Horizontal Transfer of Malignant Traits and the Involvement of Extracellular Vesicles in Metastasis.

Metastases are responsible for the vast majority of cancer deaths, yet most therapeutic efforts have focused on targeting and interrupting tumor growth rather than impairing the metastatic process. Traditionally, cancer metastasis is attributed to the dissemination of neoplastic cells from the primary tumor to distant organs through blood and lymphatic circulation. A thorough understanding of the metastatic process is essential to develop new therapeutic strategies that improve cancer survival. Since Paget's original description of the "Seed and Soil" hypothesis over a hundred years ago, alternative theories and new players have been proposed. In particular, the role of extracellular vesicles (EVs) released by cancer cells and their uptake by neighboring cells or at distinct anatomical sites has been explored. Here, we will outline and discuss these alternative theories and emphasize the horizontal transfer of EV-associated biomolecules as a possibly major event leading to cell transformation and the induction of metastases. We will also highlight the recently discovered intracellular pathway used by EVs to deliver their cargoes into the nucleus of recipient cells, which is a potential target for novel anti-metastatic strategies.

Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum.

Extracellular vesicles (EVs) are mediators of intercellular communication under both healthy and pathological conditions, including the induction of pro-metastatic traits, but it is not yet known how and where functional cargoes of EVs are delivered to their targets in host cell compartments. We have described that after endocytosis, EVs reach Rab7+ late endosomes and a fraction of these enter the nucleoplasmic reticulum and transport EV biomaterials to the host cell nucleoplasm. Their entry therein and docking to outer nuclear membrane occur through a tripartite complex formed by the proteins VAP-A, ORP3 and Rab7 (VOR complex). Here, we report that the antifungal compound itraconazole (ICZ), but not its main metabolite hydroxy-ICZ or ketoconazole, disrupts the binding of Rab7 to ORP3-VAP-A complexes, leading to inhibition of EV-mediated pro-metastatic morphological changes including cell migration behaviour of colon cancer cells. With novel, smaller chemical drugs, inhibition of the VOR complex was maintained, although the ICZ moieties responsible for antifungal activity and interference with intracellular cholesterol distribution were removed. Knowing that cancer cells hijack their microenvironment and that EVs derived from them determine the pre-metastatic niche, small-sized inhibitors of nuclear transfer of EV cargo into host cells could find cancer therapeutic applications, particularly in combination with direct targeting of cancer cells.

Biomechanical characterization of a chronic type a dissected human aorta.

Aortic dissection is one of the most lethal cardiovascular diseases. A chronic Type A (Stanford) dissected aorta was retrieved for research from a 73-year-old male donor without diagnosed genetic disease. The aorta presented a dissection over the full length, and it reached a diameter of 7.7 cm in its ascending portion. The descending thoracic aorta underwent layer-specific quasi-static and dynamic mechanical characterizations after layer separation. Mechanical tests showed a physiological (healthy) behavior of the intima and some mechanical anomalies of the media and the adventitia. In particular, the static stiffness of both these layers at smaller strains was three times smaller than any one measured for twelve healthy aortas. When the viscoelastic properties were tested, adventitia presented a larger relative increase of the dynamic stiffness at 3 Hz with respect to most of the healthy aortas. The loss factor of the adventitia, which is associated with dissipation, was at the lower limit of those measured for healthy aortas. It seems reasonable to attribute these anomalies of the mechanical properties exhibited by the media and the adventitia to the severe remodeling secondary to the chronic nature of the dissection. However, it cannot be excluded that some of the mechanical anomalies were present before remodeling.

Prevention of perineal hernia after laparoscopic and robotic abdominoperineal resection: review with illustrative case series of internal hernia through pelvic mesh.

ABSTRACT: This review is intended to raise awareness of placing a pelvic mesh to prevent perineal hernias in cases of minimally invasive (MIS) abdominoperineal resections (APR) and, in doing so, causing internal hernias through the mesh. In this article, we review the published literature and present an illustrative series of 4 consecutive cases of early internal hernia through a pelvic mesh defect. These meshes were placed to prevent perineal hernias after laparoscopic or robotic APRs. The discussion centres on 3 key questions: Should one be placing a pelvic mesh following an APR? What are some of the technical details pertaining to the initial mesh placement? What are the management options related to internal hernias through such a mesh?

RESUME: L'objectif du présent examen est de sensibiliser les praticiens au risque associé à la pose d'un treillis pelvien visant à prévenir les hernies périnéales après une résection abdominopérinéale à effraction minimale, pratique qui peut entraîner une hernie interne. Nous nous penchons ici sur les articles publiés à ce sujet et présentons une série éloquente de 4 cas consécutifs de hernies internes précoces attribuables à un défaut du treillis. Les dispositifs avaient été mis en place pour prévenir une hernie périnéale après des résections laparoscopiques ou robotiques. La discussion porte sur 3 questions centrales : Devrait-on poser un treillis pelvien à la suite d'une résection abdominopérinéale? Quels sont les éléments techniques à surveiller lors de la pose initiale? Quelles sont les options de prise en charge des hernies internes causées par les treillis?

Total sacrectomy for recurrent rectal cancer - A case report featuring technical details and potential pitfalls.

INTRODUCTION: Total sacrectomy for recurrent rectal cancer is controversial. However, recent publications suggest encouraging outcomes with high sacral resections. We present the first case report describing technical aspects, potential pitfalls and treatment of complications associated with total sacrectomy performed as a treatment of recurrent rectal cancer. PRESENTATION OF CASE: A fifty-three year old man was previously treated at another institution with a low anterior resection (LAR) followed by chemo-radiation and left liver tri-segmentectomy for metastatic rectal cancer. Three years following the LAR, the patient developed a recurrence at the site of colorectal anastomosis, manifesting clinically as a contained perforation, forming a recto-cutaneous fistula through the sacrum. Abdomino-perineal resection (APR) and complete sacrectomy were performed using an anterior-posterior approach with posterior spinal instrumented fusion and pelvic fixation using iliac crest bone graft. Left sided vertical rectus abdominis muscle flap and right sided gracilis muscle flap were used for hardware coverage and to fill the pelvic defect. One year after the resection, the patient remains disease free and has regained the ability to move his lower limbs against gravity. DISCUSSION: The case described in this report features some formidable challenges due to the previous surgeries for metastatic disease, and the presence of a recto-sacral cutaneous fistula. An approach with careful surgical planning including considerationof peri-operative embolization is vital for a successful outcome of the operation. A high degree of suspicion for pseudo-aneurysms formation due infection or dislodgement of metallic coils is necessary in the postoperative phase. CONCLUSION: Total sacrectomy for the treatment of recurrent rectal cancer with acceptable short-term outcomes is possible.A detailed explanation to the patient of the possible complications and expectations including the concept of a very high chancefor recurrence is paramount prior to proceeding with such a surgery.

Cerebrospinal fluid drainage to prevent paraplegia during thoracic and thoracoabdominal aortic aneurysm surgery: a systematic review and meta-analysis.

OBJECTIVES: We undertook a quantitative systematic review of randomized controlled trials (RCTs) and observational studies to determine the effectiveness of cerebrospinal fluid (CSF) drainage to prevent paraplegia in thoracic aneurysm (TA) and thoracoabdominal aortic aneurysm (TAAA) surgery. METHODS: We included RCTs and cohort studies that met the following criteria: elective or emergent aneurysm surgery involving the thoracic or thoracoabdominal aorta, documentation of postoperative neurologic deficits, and patient age older than 18 years. We excluded studies that reported results in 10 or fewer patients and duplicate publications. We identified eligible studies by searching computerized databases, our own files, and the reference lists of relevant articles and review articles. Database searching, eligibility decisions, relevance and method quality assessments, and data extraction were performed in duplicate with prespecified criteria. RESULTS: Of 372 publications identified in our search, 14 met our eligibility criteria. Three RCTs reported 289 patients with type I or type II TAAA. Lower limb neurologic deficits occurred in 12% of patients who underwent CSF drainage and 33% of control subjects (number needed to treat, 9; 95% confidence interval [CI], 5-50). The pooled odds ratio (OR) for development of paraplegia in patients in the CSF drainage group was 0.35 (P =.05; 95% CI, 0.12-0.99). Similar results were found in five cohort studies with a control group (pooled OR, 0.26; P =.0002; 95% CI, 0.13-0.53). When all studies were considered together the pooled OR of TA and TAAA was 0.3 (95% CI, 0.17-0.54). There was no statistical heterogeneity among studies included in the meta-analysis. In six cohort studies without a control group, the incidence of paraplegia in high-risk TA and TAAA was 7.6%. CONCLUSIONS: Evidence from randomized and nonrandomized trials and from cohort studies support the use of CSF drainage as an adjunct to prevent paraplegia when this adjunct is used in centers with large experience in the management of TAAA.