 24 did not. A significant difference in the distribution of the signal was found between the 2 groups (p = 0.01). High signal intensity of the bladder wall was related to the presence of a BPS/IC with a sensitivity of 28% and a specificity of 88%. No signal intensity of the bladder wall was related to the absence of a BPS/IC with a sensitivity of 96% and a specificity of 29%. CONCLUSIONS: In -DWMRI, high bladder wall signal intensity helps to affirm a BPS/IC, whereas the absence of signal helps to exclude the diagnosis. Further studies are needed to confirm these preliminary results.

Diagnostic imaging requisition quality when using an electronic medical record: a before-after study.

Diagnostic imaging requisition (DIR) content is legally constrained for care quality and patient safety concerns. A French national indicator, based on administrative and clinical data, has been introduced to monitor nationwide the conformity of such documents (CDIR). The purpose of this study was to assess the effect on CDIR of the deployment of the ORBIS™ electronic medical record at the Tenon hospital (Paris, France). A before-after study has been carried out. A significant increase of CDIR, from 37.0% (n=676) to 49.1% (n=800), was observed (p < 10⁻5). Conformity of administrative criteria improved, but there was no statistical difference of clinical criteria conformity, despite the improvement of clinical history documentation (100%). Up to five different paper-based requisition forms were used by clinical departments in the before period. In the after period, only 27.1% of requisitions were ORBIS-edited with a CDIR of 66.8% (n=217). In both periods, CDIR was correlated to the level of standardization of the forms.

Small bowel adenocarcinoma in Crohn disease: CT-enterography features with pathological correlation.

PURPOSE: The aim of this study was to analyze the clinical, pathological, and CT-enterography findings of small bowel adenocarcinomas in Crohn disease patients. MATERIALS AND METHODS: Clinical, histopathological, and imaging findings were retrospectively evaluated in seven Crohn disease patients with small bowel adenocarcinoma. CT-enterography examinations were reviewed for morphologic features and location of tumor, presence of stratification, luminal stenosis, proximal dilatation, adjacent lymph nodes, and correlated with findings at histological examination. RESULTS: The tumor was located in the terminal (n = 6) or distal (n = 1) ileum. On CT-enterography, the tumor was visible in five patients, whereas two patients had no visible tumor. Four different patterns were individualized including small bowel mass (n = 2), long stenosis with heterogeneous submucosal layer (n = 2), short and severe stenosis with proximal small bowel dilatation (n = 2), and sacculated small bowel loop with irregular and asymmetric circumferential thickening (n = 1). Stratification, fat stranding, and comb sign were present in two, two, and one patients, respectively. CONCLUSION: Identification of a mass being clearly visible suggests strongly the presence of small bowel adenocarcinoma in Crohn disease patients but adenocarcinoma may be completely indistinguishable from benign fibrotic or acute inflammatory stricture. Knowledge of these findings is critical to help suggest the diagnosis of this rare but severe complication of Crohn disease.

Aortic aneurysms in a rat model: in vivo MR imaging of endovascular cell therapy.

PURPOSE: To prospectively evaluate in rats whether magnetic cell labeling can be used to noninvasively assess the technical success of endovascular cell therapy for abdominal aortic aneurysms (AAAs). MATERIALS AND METHODS: The study was approved by an institutional animal care and use committee. Vascular smooth muscle cells (VSMCs) labeled with iron oxide nanoparticles were seeded endovascularly in already formed AAAs. T2*-weighted gradient-echo and T2-weighted spin-echo magnetic resonance (MR) imaging was performed in vivo at 1.5 T before and 30 minutes after the injection of iron-loaded VSMCs (14 rats), nonlabeled VSMCs (three rats), or iron-free particles (three rats). Ten rats were euthanized shortly after the injection (day 0). Of the 10 remaining rats, which were seeded with iron-loaded cells, three were imaged on day 7 after cell delivery; three, on day 14; and four, on day 28; then they were euthanized. Ex vivo high-field-strength MR imaging of two AAAs was performed 28 days after cell delivery. Histologic examination of cross sections of all AAAs was performed. Statistical evaluations were performed with a nonparametric Wilcoxon correlation test. RESULTS: Magnetic cell labeling did not alter the capability of VSMCs to stabilize the diameter of the aneurysms. T2*-weighted gradient-echo images showed areas of hypointense signal within the aortic wall immediately and up to 1 month after cell therapy. The mean signal intensity decreased significantly after cell delivery (from 2362 +/- 244 [standard deviation] before to 434 +/- 275 after delivery, P < .001). Areas of hypointense signal and iron-loaded VSMCs were colocalized in the area of aortic wall reconstruction at both high-field-strength MR imaging and histologic analysis. CONCLUSION: MR imaging with magnetic cell labeling can be used to document endovascular cell delivery in already formed AAAs in rats.

Abdominal and iliac arterial stenoses: comparative double-blinded randomized study of diagnostic accuracy of 3D MR angiography with gadodiamide or gadopentetate dimeglumine.

PURPOSE: To prospectively evaluate accuracy of gadolinium-enhanced three-dimensional (3D) magnetic resonance (MR) angiography with gadodiamide and gadopentetate dimeglumine (0.1 mmol/kg), with intraarterial DSA as reference standard, for imaging abdominal and iliac arterial stenoses. MATERIALS AND METHODS: The study was approved by all institutional review boards; informed consent was obtained from each subject before procedures. Two hundred forty-seven subjects were included; 240 received either contrast agent and were available for safety analysis; 222 were available for accuracy analysis. Enhanced 3D MR angiography and DSA were performed; image data were evaluated in a double-blinded randomized study. Stenoses were classified as not relevant (<50% stenosis) or relevant (> or =50%). For detection of main stenosis, accuracy with enhanced 3D MR angiography compared with that with DSA was determined. RESULTS: The difference in accuracy for imaging with gadodiamide and gadopentetate was 3.6%. Noninferiority was inferred because the lower bound of the exact two-sided 95% confidence interval was -10.1 and was above the noninferiority margin (-15%). Accuracy for detection of the main stenosis was low, 56.4% for gadodiamide and 52.8% for gadopentetate group. Subgroup analysis with exclusion of inferior mesenteric artery and internal iliac arteries and the most false-positive stenosis classifications yielded better results: 76.6% and 71.6%, respectively. Sensitivity, specificity, and negative and positive predictive values did not differ substantially between study groups. In the main analysis, values were 44%, 96%, 35%, and 97% for gadodiamide and 44%, 83%, 30%, and 90% for gadopentetate, respectively. In the subgroup analysis, values were 66%, 95%, 61%, and 96% for gadodiamide and 63%, 86%, 58%, and 88% for gadopentetate, respectively. CONCLUSION: Noninferiority of gadodiamide versus gadopentetate was verified based on the primary end point, which was accuracy for detection of the main stenosis with enhanced 3D MR angiography compared with DSA.

Iron oxide nanoparticle-labeled rat smooth muscle cells: cardiac MR imaging for cell graft monitoring and quantitation.

PURPOSE: To perform a quantitative analysis of anionic maghemite nanoparticle-labeled cells in vitro and determine the effect of labeling on signal intensity at magnetic resonance (MR) imaging. MATERIALS AND METHODS: The study was approved by the institutional animal care and use committee at Hôpital Bichat. In vitro cell proliferation, iron content per cell, and MR signal intensity of cells were measured in agarose phantoms for 0-14 days of culture after labeling of rat smooth muscle cells with anionic maghemite nanoparticles. Next, iron oxide-labeled smooth muscle cells were injected into healthy hearts and hearts with ischemic injury in seven live Fisher rats. Ex vivo MR imaging experiments in excised hearts 2 and 48 hours after injection were performed with a 1.5-T medical imaging system by using T2-weighted gradient-echo and spin-echo sequences. Histologic sections were obtained after MR imaging. Correlation analyses between division factor of iron load and cell amplification factor and between 1/T2 and number of labeled cells or number of days in culture were performed by using linear regression. RESULTS: Viability of smooth muscle cells was not affected by magnetic labeling. Transmission electron micrographs of cells revealed the presence of iron oxide nanoparticles in vesicles up to day 14 of culture. Intracellular iron concentration decreased in parallel with cell division (r2 = 0.99) and was correlated with MR signal intensity (r2 = 0.95). T2*-weighted MR images of excised rat hearts showed hypointense signal in myocardium at 2 and 48 hours after local injection of labeled cells. Subsequent histologic staining evidenced iron oxide nanoparticles within cells and confirmed the presence of the original cells at 2 and 48 hours after implantation. CONCLUSION: Magnetic labeling of smooth muscle cells with anionic maghemite nanoparticles allows detection of cells with MR imaging after local transplantation in the heart.

Gadolinium-enhanced MR angiography as first-line preoperative imaging in high-risk patients with lower limb ischemia.

PURPOSE: To assess the clinical relevance of gadolinium-enhanced MR angiography (Gd-MRA) as the first-line angiographic examination for planning lower limb revascularization in patients at high risk of complications after contrast arteriography (CA). METHOD: Forty-five consecutive patients at high risk of post-CA complications because of chronic renal insufficiency, diabetes mellitus, advanced age, or the need for brachial artery catheterization or graft puncture had Gd-MRA as first-line angiography before a surgical or endovascular procedure for lower limb ischemia. RESULTS: After Gd-MRA, 59 procedures were performed, including 38 surgical reconstructions, 17 endovascular procedures, and four amputations. Complementary CA was only required in seven patients for whom a below-knee bypass was planned. Cumulative patency rates at 1 and 24 months were, respectively, 91% and 91% for suprainguinal bypasses, 100% and 92% for infrainguinal above-knee bypasses, 80% and 57% for below-knee bypasses, and 92% and 76% for iliofemoral angioplasties. After 24 months of follow-up, limb salvage, amputation, and mortality rates were, respectively, 86%, 3.5%, and 7% for stage II ischemia and 48%, 11%, and 30% for stages III and IV. CONCLUSION: Gd-MRA can be proposed for first-line preoperative imaging in the management of lower limb ischemia for patients at high risk and permits the selective use of CA as a second-line examination if a below-knee bypass is required.

Fast breath-hold T2-weighted MR imaging reduces interobserver variability in the diagnosis of adenomyosis.

OBJECTIVE: We compared two rapid MR imaging T2-weighted pulse sequences with high-resolution turbo spin-echo for the diagnosis of adenomyosis, and we evaluated interobserver variability. SUBJECTS AND METHODS: Fifty-six consecutive patients referred for hysterectomy prospectively underwent MR imaging. Two fast pulse sequences using a breath-hold technique-true fast imaging with steady-state free precession (FISP) and turbo inversion recovery-and turbo spin-echo T2-weighted images of the pelvis were obtained in each patient. The images were analyzed in a blinded manner and independently by three reviewers with different levels of experience for the accuracy of adenomyosis diagnosis, image quality, anatomic visualization, and image artifacts. The accuracy for the diagnosis of adenomyosis on turbo spin-echo T2-weighted imaging combined with one or two fast pulse sequences was evaluated for each reviewer. RESULTS: Twenty-four patients (42.9%) had a histologic diagnosis of adenomyosis. The accuracy for the diagnosis of adenomyosis for reviewers 1, 2, and 3 using turbo spin-echo T2-weighted, true FISP, and turbo inversion recovery sequences was 83.9%, 67.8%, 75%; 83.9%, 67.8, 78.5%; and 87.5%, 73.2%, and 75%, respectively. A difference in the accuracy rate was found among the observers for the three sequences (p < 0.001). Whatever the pulse sequence, the accuracy rate was higher for the reviewer with more experience in gynecologic imaging. The combination of turbo spin-echo T2-weighted imaging with at least one rapid sequence increased the accuracy of observers with little experience in gynecology. With turbo inversion recovery sequences, the image quality score was low for the three reviewers compared with turbo spin-echo T2-weighted and true FISP sequences. The combination of turbo spin-echo T2-weighted and true FISP sequences gave the highest image quality scores. CONCLUSION: Breath-hold T2-weighted sequences optimize the accuracy of MR imaging for the diagnosis of adenomyosis and reduce interobserver variability.

Low molecular weight fucoidan prevents neointimal hyperplasia in rabbit iliac artery in-stent restenosis model.

OBJECTIVE: Smooth muscle cell (SMC) proliferation within the intima is regulated by heparan sulfates. We studied a low molecular weight (LMW) fucoidan (sulfated polysaccharide from brown seaweed) on SMC proliferation in vitro and intimal hyperplasia in vivo. METHODS AND RESULTS: In vitro study revealed that LMW fucoidan reduces rabbit SMC proliferation and is internalized in SMC perinuclear vesicles. On rabbit iliac arteries perfused in vivo with fluorolabeled LMW fucoidan after angioplasty, the labeling was mainly located on sites of injury. Pharmacokinetic studies showed that LMW fucoidan exhibited in rats an elimination half-life of 56+/-25 minutes (n=8) after intravenous administration and a constant plasma rate for > or =6 hours after intramuscular administration. After stent implantation in their iliac arteries, rabbits were also treated with LMW fucoidan (5 mg/kg IM twice a day). Histomorphometric analysis at day 14 indicated that LMW fucoidan reduced intimal hyperplasia by 59% (1.79+/-0.4 versus 0.73+/-0.2 mm2, P<0.0001) and luminal cross-sectional area narrowing by 58% (0.38+/-0.08 versus 0.16+/-0.04, P<0.0001). Blood samples showed no anticoagulant activity due to LMW fucoidan. CONCLUSIONS: This natural polysaccharide with high affinity for SMCs and sustained plasma concentration markedly reduced intimal hyperplasia, suggesting its use for the prevention of human in-stent restenosis.

Gadolinium-enhanced digital subtraction angiography of hemodialysis fistulas: a diagnostic and therapeutic approach.

OBJECTIVE: The aim of our study was to evaluate the feasibility, safety, and potential role of the contrast agent gadoterate meglumine for digital subtraction angiography as a single diagnostic procedure or before percutaneous transluminal angioplasty of malfunctioning native dialysis fistulas. MATERIALS AND METHODS: Over a 20-month period, 23 patients (15 women, eight men) with an age range of 42-87 years (mean, 63 years) having end-stage renal insufficiency and with recent hemodialysis fistula surgical placement underwent gadoterate-enhanced digital subtraction angiography with a digital 1024 x 1024 matrix. Opacification was performed on the forearm, arm, and chest with the patient in the supine position using an injection (retrograde, n = 14; anterograde, n = 8; arterial, n = 1) of gadoterate meglumine into the perianastomotic fistula segment at a rate of 3 mL/sec for a total volume ranging from 24 to 32 mL. Percutaneous transluminal angioplasty was performed in three patients and required an additional 8 mL per procedure. Examinations were compared using a 3-step confidence scale and a two-radiologist agreement (Cohen's kappa statistic) for diagnostic and opacification quality. Tolerability was evaluated on the basis of serum creatinine levels and the development of complications. RESULTS: No impairment of renal function was found in the 15 patients who were not treated with hemodialysis. Serum creatinine level change varied from -11.9% to 11.6%. All studies were of diagnostic quality. The presence of stenosis (n = 14) or thrombosis (n = 3) in arteriovenous fistulas was shown with good interobserver agreement (kappa = 0.71-0.80) in relation to opacification quality (kappa = 0.59-0.84). No pain, neurologic complications, or allergiclike reactions occurred. Three percutaneous transluminal angioplasty procedures (brachiocephalic, n = 2; radiocephalic, n = 1) were successfully performed. CONCLUSION: Gadoterate-enhanced digital subtraction angiography is an effective and safe method to assess causes of malfunction of hemodialysis fistulas. It can also be used to plan and perform percutaneous transluminal angioplasty.

Histomorphometric evaluation of (198)Au endovascular brachytherapy in a renal artery restenosis model in rabbits.

OBJECTIVE: The main mid-term complication of percutaneous transluminal angioplasty of the renal artery is restenosis, which occurs in up to 50% of patients. Although no pharmacologic agent to date has been effective in preventing restenosis, both beta-ray emitters and gamma-ray emitters used in endovascular brachytherapy have been shown to reduce coronary restenosis. The objectives of this study were to evaluate the efficacy of (198)Au endovascular brachytherapy in preventing restenosis after percutaneous transluminal renal angioplasty and to determine the radiation dose to the operator. MATERIALS AND METHODS: Twenty-one New Zealand white rabbits (10 females and 11 males) weighing an average of 3.5 kg (range, 3.2-3.8 kg) who had been fed a normal diet underwent bilateral 33% overdilatation with deendothelialization of the renal arteries. After 7 weeks, the induced renal artery stenoses were treated by percutaneous transluminal renal angioplasty. The rabbits were randomly assigned to one of three groups before receiving endovascular 25-Gy irradiation at a radial 2.0-mm depth with a 0.5 x 15 mm (198)Au wire (106 MBq). The right renal artery was irradiated in group A; the left, in group B. The rabbits in group C randomly received a right- or left-sided dummy wire. Operator exposure to radiation was measured using thermoluminescent dosimeters and ionization chambers. The rabbits were sacrificed after 3 weeks. The aorta and renal arteries were perfusion-fixed. The renal arteries were removed for histologic and histomorphometric study. RESULTS: Forty-two renal arteries were cut into a series of 4- micro m-thick slices. Five arteries were thrombosed (two in the irradiated group and three in the control group, p > 0.05). In the patent arteries (n = 37), the average neointimal area was 0.068 mm(2) (range, 0.009-0.234 mm(2)) in 15 irradiated segments (315 slices total), whereas the average neointimal area was 0.135 mm(2) (range, 0.016-0.324 mm(2)) in 22 control segments (462 slices total) (analysis of variance, p < 0.009), showing a percentage area of restenosis of 10.4% in irradiated arteries and 43.4% in non-irradiated arteries (p < 0.0003). Radiation dose per procedure to the operator was 0.034 mSv in the index finger, 0.024 mSv in the wrist, and undectable in the body. CONCLUSION: Endovascular brachytherapy with (198)Au appears to inhibit early renal artery restenosis and exposes the operator to a safe level of radiation.

A chemically modified dextran inhibits smooth muscle cell growth in vitro and intimal in stent hyperplasia in vivo.

PURPOSE: Intimal smooth muscle cell (SMC) hyperplasia is a main component of the arterial wall response to injury. We have investigated the capacity of a water-soluble nonanticoagulant functionalized dextran (E9) in inhibition of SMC growth in vitro and in vivo. METHODS: E9 was obtained with chemical substitutions with anionic and hydrophobic groups on the dextran backbone. SMC proliferation (cell counting, thymidine uptake, cell cycle analysis) was followed in culture in the presence of E9. Western blot analysis against phosphorylated mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase 1/2, and assessment of MAPK activity on serum-stimulated SMCs also were investigated. Binding/displacement experiments, electron microscopy, and cell fractionations were used to follow the binding and internalization of radiolabeled and fluorescentlabeled E9. New Zealand white rabbit iliac arteries were injured with balloon dilatation and stent deployment. Animals were treated for 14 days with saline solution or E9 (5 mg/kg injected subcutaneously, twice daily). Morphometric analyses were carried out in each group (n = 6 arteries, 18 sections). RESULTS: Nonanticoagulant E9 inhibited SMC proliferation in vitro. Tyrosine phosphorylation of MAPK 1/2 and MAPK activity were inhibited with E9 within 5 minutes of incubation. The binding and rapid cytoplasmic internalization of the synthetic compound was evidenced, but, in contrast to heparin, we did not detect any nuclear localization of the antiproliferative E9. In the in vivo model, qualitative modifications of neointimal structure with a thinner fibrocellular neointima were noticed after E9 treatment. Morphometric analyses of stented arteries in E9-treated animals indicated an important reduction (P <.01) of intimal growth: 33% and 45% for intimal area and intima/media ratio, respectively. CONCLUSION: Cytoplasmic internalization of the synthetic polysaccharide correlated to the SMC growth inhibition that involved the MAPK pathway. In vivo inhibition of intimal instent hyperplasia with this nonanticoagulant derived dextran is shown providing a new candidate for a potential selective treatment of SMC proliferation.