Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial.

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor-ligand inhibition should be investigated.

Substitution of a hydroxamic acid anchor into the MK-2 dye for enhanced photovoltaic performance and water stability in a DSSC.

An efficient synthetic protocol to functionalize the cyanoacrylic acid anchoring group of commercially available MK-2 dye with a highly water-stable hydroxamate anchoring group is described. Extensive characterization of this hydroxamate-modified dye (MK-2HA) reveals that the modification does not affect its favorable optoelectronic properties. Dye-sensitized solar cells (DSSCs) prepared with the MK-2HA dye attain improved efficiency (6.9%), relative to analogously prepared devices with commercial MK-2 and N719 dyes. The hydroxamate anchoring group also contributes to significantly increased water stability, with a decrease in the rate constant for dye desorption of MK-2HA relative to MK-2 in the presence of water by as much as 37.5%. In addition, the hydroxamate-anchored dye undergoes essentially no loss in DSSC efficiency and the external quantum efficiency improves when up to 20% water is purposefully added to the electrolyte. In contrast, devices prepared with the commercial dye suffer a 50% decline in efficiency under identical conditions, with a concomitant decrease in external quantum efficiency. Collectively, our results indicate that covalent functionalization of organic dyes with hydroxamate anchoring groups is a simple and efficient approach to improving the water stability of the dye-semiconductor interface and overall device durability.

Diagnosis of acute cortical necrosis in renal transplantation by contrast-enhanced ultrasound: a preliminary experience.

PURPOSE: To evaluate the use of contrast-enhanced ultrasound (CEUS) for diagnosis of cortical necrosis in renal allografts. MATERIALS AND METHODS: We reviewed the medical records and imaging studies of five patients who underwent emergency transplantectomy and a histological diagnosis of cortical necrosis in the period between May 2009 and May 2011. US examinations included initially B-mode and color Doppler and then contrast-enhanced ultrasound with low mechanical index after injection of 2.4 ml of a second generation echo-signal enhancer. Renal transplant vascularization was evaluated during a period of 4 minutes including arterial, corticomedullary and nephrographic phases. Radiologic-pathologic correlation was obtained after transplantectomy in all cases. RESULTS: Five patients with an age range between 30 and 48 years. Post-transplant color Doppler ultrasound showed decreased renal parenchymal vascularization and difficulty to find the spectral waveforms with resistive indexes greater than 0.7 in 4 of 5 patients. CEUS showed enhancement of the main arteries, followed by the enhancement of medullary pyramids, but with an unenhanced peripheral cortical continuous band viewed in all phases, a similar finding to the peripheral rim sign, pathognomonic of cortical necrosis on CT or MRI. The pathologic assessment showed violet kidneys macroscopically with hemorrhagic foci in the outer cortical that drew a well-defined band, findings agreed with CEUS findings. CONCLUSION: CEUS can show the typical peripheral rim sign in cases of cortical necrosis allowing a reliable and fast diagnosis of this condition and it could obviate further imaging studies or biopsy, allowing an earlier decision of nephrectomy.

Effect of Pristine Graphene on Methylammonium Lead Iodide Films and Implications on Solar Cell Performance.

The relatively low stability of solar cells based on hybrid halide perovskites is the main issue to be solved for the implementation in real life of these extraordinary materials. Degradation is accelerated by temperature, moisture, oxygen, and light and mediated by halide easy hopping. The approach here is to incorporate pristine graphene, which is hydrophobic and impermeable to gases and likely limits ionic diffusion while maintaining adequate electronic conductivity. Low concentrations of few-layer graphene platelets (up to 24 × 10-3 wt %) were incorporated to MAPbI3 films for a detailed structural, optical, and transport study whose results are then used to fabricate solar cells with graphene-doped active layers. The lowest graphene content delays the degradation of films with time and light irradiation and leads to enhanced photovoltaic performance and stability of the solar cells, with relative improvement over devices without graphene of 15% in the power conversion efficiency, PCE. A higher graphene content further stabilizes the perovskite films but is detrimental for in-operation devices. A trade-off between the possible sealing effect of the perovskite grains by graphene, that limits ionic diffusion, and the reduction of the crystalline domain size that reduces electronic transport, and, especially, the detected increase of film porosity, that facilitates the access to atmospheric gases, is proposed to be at the origin of the observed trends. This work demonstrated how the synergy between these materials can help to develop cost-effective routes to overcome the stability barrier of metal halide perovskites, introducing active layer design strategies that allow commercialization to take off.

Usefulness of intestinal ultrasound in inflammatory bowel disease. / Utilidad de la ecografía intestinal en la enfermedad inflamatoria intestinal.

Imaging techniques play a fundamental role in the initial diagnosis and follow-up of inflammatory bowel disease. Intestinal ultrasound has high sensitivity and specificity in patients with suspected Crohn's disease and in the detection of inflammatory activity. This technique enables the early diagnosis of intra-abdominal complications such as stenosis, fistulas, and abscesses. It has also proven useful in monitoring the response to treatment and in detecting postsurgical recurrence. Technical improvements in ultrasound scanners, technological advances such as ultrasound contrast agents and elastography, and above all increased experience have increased the role of ultrasound in the evaluation of the gastrointestinal tract. The features that make ultrasound especially attractive include its wide availability, its noninvasiveness and lack of ionizing radiation, its low cost, and its good reproducibility, which is important because it is easy to repeat the study and the study is well tolerated during follow-up. This review summarizes the role of intestinal ultrasound in the detection and follow-up of inflammatory bowel disease.

Enhanced Nonlinear Optical Coefficients of MAPbI3 Thin Films by Bismuth Doping.

The poor photostability under ambient conditions of hybrid halide perovskites has hindered their recently explored promising nonlinear optical properties. Here, we show how Bi3+ can partially substitute Pb2+ homogeneously in the commonly studied MAPbI3, improving both environmental stability and photostability under high laser irradiation. Bi content around 2 atom % produces thin films where the nonlinear refractive (n2) and absorptive coefficients (ß), which modify the refractive index (Δn) of the material with light fluence (I), increase up to factors of 4 and 3.5, respectively, compared to undoped MAPbI3. Higher doping inhibits the nonlinear parameters; however, the samples show higher fluence damage thresholds. Thus, these results provide a road map on how MAPbI3 can be engineered for practical cost-effective nonlinear applications by means of Bi doping, including optical limiting devices and multiple-harmonic generation into optoelectronics devices.

Positive Predictive Value of Abdominal Sonography in the Diagnosis of Ischemic Colitis.

AIM: The aim was to prospectively evaluate the positive predictive value of ultrasound in the diagnosis of ischemic colitis, with colonoscopy as the reference standard. METHODS: During a 2-year period we included consecutive patients over 50 years of age with sudden abdominal pain and/or rectal bleeding who underwent abdominal sonography in an emergency setting with a thickened segment of colon with a length of more than 10 cm. This clinical-sonographic triad was considered diagnostic for ischemic colitis. A thickened bowel location or color Doppler flow findings on ultrasound examination were evaluated but were not considered to make the diagnosis of ischemic colitis. Basic descriptive statistics were used to characterize the study patients. The positive predictive value was calculated as: number of patients with the definitive diagnosis of ischemic colitis (colonoscopic or follow-up)/number of patients with a sonographic diagnosis of ischemic colitis. RESULTS: A total of 48 patients had the clinical-sonographic triad; mean age: 74.3 years (range 54-90 years). The most frequent clinical manifestation was rectal bleeding (83% of the cases) followed by abdominal pain (81%) and diarrhea (45%). A total of 42 cases of ischemic colitis were confirmed by endoscopy (n=35) and biopsy (n=34) or clinical evaluation (n=7). The positive predictive value of the clinical-sonographic diagnosis of ischemic colitis was 87.5%. Thickening of the colon wall was detected on the left side in 35 patients with ischemic colitis, on the right side in 3 and pancolitis was identified in 5 patients. CONCLUSION: In an appropriate clinical setting, ultrasound has a high positive predictive value for the diagnosis of ischemic colitis.

Diseases that simulate acute appendicitis on ultrasound.

Ultrasound is useful in the assessment of patients with possible appendicitis. A diagnosis of appendicitis can be made in patients with persistent right lower quadrant pain when a non-compressible appendix greater than 6 mm in diameter is shown. When a normal appendix is affected by an adjacent lesion, reactive inflammation can cause secondary enlargement of the appendix. This article reviews ultrasound findings in conditions which can clinically mimic acute appendicitis. Examples of Crohn's disease, tuboovarian abscess, typhilitis, sigmoid diverticulitis, perforated sigmoid neoplasm, perforated peptic ulcer, perforated acute cholecystitis, caecal carcinoma and appendiceal tumours are included.

Utility of intrarenal Doppler ultrasound in the diagnosis of renal artery stenosis.

PURPOSE: To determine the utility of intrarenal Doppler parameters and waveform analysis in a hypertensive population screened for renal artery stenosis (RAS). MATERIALS AND METHODS: Sixty five patients were studied (122 kidneys) with intrarenal Doppler sonography. Doppler waveforms of three different areas from each kidney were obtained (superior, middle and inferior level). Waveform morphology, acceleration time (AT), acceleration (Ac) and resistive index (RI) were evaluated in each kidney, comparing retrospectively the Doppler findings with the angiographic results. RESULTS: Arteriography demonstrated 33 (27.2%) renal arteries with stenosis (18 with RAS>75%). Statistically significant differences for AT and Ac were found among the patients with RAS>75% and the other groups (P<0.01). An AT>80 ms and an Ac< or =1 m/s(2) showed a sensitivity of 89% and a specificity of 99%, for the diagnosis of RAS>75%. Better results were obtained in patients less than 50 years old (100% of sensitivity and specificity). The morphologic analysis of the Doppler waveform had poor results but the detection of a waveform grade 0 had a high specificity (98%). An additional comparison of both kidneys didn't improve the results. CONCLUSION: Intrarenal Doppler waveform analysis using quantitative measurements (AT and Ac) is an adequate technique for the diagnosis of severe RAS in previously selected patients, especially in younger patients (<50 years).

Hepatic and splanchnic perfusion and oxygenation after transjugular intrahepatic portosystemic shunt.

OBJECTIVE: in patients with cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) decreases the pressure in the portal vein by rerouting nearly all the portal blood flow to the systemic circulation. This may lead to hypoperfusion of the liver and worsening function. Our aim was to investigate whether TIPS actually reduced hepatic and splanchnic perfusion. METHODS: we studied 25 patients who required placement of a TIPS (20 for variceal bleeding and 5 for refractory ascites). We evaluated the clinical condition, laboratory results, blood velocity in the portal vein and hepatic artery by echo-Doppler ultrasonography, systemic hemodynamic-oxygenation status and hemodynamic-oxygenation status in the portal and suprahepatic veins before TIPS, 15 min after the procedure, and 30 days later. Hepatic and splanchnic perfusion were evaluated as the arteriovenous difference in O2 content and as the O2 extraction rates in the hepatic and splanchnic territories. RESULTS: TIPS induced an immediate decrease in portal pressure, a significant increase in systemic hyperdynamic state, and an increase in blood flow velocity in the portal vein and hepatic artery. Thirty days after the procedure these changes persisted, although they were somewhat attenuated. Although splanchnic and liver perfusion were not changed 15 min or 30 days after TIPS, there was a slight tendency toward a decrease in liver perfusion during follow-up. CONCLUSIONS: TIPS increased the hyperdynamic state in the systemic side. However, portal blood shunting did not change liver or splanchnic perfusion.

[Value of C-reactive protein level in the detection of necrosis in acute pancreatitis]. / Valor de la proteína C reactiva en la detección de la necrosis en la pancreatitis aguda.

OBJECTIVES: To evaluate the utility of C-reactive protein (CRP) in the detection of necrosis in acute pancreatitis and to determine the best cut-off point for CRP used for this purpose. MATERIAL AND METHODS: We performed a retrospective study of 157 patients with acute pancreatitis who underwent computed tomography (CT) with intravenous contrast material between 72 h and 8 days after the onset of symptoms and whose serum CRP values were determined by nephelometry 24 h or later after the onset of pain. RESULTS: Ninety-four patients were men and 63 were women, with a mean age of 61 years (range, 15-96 years). The cause of pancreatitis was biliary lithiasis in 53.5%, alcohol in 20.4%, and idiopathic in 10.8%. Other causes were found in 15.3%. The mean (standard deviation) time elapsed between symptom onset and extraction to evaluate CRP was 3.21 (1.7) days. The patients were divided into two groups according to the results of CT: 132 patients with acute intersitial edematous pancreatitis and 25 patients with acute necrotizing pancreatitis. The mean CRP concentrations were: 322 mg/l (range, 10.7-538) in patients with acute necrotizing pancreatitis and 133 mg/l (range, 3-442) in those with acute interstitial pancreatitis; this difference was statistically significant (p < 0.001). The area under the ROC curve of CRP vs. the occurrence of necrosis was 0.862 (95% CI, 0.778, 0.946). To evaluate the presence of pancreatic necrosis a cut-off level of 200 mg/l showed a sensitivity of 88% and a specificity of 75% while a cut-off level of 279 mg/l presented a sensitivity of 72% and a specificity of 88%. CONCLUSIONS: In acute pancreatitis, a CRP value of less than or equal to 200 mg/l obtained at 72 h of symptom onset is useful for ruling out, with a high degree of probability, the presence of necrosis. With higher values, additional investigations should be performed to determine the presence of pancreatic necrosis; nevertheless, with values higher than 279 mg/l the risk of necrosis markedly increases.

[Lymphadenomegaly in patients with chronic liver disease]. / Linfadenomegalias en pacientes con hepatopatía crónica.

Abdominal lymphadenomegaly is a frequent ultrasonographic finding in patients with chronic liver disease. Its clinical significance is not well understood. The aim of this study was to determine the relationship between this finding and several characteristics of liver disease in 44 patients with chronic liver disease (79.5% due to hepatitis C virus). To do this, all patients underwent simultaneous liver biopsy and abdominal ultrasonography, in which the number and localization of the enlarged abdominal lymph nodes were confirmed. Viral load in patients with chronic hepatitis C virus infection was determined. No significant differences were found in serum hepatitis C RNA concentrations between patients who presented lymphadenomegaly and those who did not. However, the presence of lymphadenomegaly was associated with greater histological activity. If this finding were confirmed in studies with larger samples, the presence of ultrasonographically-detected enlarged abdominal lymph nodes in patients with chronic liver disease due to hepatitis C virus infection would indicate more severe histological lesions.

Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn's disease.

BACKGROUND: Cross-sectional imaging techniques, including ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI), are increasingly used for evaluation of Crohn's disease (CD). Aim To perform an assessment of the diagnostic accuracy of cross-sectional imaging techniques for diagnosis of CD, evaluation of disease extension and activity and diagnosis of complications, and to provide recommendations for their optimal use. METHODS: Relevant publications were identified by literature search and selected based on predefined quality parameters, including a prospective design, sample size and reference standard. A total of 68 publications were chosen. RESULTS: Ultrasonography is an accurate technique for diagnosis of suspected CD and for evaluation of disease activity (sensitivity 0.84, specificity 0.92), is widely available and non-invasive, but its accuracy is lower for disease proximal to the terminal ileum. MRI has a high diagnostic accuracy for the diagnosis of suspected CD and for evaluation of disease extension and activity (sensitivity 0.93, specificity 0.90), and is less dependent on the examiner and disease location compared with US. CT has a similar accuracy to MRI for assessment of disease extension and activity. The three techniques have a high accuracy for identification of fistulas, abscesses and stenosis (sensitivities and specificities >0.80), although US has false positive results for abscesses. As a result of the lack of radiation, US or MRI should be preferred over CT, particularly in young patients. CONCLUSIONS: Cross-sectional imaging techniques have a high accuracy for evaluation of suspected and established CD, reliably measure disease severity and complications; they may offer the possibility to monitor disease progression.

[Update on the use of contrast agents in ultrasonography: a review of the clinical guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB)]. / Actualización del uso de contrastes en ecografía. Revisión de las guías clínicas de la Federación Europea de Ecografía (EFSUMB).

The aim of this article is to review the current indications for the use of contrast agents in ultrasonography in imaging departments with reference to the guidelines and recommendations recently published by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). The article begins with a brief description of currently available contrast agents, of their adverse effects and contraindications, and of the specific techniques that enable the signal emitted from the microbubbles in the contrast to be detected. Next, we review the indications for ultrasound contrast agents both in the liver (detecting and characterizing focal lesions as well as guiding and monitoring percutaneous treatments) and outside the liver (in the kidney, vesicoureteral reflux, pancreas, traumatisms, and cerebral circulation). For each of the indications, first we describe the interpretation of the findings, then the recommended uses, and finally the limitations of the technique. Finally, we review all the other applications that have yet to be included in the EFSUMB guidelines.

[Ultrasound and CT study of duodenal pathology]. / Ecografía y tomografía computarizada de la patología duodenal.

The radiological evaluation of the duodenum has traditionally been based on barium transit studies; however, ultrasound (US) and computed tomography (CT) are becoming more important in the assessment of this portion of the intestine and the structures that surround it. This report describes and illustrates the CT and US findings for different entities that affect the duodenum, including diseases of the duodenum itself and those of neighboring organs that affect this portion of the small intestine. We classify the pathologies by etiology into congenital, traumatic, iatrogenic and foreign bodies, bezoars, hematologic, inflammatory and neoplastic. Moreover, we present the incidental duodenal and periduodenal findings in US and CT that radiologists should be familiar with given the widespread use of these techniques.

Pancreatic pseudotumor in Meckel diverticulum.

This report describes the ultrasonic appearance of an ectopic pancreatic rest presenting as a mass within an intussusception due to an inverted Meckel diverticulum. Familiarity with the ultrasound appearance of this entity may be useful to obviate unnecessary imaging workup.

Appendicular involvement in perforated sigmoid disease: US and CT findings.

We describe four patients in whom ultrasound (US) and/or computed tomography (CT) demonstrated a thickened appendix, secondarily enlarged due to perforated sigmoid diverticulitis (n = 2) or carcinoma (n = 2). The underlying pathology was correctly recognized in all cases. Secondary thickening of the appendix due to perforated sigmoid disease provides a potential pitfall mainly on US and may lead to an incorrect diagnosis and thus to unnecessary surgery or a wrong surgical intervention. Although US alone is enough to diagnose periappendicitis and sigmoid disease, combined use of US and CT may improve assessment of its origin and extension.

Gastrointestinal bezoars: sonographic and CT characteristics.

OBJECTIVE: The purpose of this study was to assess the value of imaging studies--conventional abdominal radiographs, sonography, and CT--in the diagnosis of gastrointestinal bezoars. METHODS AND METHODS: A review was made of the radiologic findings of 17 consecutive patients with surgically verified gastrointestinal bezoars over a period of 51 months. RESULTS: Twelve patients had a history of previous gastric surgery. In no patient was a bezoar clinically suspected. Phytobezoars were recorded in 16 patients and a trichobezoar in only one. A total of 33 bezoars were identified at surgery. Two patients had isolated gastric bezoars, whereas 15 patients had bezoars located in the small bowel. Among the latter group, associated gastric bezoars were found in eight patients, and five patients had multiple intestinal bezoars. Abdominal radiographs revealed bezoars in three patients, sonography revealed bezoars in 15, and CT revealed bezoars in all 17. Seven patients had associated gastric bezoars revealed at CT versus only two patients with gastric bezoars revealed at sonography. CT revealed multiple intestinal bezoars in five patients whereas sonography revealed them in only two patients. CONCLUSION: Both sonography and CT are reliable methods for diagnosing gastrointestinal bezoars. CT is more accurate, however, and exhibits a quite characteristic bezoar image; in addition, this imaging technique is able to reveal the presence of additional gastrointestinal bezoars.

Primary epiploic appendagitis: US and CT findings.

A retrospective review is presented of seven cases of epiploic appendagitis, with surgical confirmation in one case. The main clinico-analytical data and the US and CT findings are described, as well as the histopathologic features in the sole case that underwent surgical resection. We also calculated the frequency of this entity in patients undergoing emergency abdominal US on clinical suspicion of diverticulitis. In all seven cases the clinico-analytical evidence was nonspecific (localized acute abdominal pain and slight leukocytosis), mimicking in six cases the clinical presentation of sigmoid diverticulitis and in one case that of acute appendicitis. US imaging findings were characteristic: a hyperechoic mass localized under the point of maximum pain, adjacent to the anterior peritoneal wall and fixed during deep breathing. In none of the cases did color Doppler US show flow. CT findings were also typical and showed a mass with a peripheral hyperattenuated rim surrounding an area of fatty attenuation. Overall 7.1 % of patients investigated to exclude sigmoid diverticulitis finally showed findings of primary epiploic appendagitis. Primary epiploic appendagitis thus shows characteristic US and CT findings that allow its diagnosis and follow-up. This entity is much more frequent than previously reported, especially in patients referred for US to exclude sigmoid diverticulitis.