What is the role of nanotechnology in diagnosis and treatment of metastatic breast cancer? Promising scenarios for the near future

Metastatic breast cancer represents a diagnostic and therapeutic challenge due to tumor heterogeneity and to various physiological barriers that hinder drug delivery to the metastatic sites. To overcome these limitations, nanoformulated drugs have been developed and tested in preclinical studies, and few of them have been successfully translated into clinical practice. In particular, liposomal anthracyclines and nanoformulated albumin-bound paclitaxel have revealed an improved therapeutic index when compared to conventional chemotherapy, with significant reduction of drugs toxicity. Several strategies for nanoparticles engineering have more recently been explored to increase selectivity for tumor cells and to reach poorly accessible metastatic districts. Targeted nanoparticles, directed toward tumor markers and tissue-specific metastases, may provide effective devices in case of lowvascularized and small-sized metastases, thus paving the way for a real change in the natural history of metastatic disease. A number of targets have been identified and exploited for surface functionalization of different types of nanoparticles, which are currently undergoing preclinical studies. The aim of this review is to provide an overview of current nanotechnology applied to metastatic breast cancer diagnosis and treatment. Promising results encourage an upcoming translation of this research into clinical practice for an effective management of the disease in the near future

Impact of highly active antiretroviral therapy on outcome of cholecystectomy in patients with human immunodeficiency virus infection

Background: Highly active antiretroviral therapy (HAART) reduces virus proliferation and significantly decreases the rate of septic and opportunistic complications in patients infected with human immunodeficiency virus (HIV). Although surgery is performed routinely on patients receiving HAART, the effect of this treatment on surgical outcome has not been examined in detail. Methods: This retrospective study reviewed 54 consecutive patients with HIV infection who underwent surgical cholecystectomy: 31 patients were on HAART, 13 on nucleoside analogue reverse transcriptase inhibitors (NRTIs) and ten were receiving no specific therapy. Characteristics of HIV-1 infection, laboratory investigations, characteristics of the gallbladder disease, type of operation, postoperative course, morbidity and mortality were recorded. Univariable analysis and unconditional logistic regression were performed to determine factors related to postoperative complications and death. Results: The three groups were similar in terms of HIV-1 infection characteristics. In univariable analysis HAART and laparoscopic cholecystectomy were associated with a significantly lower complication rate, whereas only HAART was shown to be protective by logistic regression analysis. A low HIV RNA load and a high CD4(+) cell count were significant predictors of uncomplicated surgical outcomes. Conclusion: HAART significantly reduces the risk of complications after cholecystectomy in patients with HIV infection or acquired immune deficiency syndrome

Protein Oriented Ligation on Nanoparticles Exploiting O6-Alkylguanine-DNA Transferase (SNAP) Genetically Encoded Fusion

A bimodular genetic fusion comprising a delivery module (scFv) and a capture module (SNAP) is proposed as a novel strategy for the site-specific covalent conjugation of targeting peptides to nanoparticles. An scFv mutant selective for HER2 tumor antigen is chosen as the targeting ligand. SNAP-scFv is immobilized on magnetofluorescent nanoparticles and its targeting efficiency against HER2-positive cells is assessed by flow cytometry and immunofluorescence. Copyrigh

Plasma cholecystokinin levels after vertical banded gastroplasty : effects of an acidified meal

BACKGROUND: Although cholecystokinin (CCK) is involved in the short-term regulation of satiety, it has not been investigated in obese patients subjected to bariatric restrictive operations. METHODS: 8 morbidly obese patients (BMI 49.1 +/- 6.9), 7F and 1M, were investigated before and after vertical banded gastroplasty (VBG). 6 healthy lean volunteers served as the control group. CCK was determined (RIA) after an overnight fast and after the administration of an acidified (pH 3) liquid meal. Blood samples were taken 45 min before the meal, 5 min after it and then every 30 min for 3 hours. RESULTS: There were no differences between groups in basal CCK levels. However, the peak of CCK after the meal was significantly higher (P <0.01) in obese patients after VBG (24.9 +/- 18 pmol/l) than before VBG (9.8 +/- 6.7 pmol/l) and when compared with the control group (8.0 +/- 6.3 pmol/l).The time needed to reach the peak was longer in healthy volunteers (105 +/- 24.9 min) than in obese patients before VBG (45 +/- 40 min) and after VBG (7.5+/- 12 min) (P<0.01). CONCLUSIONS: VBG increases the peak of CCK secretion and shortens the time to reach it. These changes could contribute to the satiety effects of gastric restrictive operations

Prospective study of long-term results and prognostic factors after conservative surgery for small bowel Crohn's disease

BACKGROUND & AIMS: Several bowel-sparing techniques have been proposed for treating patients with CD, but there have been no prospective studies analyzing risk factors and long-term outcome. We prospectively evaluated safety and long-term efficacy of conservative surgery for patients with complicated CD. METHODS: From 1993-2007, 393 of 502 consecutive patients underwent surgery for complicated CD of the small bowel. Those with colonic involvement were excluded. The Student t test, chi(2) test, Kaplan-Meier estimates, and Cox proportional hazard model were used to analyze postoperative complications and long-term outcome. RESULTS: A total of 865 jejunoileal segments underwent 318 small bowel resections and 367 strictureplasties (either classic or nonconventional). There were no deaths; the complication rate was 5.6%, and the cumulative 10-year recurrence rate was 35%. None of the prognostic factors were correlated with postoperative complications. Younger age, an upper jejunoileal location, stricturing behavior, and small-bowel wall thickening 12 months after surgery showed hazard ratios of 2.4 (95% confidence interval [CI], 1-5.4; P = .03), 2.5 (95% CI, 1.3-4.7; P = .004), 2.2 (95% CI, 1.1-4.1; P = .01), and 4.5 (95% CI, 2.3-8.6; P = .000), respectively. Immunomodulator therapy failed to reduce long-term surgical recurrence. CONCLUSIONS: Young patients with extended and stricturing disease are at high risk for disease recurrence after surgery. Bowel wall thickening was a reliable prognostic factor for these patients. Conservative surgery is safe and effective in treating patients with jejunoileal CD and should be considered as the first-line surgical treatment, preventing the risk of short bowel syndrome caused by repeated resections

Alteration of elastin, collagen and their cross-links in abdominal aortic aneurysms

OBJECTIVES: although the mechanism of arterial dilation and aneurysm development has not been clarified, the degradation of elastin and collagen plays undoubtedly a critical role. We evaluated the elastin and collagen content through the detection of their cross-links in aneurysmal and non-aneurysmal abdominal aortic walls. MATERIALS AND METHODS: in 26 human abdominal aortic aneurysm specimens obtained during surgery and in 24 autopsy control samples of non-aneurysmal abdominal aorta the tissue content of elastin and collagen cross-links were measured by HPLC. Collagen was also detected by evaluating two characteristic amino acids, 4-hydroxyproline (4-hypro) with a colorimetric method and 5-hydroxylysine (5-hylys) by gas chromatography. RESULTS: significantly fewer elastin cross-links were found in aneurysm samples compared to controls (desmosines and isodesmosines: 90% reduction; p<0.01). The opposite was true for pyridinoline collagen cross-links (350% increase) and deoxypyridinolines (100% increase, p=0.01). Tissue content of 5-hylys, 4-hypro and total amino acids were reduced significantly by 50% in aneurysmal samples. CONCLUSIONS: beside confirming decreased elastin content in aneurysmal walls, these results show a concurrent increase of collagen cross-links. Since total collagen markers were decreased (decreased 4-hypro and 5-hylys) it is reasonable to suggest that in aneurysmal aortic walls old collagen accumulates cross-links while new collagen biosynthesis is somehow defective

Sentinel node biopsy in ductal carcinoma in situ of the breast: never justufied?

Sentinel lymph node biopsy for ductal carcinoma in situ (DCIS) of the breast is not standard of care. However, nodal involvement for DCIS patients is reported. Aim of our study was to identify preoperative features predictive of nodal involvement in DCIS patients. We have retrospectively reviewed 175 patients with a preoperative diagnosis of DCIS following a vacuum-assisted breast biopsy, and undergoing surgery with sentinel node biopsy. Variables distribution was compared between patients upstaged to invasive cancer at final pathology and patients with a confirmed DCIS, and between positive vs negative sentinel node patients. Univariate and multivariate analyses were performed for risk of a positive node. Lymph node biopsy was positive in 13 (7.4%) patients, with 8 (61.5%) macrometastases and 5 (38.5%) micrometastases. In these patients, Breast Imaging Reporting and Data System (BI-RADS) index &gt;4 (OR 4.69, 95% CI 1.282-17.224, P = .02), lesion extension 6520 mm (OR 4.25, 95% CI 1.255-14.447, P = .02), multifocal disease (OR 4.12, 95% CI 0.987-17.174, P = .05), comedo type (OR 3.54, 95% CI 1.044-11.969, P = .04), and upstaging (OR 4.56, 95% CI 1.080-19.249, P = .04) were all predictive of nodal involvement, although upstaging could not be predicted preoperatively. By multivariate analysis, the only independent factor predictive for positive sentinel node was multifocal disease (OR 5.14, 95% CI 1.015-26.066, P &lt; .05). A preoperative diagnosis of DCIS, also including advanced biopsy systems such as vacuum-assisted breast biopsy, may be not always sufficient to exclude patients from sentinel node biopsy. DCIS patients with associated BI-RADS &gt;4, lesion extension 6520 mm, comedo type, and above all multifocal disease should be considered for axillary evaluation

Raman analysis reveals biochemical differences in plasma of Crohn&apos;s Disease patients

Backgrounds and Aims: There is no accurate and reliable circulating biomarker to diagnose Crohn's disease [CD]. Raman spectroscopy is a relatively new approach that provides information on the biochemical composition of samples in minutes and virtually without any sample preparation. We aimed to test the use of Raman spectroscopy analysis of plasma samples as a potential diagnostic tool for CD. Methods: We analysed by Raman spectroscopy dry plasma samples obtained from 77 CD patients [CD] and 45 healthy controls [HC]. In the dataset obtained, we analysed spectra differences between CD and HC, as well as among CD patients with different disease behaviours. We also developed a method, based on principal component analysis followed by a linear discrimination analysis [PCA-LDA], for the automatic classification of individuals based on plasma spectra analysis. Results: Compared with HC, the CD spectra were characterised by less intense peaks corresponding to carotenoids [p &lt;10-4] and by more intense peaks corresponding to proteins with \u3b2-sheet secondary structure [p &lt;10-4]. Differences were also found on Raman peaks relative to lipids [p = 0.0007] and aromatic amino acids [p &lt;10-4]. The predictive model we developed was able to classify CD and HC subjects with 83.6% accuracy [sensitivity 80.0% and specificity 85.7%] and F1-score of 86.8%. Conclusions: Our results indicate that Raman spectroscopy of blood plasma can identify metabolic variations associated with CD and it could be a rapid pre-screening tool to use before further specific evaluation

Single-domain protein A-engineered magnetic nanoparticles : toward a universal strategy to site-specific labeling of antibodies for targeted detection of tumor cells

Highly monodisperse magnetite nanocrystals (MNC) were synthesized in organic media and transferred to the water phase by ultrasound-assisted ligand exchange with an iminodiacetic phosphonate. The resulting biocompatible magnetic nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, and magnetorelaxometry, indicating that this method allowed us to obtain stable particle dispersions with narrow size distribution and unusually high magnetic resonance T2 contrast power. These nanoparticles were conjugated to a newly designed recombinant monodomain protein A variant, which exhibited a convincingly strong affinity for human and rabbit IgG molecules. Owing to the nature of antibody-protein A binding, tight antibody immobilization occurred through the Fc fragment thus taking full advantage of the targeting potential of bound IgGs. If necessary, monoclonal antibodies could be removed under controlled conditions regenerating the original IgG-conjugatable MNC. As a proof of concept of the utility of our paramagnetic labeling system of human IgGs for biomedical applications, anti-HER-2 monoclonal antibody trastuzumab was immobilized on hybrid MNC (TMNC). TMNC were assessed by immunoprecipitation assay and confocal microscopy effected on HER-2-overexpressing MCF-7 breast cancer cells, demonstrating excellent recognition capability and selectivity for the target membrane receptor