Strategies to tackle RAS-mutated metastatic colorectal cancer.

The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.

Time and space scattered volcanism of Mt. Etna driven by strike-slip tectonics.

High-resolution seismic reflection, magnetic and gravity data, acquired offshore of Etna volcano, provide a new insight to understanding the relationship between tectonics and spatial-temporal evolution of volcanism. The Timpe Plateau, a structural high pertaining to the Hyblean foreland domain, located offshore of southeastern Mt. Etna, is speckled by volcanics and strongly affected by strike-slip tectonics. Transpressive deformation produced a push-up and a remarkable shortening along WNW-ESE to NW-SE trending lineaments. Fault segments, bounding basinal areas, show evidence of positive tectonic inversion, suggesting a former transtensive phase. Transtensive tectonics favoured the emplacement of deep magmatic intrusive bodies and Plio-Quaternary scattered volcanics through releasing zones. The continuing of wrench tectonics along different shear zones led to the migration of transtensive regions in the Etna area and the positive inversion of the former ones, where new magma ascent was hampered. This process caused the shifting of volcanism firstly along the main WNW-ESE trending "Southern Etna Shear Zone", then towards the Valle del Bove and finally up to the present-day stratovolcano.

Slab narrowing in the Central Mediterranean: the Calabro-Ionian subduction zone as imaged by high resolution seismic tomography.

A detailed 3D image of the Calabro-Ionian subduction system in the central Mediterranean was obtained by means of a seismic tomography, exploiting a large dataset of local earthquakes and computing algorithms able to build a dense grid of measure nodes. Results show that the slab is continuous below the southern sector of the Calabro-Peloritan Arc, but the deformation processes developing at its edges are leading to its progressive narrowing, influencing tectonics and magmatism at the surface, and with possible stress concentration in the tip zones. In the southwest, the deformation occurring at a free slab edge lead to propagation of a vertical lithospheric tear in the overriding plate, which extends along a NW-SE fault system (Aeolian-Tindari-Letojanni) up to about 30 km into the Ionian Sea; further southeast, the lithosphere appears only flexed and not broken yet. In the northeast, the slab seems to break progressively, parallel to the trench. Finally, northwest of Mt. Etna, the tomography highlights low VP that can be related to an upwelling of deep mantle material likely flowing laterally through a window opened by the complete slab detachment.

Spatially resolved SO2 flux emissions from Mt Etna.

We report on a systematic record of SO2 flux emissions from individual vents of Etna volcano (Sicily), which we obtained using a permanent UV camera network. Observations were carried out in summer 2014, a period encompassing two eruptive episodes of the New South East Crater (NSEC) and a fissure-fed eruption in the upper Valle del Bove. We demonstrate that our vent-resolved SO2 flux time series allow capturing shifts in activity from one vent to another and contribute to our understanding of Etna's shallow plumbing system structure. We find that the fissure eruption contributed ~50,000 t of SO2 or ~30% of the SO2 emitted by the volcano during the 5 July to 10 August eruptive interval. Activity from this eruptive vent gradually vanished on 10 August, marking a switch of degassing toward the NSEC. Onset of degassing at the NSEC was a precursory to explosive paroxysmal activity on 11-15 August.

[Project work: formation of health-care personnel for self-care of tunnelled central venous catheters in hemodialysis patients of the territory]. / Project work: formazione infermieristica per l'autocura educativa dei cateteri venosi tunnellizzati nei pazienti emodializzati del territorio.

BACKGROUND: Scientific data from current literature demonstrate an incidence of bacteraemia due to tunnelled central venous catheter (tCVC) use accounting for 1.6 / 1000 days per tCVC, with a range of 1.5 to 1.8. In Sicily no data on the incidence of tCVC- related bacteraemia are available. In our hospital, tCVC infection occurs 2.4 times in 1000 days during CVC use. A retrospective analysis carried out from 2006 to 2012 was performed on 650 patients with tunnelled catheters. Of the subjects who received tCVC in our hospital, 90% were destined to undergo haemodialysis in a private health care environment outside our hospital. MATERIALS AND METHODS: In order to improve the aforementioned infection outcome, we planned and implemented a specific work project. The work project (WP) was subdivided into two steps: 1) The first step was further subdivided into two sub-phases. The first was principally concerned with the implementation of educational courses, conducted directly on the ward and aimed at the implementation of meticulous nursing regimes for the care of tCVC by our health care nurse. The courses were entitled Management of Vascular Access: from doing - to teaching to do!. These educational courses were organized by the Nephrology Department, which takes care of the management and handling of the major complications of tCVCs for the maintenance of haemodialysis. After this first step, the nurses who had participated became the promoters of the second part of the course, which concerned the development of know-how within an outpatient clinic, which deals exclusively with the nursing management of tCVCs. 2) The title of the second phase was Therapeutic Education: self-Care and understanding and managing your venous access at home. The aim of this step was the integration of correct in-hospital care with that available in outsourced private institutions, via the involvement of the patient in the management of their own central venous access. During our training project, a more detailed analysis of the stakeholder as well as a swot analysis on the feasibility of the project were used to determine ad interim and final targets of the study. A summary of operative planning is included to explain in greater detail the study design, timing and costs of the various phases. Risk management and corrective measures adopted during the project are also mentioned and monitoring of the phases is described in relation to the fulfilling of intermediate goals. The prompt correction of mistakes allows for safer realisation of outcomes. CONCLUSION: From our experience with this work project, we can conclude that a more accurate management of tCVCs can significantly reduce the morbidity and mortality of patients. The project offers a positive cost-benefit balance through a decrease in costs of hospitalisation for tCVC-related infections and other life.threatening conditions related to the use of tCVCs an important goal for any spending review.

Surgery of the aortoduodenal fistula: two cases with survival.

We report on two cases of aortoduodenal fistula. The patients underwent the positioning of an aortic stent 1.9 and 5 yearly before, respectively. They complained of fever and abdominal pain and were admitted to the hospital. A stent infection was suspected and an angio-CT confirmed the suspicion. Each patient was brought immediately to the operating room, where the fistula was individuated and resected, with closure of the aortic wall and excision of a part of the ulcerated intestinal loop involved. The infected stent was removed and an extra-anatomic bypass was performed. The patients survived and were discharged from hospital 38 and 29 days after the surgery, respectively, with no postsurgical sequelae and in good health. These patients are alive and in good health respectively 18 and 19 months (mo) after the procedure. If performed immediately upon diagnosis, this technique permits achievement of an optimal result.

[Steno-obstructions of haemodialytic FAV: new aspects of endovascular treatments]. / Trattamento endovascolare delle complicanze steno-ostruttive delle fistole artero-venose emodialitiche: nuovi aspetti di intervento con radiologia interventistica.

Angioplasty is the usual method for the treatment of stenosis of arteriovenous fistulas for hemodialysis, along with fibrinolysis and thrombus aspiration. We evaluated the efficacy and safety of interventional radiology procedures in the treatment of stenosis or occlusion of arteriovenous fistulas. One hundred thirteen patients suffering from malfunction of arteriovenous fistulas underwent interventional radiological procedures (140 treatments). In all patients color-Doppler was performed beforehand. Stenosis at the site of the fistula was found in all patients and was treated with percutaneous transluminal angioplasty (PTA); stenosis at the anastomosis site was found in 63 cases and was treated by angioplasty with a microcatheter. In 40 patients suffering from recent thrombotic occlusion, locoregional thrombolysis and PTA were necessary. Technical and clinical success was achieved in 107 patients (94.6%); in 1 of 6 unsuccessful treatments the procedure had to be interrupted due to the rupture of a vein. Follow-up exams demonstrated primary patency in 92.5%, 71.9% and 49.5% of patients at 6 months, 1 year and 2 years, respectively. In 19 patients (17.7%) hemodynamically significant restenosis was observed, which was treated with multiple PTAs (27 treatments, only 1 of which with a negative outcome), resulting in a 94.2% success rate; only 1 patient had to undergo a fourth PTA. The overall patency rate was 95%, 87.2%, 62.3% at 6 months, 1 year and 2 years, respectively. In our experience immediate success and excellent patency rates were observed, which persisted in the medium and long term. PTA, with thrombolysis and thromboaspiration, is the treatment of choice in cases of malfunctioning arteriovenous fistulas. PTA should always be attempted before making a new surgical access in order to preserve the vascular tree.

Topology-induced anomalous defect production by crossing a quantum critical point.

We study the influence of topology on the quench dynamics of a system driven across a quantum critical point. We show how the appearance of certain edge states, which fully characterize the topology of the system, dramatically modifies the process of defect production during the crossing of the critical point. Interestingly enough, the density of defects is no longer described by the Kibble-Zurek scaling, but determined instead by the nonuniversal topological features of the system. Edge states are shown to be robust against defect production, which highlights their topological nature.

[Use of venae comitantes in the creation of arteriovenous fistulas: retrospective evaluation of our experience]. / L'utilizzo della vena comitans nel confezionamento delle fistole artero-venose: valutazione retrospettiva della nostra esperienza.

In order to estimate the outcome of arteriovenous fistula (AVF) for hemodialysis, we reviewed our experience in the construction of AVFs using the venae comitantes in patients without an adequate superficial venous vascular territory. The study included 34 patients affected by end-stage renal disease in whom an AVF was created using the deep venous system. In 26 of them we performed an anastomosis between the brachial artery and its vena comitans. Immediate success, defined by the presence of a thrill at the end of the anastomosis, was obtained in 84%, while primary failure of the AVF (immediate postoperative failure) occurred in 3 patients (12%). Early failure, defined as failure within 6 weeks of AVF placement, occurred in 4% of patients. Of the 22 patients with a functioning AVF, 8 (36%) subsequently requested a second operation to bring the fistula to the surface. Some of these involved the placement of synthetic grafts for better accessibility. The primary patency of the AVFs was equal to 64%, while the patency after a second intervention was 91%. Among the 26 AVFs created with venae comitantes, total patency at 50 weeks was 62%. Our experience with the placement of prosthetic grafts draining into the venae comitantes has not provided encouraging results. We believe that for adequate exploitation of venae comitantes it is important to use native veins that have to meet specific anatomical and functional requirements. The creation of an AVF with a native vein, taking advantage of the deep venous system, is feasible under the right circumstances.

[Central venous stenting in patients on hemodialysis: review of our case series and long-term follow-up]. / Stenting venoso centrale in pazienti emodializzati: revisione della nostra casistica e follow-up a distanza.

Aims of the study was validate the venous stenting technique as the treatment of choice in patients affected by stenosis or occlusion of the central venous area. To evaluate the long-term patency of placed stents in our series and to detect factors predisposing to restenosis. Twenty-three hemodialyzed patients were treated by PTA or placement of a metallic self-expandable stent in the central venous area because of occlusion or severe stenosis caused by repeated central venous access puncture for Port-A-Cath or pacemaker placement. All patients were examined every 3 months after treatment by clinical examination and color-Doppler ultrasound. Stents were placed with success in all cases but one, where it was impossible to get past the occlusion. Restenosis was observed in 12 cases at 4 to 12 months (average 8 months). Intrastent restenoses were treated with success by PTA alone and stent placement in 4 cases. A new restenosis was observed in 4 retreated patients in whom the stent was short or angled. In the other patients restenosis was attributable to disregard of anticoagulant therapy. In conclusions, the availability of new devices and dedicated stents is still necessary. There is a limited relationship between patency and wrong stent placement. Patients undergoing stenting should be controlled by clinical examination and color-Doppler ultrasound in hospitals where skilled interventional radiologists are available.

Time-resolved seismic tomography detects magma intrusions at Mount Etna.

The continuous volcanic and seismic activity at Mount Etna makes this volcano an important laboratory for seismological and geophysical studies. We used repeated three-dimensional tomography to detect variations in elastic parameters during different volcanic cycles, before and during the October 2002-January 2003 flank eruption. Well-defined anomalous low P- to S-wave velocity ratio volumes were revealed. Absent during the pre-eruptive period, the anomalies trace the intrusion of volatile-rich (>/=4 weight percent) basaltic magma, most of which rose up only a few months before the onset of eruption. The observed time changes of velocity anomalies suggest that four-dimensional tomography provides a basis for more efficient volcano monitoring and short- and midterm eruption forecasting of explosive activity.

[Use of the Floating Ball for hepatic resection in cirrhotic patients affected by hepatocellular carcinoma]. / Utilizzo del floating Ball nella chirurgia resettiva del carcinoma epatocellulare in pazienti cirrotici.

Done to the improvement of knowledges in hepatic surgery and postoperative care, hepatocellular carcinoma (HCC) have been treated more and more frequently by hepatic resection. Aim of this study is to report an initial series of patients affected by HCC treated by hepatic resection utilizing a new water-cooled, high-density, monopolar device, the Tissuelink Monopolar Floating Ball (Tissuelink Medical Inc., Dover, NH, U.S.A.), in order to avoid bleeding during hepatic surgery. Sex, age, kind of disease, viral and Child status, type of surgical procedure, in association to lenght of surgical procedure, blood loss, utilization of the vascular clamping of the liver, hospital stay, morbidity and mortality have been analized. Six liver resections have been performed utilizing this new device. No vascular clamping was established except one. No mortality was recorded. Morbidity was ascites in one case and pleural effusion in a second one. In conclusion the Floating Ball reduces the intraoperative bleeding during hepatic resection in patients with HCC.

Does the adjunct of ecographic contrast medium Levovist improve the detection rate of prostate cancer?

OBJECTIVES: To evaluate whether the adjunct of an ultrasound contrast medium improves the detection rate of prostate cancer. METHOD: In 34 patients, scheduled to undergo a trans-perineal extended prostate biopsy, we carried out a color-Doppler ultrasound (CDU) of the prostate before and after i.v. injection of Levovist, an ultrasound contrast medium. Further bioptic samples were taken in the areas where a marked increase in vascularization was noticed. RESULTS: The overall diagnostic sensitivity, specificity and efficiency were respectively 72.7, 56.2 and 62.9% for transrectal ultrasound (TRUS); 80, 56.2 and 65.3% for CDU and 88.8, 54.5 and 68% for CDU after Levovist injection; 66.5, 72.6 and 65.1% for digito-rectal examination (DRE); 100, 51.4 and 65.4% for total PSA; and 100, 88.8 and 94.3% for PSA free/total. In the 16 patients with prostate carcinoma, the sensitivity of CDU after Levovist was 92.3, 66% for both DRE and TRUS, and 80% for DRE plus TRUS. CONCLUSIONS: Considering the cost and the results obtained (high sensitivity and low specificity), a routine use of Levovist does not seem indicated in patients undergoing prostatic biopsy. An exception may be represented by patients with both negative DRE and TRUS.

[CT in the staging of neoplasms of the gallbladder]. / La TC nello staging delle neoplasie della colecisti.

The authors report the results of 50 cases of gallbladder carcinoma studied by means of CT, which were observed since 1984. Twenty-five cases were confirmed at surgery and 25 were selected among those in which CT, clinical history, natural disease evolution and matching with other instrumental and laboratory examinations were highly suggestive of gallbladder carcinoma. The high incidence is reported of such CT signs, which may be considered typical, as the presence of soft tissue in gallbladder area (92%), liver infiltration (78%), and the presence of metastatic lymph nodes (36%); they may or may not be associated to less specific signs. CT appears as the most reliable examination for both diagnosis and staging of the disease. Unfortunately, due to the wide range of aspecific clinical signs, diagnosis is in most cases late and the disease has therefore a fatal outcome.

Transvenous sclerotherapy of the gonadal veins for treatment of varicocele: long-term results.

Percutaneous occlusion of the spermatic vein has been performed on 136 consecutive patients with varicocele scroti during the last six years. The authors report their long-term results on the first 119 cases to have a follow-up of at least six months. Occlusion of the insufficient gonadal vein is induced by the selective transcatheter injection of sclerosing agent with local anesthesia. Their patients are always evaluated before and after the procedure by Doppler examination. A spermiogram is done before the procedure and after six months. In this series they registered only 4 recurrences with no major complications.

[Embolization of the splenic artery in cirrhotic patients with portal hypertension. Ultrasound results and follow-up]. / L'embolizzazione dell'arteria splenica nei pazienti cirrotici con ipertensione portale. Risultati e controlli ecografici.

Over the last four years the authors performed transcatheter embolization of the splenic artery by Gianturco coils in 32 consecutive cirrhotic patients with portal hypertension, splenomegaly, cytopenia and gastro-esophageal varices endoscopically proved. This procedure was especially useful for treatment of splenomegaly and cytopenia because a constant reduction of spleen dimensions and increase in platelet count were registered. The effectiveness of transcatheter embolization and follow-up are based on clinic, hematologic and sonographic findings. We believe sonographic monitoring to be very useful both to evaluate splenomegaly and signs of portal hypertension and to reveal splenic complications (abscesses). We never registered severe complications.

Therapeutic embolization of renal artery to control severe hypertension due to renal trauma.

In a young patient with a post-traumatic renal hematoma, severe systemic hypertension, secondary to the activation of the renin-angiotensin axis, developed. Because of persistent hypertension, after 3 months of drug therapy, selective percutaneous embolization of the damaged vessels was performed. One year after procedure, the patient is normotensive without drugs.

[Hemobilia: comparison of diagnostic technics. Considerations on 14 patients]. / Emobilia: tecniche diagnostiche a confronto. Considerazioni su 14 pazienti.

Fourteen cases of hemobilia of traumatic (six), vascular (six) or neoplastic (two) origin were reviewed. Eleven patients obtained correct diagnosis only be integration of at least two diagnostic procedures out of Ultrasonography, Computed Tomography, arteriography and cholangiography. Although US and CT are extremely useful as screening procedures, correct diagnosis should be only possible by integration of more diagnostic technics. Arterial embolization represents a successful alternative to surgical intervention; moreover US may also be helpful for follow-up of treated patients.

[Pleural colonization of thymoma]. / Le colonizzazioni pleuriche del timoma.

Six observations of peculiar pleural implants completely separated from invasive thymomas (examined by conventional chest x-ray and CT) were reviewed. CT was more effective than chest x-ray; number, size and extent of pleural lesions were underestimated by plain film studies. Moreover CT provides a densitometric evaluation of the pleural pathology being useful in differential diagnosis. CT can also be helpful as a guide to needle biopsy.

[Percutaneous treatment of varicocele]. / Trattamento percutaneo del varicocele.

Percutaneous occlusion of the spermatic vein has been performed in 104 patients with varicocele in the last five years. We report our long-term results on the first 87 cases with a follow-up of at least six months. The occlusion of the gonadal vein is generally induced by selective transcatheter injection of sclerosing agent. Our patients are always evaluated before and after sclerotherapy by telethermography and/or doppler examination. Furthermore spermiogram is obtained before and six months after therapy. We registered only four recurrences with no major complications.