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.
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.
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.
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%.
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.
ABSTRACT
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.
We report three cases of ruptured mycotic thoracoabdominal aortic aneurysms (TAAAS) and a review of the literature. Escherichia coli and Streptococcus pneumoniae (2 patients) were the responsible ...organisms. Surgical management consisted of wide debridement of necrotic tissue and in situ repair with a Dacron graft. Antibiotics were administered intravenously in the hospital and continued orally after discharge for at least 6 weeks, until clinical and laboratory parameters were normalized. A review of the literature showed that Gram-negative microorganisms are found in 47% of mycotic TAAAs. A trend toward increased mortality for these organisms, compared with Gram-positive microorganisms, was observed (P =.09). Lifelong antimicrobial therapy is controversial. No difference in survival or recurrence rate was found between series advocating lifelong therapy and those suggesting prolonged (6 weeks to 12 months) therapy (median follow-up period, 18 and 19 months, respectively). In situ repair with synthetic material can be successful if prompt confirmation of infection is obtained, all possibly infected tissue is resected, and antibiotic therapy based on sensitivity data is administered for a prolonged period. A short-term survival rate as high as 82% can be expected with this strategy, but data on long-term survival rates are limited. Polytetrafluoroethylene-expanded grafts, homografts, and antibiotic-bonded grafts may offer advantages over Dacron grafts, but data are insufficient to draw conclusions. Careful long-term follow-up is an important element of the treatment of these patients. We suggest antibiotic treatment until biochemical parameters of inflammation (white cell count, erythrocyte sedimentation rate, or C-reactive protein) return to normal and a computerized tomography scan every 3 months for 1 year, then annually. (J Vasc Surg 2001;33:861-7.)
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.
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? 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?
Right-sided aortic arch is a rare variant of the thoracic vascular anatomy that may be accompanied by an aberrant origin of the left subclavian artery. We report a true aneurysm of the distal arch ...and descending thoracic aorta in a patient with right-sided arch and review previous descriptions of aneurysms of anomalous right-sided aortas. In our patient, the left subclavian artery originated at the junction between the distal arch and the descending thoracic aorta located in the right chest and was aneurysmal (Kommerell’s diverticulum); the thoracic aorta was also aneurysmal. Extra-anatomic left subclavian-to-carotid transposition was performed before the intrathoracic procedure. Subsequently, a right thoracotomy provided adequate exposure for repairing the aortic aneurysm and oversewing the aneurysmal origin of the subclavian artery. Because the distal aortic arch was involved, deep hypothermia and circulatory arrest were used. Only five previous instances of true aneurysms of a right-sided aortic arch have been reported; four of these patients underwent operative repair (via bilateral thoracotomy, median sternotomy, or right thoracotomy). We believe that a right thoracotomy provides good exposure and avoids the morbidity associated with bilateral thoracotomy. The reconstruction of the subclavian artery has not previously been reported in this setting. Performing subclavian reconstruction as an extrathoracic procedure before the intrathoracic repair would be expected to reduce the subsequent risk of distal ischemia or subclavian steal without increasing the overall morbidity associated with the procedure. (J Vasc Surg 2000;32:1208-14.)
This report focuses on the surgical management of aggressive intracranial dural arteriovenous fistulae (d-AVFs), which are defined as fistulae with arterialized leptomeningeal veins (red veins). ...Particular attention is paid to the accurate identification of the venous drainage pattern and to the choice of the proper treatment strategy.
Thirty-four consecutive patients with aggressive intracranial d-AVFs were treated between 1994 and 1998. Angiographic studies allowed the identification of two main types of aggressive lesions, i.e., d-AVFs with sinus drainage and reflow into leptomeningeal veins (12 patients), which we designated sinus fistulae, and d-AVFs drained exclusively by leptomeningeal veins without sinus interposition (22 patients), which we designated nonsinus fistulae. All patients underwent surgical treatment, which consisted of resection of the fistulous sinus tract in 12 cases of sinus fistulae and interruption of the draining veins at their dural origin in 22 cases of nonsinus fistulae. Surgical preparation via multistage transarterial embolization was required in all 12 cases of sinus fistulae and in 4 of 22 cases of nonsinus fistulae.
The mortality rate was 0%, and there were no instances of lasting morbidity. Radioanatomic cures were achieved in all cases. There was no case of venous hypertension or venous infarction after resection of the affected sinus or interruption of the draining veins. No arteriovenous shunts recurred during the follow-up period.
Careful preoperative identification of the venous drainage pattern seems critical for planning of the correct surgical strategy to treat aggressive intracranial d-AVFs. If the fistula exhibits sinus drainage with reflow into leptomeningeal veins, surgical excision of the fistulous sinus segment represents a safe and definitive treatment option. In these cases, the affected sinus may be safely removed, provided that preoperative angiograms demonstrate participation of the sinus in drainage of the lesion, indicating that the sinus is nonfunctional. Conversely, if the fistula exhibits pure leptomeningeal drainage, the sinus does not participate in drainage of the lesion and cannot be excised. In these cases, the best treatment involves interruption of the draining veins at the point at which they exit the dural wall of the sinus. This simple easy treatment has been proven to be safe and highly effective in permanently eliminating arteriovenous shunts.
Abstract 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.
Anthropogenic disturbance of tropical humid forests leads to habitat loss, biodiversity decline, landscape fragmentation, altered nutrient cycling and carbon sequestration, soil erosion, ...pest/pathogen outbreaks, among others. Nevertheless, the impact of these alterations in multitrophic interactions, including host–pathogen and vector–pathogen dynamics, is still not well understood in wild plants. This study aimed to provide insights into the main drivers for the incidence of herbivory and plant pathogen damage, specifically, into how vegetation traits at the local and landscape scale modulate such interactions. For this purpose, in the tropical forest of Calakmul (Campeche, Mexico), we characterised the foliar damage caused by herbivores and pathogens in woody vegetation of 13 sampling sites representing a gradient of forest disturbance and fragmentation in an anthropogenic landscape from well preserved to highly disturbed and fragmented areas. We also evaluated how the incidence of such damage was modulated by the vegetation and landscape attributes. We found that the incidence of damage caused by larger, mobile, generalist herbivores, was more sensitive to changes in landscape configuration, while the incidence of damage caused by small and specialised herbivores with low dispersal capacity was more influenced by vegetation and landscape composition. In relation to pathogen symptoms, the herbivore-induced foliar damage seems to be the main factor related to their incidence, indicating the enormous importance of herbivorous insects in the modulation of disease dynamics across tropical vegetation, as they could be acting as vectors and/or facilitating the entry of pathogens by breaking the foliar tissue and the plant defensive barriers. The incidence of pathogen damage also responded to vegetation structure and landscape configuration; the incidence of anthracnose, black spot, and chlorosis, for example, were favoured in sites surrounded by smaller patches and a higher edge density, as well as those with a greater aggregation of semi-evergreen forest patches. Fungal pathogens were shown to be an important cause of foliar damage for many woody species. Our results indicate that an increasing transformation and fragmentation of the tropical forest of southern Mexico could reduce the degree of specialisation in plant–herbivore interactions and enhance the proliferation of generalist herbivores (chewers and scrapers) and of mobile leaf suckers, and consequently, the proliferation of some symptoms associated with fungal pathogens such as fungus black spots and anthracnose. The symptoms associated with viral and bacterial diseases and to nutrient deficiency, such as chlorosis, could also increase in the vegetation in fragmented landscapes with important consequences in the health and productivity of wild and cultivated plant species. This is a pioneering study evaluating the effect of disturbances on multitrophic interactions, offering key insights on the main drivers of the changes in herbivory interactions and incidence of plant pathogens in tropical forests.
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