The successful management of a Bronchoesophageal fistula after lung transplantation: a case report

We describe an unprecedented, disastrous complication after bilateral lung transplantation (BLT), a bilateral bronchial dehiscence with a right bronchoesophageal fistula leading to life‐threatening septic shock. We also report the successful endoscopic management of this complication by double stenting and stress the efficacy of the multidisciplinary approach to this critical case.     

Biphasic Diurnal Periodicity in Bleeding from Peptic Ulcer

Objective : To evaluate if tbere was periodicity in the manifestations of gastrointestinal bleeding (hemateme-sis and melena). Method : This is a multicenter prospective study carried out in the Endoscopy Units of eight hospitals. At the time of the emergency endoscopy, the following data were collected: age, sex, endoscopic diagnosis, solar hour of the first hematemesis (vomiting of bright red or tarry black material) and of the first melena (black or bloody soft stools), and any drugs taken during the week before the bleeding episode, regardless of the dose. Results : 806 patients were studied. Bleeding was from peptic ulcer in 405 patients (50%), from esophageal varices in 197 (24%), and from other sources in the remainder. Analysis using single cosinor statistics showed a nonrandom distribution in bleeding from peptic ulcer, whether presenting first with hematemesis (p = 0.02) or melena (p = 0.03). There were two peaks at 6:45 AM and 6:45 PM for hemate-mesis and at 7:25 AM and 7:25 PM for melena, representing a biphasic diurnal (ultradian) rhythm. Conclusions : This study shows that bleeding due to peptic ulcer has a biphasic diurnal periodicity. 1 his has potential importance for the pathogenesis of bleeding, for the management of gastrointestinal hemorrhage and the administration of drugs known to cause peptic ulcer bleeding.     

Biological and clinical relevance of matrix metalloproteinases 2 and 9 in acute myeloid leukaemias and myelodysplastic syndromes

We analysed by immunocytochemistry metalloproteinase (MMP)-2 and MMP-9 expression in bone marrow cells from 54 acute myeloid leukaemia (AML) patients, 153 myelodysplastic syndrome (MDS) patients, and 52 non-haemopathic subjects, in order to evaluate whether MMP expression abnormalities were associated with relevant laboratory or clinical findings. In normal samples MMP-2 was detected in rare myeloid cells, MMP-9 in most maturing myeloid cells. In MDS MMP-2 myeloid levels were higher than in controls (P < 0.0001); MMP-2 and MMP-9 were often co-expressed. Also many erythroblasts expressed MMP-2. There was a positive correlation between MMP-2 erythroblast expression and erythroid dysplasia (P = 0.002) and an inverse correlation between MMP-2 or MMP-9 myeloid expression and blast cell percentage (P = 0.05 and P = 0.04 respectively). High MMP levels in myeloid cells were associated with longer overall survival (P = 0.03) and evolution-free survival (P = 0.04). In AML MMP-2 levels were lower than in MDS (P < 0.0001) and MMP-9 levels lower than in MDS and controls (P < 0.0001). MMP levels did not predict response to therapy. The release of active MMPs was detected by colorimetric analysis in cell cultures from representative MDS and AML cases. In conclusion, we have demonstrated an abnormal MMP expression in AML as well as in MDS. The production and release of these enzymes may influence haematopoietic cell behaviour. In MDS, the detection of MMP deregulated expression may be important also from the clinical point of view: it may provide a useful tool for diagnosis, prognosis and a possible target for experimental treatments.     

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.A long-term goal in contemporary cancer nanomedicine has been to design and generate drug delivery systems that improve the narrow therapeutic window associated with conventional chemotherapeutics (1, 2). Conceptually, several nanotechnology-based entity candidates, including protocells (3), biosynthetic nanoparticles (NPs), viruses, and liposome-based nanoparticles, could be targeted for active delivery through a defined cell surface ligand receptor system and/or physically triggered for finely tuned cargo release (2, 4, 5).Numerous efforts have been made to functionalize NPs by combining them with antibodies, aptamers, peptides, vitamins, or carbohydrates (6–8), but the majority of studies involve untargeted nanoplatforms (4, 9). In practice, targeting NPs is far from trivial, and ongoing challenges include synthesis and purification, selection of an appropriate ligand receptor, and specific composition for NP conjugation. Even the conjugation reaction itself may alter the binding of the tumor-targeting moiety to its receptor through conformational changes, steric freedom restriction, or orientation distortion (10, 11). Unfortunately, the cost-to-benefit ratio of these modifications often elevate the complexity of the NP synthesis, complicating regulatory hurdles because of formulations that are heterogeneous or difficult to reproduce (10, 12, 13).To minimize such drawbacks, NPs can be functionalized via virus-based nanoplatforms as an alternative for targeted cargo delivery (14–16). In particular, filamentous bacteriophage (phage)—a prokaryotic virus—is an attractive candidate to develop a bionanomedicine for cancer therapeutics because phage particles are cost-effectively produced with biological uniformity, as well as being physically robust and stable under harsh conditions (17). Notably, phage-based nanoplatforms are biocompatible and nonpathogenic with eukaryotic organisms and are able to preserve the desired cell targeting and internalization (18). Moreover, phage particles are ideal for incorporating other NPs, which can be released after reaching the tumor site. An admixture of colloidal gold NP (AuNP) with phage particles spontaneously organizes into hydrogel network-like fractal structures (19, 20). These hydrogel networks offer convenient multifunctional integration within a single entity for tumor targeting, enhanced fluorescence and dark-field microscopy, near-infrared (NIR) photon-to-heat conversion, and surface-enhanced Raman scattering (SERS)-based detection (20, 21).In the present work, we developed a tumor targeting theranostic (meaning a combination of therapeutics and diagnostics) hydrogel-based nanoplatform that enables ligand-directed tumor targeting, multimodal imaging capability, and triggered therapeutic cargo release. Our data suggest that targeted hydrogel photothermal therapy represents a functional theranostic approach (fostering “see and treat, treat and see”) in the diagnosis and management of tumors.     

Comparison between the two systems to evaluate the appropriateness of endoscopy of the upper digestive tract

OBJECTIVES: The aim of this study was to compare the diagnostic performance of the two systems for the evaluation of the appropriateness of upper digestive endoscopy suggested by the American Society of Gastrointestinal Endoscopy (ASGE) and by the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE). METHODS: Patients referred for the upper digestive endoscopy (EGD) to a University Outpatients Clinic of Northeastern Italy were consecutively included in this prospective observational study. Before the EGD, the endoscopist assigned the patients to one of the ASGE appropriateness classes; another endoscopist then identified the detailed clinical scenario for the patients, which corresponds to scenarios examined by EPAGE by using a nine-point scale: 1-3 inappropriate; 4-6 uncertain; and 7-9 appropriate. The relationship between the appropriateness of use and the presence of relevant endoscopic lesions (neoplasms, ulcers, esophagitis, erosive gastritis/duodenitis, stenosis, and varices) was assessed, calculating the sensitivity and the specificity for each of the ASGE criteria, and each of the EPAGE scores, and plotting them to form a receiver operating characteristic (ROC) curve. The area under the ROC curve (AUC) provides a summary measure of test performance, and can vary from a minimum of 0.5 to a maximum of 1.0. We compared the AUC of the ROC curve derived from the ASGE criteria against that derived from the EPAGE criteria. RESULTS: A total of 2,300 consecutive patients were included in the study (42% men; mean age: 57.3; range: 12-99); comparison of appropriateness criteria according to the ASGE and EPAGE could be made for 2,000 patients. The AUC of the ROC curve derived from the ASGE criteria was 0.553 (95% CI: 0.527-0.579), significantly higher than the AUC of the ROC curve derived from the EPAGE score: 0.523 (95% CI: 0.497-0.549; p < 0.05). CONCLUSIONS: We suggest that the diagnostic yield for relevant endoscopic findings obtained by both the systems (ASGE and EPAGE) is low; slightly better results could be accomplished by the ASGE criteria.     

Left ventricular mass regression in the LIFE study: effect of previous antihypertensive treatment

BACKGROUND: Whether to include only those patients who have not had prior hypertension treatment in clinical trials of left ventricular (LV) mass reduction is controversial. Accordingly, our aim was to study the relationship between prior treatment and both baseline and 1-year echocardiographic LV mass in subjects enrolled in the Losartan Intervention For Endpoint reduction (LIFE) study. METHODS: We studied clinical and baseline echocardiographic data on 960 patients with electrocardiographically confirmed left ventricular hypertrophy enrolled in the electrocardiographic substudy of the LIFE study, 847 of whom had LV mass remeasured after 1 year of blinded treatment. The majority (75%) of these patients had prior medical treatment for hypertension. RESULTS: In multivariable regression analysis, controlling for age, sex, blood pressure (BP), body mass index, and indices of pump and myocardial function, prior antihypertensive treatment was not associated with either greater LV mass or relative wall thickness on the baseline study. Moreover, there was no significant difference between the 637 subjects who were previously treated and the 210 who were not treated with regard to the mean reduction in systolic or diastolic pressures (-25 +/- 17 v -24 +/- -16 and -13 +/- 9 mm Hg v -12 +/- 9 mm Hg), LV mass (-27 +/- 38 v -29 +/- 34 g), or LV mass/body surface area (-14 +/- 20 v -15 +/- 18 g/m(2)), all P >.05. CONCLUSIONS: Prior treatment is not associated with either greater LV mass or greater relative wall thickness when age, body mass index, sex, systolic BP, heart rate, or indices of LV volume load and systolic function are taken into account. In addition, prior treatment is not associated with lesser degrees of LV mass reduction. For design of future clinical trials, restriction of inclusion criteria to only previously untreated patients does not appear to be necessary when the selection criterion is electrocardiographically determined left ventricular hypertrophy.     

Criteria for the selective use of contrast-enhanced intra-operative ultrasound during surgery for colorectal liver metastases

Background

Contrast-enhanced intra-operative ultrasound (CE-IOUS) for colorectal liver metastases (CLMs) has become a part of clinical practice. Whether it should be selectively or routinely applied remains unclear. The aim of this study was to define criteria for the use of CE-IOUS.

Methods

One-hundred and twenty-seven patients underwent a hepatectomy for CLMs using IOUS and CE-IOUS. All patients underwent computed tomography (CT) and/or magnetic resonance imaging (MRI) within 2 weeks prior to surgery. The reference was histology, and imaging at 6 months after surgery. Univariate and multivariate analyses were performed. Statistical significance was set at P = 0.05.

Results

Using IOUS an additional 172 lesions in 51 patients were found. CE-IOUS found 14 additional lesions in 6 patients. Seventy-eight CLMs in 38 patients appeared within 6 months after surgery. The sensitivity, specificity, positive- and negative-predictive value were 63%, 98%, 100% and 27% for pre-operative imaging, 87%, 100%, 100% and 52% for IOUS, and 89%, 100%, 100% and 56% for IOUS+CE-IOUS, respectively. CE-IOUS allowed better tumour margin definition in 23 patients (18%), thus assisting resection. Analyses indicated that the presence of multiple (P = 0.014), and isoechoic CLMs (P = 0.049) were independently correlated with new findings at CE-IOUS.

Conclusions

Compared with IOUS, CE-IOUS improved detection and resection guidance. These additions are significant and demand its use in cases with multiple and isoechoic CLMs.