Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells.

A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer's Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1ß and IL-6 mRNA in the brain´s prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APPNL-G-F/NL-G-F Alzheimer´s mouse model. In all cases, the improvement in learning capacity was associated with a downregulation of IL-1ß mRNA. Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimer´s disease. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNS-related diseases.

[Irreversible electroporation: present and future in the treatment of hepatocellular carcinoma].

Currently, among the possible treatments for hepatocellular carcinoma there is group of minimally invasive ablation techniques with wide clinical acceptance due to their greater efficacy and safety in comparison to traditional therapies, low cost, and no need of being admitted to hospital (outpatient treatment program). Irreversible electroporation is a non-thermal ablation technique in which electrical fields are used to create nanopores in the cell membrane that induce tumor cell death. Irreversible electroporation has shown promising results in numerous clinical trials; however, its control on long-term tumor growth and recurrence is inferior in comparison to that of radiofrequency. Combining irreversible electroporation with immunological agents may increase its efficacy in the treatment of focal lesions and metastases. In this work, we present an update on IRE including procedure, mechanism of action, application as a treatment for HCC, and the improvements that have been made in the past few years.

Electroporación irreversible: presente y futuro en el tratamiento del carcinoma hepatocelular / Irreversible electroporation: present and future in the treatment of hepatocellular carcinoma

Entre los tratamientos actuales para el carcinoma hepatocelular se encuentra un grupo de técnicas de ablación mínimamente invasivas con gran aceptación clínica por su mayor eficacia y seguridad respecto a las terapias tradicionales, bajo coste económico y aplicación ambulatoria. La electroporación irreversible es una técnica de ablación no térmica que crea nanoporos en la membrana celular mediante administración de campos eléctricos, induciendo la muerte de las células tumorales. Aunque la electroporación irreversible presenta resultados prometedores en numerosos ensayos clínicos, su control a largo plazo del crecimiento y de las recidivas tumorales es inferior al de la radiofrecuencia. La combinación de electroporación irreversible con agentes inmunológicos podría aumentar su eficacia tanto en el tratamiento de lesiones focales como de metástasis. Esta revisión realiza una actualización sobre la electroporación irreversible: procedimiento, mecanismo de acción, aplicación como tratamiento del carcinoma hepatocelular y alternativas de mejora que están aflorando en los últimos años.(AU)

Currently, among the possible treatments for hepatocellular carcinoma there is group of minimally invasive ablation techniques with wide clinical acceptance due to their greater efficacy and safety in comparison to traditional therapies, low cost, and no need of being admitted to hospital (outpatient treatment program). Irreversible electroporation is a non-thermal ablation technique in which electrical fields are used to create nanopores in the cell membrane that induce tumor cell death. Irreversible electroporation has shown promising results in numerous clinical trials; however, its control on long-term tumor growth and recurrence is inferior in comparison to that of radiofrequency. Combining irreversible electroporation with immunological agents may increase its efficacy in the treatment of focal lesions and metastases. In this work, we present an update on IRE including procedure, mechanism of action, application as a treatment for HCC, and the improvements that have been made in the past few years.(AU)

Critical stenosis of the celiac trunk by the arcuate ligament, successfully treated by a laparoscopic approach.

A 56-year-old female was referred to our department with a five-month history of progressive abdominal pain related to physical exertion and copious meals. The pain was located in the mesogastric region and the right flank and remitted when the patient lay in the recumbent position with the knees bent. The patient reported nausea and a weight loss of 12 kg over the previous ten years. She had been diagnosed 18 years previously with hereditary leiomyomatosis and renal cancer and had undergone a hysterectomy and partial nephrectomy.

Testicular Pain as A Warning Symptom of a Symptomatic Abdominal Aortic Aneurysm: Case Report and Review of The Literature.

BACKGROUND: Isolated testicular pain is an unusual clinical presentation of symptomatic abdominal aortic aneurysms (AAA). We present two patients hemodynamically stable with an isolated acute testicular pain related to an AAA and a review of the published literature up to present. METHODS: Two adult-old males with an acute isolated testicular pain presented to the emergency department. Although both cases had their symptoms for more than 24 hours and were hemodynamically stable, the misdiagnosis of a urological condition in one case and a delay of the intervention in the second resulted in a sudden drop of vital signs and the need of an urgent open surgery. RESULTS: A bibliographic review of the 15 published cases is presented. Most cases occurred without a previous diagnosis of AAA. Aneurysms were characteristically very large (mean 10 cm). The initial diagnosis was frequently wrong, attributing the pain mostly to genito-urinary conditions. The testicular pain presented days and even weeks before rupture, which may offer a convenient window of hemodynamic stability for repair. CONCLUSIONS: Acute testicular pain in adult-old patients with aneurysm risk factors and specially with a first urological evaluation discarding a genitourinary disorder should alert clinicians to consider the diagnosis of a symptomatic abdominal aortic aneurysm. The early and accurate recognition of these cases may increase the survival.

A proof-of-concept study of the in-vivo validation of a computational fluid dynamics model of personalized radioembolization.

Radioembolization (RE) with yttrium-90 (90Y) microspheres, a transcatheter intraarterial therapy for patients with liver cancer, can be modeled computationally. The purpose of this work was to correlate the results obtained with this methodology using in vivo data, so that this computational tool could be used for the optimization of the RE procedure. The hepatic artery three-dimensional (3D) hemodynamics and microsphere distribution during RE were modeled for six 90Y-loaded microsphere infusions in three patients with hepatocellular carcinoma using a commercially available computational fluid dynamics (CFD) software package. The model was built based on in vivo data acquired during the pretreatment stage. The results of the simulations were compared with the in vivo distribution assessed by 90Y PET/CT. Specifically, the microsphere distribution predicted was compared with the actual 90Y activity per liver segment with a commercially available 3D-voxel dosimetry software (PLANET Dose, DOSIsoft). The average difference between the CFD-based and the PET/CT-based activity distribution was 2.36 percentage points for Patient 1, 3.51 percentage points for Patient 2 and 2.02 percentage points for Patient 3. These results suggest that CFD simulations may help to predict 90Y-microsphere distribution after RE and could be used to optimize the RE procedure on a patient-specific basis.

Intratumoral STING Agonist Injection Combined with Irreversible Electroporation Delays Tumor Growth in a Model of Hepatocarcinoma.

BACKGROUND/AIM: Irreversible electroporation (IRE) showed promising results for small-size tumors and very early cancers. However, further development is needed to evolve this procedure into a more efficient ablation technique for long-term control of tumor growth. In this work, we show that it is possible to increase the antitumor efficiency of IRE by simmultaneously injecting c-di-GMP, a STING agonist, intratumorally. MATERIALS AND METHODS: Intratumoral administration of c-di-GMP simultaneously to IRE was evaluated in murine models of melanona (B16.OVA) and hepatocellular carcinoma (PM299L). RESULTS: The combined therapy increased the number of tumor-infiltrating IFN-γ/TNF-α-producing CD4 and CD8 T cells and delayed tumor growth, as compared to the effect observed in groups treated with c-di-GMP or IRE alone. CONCLUSION: These results can lead to the development of a new therapeutic strategy for the treatment of cancer patients refractory to other therapies.

Minimally Invasive Surgical Approach for the Treatment of Superior Mesenteric Artery Syndrome: Long-Term Outcomes.

BACKGROUND: Latero-lateral duodenojejunostomy is the treatment of choice for superior mesenteric artery syndrome (SMAS). The present study analyzes the long-term outcomes in 13 patients undergoing laparoscopic surgery for SMAS. MATERIALS AND METHODS: A retrospective study of 10 females and three males undergoing surgery between 2001 and 2013 was performed. Demographic, clinical and radiologic data and long-term surgical outcomes were recorded. In 12 patients latero-lateral duodenojejunostomy and in one patient distal laparoscopic gastrectomy with Roux-en-Y reconstruction were performed. The median age was 24 years (20-28), and the median duration of symptoms was 24 months (5-24). The most frequent symptoms were abdominal pain (n = 11; 92.3%), nausea and vomiting (n = 10; 77%) and weight loss (n = 9; 69.2%). The median operating time was 98 min (86-138) and hospital stay was 3 days (1-14). RESULTS: No reconversions occurred, and one patient experienced gastric emptying delay in the immediate postoperative period with spontaneous resolution. In four patients, SMAS was associated with severe stenosis of the celiac trunk which was treated in the same operation, and four patients presented stenosis of the left renal vein (the "nutcracker" phenomenon). With a median follow-up of 94 months (SD 65.3), eight patients (61.5%) had excellent results. One patient had a relapse of symptoms 4 years after surgery requiring distal gastrectomy, two patients presented delay in gastric emptying following temporary improvement and one patient experienced no improvement. CONCLUSIONS: Latero-lateral duodenojejunostomy yields good results in SMAS although it requires other gastric motility disorders to be ruled out for appropriate treatment to be established.

Whole-body computed tomography: a new point of view in a hospital check-up unit? Our experience in 6516 patients.

BACKGROUND: There is a growing awareness that prevention and early diagnosis may reduce the high mortality associated with cancer, cardiovascular and other diseases. The role of whole-body computed tomography (WB-CT) in self-referred and asymptomatic patients has been debated. AIM: To determine frequency and spectrum of WB-CT findings in average-risk subjects derived from a Medical-Check-Up-Unit, to evaluate recommendations reported and distribution according to sex and age-groups. MATERIALS AND METHODS: We retrospectively reviewed 6516 subjects who underwent WB-CT (June 2004/February 2015). All were > 40 years and referred by Medical-Check-Up-Unit of our hospital. The main findings were categorized and classified as normal or not. Its distribution according to sex and age-groups was evaluated using Chi-square test and linear-by-linear association test, respectively. Number of recommendations, type and interval of follow-up were recorded. Descriptive statistics were used. RESULTS: WB-CT performed in 6516 patients (69% men, 31% women, mean age = 58.4 years) revealed chest (81.4%), abdominal (93.06%) and spine (65.39%) abnormalities. Only 1.60% had completely normal exploration. Abnormal WB-CT in men was significantly higher than women (98.64% vs. 97.87%; p = 0.021), with significant increase as age was higher (40-49 years: 95.65%; 50-59 years: 98.33%; 60-69 years: 99.47%; > 69 years: 99.89%) (p < 0.001). Although most findings were benign, we detected 1.47% primary tumors (96, mainly 35 kidneys and 15 lungs). 17.39% of patients received at least one recommendation predominantly in chest (78.19%) and follow-up imaging (69.89%). CONCLUSION: The most common WB-CT findings in asymptomatic subjects are benign. However, this examination allows identifying an important number of relevant and precocious findings that significantly increase with age, involving changes in lifestyle and precocious treatment.

Therapeutic Effect of Irreversible Electroporation in Combination with Poly-ICLC Adjuvant in Preclinical Models of Hepatocellular Carcinoma.

PURPOSE: To evaluate the therapeutic efficacy of irreversible electroporation (IRE) combined with the intratumoral injection of the immunogenic adjuvant poly-ICLC (polyinosinic-polycytidylic acid and poly-L-lysine, a dsRNA analog mimicking viral RNA) inmediately before IRE. MATERIALS AND METHODS: Mice and rabbits bearing hepatocellular carcinoma tumors (Hepa.129 and VX2 tumor models, respectively) were treated with IRE (2 pulses of 2500V), with poly-ICLC, or with IRE + poly-ICLC combination therapy. Tumor growth in mice was monitored using a digital caliper and by computed tomography in rabbits. RESULTS: Intratumoral administration of poly-ICLC immediately before IRE elicited shrinkage of Hepa.129 cell-derived tumors in 70% of mice, compared to 30% and 26% by poly-ICLC or IRE alone, respectively (P = .0004). This combined therapy induced the shrinkage of VX-2-based hepatocellular carcinoma tumors in 40% of rabbits, whereas no response was achieved by either individual treatment (P = .045). The combined therapy activated a systemic antitumor response able to inhibit the growth of other untreated tumors. CONCLUSIONS: IRE treatment, immediately preceded by the intratumoral administration of an immunogenic adjuvant such as poly-ICLC, might enhance the antitumor effect of the IRE procedure. This combination might facilitate the induction of a long-term systemic response to prevent tumor relapses and the appearance of metastases.

Chronic active hepatitis induced by Pazopanib mimicking hypervascular liver metastases in a patient with recurrent soft tissue sarcoma: A case report.

Pazopanib is the first multitargeted tyrosine-kinase inhibitor approved for the treatment of patients with advanced non-adipocytic soft tissue sarcoma (STS). It has been demonstrated to improve progression-free survival without impairing health-associated quality of life. However, Pazopanib is associated with several adverse side effects associated with inhibition of the vascular endothelial growth factor receptor. These include hepatotoxicity, as manifested by abnormal liver function tests. To the best of our knowledge, the current study presents the first case of a patient with recurrent STS who developed biopsy proven Pazopanib-induced chronic active hepatitis and whose previous computed tomography examination demonstrated multiple hypervascular liver lesions. These lesions were indistinguishable from metastases and to the best of our knowledge, have not been described previously. These lesions therefore appear to be a novel finding of Pazopanib-induced chronic active hepatitis. It is crucial to be aware of this unusual finding within a clinical setting, to avoid overstaging and early discontinuation of effective treatment.

Laparoscopic Treatment of Median Arcuate Ligament Syndrome: Analysis of Long-Term Outcomes and Predictive Factors.

BACKGROUND: Laparoscopic arcuate ligament release has been demonstrated a valid therapeutic option for arcuate ligament syndrome. Nevertheless, long-term follow-up and predictive factors have not been described for this treatment. METHODS: Clinical and surgical data and short- and long-term outcomes together with the impact of the degree of stenosis of the celiac trunk were analyzed in 13 consecutive patients who underwent laparoscopic arcuate ligament release between 2001 and 2013. RESULTS: Thirteen patients (12 F/1 M) underwent surgery. The median age was 32 years old, and their mean body mass index was 20.7 (range 14.7-25). The 13 patients presented with intense postprandial abdominal pain. Ten cases were associated with weight loss. The median duration of symptoms was 24 months (range 2-240). Three patients presented symptoms associated with superior mesenteric artery syndrome. Median operative time was 120 min (range 90-240), and there were no conversions to open surgery. Median hospital stay was 3 days (range 2-14). Over a median follow-up of 117 months (range 45-185), nine patients had excellent results although two required endovascular procedures at 70 and 24 months after surgery. Four patients (30.7%) experienced poor outcomes. When we analyzed the impact of the degree of occlusion of the celiac trunk, we observed that in patients with severe occlusion (> 70%), better results were obtained, with complete resolution of symptoms in 71% of cases. CONCLUSION: Laparoscopic arcuate ligament release constitutes an excellent treatment for arcuate ligament syndrome. The degree of occlusion of the celiac trunk may be a factor predictive of long-term outcomes.

Gastric diverticulum mimicking cystic lesion in left adrenal gland.

Adrenal pseudotumors can have many origins. We report the case of a gastric subcardial diverticulum misdiagnosed as a left adrenal cystic lesion on magnetic resonance imaging. A retrospective study of a previous computed tomography scan detected a previously unnoticed gastric diverticulum. The embryology, clinical aspects, and explanation of the misdiagnosis are exposed.

CT-guided permanent brachytherapy for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC).

Seven patients with early stage T1N0M0 NSCLC who had medical contraindications for surgical resection were treated with CT-guided percutaneous implantation of (103)Pd or (125)I seeds. After the procedure, two patients developed pneumothorax and hemo/pneumothorax that was managed with aspirative drainage. One patient developed a focal pneumonitis 3 months after the procedure. After a median follow-up of 13 months (4.6-41.0+ months), no patient has developed local or regional failure.

Intervascular anastomoses created by an endovascular approach: technical aspects and initial results in an animal study.

PURPOSE: The current article describes the initial results after the creation of intervascular connections with use of an exclusively endovascular approach. Connections of two vessels were performed in the thoracic and abdominal areas with use of a kinematic needle without traversing a solid organ. The materials developed specifically for this technique are described. MATERIALS AND METHODS: The procedure was carried out in 11 animals and consisted of bringing together two vascular structures with use of magnets, performing a puncture from the lumen of one vessel to that of the other, and inserting a prosthesis between the two. The prosthesis has a biconical morphology and is made with a 0.016-inch monofilament of nitinol. Its most outstanding feature is that, when it is dilated with a balloon, it shortens and "rolls up," flattening its ends. This allows good fixation to the vessel wall, avoiding the protrusion of metal into the lumen of the native vessel. RESULTS: On four occasions, the aorta was connected to another nearby vessel: the abdominal aorta to the inferior vena cava (IVC; n = 1), the ascending aorta to the trunk of the pulmonary artery (n = 1), and the descending aorta to the left pulmonary artery (n = 2). On another four occasions, two veins were connected: the portal vein and the IVC. Finally, on three occasions, the right pulmonary artery was connected to the superior vena cava. The connection was safely and accurately performed with passage of a guide wire in all cases. In two experiments, the prosthesis was too short and leakage with massive bleeding was observed after a successful initial deployment of the prosthesis CONCLUSION: Intervascular anastomoses created by an endovascular approach are feasible in the authors' experimental model for several different vessel pairings.

Embolización portal prequirúrgica / Presurgical portal embolization

En pacientes con tumores hepáticos, el tratamiento más eficaz es la cirugía. Sin embargo, no todos pueden ser tratados de esta manera. Uno de los motivos que contraindican el tratamiento quirúrgico es que el parénquima hepático que queda tras la resección de la zona tumoral sea insuficiente para asegurar la función hepática del paciente. Es conocido que el hepatocito, tras determinados estímulos, tiene la posibilidad de desdiferenciarse y clonarse. La embolización portal prequirúrgica (EPP) del volumen hepático que se va a resecar puede generar, tras este estímulo y respuesta (que será diferente en hígados fibróticos y no fibróticos), un crecimiento hepático que alcanzará niveles adecuados en 3-4 semanas. Por tanto, la EPP puede incrementar el número de candidatos a recibir tratamiento quirúrgico y, del mismo modo, puede disminuir la aparición de posibles complicaciones postoperatorias. En este artículo se presentan lo criterios de inclusión y exclusión que, de forma comúnmente aceptada, se utilizan para realizar una EPP. No hay acuerdo, sin embargo, sobre la técnica más adecuada para acceder al sistema portal, por ejemplo, la vía contralateral (con punción de los segmentos portales que no van a ser resecados) tiene considerables ventajas técnicas, pero pone en riesgo de trombosis a las ramas portales del tejido hepático sano. Son muchos los materiales embolizantes que se han usado en EPP, algunos autores recomiendan el empleo de «pegamentos», pues son relativamente sencillos de utilizar, de bajo coste y altamente eficaces pero, por otra parte, generan una importante inflamación periportal que puede dificultar la resección quirúrgica. Si se emplean partículas, éstas deben ser de un tamaño que oscile entre las 100 y las 300 micras. En conclusión, aunque todavía hay muchos aspectos de la EPP que requieren ser investigados, la técnica debería de estar disponible en todos los centros en los que se realice cirugía hepática, pues los beneficios clínicos derivados de ésta son muy satisfactorios

Surgery is the most efficacious treatment for hepatic tumors; however, not all patients with hepatic tumors can be treated surgically. One condition in which surgery is contraindicated is when the amount of liver parenchyma remaining after resection of the affected zone is considered to be insufficient to ensure hepatic function. The hepatocyte is known to be able to dedifferentiate and clone itself after certain stimuli. Presurgical portal embolization (PPE) of the hepatic volume to be resected can generate hepatic growth after this stimulus and response (which will be different in fibrotic and nonfibrotic livers), achieving adequate levels within 3-4 weeks. Therefore, PPE can increase the number of candidates for surgical treatment and decrease the number of possible postsurgical complications. This article describes the commonly accepted inclusion and exclusion criteria used for PPE. There is no consensus, however, regarding the most appropriate technique for accessing the portal system. For example, the contralateral approach (with puncture of the portal segments that are not to be resected) has considerable technical advantages, but places the portal branches of healthy liver tissue at risk for thrombosis. Many different materials have been used for embolization in PPE. Some authors recommend the use of "glues", as these are relatively easy to use, low cost, and highly efficacious; however, they also generate significant periportal inflammation that can make surgical resection more difficult. If particles are used, they should measure between 100-300 micras. In conclusion, although many aspects of PPE still need to be investigated, this technique should be made available in all centers performing hepatic surgery, as it can result in significant clinical benefits