Contrast enhanced endoscopic ultrasound in the diagnosis of pancreatic metastases.

AIM: Less than 5% of pancreatic masses represent metastases and differentiation from primitive tumors using endo-scopic ultrasound (EUS) is difficult. The aim of our work was to assess the diagnostic value of contrast-enhanced harmonic endoscopic ultrasound (CH-EUS) for pancreatic metastases. MATERIAL AND METHODS: We retrospectively analyzed patients with pancreatic metastasis identified during a 8 year period in a tertiary medical center. RESULTS: We included in the study 20 patients evaluated with EUS and CH-EUS. The primary tumor was localized in the kidney (6 cases), lung (5 cases), colon (3 cases), skin (2 patients) and stomach, breast, ovary and liver (1 patient each). Only 11 patients (55%) (kidney, lung, liver, ovary or skin metastases), presented hypervascularity at EUS and arterial hyperenhancement on CH-EUS, with similar diag-nostic value. All renal metastases were hyperenhanced (the negative predictive value 100%) and the stomach, colon and ovary metastases were hypoenhanced. The fast wash-out of contrast substance was encountered in all cases or renal, pulmonary and digestive metastases, but with 53.3-64.3% specificity for the different origin of pancreatic metastases. CONCLUSIONS: The vascularity assessments on conventional EUS or CH-EUS are similar for pancreatic metastases of different origin. EUS tissue acquisition remains mandatory for the diagnosis.

Endoscopic management of enteral tubes in adult patients - Part 2: Peri- and post-procedural management. European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

ESGE recommends the "pull" technique as the standard method for percutaneous endoscopic gastrostomy (PEG) placement.Strong recommendation, low quality evidence.ESGE recommends the direct percutaneous introducer ("push") technique for PEG placement in cases where the "pull" method is contraindicated, for example in severe esophageal stenosis or in patients with head and neck cancer (HNC) or esophageal cancer.Strong recommendation, low quality evidence.ESGE recommends the intravenous administration of a prophylactic single dose of a beta-lactam antibiotic (or appropriate alternative antibiotic, in the case of allergy) to decrease the risk of post-procedural wound infection.Strong recommendation, moderate quality evidence.ESGE recommends that inadvertent insertion of a nasogastric tube (NGT) into the respiratory tract should be considered a serious but avoidable adverse event (AE).Strong recommendation, low quality evidence.ESGE recommends that each institution should have a dedicated protocol to confirm correct positioning of NGTs placed "blindly" at the patient's bedside; this should include: radiography, pH testing of the aspirate, and end-tidal carbon dioxide monitoring, but not auscultation alone.Strong recommendation, low quality evidence.ESGE recommends confirmation of correct NGT placement by radiography in high-risk patients (intensive care unit [ICU] patients or those with altered consciousness or absent gag/cough reflex).Strong recommendation, low quality evidence.ESGE recommends that EN may be started within 3 - 4 hours after uncomplicated placement of a PEG or PEG-J.Strong recommendation, high quality evidence.ESGE recommends that daily tube mobilization (pushing inward) along with a loose position of the external PEG bumper (1 - 2 cm from the abdominal wall) could mitigate the risk of development of buried bumper syndrome.Strong recommendation, low quality evidence.

Endoscopic management of enteral tubes in adult patients - Part 1: Definitions and indications. European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

ESGE recommends considering the following indications for enteral tube insertion: (i) clinical conditions that make oral intake impossible (neurological conditions, obstructive causes); (ii) acute and/or chronic diseases that result in a catabolic state where oral intake becomes insufficient; and (iii) chronic small-bowel obstruction requiring a decompression gastrostomy.Strong recommendation, low quality evidence.ESGE recommends the use of temporary feeding tubes placed through a natural orifice (either nostril) in patients expected to require enteral nutrition (EN) for less than 4 weeks. If it is anticipated that EN will be required for more than 4 weeks, percutaneous access should be considered, depending on the clinical setting.Strong recommendation, low quality evidence.ESGE recommends the gastric route as the primary option in patients in need of EN support. Only in patients with altered/unfavorable gastric anatomy (e. g. after previous surgery), impaired gastric emptying, intolerance to gastric feeding, or with a high risk of aspiration, should the jejunal route be chosen.Strong recommendation, moderate quality evidence.ESGE suggests that recent gastrointestinal (GI) bleeding due to peptic ulcer disease with risk of rebleeding should be considered to be a relative contraindication to percutaneous enteral access procedures, as should hemodynamic or respiratory instability.Weak recommendation, low quality evidence.ESGE suggests that the presence of ascites and ventriculoperitoneal shunts should be considered to be additional risk factors for infection and, therefore, further preventive precautions must be taken in these cases.Weak recommendation, low quality evidence.ESGE recommends that percutaneous tube placement (percutaneous endoscopic gastrostomy [PEG], percutaneous endoscopic gastrostomy with jejunal extension [PEG-J], or direct percutaneous endoscopic jejunostomy [D-PEJ]) should be considered to be a procedure with high hemorrhagic risk, and that in order to reduce this risk, specific guidelines for antiplatelet or anticoagulant use should be followed strictly.Strong recommendation, low quality evidence.ESGE recommends refraining from PEG placement in patients with advanced dementia.Strong recommendation, low quality evidence.ESGE recommends refraining from PEG placement in patients with a life expectancy shorter than 30 days.Strong recommendation, low quality evidence*.

Epidermal Growth Factor Receptor and Its Role in Pancreatic Cancer Treatment Mediated by Nanoparticles.

Pancreatic adenocarcinoma (PDAC) is a disease with a high incidence and a dreary prognosis. Its lack of symptomatology and late diagnosis contribute to the dearth and inefficiency of therapeutic schemes. Studies show that overexpressed epidermal growth factor receptor (EGFR) is a common occurrence, linking this to the progression of pancreatic cancer, although the association between its expression and the survival rate is rather controversial. EGFR-targeted therapy has not shown the results expected, leaving at hand more questions than answers; clearly, there is a need for a better understanding of the molecular pathways involved. Nanoparticles have been used in trying to improve the efficacy of antitumor treatment; thus, using EGFR's ligand, EGF, for nanoconjugation, showed promising results in increasing the cellular uptake mechanisms and apoptosis of the targeted cells.

Nanotechnology in metastatic cancer treatment: Current Achievements and Future Research Trends.

The systemic spread of malignant cells from a primary site, a process termed metastasis represents a global challenge in cancer treatment. There is a real need to develop novel therapy strategies and nanomedicine may have remarkable and valuable contribution through specific and selective delivery of chemotherapeutic agents, through its intrinsic cytotoxic activity or through imaging applications, appealing also in the context of cancer personalized therapy. This review is focused on the applications of nanoparticles in the treatment of metastatic cancer, particularly on the possible effect on cell stabilization, growth inhibition, eventual interaction with adhesion molecules and antiangiogenic effect.

Laser thermal ablation of multidrug-resistant bacteria using functionalized gold nanoparticles.

The issue of multidrug resistance (MDR) has become an increasing threat to public health. One alternative strategy against MDR bacteria would be to construct therapeutic vectors capable of physically damaging these microorganisms. Gold nanoparticles hold great promise for the development of such therapeutic agents, since the nanoparticles exhibit impressive properties, of which the most important is the ability to convert light into heat. This property has scientific significance since is exploited to develop nano-photothermal vectors to destroy bacteria at a molecular level. The present paper summarizes the latest advancements in the field of nanotargeted laser hyperthermia of MDR bacteria mediated by gold nanoparticles.

Maximizing the endosonography: The role of contrast harmonics, elastography and confocal endomicroscopy.

New technologies in endoscopic ultrasound (EUS) evaluation have been developed because of the need to improve the EUS and EUS-fine needle aspiration (EUS-FNA) diagnostic rate. This paper reviews the principle, indications, main literature results, limitations and future expectations for each of the methods presented. Contrast-enhanced harmonic EUS uses a low mechanical index and highlights slow-flow vascularization. This technique is useful for differentiating solid and cystic pancreatic lesions and assessing biliary neoplasms, submucosal neoplasms and lymph nodes. It is also useful for the discrimination of pancreatic masses based on their qualitative patterns; however, the quantitative assessment needs to be improved. The detection of small solid lesions is better, and the EUS-FNA guidance needs further research. The differentiation of cystic lesions of the pancreas and the identification of the associated malignancy features represent the main indications. Elastography is used to assess tissue hardness based on the measurement of elasticity. Despite its low negative predictive value, elastography might rule out the diagnosis of malignancy for pancreatic masses. Needle confocal laser endomicroscopy offers useful information about cystic lesions of the pancreas and is still under evaluation for use with solid pancreatic lesions of lymph nodes.

Selective ex vivo photothermal nano-therapy of solid liver tumors mediated by albumin conjugated gold nanoparticles.

We have used albumin (BSA) bound to gold nanoparticles (GNPs) as active vectors to target liver cells. Our incentive to develop an original model of living liver cancer sprang from the ethical drawbacks that hindered the assessment of the selective character and the therapeutic capacity of these nano-biosystems in cancer patients. Ex vivo-perfused liver specimens were obtained from hepatocellular carcinoma patients similarly to the surgical technique of transplantation. Albumin bound to GNPs was inoculated intra-arterially onto the resulting specimen and determined the specific delivery of the nano-bioconjugate into the malignant tissue by means of the capillary bed. The extent of necrosis was considerable following laser therapy and at the same time surrounding parenchyma was not seriously affected. The selective photothermal ablation of the malignant liver tissue was obtained after the selective accumulation of BSA bound to GNPs into tumor cells following ex-vivo intra-vascular perfusion.

Selective in vitro photothermal nano-therapy of MRSA infections mediated by IgG conjugated gold nanoparticles.

There are serious systemic infections associated with methicillin-resistant Staphylococcus aureus (MRSA) and several other types of bacteria leading to the deaths of millions of people globally. This type of mortality is generally caused by the increasing number of antibiotic-resistant organisms, a consequence of evolution via natural selection. After the synthesis of gold nanoparticles (GNPs) by wet chemistry, bio-functionalization with IgG molecules was performed. Following administration of IgG-GNPs to MRSA cultures at various concentrations and various incubation time laser irradiation was performed. To assess the selectivity and specificity of the proposed treatment the following methods were used: flow cytometry, contrast phase microscopy, and by fluorescence microscopy. The results in our study indicate that following administration of IgG-GNPs biomolecule an extended and selective bacterial death occurs following laser irradiation in a dose dependent manner. Therefore, the new findings might impel studies on these antibacterial nanomaterials and their biological and medical applications.

Selective Laser Ablation of Methicillin-Resistant Staphylococcus Aureus with IgG Functionalized Multi-Walled Carbon Nanotubes.

Severe infections caused by Methicillin-resistant Staphylococcus aureus (MRSA) and other bacteria are responsible for millions of deaths each year. One of the main objectives of future antibiotic strategies is to develop new anti-infective agents, which would be highly effective and drug-resistant (antimicrobial resistance being currently exhibited by MRSA), using specific antibodies conjugated to thermally active nanomaterials such as NIR-responsive photothermal contrast agents. Multi-walled carbon nanotubes (MWCNTs) covalently functionalized with immunoglobulin G (IgG, an antagonist of Staphylococcal protein A-SpA, which is a MRSA membrane associated protein) were selectively delivered (at various concentrations and incubation times) into MRSA bacteria. Following treatment, cultures were irradiated using an 808 nm 2 w laser diode. The post irradiation death rate ranged from 39.6% (for 1 mg/L) to 79.2% (for 50 mg/L) at 60 seconds (p < 0.001), while at 30 minutes, the death rate increased from 45.2% (1 mg/L) to 85.72% (50 mg/L), p < 0.001. Irradiated MRSAs treated with MWCNTs alone (control) for 60 seconds and 30 minutes, at concentrations ranging from 1 mg/L to 50 mg/L, resulted in significantly lower death rates (7.1-34.1% for 60 seconds, 11.7-48.8% for 30 minutes). Using IgG molecules bound to MWCNTs, followed by laser irradiation, we obtained a very efficacious nanoshell-mediated laser therapy of individual MRSA agents providing highly localized killing effects for IgG-MWCNTs targeted bacteria.

Advances in cancer research using gold nanoparticles mediated photothermal ablation.

Recent research suggests that nanotechnologies may lead to the development of novel cancer treatment. Gold nanoparticles with their unique physical and chemical properties hold great hopes for the development of thermal-based therapies against human malignancies. This review will focus on various strategies that have been developed to use gold nanoparticles as photothermal agents against human cancers.

Photothermal treatment of liver cancer with albumin-conjugated gold nanoparticles initiates Golgi Apparatus-ER dysfunction and caspase-3 apoptotic pathway activation by selective targeting of Gp60 receptor.

We present a method of enhanced laser thermal ablation of HepG2 cells based on a simple gold nanoparticle (GNP) carrier system such as serum albumin (Alb), and demonstrate its selective therapeutic efficacy compared with normal hepatocyte cells. HepG2 or hepatocytes were treated with Alb-GNPs at various concentrations and various incubation times, and further irradiated using a 2 W, 808 nm laser. Darkfield microscopy and immunochemical staining was used to demonstrate the selective internalization of Alb-GNPs inside the HepG2 cells via Gp60 receptors targeting. The postirradiation apoptotic rate of HepG2 cells treated with Alb-GNPs ranged from 25.8% (for 5 µg/mL) to 48.2% (for 50 µg/mL) at 60 seconds, while at 30 minutes the necrotic rate increased from 35.7% (5 µg/mL) to 52.3% (50 µg/mL), P-value <0.001. Significantly lower necrotic rates were obtained when human hepatocytes were treated with Alb-GNPs in a similar manner. We also showed by means of immunocytochemistry that photothermal treatment of Alb-conjugated GNPs in liver cancer initiates Golgi apparatus-endoplasmic reticulum dysfunction with consequent caspase-3 apoptotic pathway activation and cellular apoptosis. The presented results may become a new method of treating cancer cells by selective therapeutic vectors using nanolocalized thermal ablation by laser heating.

Gold nanoparticles conjugated with cisplatin/doxorubicin/capecitabine lower the chemoresistance of hepatocellular carcinoma-derived cancer cells.

BACKGROUND AND AIMS: The aim of the current study was to evaluate in vitro the anti-tumor efficacy of gold nanoparticles (GNPs) conjugated with conventional chemotherapy drugs for the treatment of liver cancer. This approach based on gold proposes a novel platform therapy with minimal toxicity and increased efficacy profiles for the destruction of hepatic cancer cells. METHODS: GNPs, stabilized with a monolayer of L-aspartate and additional cytostatic drugs, were successfully used as a complex tumor-targeting drug-delivery system. The drugs (doxorubicin, cisplatin, and capecitabine) were non-covalently conjugated onto the hydrophilic assemblies of GNPs-L-Aspartate nanostructure. Transmission electron microscopy was used to characterize the morphological and structural properties of these drug-metallic nanostructures. RESULTS: The cellular proliferation rates in the presence of the anti-cancer drugs delivered by the GNPs were found to be statistically lower than those of cells exposed to the cytostatic drugs alone, indicating that GNPs facilitated an increased susceptibility of cancer cells to cisplatin, doxorubicin, and capecitabine plus ribavirin. CONCLUSION: This approach could offer a new chemotherapy strategy for patients diagnosed with unresectable hepatocellular carcinoma (HCC).

Arsenic trioxide plus cisplatin/interferon α-2b/doxorubicin/capecitabine combination chemotherapy for unresectable hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: The failure of existing treatments for liver cancer has recently been attributed to the existence of cancer stem cells, which are difficult to kill using current drugs due to their chemoresistant properties as well as their ability to stimulate neoangiogenesis. The aim of the current study was to evaluate in vitro the antitumor efficacy of arsenic trioxide in combination with conventional chemotherapy, as proposed by the concept of "differentiation therapy" in anticancer research. MATERIALS AND METHODS: Cancer stem cells showed enhanced chemoresistance to cancer drugs (carboplatin and doxorubicin) and had the ability to exclude rhodamine 123 dye, proving the existence of the multidrug resistance efflux pump. Arsenic trioxide was added prior to a tyrosine kinase inhibitor or to a slightly modified PIAF regimen with capecitabine replacing 5-fluorouracil. We also compared both cancer and normal stem cell lines with the hepG2 non-stem liver cancer cell line to investigate the differences between differentiated and more anaplastic cells. Molecular characterization (immunocytochemistry and RT-PCR analysis) of all the cell lines was carried out. RESULTS: Initially, the cells had a high proliferative potential, even when cultured in a medium supplemented with cytostatics, eliminated rhodamine 123 immediately in culture and also formed spheroids in suspension. The molecular characterization showed the expression of albumin, α1-antitrypsin, α-fetoprotein, citokeratin-18, telomerase, CD90 and CD133. Low concentrations of arsenic trioxide lead to morphologic differentiation and differentiation-associated cytochemical features, like increased sensitivity to cytostatic drugs. CONCLUSION: Our study suggests that arsenic trioxide sensitizes liver stem-like cancer cells to conventional chemotherapy. Still, further studies on animal models will be needed before we implement this idea in human clinical trials.

Endoscopic submucosal dissection of superficial digestive tumors after evaluation through magnification chromoendoscopy and endoscopic ultrasound with miniprobes. Report of three cases.

Magnification chromoendoscopy (MCE) and miniprobes are able to select the tumors suitable for curative endoscopic treatment. Endoscopic submucosal dissection (ESD) is a new endoscopic technique that has a higher complete resection rate and a very low recurrence rate. We present three cases of superficial epithelial digestive tumors that were first evaluated with MCE and miniprobes before being treated by ESD. A complete one-fragment resection was performed with no major complications in all cases.

Stem-like cells in colorectal oncology.

Although the treatment for colorectal cancer has seen considerable progress during the past few years, the mortality associated with this type of tumor remains high. This article presents the existing methods of treatment, focusing on the new treatments made possible by the advances in the field of normal and tumor stem cells. Starting from the normal architecture of the colon and the properties of the cells identified in it, we sought to present a few notions concerning these cells which have a direct relevance for both pathology and treatment. The manner in which they divide (symmetrically or asymmetrically) as well as the molecules which control their circulation through the body are just a few examples which are likely to influence the treatment of colorectal cancer in the future.

Endoscopic therapy of Barrett's esophagus and esophageal adenocarcinoma.

The normal squamous esophageal epithelium reacts as a chronic inflammation to the severe gastro-esophageal reflux. Esophagitis will progress to Barrett metaplasia in 10% of patients who would be of minor clinical interest if it then did not advance to low, high grade dysplasia and invasive carcinoma. The rise of esophageal adenocarcinoma (EAC) incidence surpasses any other cancer, including melanoma, lymphoma and small cell lung cancer. There is no clear proof that medical therapy could prevent the neoplastic progression. It seems that this population has a variable answer to proton pump inhibitors therapy. A multimodal approach of Barrett's esophagus with high grade dysplasia is required, including endoscopic mucosal resection, photodynamic therapy and thermal ablation. Photodynamic therapy could be used for the management of patients with high grade dysplasia, early EAC, local recurrence post radical therapy, microscopic involvement of tumor borders post radical resection, patient unfit / unwilling to undergo surgery. The palliation of non-resectable EAC by stenting represents the first choice. The correction of the malignant esophageal obstruction improves the symptomatology and life quality, but not survival. Because of the dismal prognosis and the frequent treatment failure of conventional treatment strategies, it seems reasonable to look for new palliative strategies.

Isolation and characterization of hepatic cancer cells with stem-like properties from hepatocellular carcinoma.

BACKGROUND & AIMS: Major burdens in the treatment of hepatocellular carcinoma (HCC) are the high percentage of recurrence and resistance to chemotherapy. Hepatic cancer stem cells provide a reservoir of cells that can self-renew, maintain the tumor by generating differentiated non-stem cells which make up the bulk of the tumor and are responsible for recurrence after ablative surgery and chemoradiotherapy. The objective of this study was to identify and characterize a self-renewing subpopulation of human liver tumor cells with a distinctive genetic profile that adds the capacity to proliferate despite chemotherapy and promotes cancer recurrence. METHODS: Stemness properties of tumor cells isolated from a HCC biopsy were established by their capacity to form spheroids and by cell proliferation assays. The cells also showed enhanced chemoresistance to cancer drugs. The up-regulation of stem cell markers is proven by immunocytochemistry stainings and reverse transcription-PCR. RESULTS: Cells had a high proliferative potential, even when cultured in medium supplemented with doxorubicin and carboplatin, eliminated Rhodamine 123 immediately in culture and also formed spheroids in suspension. Molecular diagnosis techniques showed that cells expressed the stem cell markers Oct 3/4 and CXCR4. Cells were also positive for CD133 and CD90 cancer stem cell specific markers, with monoclonal antibody staining. CONCLUSION: The unique characteristics identified in cancer stem cells explain self-renewal and could drive metastasis in patients that have received treatment for cancer. The identification and cloning of such cells can aid in developing of better therapeutic approaches for patients with HCC, as chemosensitive pretherapeutic assays or targeted therapies.

Intraductal ultrasonography for the assessment of preoperative biliary and pancreatic strictures.

Diseases of the biliary and pancreatic ducts are often difficult to diagnose. Although transcutaneous ultrasonography, computer tomography and magnetic resonance greatly improved in performance, two major problems have not been completely solved yet: first, the differentiation of malignant and benign bile duct strictures, and, second, the assessment of the resectability of carcinomas underlying biliary strictures. Ultrasound probes can be inserted through the working channel of the duodenoscope and passed selectively both into the biliary and pancreatic ducts. Ultrasound frequencies of 20 or 30 MHz enable a penetration of up to 2 cm and a resolution of 0.07 to 0.18 mm. The main clinical indication for intraductal ultrasonography of the biliary tract is obstructive jaundice, which requires assessment of bile duct strictures and local tumor staging. Miniprobes can contribute to the differential diagnosis of strictures localized in the main pancreatic duct, and also to localizing small endocrine tumors. Small tumors of the papilla of Vater can be staged before a possible endoscopic resection. Feasibility of the method is excellent in expert hands with almost no added morbidity.