Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling.

BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.

Self-heating of dried industrial tannery wastewater sludge induced by pyrophoric iron sulfides formation.

Similarly to many powders of solids, dried sludge originated from tannery wastewater may result in a self-heating process, under given circumstances. In most cases, it causes a moderate heating (reaching 70-90°C), but larger, off-design residence times in the drier, in a suboxic atmosphere, extremely reactive solids can be produced. Tannery waste contains several chemicals that mostly end up in the wastewater treatment sludge. Unexpected and uncontrolled self heating could lead to a combustion and even to environmental problems. Elaborating on previous studies, with the addition of several analytical determinations, before and after the self-heating, we attempted to formulate a mechanism for the onset of heating. We demonstrated that the system Fe/S/O has been involved in the process. We proved that the formation of small quantities of pyrophoric iron sulfides is the key. They are converted to sulfated by reaction with water and oxygen with exothermic processes. The pyrite/pyrrhotite production depends on the sludge drying process. The oxidation of sulfides to oxides and sulfates through exothermic steps, reasonably catalyzed by metals in the sludge, occurs preferentially in a moist environment. The mechanism has been proved by reproducing in the laboratory prolonged heating under anoxic/suboxic atmosphere.

In vitro comparison of the bond strength to the enamel of conventional and self-etching dental fissure sealants.

AIM: Dental caries in pits and fissures of molars is still very common in young people, despite a gradual reduction in their incidence and prevalence. Prevention with the aid of dental fissure sealants can help to reduce the onset of decay. In vitro tests were conducted to compare the bond strength to enamel of self-etching sealants versus those applied using the conventional procedure. METHODS: The lingual surface of 40 extracted, caries-free, mandibular third molars was milled to make them flat. The prepared teeth were randomly divided into two groups of 20 teeth each: those in Group A were treated with Clinpro (3M ESPE, St. Paul, MN, USA); those in Group B with Quick Seal (BJM Laboratories Ltd, Or-Yehuda, Israel). Cylinders of sealant were attached to the enamel of the flat surfaces of the samples using a polymerisation process treating the surfaces involved according to the type of material. All samples underwent load testing by means of a universal test machine. RESULTS: The results of the load testing, measured in MPa, were analysed using the Student's t-test for independent samples and the differences proved significant, indicating that the traditionally- applied sealant (mean strength 21.06 MPa) assured a significantly stronger bond (p <.05) than the self-etching sealant (mean strength 10.43 MPa) under our experimental conditions. CONCLUSION Conventional sealants generally provide a considerably higher bond strength than self-etching sealants.

Follow-up of coiled cerebral aneurysms at 3T: comparison of 3D time-of-flight MR angiography and contrast-enhanced MR angiography.

BACKGROUND AND PURPOSE: Our aim was to compare contrast-enhanced MR angiography (CE-MRA) and 3D time-of-flight (TOF) MRA at 3T for follow-up of coiled cerebral aneurysms. MATERIALS AND METHODS: Fifty-two patients treated with Guglielmi detachable coils for 54 cerebral aneurysms were evaluated at 3T MRA. 3D TOF MRA (TR/TE = 23/3.5; SENSE factor = 2.5) and CE-MRA by using a 3D ultrafast gradient-echo sequence (TR/TE = 5.9/1.8; SENSE factor = 3) enhanced with 0.1-mmol/kg gadobenate dimeglumine were performed in the same session. Source images, 3D maximum intensity projection, 3D shaded surface display, and/or 3D volume-rendered reconstructions were evaluated in terms of aneurysm occlusion/patency and artifact presence. RESULTS: In terms of clinical classification, the 2 MRA sequences were equivalent for 53 of the 54 treated aneurysms: 21 were considered fully occluded, whereas 16 were considered to have a residual neck and 16 were considered residually patent at follow-up MRA. The remaining aneurysm appeared fully occluded at TOF MRA but had a residual patent neck at CE-MRA. Visualization of residual aneurysm patency was significantly (P = .001) better with CE-MRA compared with TOF MRA for 10 (31.3%) of the 32 treated aneurysms considered residually patent with both sequences. Coil artifacts were present in 5 cases at TOF MRA but in none at CE-MRA. No relationship was apparent between the visualization of patency and either the size of the aneurysm or the interval between embolization and follow-up. CONCLUSION: At follow-up MRA at 3T, unenhanced TOF and CE-MRA sequences are similarly effective at classifying coiled aneurysms as occluded or residually patent. However, CE-MRA is superior to TOF MRA for visualization of residual patency and is associated with fewer artifacts.

Introduction of GDC embolization in the clinical practice as treatment synergical to surgery: impact on overall outcome of patients with subarachnoid hemorrhage.

The GDC endovascular approach represent an effective alternative to surgery for treatment of intracranial aneurysms. Anyway no data are available about the impact of endovascular embolization with GDC on overall outcome of patients with subarachnoid hemorrhage. We analyse retrospectively a series of 234 patients admitted for ruptured intracranial aneurysm. Results were then compared with results of three surgical series from the literature. The 95.7% of patients underwent aneurysm treatment; 56.4% of patients were classified as good recovery, 12.8% presented moderate disability, 10.3% were severely disabled, 3% were in persistent vegetative state and 17.5% were dead. Patients older than 60 years accounted for 37% of all cases and good outcome in this group accounted for 54.7%. Good results were obtained in 90.1%, 61.7% and 22.8% of patients with Hunt-Hess grade I-II, III and IV-V respectively. Finally good outcome was observed in 82.8% of patients with aneurysms of the posterior circulation. Introduction of GDC embolization in clinical practice contributed to the extension of indication for aneurysm treatment leading to a reduction of overall mortality. GDC utilisation does not affect the overall percentage of patients with good outcome reflecting an increase of severely disabled patients. Endovascular treatment seems an effective theraputic choice in selected grade I-II patients. Results in grade III patients suggest that surgery may be advantageous because of washing and decompression of the basal cisterns while results in grade IV and V patients are unsatisfactory. GDC embolization clearly improves the prognosis of patients with posterior circulation aneurysms and probably is an advantageous theraputic choice in elderly patients.

Stent-graft treatment of a common carotid artery pseudoaneurysm.

PURPOSE: To report a case demonstrating successful endovascular treatment of a right common carotid artery pseudoaneurysm using a commercially prepared balloon-expandable covered stent. METHODS AND RESULTS: A 50-year-old man was evaluated for syncopal episodes. He had a history of severe trauma sustained in a motor vehicle accident 3 years before symptom onset. Doppler ultrasound scanning detected a pseudoaneurysm at the origin of the right common carotid artery. The defect measured 25 mm x 20 mm with a 22-mm-long neck on angiography and computed tomography; there was no evidence of carotid stenosis or associated vascular pathology. Via a percutaneous femoral access, 2 Jostent peripheral stent-grafts were placed at the level of the aneurysm, safely achieving complete repair of the arterial wall defect. The patient was asymptomatic at his 12-month evaluation. Color flow duplex scans showed continued exclusion of the pseudoaneurysm. CONCLUSIONS: Wide-necked aneurysms in the extracranial carotid arteries may be treated with stent-grafts, which can achieve complete and permanent reconstruction of the arterial wall by excluding the aneurysm.

Three-dimensional time-of-flight MR angiography in the evaluation of intracranial aneurysms treated with Guglielmi detachable coils.

BACKGROUND AND PURPOSE: Intravascular treatment of intracranial aneurysms is a relatively new therapeutic technique and long-term controlled angiographic trials are needed to assess persistence of aneurysm occlusion. Our purpose was to evaluate the effectiveness of 3D time-of-flight (3D-TOF) MR angiography as a noninvasive screening tool in the follow-up of cerebral aneurysms treated with Guglielmi detachable coils (GDCs). METHODS: Forty-nine patients with 50 intracranial aneurysms previously treated with GDCs were studied with both DSA and 3D-TOF MR angiography. In 14 cases, a second follow-up examination was performed, for a total of 64 aneurysms evaluated. In 25 aneurysms, both pre- and postcontrast MR angiographic studies were obtained. RESULTS: In seven of 64 aneurysms, the MR angiographic studies were considered to be unreliable owing to the presence of artifacts that obscured part of the parent artery and did not allow an accurate evaluation of the aneurysm neck. These seven aneurysms, however, all were shown to be completely occluded at digital subtraction angiography (DSA). In the remaining 57 aneurysms, DSA revealed complete occlusion in 39 and the presence of residual patency in 18, whereas MR angiography showed complete occlusion in 38 and residual patency in 19. Enhanced MR angiography proved to be useful in evaluating residual patency in large and giant aneurysms and in better depicting the distal branch arteries. CONCLUSION: Although artifacts related to the presence of coils are evident on a considerable number of imaging studies, our findings indicate that MR angiography is useful in the evaluation of residual patency of cerebral aneurysms treated with GDCs and may eventually prove valuable in the follow-up of those cases in which a good initial correlation with DSA was demonstrated.

Emergency endovascular treatment of a life-threatening hemorrhage from traumatic rupture of the left extracranial vertebral artery.

Hemorrhagic complications from transection of cervical arteries in blunt traumas are rare. We report a case of potentially fatal hemorrhage from rupture of the left vertebral artery in a closed trauma, successfully treated by endovascular injection of glue. Endovascular embolization may be considered as an alternative to surgical exploration in the treatment of traumatic lesions of vertebral arteries.

Post-traumatic dissecting aneurysm of extracranial internal carotid artery: endovascular treatment with stenting.

Traumatic internal carotid dissection occurs frequently in motor vehicle accidents, typically extracranially, close to the skull base. Dissection may lead to stenosis or occlusion of the vessel, possibly with a pseudoaneurysm, symptoms ranging from neck pain to neurological deficits. In symptomatic patients and in cases of pseudoaneurysm, when conservative medical treatment fails, surgery or endovascular treatment are indicated. We report a post-traumatic dissecting aneurysm of the extracranial internal carotid artery successfully treated with stenting via a transfemoral approach.

Endovascular treatment of bacterial intracranial aneurysms.

We report three patients with bacterial intracranial aneurysms treated by the endovascular approach: two presented with sudden severe neurological deficits after a diagnosis of endocarditis; the other had suspected vasculitis. CT showed an intracerebral haematoma in all cases; angiography revealed bacterial aneurysms of distal branches of the middle cerebral artery in one. Because of the patients' condition and the location of the aneurysms, endovascular treatment was considered the fastest and safest treatment. Hyperselective catheterisation of the parent branch, close to the aneurysm, was performed with a microcatheter. A small amount of glue was injected to occlude both the aneurysm and a short segment of the diseased vessel. Follow-up angiography revealed occlusion of the aneurysm in all cases. One patient recovered completely; one recovered over some months, with neurological deficit due to the haematoma. The third patient suddenly worsened and died 9 days after treatment for a contralateral haematoma, due to rupture of a new bacterial aneurysm of the middle cerebral artery. Endovascular occlusion of the aneurysm and parent vessel may be an alternative to surgery in selected, severe cases of deep or distal bacterial intracranial aneurysms.