Transaxillary Tri-Branch Aortic Endovascular Graft Repair of Recurrent Thoracoabdominal Aneurysm With Pararenal Aortic Occlusion.

The absence of an adequate ileo-femoral access is usually considered an absolute contraindication to fenestrated and branched aortic repairs. Alternative routes and dedicated stent-graft designs have been advocated. Hereby, we describe the case of a 73-year-old man with a recurrent type IV thoracoabdominal aortic aneurysm and complete thrombotic pararenal aortic occlusion treated successfully with a tri-branch custom-made endograft deployed via a transaxillary access.

Amphibian regeneration and mammalian cancer: Similarities and contrasts from an evolutionary biology perspective: Comparing the regenerative potential of mammalian embryos and urodeles to develop effective strategies against human cancer.

Here we review and discuss the link between regeneration capacity and tumor suppression comparing mammals (embryos versus adults) with highly regenerative vertebrates. Similar to mammal embryo morphogenesis, in amphibians (essentially newts and salamanders) the reparative process relies on a precise molecular and cellular machinery capable of sensing abnormal signals and actively reprograming or eliminating them. As the embryo's evil twin, tumor also retains common functional attributes. The immune system plays a pivotal role in maintaining a physiological balance to provide surveillance against tumor initiation or to support its initiation and progression. We speculate that susceptibility to cancer development in adult mammals may be determined by the loss of an advanced regenerative capability during evolution and believe that gaining mechanistic insights into how regenerative capacity linked to tumor suppression is postnatally lost in mammals might illuminate an as yet unrecognized route to cancer treatment.

Long-term results of treatment of infrarenal aortic aneurysms with low-profile stent grafts in a multicenter registry.

OBJECTIVE: In recent years, manufacturers have developed new stent grafts with lower profiles to increase the endovascular aneurysm repair applicability. As reported by the current European Society for Vascular Surgery guidelines, long-term evaluation of such low-profile platforms is strongly recommended. This study aims to report outcomes beyond 5 years from a multicenter registry, including a real-world cohort of patients electively treated with low-profile stent grafts. METHODS: A retrospective data collection of patients who had undergone elective implantation of low-profile endograft ≤16 Fr. (Zenith LP, Ovation, Incraft) was performed in nine centers. The primary endpoint was a long-term primary clinical success. Secondary endpoints were survival rate, freedom from abdominal aortic aneurysm (AAA)-related death, freedom from type I to III endoleak, limb patency, and freedom from all reinterventions. The Kaplan-Meier curves were stratified for investigative devices. A multivariate analysis evaluated predictors of primary clinical success and reintervention rate. RESULTS: A total of 619 patients were enrolled (Ovation, n = 373; Incraft, n = 111; and Zenith LP, n = 135), with a mean follow-up of 56.8 ± 22.8 months. The overall primary and the secondary clinical success rate at 8 years was 72.1% and 93.8%, respectively. At 8 years, overall survival was 53.2%, freedom from AAA-related death was 94.4%, freedom from reintervention was 74%, freedom from type I/III endoleak was 86.9%, and limb patency was 90.4%. A significantly worse primary clinical success of the Zenith LP was recorded as dependent on more limb-related events. No differences between platforms were registered in the rate of AAA-related deaths, open conversion, sac enlargement, and type I/III endoleaks (P = .26). Multivariate analysis identified iliac tortuosity (hazard ratio, 2.053) and Zenith LP (hazard ratio, 3.818) as significant independent predictors of clinical failure and reintervention. CONCLUSIONS: Low-profile stent grafts have acceptable long-term outcomes. Overall survival and AAA-related death were in line with those reported for traditional devices. Long-term surveillance and reintervention, when necessary, remain crucial to guarantee durability.

Nitrobenzoxadiazole derivatives of the rat selective toxicant norbormide as fluorescent probes for live cell imaging.

Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats, but relatively harmless to other rodents and mammals. As a vasoactive agent, NRB induces a species-specific vasocontractile effect that is restricted to the peripheral arteries of the rat. Despite the precise mechanisms behind this phenomenon having yet to be fully clarified, it is postulated that the molecular target of NRB could be located within the plasma membrane of rat peripheral artery myocytes (e.g. rat caudal artery myocytes). As such, the primary objective of this study was to develop a fluorescently labelled derivative of NRB to investigate its subcellular distribution/localization in both NRB-sensitive (freshly isolated rat caudal artery myocytes, FIRCAMs) and NRB-insensitive (human hepatic stellate, LX2) cells. Of the examples prepared, lead structure endo-NRB-NBD-bPA subsequently demonstrated retention of the parent toxicant's pharmacological profile (in terms of its ability to induce both a vasocontractile response in rat caudal artery rings in vitro, and a lethal end-point in rats in vivo). Endo-NRB-NBD-bPA was also shown to be significantly less permeable (an integral feature in the design of fluorescent probes targeting cell-surface receptors) to both LX2 cells and FIRCAMs. Disappointingly, no fluorescence could be observed on the plasma membrane of FIRCAMs stained with endo-NRB-NBD-bPA.

Ensemble deep learning for the prediction of proficiency at a virtual simulator for robot-assisted surgery.

BACKGROUND: Artificial intelligence (AI) has the potential to enhance patient safety in surgery, and all its aspects, including education and training, will derive considerable benefit from AI. In the present study, deep-learning models were used to predict the rates of proficiency acquisition in robot-assisted surgery (RAS), thereby providing surgical programs directors information on the levels of the innate ability of trainees to facilitate the implementation of flexible personalized training. METHODS: 176 medical students, without prior experience with surgical simulators, were trained to reach proficiency in five tasks on a virtual simulator for RAS. Ensemble deep neural networks (DNN) models were developed and compared with other ensemble AI algorithms, i.e., random forests and gradient boosted regression trees (GBRT). RESULTS: DNN models achieved a higher accuracy than random forests and GBRT in predicting time to proficiency, 0.84 vs. 0.70 and 0.77, respectively (Peg board 2), 0.83 vs. 0.79 and 0.78 (Ring walk 2), 0.81 vs 0.81 and 0.80 (Match board 1), 0.79 vs. 0.75 and 0.71 (Ring and rail 2), and 0.87 vs. 0.86 and 0.84 (Thread the rings 2). Ensemble DNN models outperformed random forests and GBRT in predicting number of attempts to proficiency, with an accuracy of 0.87 vs. 0.86 and 0.83, respectively (Peg board 2), 0.89 vs. 0.88 and 0.89 (Ring walk 2), 0.91 vs. 0.89 and 0.89 (Match board 1), 0.89 vs. 0.87 and 0.83 (Ring and rail 2), and 0.96 vs. 0.94 and 0.94 (Thread the rings 2). CONCLUSIONS: Ensemble DNN models can identify at an early stage the acquisition rates of surgical technical proficiency of trainees and identify those struggling to reach the required expected proficiency level.

Bifurcated bypass in severe chronic limb threatening ischaemia.

OBJECTIVES: Revascularization according to the angiosome concept is of proven importance for limb salvage in chronic limb threatening ischaemia but it is not always practicable. Bifurcated bypasses could be considered as an option when an endovascular approach is not feasible or has already failed and a single bypass would not allow direct revascularization of the ischaemic area. Bifurcated bypasses are characterized by landing on two different arteries, the main artery (in direct continuity with the foot vessels) and the secondary one (perfusing the angiosome district). The aim of this study is to evaluate the safety and effectiveness of bifurcated bypass in chronic limb threatening ischaemia. METHODS: Thirty-five patients were consecutively treated with a bifurcated bypass for chronic limb threatening ischaemia from January 2014 to December 2019 in a single vascular surgery centre. Data from clinical records and operative registers were collected prospectively in an electronic database and retrospectively analysed. Primary and primary assisted bypass patency, amputation-free survival, morbidity and mortality rates at 12 and 24 months were analysed. RESULTS: Mean follow-up period was 25.1 months (range 2-72 months). Thirty-six bifurcated bypasses were performed on 35 patients (age 75.3 ± 7.2 years; 69.4% were male). According to Wound, Ischemia, foot Infection classification 22.2% belonged to stage 3 and 77.8% to stage 4 and the mean Rutherford's class was 5.1 ± 0.7. Immediate technical success was 100%. Early mortality and morbidity rates were respectively 5.5%, and 33.3%; foot surgery was performed in 50% of cases with wound healing in all patients. Primary patency and primary assisted bypass patency were 96.7% and 100% at 6 months; 85.2% and 92% at 12 months, 59.9% and 73.4% at 24 months, respectively. Amputation-free survival at 12 and 24 months was, respectively, 95.6% and 78.8%. Overall survival rates at 12 and 24 months were respectively 94.4% and 91.6%. CONCLUSIONS: Bifurcates bypass can provide good results in patients with chronic limb threatening ischaemia without endovascular option, especially in diabetic ones. Bifurcated bypass is a complex surgical solution, both to be planned and performed, and it is quite invasive for frail patients that should be accurately selected.

Vesicular monoamine transporters expression in pheochromocytomas and paragangliomas according to scintigraphy and positron emission tomography behavior.

BACKGROUND: The expression of vesicular catecholamine transporters (VMAT1 and 2) in pheochromocytomas (PHEOs) and paragangliomas (PGLs) and the possible relationships with [18F]FDOPA PET/CT and [123I]MIBG scintigraphy uptake are unknown. Our purpose was to investigate possible correlations of either VMAT1 and VMAT2 expression with the functional imaging in patients with PHEOs and PGLs. METHODS: An observational 3-year time study was performed by enrolling 31 consecutive patients with PHEO (N.=17) or PGL (N.=14). They underwent the same diagnostic work-up; moreover, [123I]MIBG SPECT/CT (N.=20) and [18F]FDOPA PET/CT (N.=14) were performed in a subset of patients. After surgery, routine histology and semiquantitative analysis of VMAT1/VMAT2 immunoreactivity were carried out in all cases. RESULTS: VMAT1 immunoreactivity was found in all tumors, but two PHEOs. VMAT1 immunoreactivity was higher in PGLs than in PHEOs, though at not significant extent. Elevated VMAT2 immunoreactivity score was present in all but two negative tumors. Normal [123I]-MIBG uptake was independent from VMAT1/2 immunoreactivity. Patients undergoing [18F]FDOPA PET/CT showed a high score level of both VMATs and were detected by the technique in all cases. CONCLUSIONS: VMAT1 and VMAT2 are highly expressed in most tumors, though VMAT1 immunoreactivity is apparently prevalent in PGLs as compared to PHEOs. Presence and expression of VMAT1 and VMAT2 are not limiting factors for MIBG uptake. The status of VMAT expression might help to understand why the more frequently used radiotracers do not always have the expected diagnostic performance. Finally, the present study points out the importance of developing new radiotracers with higher sensitivity, specificity and accuracy consequently reducing healthcare costs.

Development of lung metastases in mouse models of tongue squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) represents 3%-4% of all cancers. Despite the increasing incidence of OSCC distant metastasis and poor prognosis, few animal models of OSCC distant metastasis have been reported. In this study, we established mouse models of OSCC lung metastasis by orthotopic and tail vein injection of new OSCC cell lines. METHODS: For the tail vein model, we used a novel cell line isolated from lung metastases reproduced in vivo after intravenous injection of HSC-3 GFP/luciferase cells and sorted for GFP expression (HSC-3 M1 GFP/luciferase). Lung metastases were assessed by imaging techniques and further confirmed by histology. For the orthotopic model, HSC-3 GFP/luciferase cells were injected into the tongue of athymic nude mice. The primary tumor and metastases were assessed by in vivo imaging, histology, and immunohistochemistry. RESULTS: The orthotopic model presented spontaneous lung metastases in 50% of the animals and lymph node metastases were present in 83% of cases. In the tail vein model, a lung metastasis rate of 60% was observed. CONCLUSIONS: Lung metastases were successfully reproduced by orthotopic and tail vein injection. Since lymph node metastases were present, the orthotopic model with HSC-3 GFP/luciferase cells may be suitable to investigate metastatic dissemination in OSCC.

Enhancing cancer immunotherapy through nanotechnology-mediated tumor infiltration and activation of immune cells.

Cancer immunotherapy has become arguably the most promising advancement in cancer research and therapy in recent years. The efficacy of cancer immunotherapy is critically dependent on specific physiological and physical processes - collectively referred to as transport barriers - including the activation of T cells by antigen presenting cells, T cells migration to and penetration into the tumor microenvironment, and movement of nutrients and other immune cells through the tumor microenvironment. Nanotechnology-based approaches have great potential to help overcome these transport barriers. In this review, we discuss the ways that nanotechnology is being leveraged to improve the efficacy and potency of various cancer immunotherapies.

Working wellbeing between new employees and expert nurses.

INTRODUCTION: The human factor represents a fundamental element in health care processes and influences the result; never as between 2019 and 2020 has such a large number of new hires been introduced in the various public and private companies for social and health assistance. In this context, a fact-finding survey was conducted by the Decentralization Commission of Opi Genova in the months of June and July. The aim was to measure organizational health in terms of variables depending on the relationship between colleagues with different professional experience. METHODS: To conduct the survey, a structured interview was conducted with the nursing staff on work well-being and the relationship between professionals with a sample of nurses operating in different types of health organizations in Genoa. RESULTS: The results of the survey generally show the presence of stress and fatigue in all structures considered mainly due to the emotional burden of the months of the pandemic. Professional integration and general satisfaction were found in all types of structures considered. Some dimensions such as climate essentially depend on each individual case and on the personal character component of each individual. The quantitative results were represented by graphs and the qualitative results by word clouds. CONCLUSIONS: To fulfill their role it is necessary that operators are satisfied and motivated within the organization in which they operate. It is therefore necessary that all operators are satisfied and satisfied by the emotional context in which they are inserted.

A modeling platform for the lymphatic system.

We present a physiologically-based pharmacokinetic modeling platform capable of simulating the biodistribution of different therapeutic agents, including cells, their interactions within the immune system, redistribution across lymphoid compartments, and infiltration into tumor tissues. This transport-based platform comprises a distinctive implementation of a tumor compartment with spatial heterogeneity which enables the modeling of tumors of different size, necrotic state, and agent infiltration capacity. We provide three validating and three exploratory examples that illustrate the capabilities of the proposed approach. The results show that the model can recapitulate immune cell balance across different compartments, respond to antigen stimulation, simulate immune vaccine effects, and immune cell infiltration to tumors. Based on the results, the model can be used to study problems pertinent to current immunotherapies and has the potential to assist medical techniques that rely on the transport of biological species.

XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.

Percutaneous Venous Angioplasty in Patients with Multiple Sclerosis and Chronic Cerebrospinal Venous Insufficiency: A Randomized Wait List Control Study.

BACKGROUND: Venous percutaneous transluminal angioplasty (vPTA) in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI) have shown contradictory results. The aim of the study is to evaluate the efficacy of the procedure in a randomized wait list control study. METHODS: 66 adults with neurologist-confirmed diagnosis of MS and sonographic diagnosis of CCSVI were allocated into vPTA-yes group (n = 31) or vPTA-not group (n = 35, control group). vPTA was performed immediately 15 days after randomization in the PTA-yes group and 6 months later in the control group. Evoked potentials (EPs), clinical-functional measures (CFMs), and upper limb kinematic measures (ULKMs) were measured at baseline (T0) and six months after in both groups, just before the venous angioplasty in the vPTA-not group (T1). RESULTS: Comparing the vPTA-yes and vPTA-not group, the CFM-derived composite functional outcome showed 11 (37%) versus 7 (20%) improved, 1 (3%) versus 3 (8%) stable, 0 versus 7 (20%) worsened, and 19 (61%) versus 18 (51%) mixed patients (χ2 = 8.71, df = 3, P = 0.03). Unadjusted and adjusted (for baseline confounding variables) odds ratio at 95% confidence interval were, respectively, 1.93 (1.3-2.8), P value 0.0007, and 1.85 (1.2-1.7), P value 0.002. EP- and ULKM-derived composite functional outcome showed no significant difference between the two groups. CONCLUSIONS: Venous angioplasty can positively impact a few CFMs especially for the quality of life but achieving disability improvement is unlikely.

Nanotechnology and Immunotherapy in Ovarian Cancer: Tracing New Landscapes.

Ovarian cancer (OC) is the seventh most common cancer in women worldwide. Standard therapeutic treatments involve debulking surgery combined with platinum-based chemotherapies. Of the patients with advanced-stage cancer who initially respond to current treatments, 50%-75% relapse. Immunotherapy-based approaches aimed at boosting antitumor immunity have recently emerged as promising tools to challenge tumor progression. Treatments with inhibitors of immune checkpoint molecules have shown impressive results in other types of tumors. However, only 15% of checkpoint inhibitors evaluated have proven successful in OC due to the immunosuppressive environment of the tumor and the transport barriers. This limits the efficacy of the existing immunotherapies. Nanotechnology-based delivery systems hold the potential to overcome such limitations. Various nanoformulations including polymeric, liposomes, and lipid-polymer hybrid nanoparticles have already been proposed to improve the biodistribution and targeting capabilities of drugs against tumor-associated immune cells, including dendritic cells and macrophages. In this review, we examine the impact of immunotherapeutic approaches that are currently under consideration for the treatment of OC. In this review, we also provide a comprehensive analysis of the existing nanoparticle-based synthetic strategies and their limitations and advantages over standard treatments. Furthermore, we discuss how the strength of the combination of nanotechnology with immunotherapy may help to overcome the current therapeutic limitations associated with their individual application and unravel a new paradigm in the treatment of this malignancy.

Hand-assisted laparoscopic surgery versus endovascular repair in abdominal aortic aneurysm treatment.

OBJECTIVE: Hand-assisted laparoscopic surgery (HALS) for the treatment of abdominal aortic aneurysm (AAA) has shown promising initial results compared with traditional surgery, but its efficacy remains highly debated. The aim of this monocentric, retrospective study was to investigate differences in morbidity, mortality, and reintervention rates between endovascular aneurysm repair (EVAR) and HALS, in the medium- and long-term follow-up in a highly selected population. METHODS: We treated 977 patients consecutively for nonurgent AAA from January 2006 to December 2013; among them, 615 (62.9%) underwent open surgery, 173 (17.7%) HALS, and 189 (19.3%) EVAR. For this study, only patients treated with HALS or EVAR were considered. A subsequent selection process was carried out to identify the patients with clinical characteristics and aneurysm morphology amenable to either of these treatments. The final study cohort included 229 patients; 92 (40.2%) underwent HALS and 137 (69.8%) received EVAR. The two populations were homogeneous for clinical and demographic characteristics. RESULTS: The mean duration of follow-up was 57 ± 28 months (50 ± 24 months in the EVAR group and 67 ± 29 months in the HALS group; range, 2-110 months). No deaths and no statistically significant differences in severe complications or reinterventions were observed over the perioperative period (30 days). Length of stay was significantly shorter after EVAR, because the need for and length of stay in the intensive care unit were decreased. Three postoperative deaths (in-hospital mortality >30 days: HALS, 2.2%; EVAR, 0.7%; P = .7268) occurred owing to respiratory failure (two patients, one in each group) and multiorgan failure secondary to a bowel ischemia (one patient in the HALS group). Other deaths in the study population were not related to the procedure. In both groups, the major causes of death were cancer (24 cases [36.9%]), cardiovascular causes unrelated to AAA (16 [24.6%]), and chronic obstructive lung disease (10 [15.4%]). In the long-term follow-up period, there was a difference in the overall survival in favor of HALS when compared with EVAR (P = .011). CONCLUSIONS: This retrospective, single-center study shows that, within a population of similar clinical and anatomic characteristics, treatment of AAA with EVAR or HALS does not result in significant differences in early morbidity and mortality. EVAR presents significantly shorter hospital and intensive care unit length of stay, whereas HALS presents a lower aneurysm-related reintervention rate and lower perioperative cost. The strict patient selection in this trial, as is generally the case with AAA treatment, is likely the key to success for both of these techniques.

Functionalization of endovascular devices with superparamagnetic iron oxide nanoparticles for interventional cardiovascular magnetic resonance imaging.

Presently, cardiovascular interventions such as stent deployment and balloon angioplasty are performed under x-ray guidance. However, x-ray fluoroscopy has poor soft tissue contrast and is limited by imaging in a single plane, resulting in imprecise navigation of endovascular instruments. Moreover, x-ray fluoroscopy exposes patients to ionizing radiation and iodinated contrast agents. Magnetic resonance imaging (MRI) is a safe and enabling modality for cardiovascular interventions. Interventional cardiovascular MR (iCMR) is a promising approach that is in stark contrast with x-ray fluoroscopy, offering high-resolution anatomic and physiologic information and imaging in multiple planes for enhanced navigational accuracy of catheter-based devices, all in an environment free of radiation and its deleterious effects. While iCMR has immense potential, its translation into the clinical arena is hindered by the limited availability of MRI-visible catheters, wire guides, angioplasty balloons, and stents. Herein, we aimed to create application-specific, devices suitable for iCMR, and demonstrate the potential of iCMR by performing cardiovascular catheterization procedures using these devices. Tools, including catheters, wire guides, stents, and angioplasty balloons, for endovascular interventions were functionalized with a polymer coating consisting of poly(lactide-co-glycolide) (PLGA) and superparamagnetic iron oxide (SPIO) nanoparticles, followed by endovascular deployment in the pig. Findings from this study highlight the ability to image and properly navigate SPIO-functionalized devices, enabling interventions such as successful stent deployment under MRI guidance. This study demonstrates proof-of-concept for rapid prototyping of iCMR-specific endovascular interventional devices that can take advantage of the capabilities of iCMR.

Investigation of parameters that determine Nano-DC vaccine transport.

Effective migration of dendritic cells into the lymphatic system organs is the prerequisite for a functional dendritic cell vaccine. We have previously developed a porous silicon microparticle (PSM)-based therapeutic dendritic cell vaccine (Nano-DC vaccine) where PSM serves both as the vehicle for antigen peptides and an adjuvant. Here, we analyzed parameters that determined dendritic cell uptake of PSM particles and Nano-DC vaccine accumulation in lymphatic tissues in a murine model of HER2-positive breast cancer. Our study revealed a positive correlation between sphericity of the PSM particles and their cellular uptake by circulating dendritic cells. In addition, the intravenously administered vaccines accumulated more in the spleens and inguinal lymph nodes, while the intradermally inoculated vaccines got enriched in the popliteal lymph nodes. Furthermore, mice with large tumors received more vaccines in the lymph nodes than those with small to medium size tumors. Information from this study will provide guidance on design and optimization of future therapeutic cancer vaccines.

Ruptured Mycotic Aneurysm After Intravesical Instillation for Bladder Tumor.

BACKGROUND: Intravesical instillation of Bacillus Calmette-Guérin (BCG) is an effective and widely used treatment for patients with in situ bladder cancer. Major complications are quite uncommon, but a systemic dissemination of the attenuated strain of Mycobacterium bovis is possible. Few cases of aortic rupture caused by M bovis infection are described in literature. METHODS: A 70-year-old male, treated 3 months before with BCG instillation, presented to the emergency department because of a ruptured abdominal aortic aneurysm. The patient was hemodynamically stable, with a "hostile" abdomen. Therefore, an Endologix AFX endograft was deployed. During the postoperative period, his blood inflammatory markers increased, suspicious of a graft infection. Single-photon emission computed tomography (CT)/CT scan showed aortic increased uptake. Antibiotic therapy was continued, but after some days, the patient presented with hematemesis, and the CT scan showed an aortoenteric fistula. In emergency, the infected graft and aneurysm were removed, enteric fistula was closed, and an axillobifemoral bypass was performed. The patient died 25 days after endovascular aneurysm repair explantation. RESULTS: Despite the high suspicion of mycotic aortic aneurysm and graft infection by M bovis, there is no proof of this theory because of the absence of any positive culture test. M bovis is a slow-growing bacteria, and specific culture tests are required to identify it; indeed, all our blood and intraoperative samples were positive to other bacteria, probably the contaminant ones. CONCLUSIONS: Mycotic aneurysm is an extremely rare complication of intravesical BCG therapy, but it must be taken into consideration in patients with rapidly growing aortic aneurysms or rupture of a normal aorta, who have been previously submitted to this kind of instillation.

Single-Molecule Force Measurement Guides the Design of Multivalent Ligands with Picomolar Affinity.

Interaction of multiple entities and receptors, or multivalency is widely applied to achieve high affinity ligands for diagnostic and therapeutic purposes. However, lack of knowledge on receptor distribution in living subjects remains a challenge for rational structure design. Herein, we develop a force measurement platform to probe the distribution and separation of the cell surface vascular endothelial growth factor receptors (VEGFR) in live cells, and use this to assess the geometry of appropriate linkers for distinct multivalent binding modes. A tetravalent lead ZD-4, which was developed from an antitumor drug ZD6474 (Vandetanib) with combined hybrid binding effects, yielded a 2000-fold improvement in the binding affinity to VEGFR with IC50 value of 25 pm. We confirmed the improved affinity by the associated increase of tumor uptake in the VEGFR-targeting positron emission tomography (PET) imaging using U87 tumor xenograft mouse model.

DNA Thioaptamer with Homing Specificity to Lymphoma Bone Marrow Involvement.

Selective drug accumulation in the malignant tissue is a prerequisite for effective cancer treatment. However, most drug molecules and their formulated particles are blocked en route to the destiny tissue due to the existence of multiple biological and physical barriers including the tumor microvessel endothelium. Since the endothelial cells on the surface of the microvessel wall can be modulated by inflammatory cytokines and chemokines secreted by the tumor or stromal cells, an effective drug delivery approach is to enhance interaction between the drug particles and the unique spectrum of surface proteins on the tumor endothelium. In this study, we performed in vivo screening for thioaptamers that bind to the bone marrow endothelium with specificity in a murine model of lymphoma with bone marrow involvement (BMI). The R1 thioaptamer was isolated based on its high homing potency to bones with BMI, and 40-60% less efficiency in accumulation to healthy bones. In cell culture, R1 binds to human umbilical vein endothelial cells (HUVEC) with a high affinity ( Kd ≈ 3 nM), and the binding affinity can be further enhanced when cells were treated with a mixture of lymphoma cell and bone marrow cell conditioned media. Cellular uptake of R1 is through clathrin-mediated endocytosis. Conjugating R1 on to the surface of liposomal doxorubicin nanoparticles resulted in 2-3-fold increase in drug accumulation in lymphoma BMI. Taking together, we have successfully identified a thioaptamer that preferentially binds to the endothelium of lymphoma BMI. It can serve as an affinity moiety for targeted delivery of drug particles to the disease organ.