Long-term prognosis related to deep sedation in refractory status Epilepticus.

OBJECTIVE: To evaluate long-term prognosis in patients with refractory status epilepticus according to the level of sedation reached during drug-induced coma. MATERIALS AND METHODS: Longitudinal study of patients with status epilepticus who received anesthetics to induce therapeutic coma. Demographic data, clinical, and electroencephalographic characteristics were collected, as well as variables related to sedation. We considered as deep sedation the EEG burst-suppression patterns (suppression ratio > 50%). A GOSE (Glasgow Outcome Scale Extended) score of 7 or 8 was considered as good prognosis. A comparative study was carried out to identify predictors of good or poor prognosis at discharge, at 1 and 2 years of follow-up. RESULTS: We included 61 patients: 63.9% were men; mean age 53.5 ± 16.8 years (range 16-86 years), 39.3% reached deep sedation; 62.3% had > 48 h induced coma. The median hospital stay was 21 days, while 10 days in the intensive care unit (ICU). In the multiple regression analysis, an ICU length of stay ≥ 7 days was associated with poor prognosis at discharge and at long-term (P < .05), while deep sedation was associated only with poor long-term prognosis (1 and 2 years, P < .05). The Kaplan-Meier curve showed higher survival in the group that did not undergo deep sedation (P < .05). CONCLUSIONS: In refractory status epilepticus, deep sedation is associated with poor prognosis at long-term.

Efficacy, retention, and safety of brivaracetam in adult patients with genetic generalized epilepsy.

OBJECTIVE: The aim of this study was to evaluate the efficacy, tolerability, and retention of brivaracetam (BRV) in genetic generalized epilepsy (GGE) in real-life practice. METHODS: This is a retrospective cohort study of adult patients with GGE in whom BRV was started between 2016 and 2018, completing a follow-up period of ≥6 months. Clinical and electroencephalogram (EEG) characteristics were analyzed at baseline and at follow-up as outcome measures. RESULTS: Brivaracetam was started in 37 patients (mean age: 29.9 ±â€¯12.3 years; 73% women). Juvenile myoclonic epilepsy was the most common syndrome (43.2%). The primary indications for starting BRV were lack of efficacy (51.4%) and adverse events (AEs) (27%) of other antiepileptic drugs (AEDs). In total, 32.4% of patients received BRV monotherapy. Retention rate at 6 months was 81.1%; 83.8% of patients were considered responders, and 62.2% achieved seizure freedom. The primary reasons for withdrawal were treatment-emergent adverse events (TEAEs, 57.1%) and lack of efficacy (42.9%). The higher number of prior AED use was a risk factor for a lack of response [median = 4 (interquartile range (IQR): 3-4) vs 2 (IQR: 1-3); p < 0.05]. Patients with a previous response to valproic acid tended to have a higher response rate to BRV (86.7% vs 50%, p = 0.169). Eighty-three point eight percent (83.8%) of previous levetiracetam (LEV) responders also showed a good response to BRV. In terms of patients who presented LEV-related AEs, AE resolution was observed in 79.8%, particularly with regard to psychiatric AEs. Follow-up EEGs were compared with baseline EEGs in 25 patients (67.6%) during follow-up. Most patients showed a reduction (52%) or no change (36%) in interictal epileptiform discharge (IED) frequency. SIGNIFICANCE: Brivaracetam shows good responder and retention rates in GGE and is generally well tolerated. It is an appropriate alternative treatment for GGE, especially in refractory epilepsy and when other AEDs are not tolerated.

Usefulness of brain perfusion CT in focal-onset status epilepticus.

OBJECTIVE: To evaluate the perfusion computed tomography (PCT) patterns in patients with status epilepticus (SE). METHODS: We included consecutive SE patients, diagnosed by ictal encephalography (EEG) findings and clinical semiology, who prospectively underwent a dedicated PCT study of SE in the ictal phase. The perfusion maps were visually analyzed. For the quantitative assessment, regions of interest in areas where the maps suggested abnormalities were compared with the corresponding area in the unaffected contralateral cortex. Asymmetry indices between affected and unaffected hemispheres were calculated for the regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), time to peak (TTP), and mean transit time (MTT). Nine patients underwent a follow-up PCT after SE resolution, and the corresponding maps were compared to the ictal maps. In addition, we included a control group of 10 sex- and age-matched patients with SE mimics or postictal phenomena, who also underwent acute PCT during the study period. RESULTS: The study included 19 patients: mean age 69.47 ± (standard deviation) 15.9 years, 68.4% men. On visual analysis of parametric perfusion maps during the ictal phase, regional cortical hyperperfusion was depicted in 78.9% of patients. Quantitative analysis showed significantly increased rCBF (P = 0.002) and rCBV (P = 0.004) values and decreased TTP (P < 0.001) and MTT (P = 0.001) in cortical areas of the affected vs the unaffected side. The mean asymmetry index was 12.8 for rCBF, 13.7 for rCBV, -3.0 for TTP, and -3.7 for MMT. In the nine patients with a follow-up PCT, eight showed decreased intensity, rCBV (P = 0.035), and rCBF (P = 0.024) in the hyperperfusion areas. The sensitivity of hyperperfusion detection for the diagnosis of SE was 78.95%, specificity 90%, positive predictive value 93.75%, and negative predictive value 69.23%. Comparative quantitative analysis of asymmetry indices for rCBF, rCBV, and MTT between ictal PCT and control patients showed significant differences for all parameters (rCBF P = 0.001; rCBV P = 0.002; TTP P = 0.001; and MTT P = 0.001). SIGNIFICANCE: Visual and quantitative analysis of perfusion maps detects regional hyperperfusion in SE patients with good diagnostic capability. Perfusion was increased in PCT maps of the affected cerebral hemisphere as compared to the contralateral region during the ictal phase. PCT may provide valuable diagnostic information in patients with SE and complement the diagnostic value of EEG.

Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection?

BACKGROUND: For several decades now an antagonism between Trypanosoma cruzi infection and tumor development has been detected. The molecular basis of this phenomenon remained basically unknown until our proposal that T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum-resident chaperone, translocated-externalized by the parasite, may mediate at least an important part of this effect. Thus, recombinant TcCRT (rTcCRT) has important in vivo antiangiogenic and antitumor activities. However, the relevant question whether the in vivo antitumor effect of T. cruzi infection is indeed mediated by the native chaperone (nTcCRT), remains open. Herein, by using specific modified anti-rTcCRT antibodies (Abs), we have neutralized the antitumor activity of T. cruzi infection and extracts thereof, thus identifying nTcCRT as a valid mediator of this effect. METHODS: Polyclonal anti-rTcCRT F(ab')2 Ab fragments were used to reverse the capacity of rTcCRT to inhibit EAhy926 endothelial cell (EC) proliferation, as detected by BrdU uptake. Using these F(ab')2 fragments, we also challenged the capacity of nTcCRT, during T. cruzi infection, to inhibit the growth of an aggressive mammary adenocarcinoma cell line (TA3-MTXR) in mice. Moreover, we determined the capacity of anti-rTcCRT Abs to reverse the antitumor effect of an epimastigote extract (EE). Finally, the effects of these treatments on tumor histology were evaluated. RESULTS: The rTcCRT capacity to inhibit ECs proliferation was reversed by anti-rTcCRT F(ab')2 Ab fragments, thus defining them as valid probes to interfere in vivo with this important TcCRT function. Consequently, during infection, these Ab fragments also reversed the in vivo experimental mammary tumor growth. Moreover, anti-rTcCRT Abs also neutralized the antitumor effect of an EE, again identifying the chaperone protein as an important mediator of this anti mammary tumor effect. Finally, as determined by conventional histological parameters, in infected animals and in those treated with EE, less invasive tumors were observed while, as expected, treatment with F(ab')2 Ab fragments increased malignancy. CONCLUSION: We have identified translocated/externalized nTcCRT as responsible for at least an important part of the anti mammary tumor effect of the chaperone observed during experimental infections with T. cruzi.

Is It Possible to Intervene in the Capacity of Trypanosoma cruzi to Elicit and Evade the Complement System?

Chagas' disease is a zoonotic parasitic ailment now affecting more than 6 million people, mainly in Latin America. Its agent, the protozoan Trypanosoma cruzi, is primarily transmitted by endemic hematophagous triatomine insects. Transplacental transmission is also important and a main source for the emerging global expansion of this disease. In the host, the parasite undergoes intra (amastigotes) and extracellular infective (trypomastigotes) stages, both eliciting complex immune responses that, in about 70% of the cases, culminate in permanent immunity, concomitant with the asymptomatic presence of the parasite. The remaining 30% of those infected individuals will develop a syndrome, with variable pathological effects on the circulatory, nervous, and digestive systems. Herein, we review an important number of T. cruzi molecules, mainly located on its surface, that have been characterized as immunogenic and protective in various experimental setups. We also discuss a variety of parasite strategies to evade the complement system - mediated immune responses. Within this context, we also discuss the capacity of the T. cruzi infective trypomastigote to translocate the ER-resident chaperone calreticulin to its surface as a key evasive strategy. Herein, it is described that T. cruzi calreticulin inhibits the initial stages of activation of the host complement system, with obvious benefits for the parasite. Finally, we speculate on the possibility to experimentally intervene in the interaction of calreticulin and other T. cruzi molecules that interact with the complement system; thus resulting in significant inhibition of T. cruzi infectivity.

The Interactions of Parasite Calreticulin With Initial Complement Components: Consequences in Immunity and Virulence.

Because of its capacity to increase a physiologic inflammatory response, to stimulate phagocytosis, to promote cell lysis and to enhance pathogen immunogenicity, the complement system is a crucial component of both the innate and adaptive immune responses. However, many infectious agents resist the activation of this system by expressing or secreting proteins with a role as complement regulatory, mainly inhibitory, proteins. Trypanosoma cruzi, the causal agent of Chagas disease, a reemerging microbial ailment, possesses several virulence factors with capacity to inhibit complement at different stages of activation. T. cruzi calreticulin (TcCalr) is a highly-conserved, endoplasmic reticulum-resident chaperone that the parasite translocates to the extracellular environment, where it exerts a variety of functions. Among these functions, TcCalr binds C1, MBL and ficolins, thus inhibiting the classical and lectin pathways of complement at their earliest stages of activation. Moreover, the TcCalr/C1 interaction also mediates infectivity by mimicking a strategy used by apoptotic cells for their removal. More recently, it has been determined that these Calr strategies are also used by a variety of other parasites. In addition, as reviewed elsewhere, TcCalr inhibits angiogenesis, promotes wound healing and reduces tumor growth. Complement C1 is also involved in some of these properties. Knowledge on the role of virulence factors, such as TcCalr, and their interactions with complement components in host-parasite interactions, may lead toward the description of new anti-parasite therapies and prophylaxis.

Trypanosoma cruzi Calreticulin: Immune Evasion, Infectivity, and Tumorigenesis.

To successfully infect, Trypanosoma cruzi evades and modulates the host immune response. T. cruzi calreticulin (TcCalr) is a multifunctional, endoplasmic reticulum (ER)-resident chaperone that, translocated to the external microenvironment, mediates crucial host-parasite interactions. TcCalr binds and inactivates C1 and mannose-binding lectin (MBL)/ficolins, important pattern- recognition receptors (PRRs) of the complement system. Using an apoptotic mimicry strategy, the C1-TcCalr association facilitates the infection of target cells. T. cruzi infection also seems to confer protection against tumorigenesis. Thus, recombinant TcCalr has important antiangiogenic properties, detected in vitro, ex vivo, and in ovum, most likely contributing at least in part, to its antitumor properties. Consequently, TcCalr is useful for investigating key issues of host-parasite interactions and possible new immunological/pharmacological interventions in the areas of Chagas' disease and experimental cancer.

Perampanel: A therapeutic alternative in refractory status epilepticus associated with MELAS syndrome.

To our knowledge, there are no reports of status epilepticus (SE) associated with mitochondrial diseases and treated with perampanel (PER). We present three cases of patients with refractory SE associated with MELAS syndrome who responded favorably to PER. All cases were diagnosed as non-convulsive SE (focal without impairment of level of consciousness). After an initial treatment with other anti-seizure drugs, PER was added in all cases (8, 16 and 12 mg) and cessation of SE was observed within the next 4-8 hours. All the cases involved a stroke-like lesion present on brain MRI. In our patients, PER was an effective option in SE associated with MELAS syndrome.

Long-term epilepsy after early post-stroke status epilepticus.

PURPOSE: The risk of developing epilepsy at long term after post-stroke status epilepticus (PSSE) is unknown. We aimed to evaluate post-stroke epilepsy (PSE) after early-onset PSSE and its associated factors. METHOD: All consecutive patients with early-onset PSSE and no history of epilepsy admitted to our hospital between February 2011 and April 2017 were included. We analysed status epilepticus (SE) and stroke-related factors in relation to the development of PSE. RESULTS: Fifty patients with early-onset PSSE were analysed. Mean age was 74.8 ± 14.3 years and 22 (44%) were women. Median NIHSS at the onset of PSSE was 11 (IQR 4-16) and median PSSE duration was 12 h (IQR 4.69-57). Median follow-up was 214 days (IQR 7.5-747). Ten patients (20%) developed PSE at a median delay of 153 days (IQR 20-334). On multivariate analysis, NIHSS > 4 (p = 0.019; hazard ratio: 15.757; 95% CI, 1.564-158.799) and PSSE > 16 h (p = 0.023; hazard ratio: 7.483; 95% CI, 1.325-42.276) were independently associated with a greater risk of PSE. The mean time from PSSE to onset of recurrent seizures was 142 days (IQR 19-153) in patients with PSSE > 16 h and 310 days (IQR 147-480) in PSSE < 16 h (p = 0.094). CONCLUSIONS: NIHSS score >4 at the stroke presentation and PSSE duration >16 h may predict of PSE in patients with early-onset PSSE. Recurrence may develop earlier in PSSE patients with longer duration of the episode.

Prognosis of post-stroke status epilepticus: Effects of time difference between the two events.

PURPOSE: This study aimed to investigate the prognosis of patients with status epilepticus (SE) following stroke, focusing on the timing of SE after the event and other unexplored variables. METHODS: All consecutive patients experiencing post-stroke SE (PSSE) in our center were included (2011-2016). We analyzed SE- and stroke-related factors in relation to the patients' outcome. RESULTS: 95 patients with PSSE (54 ischemic and 41 hemorrhagic stroke) were analyzed; 40 were women (42.1%) and mean age was 72.7 ±â€¯13.56 years. 51(53.7%) showed prominent motor symptoms, 49(51.6%) needed >2 antiepileptic drugs, and 27(28.4%) required anesthetics. Median duration of SE was 12 h (1-240). Median time from stroke to SE was 15 days (0-532). At discharge, logistic regression identified SE within 72 h after stroke (p = 0.004), baseline mSTESS (p = 0.009), and lesion volume (p = 0.001) as independent factors predicting mortality. Female sex (p = 0.019), SE duration >12 h (p = 0.005), temporal lobe involvement (p = 0.029), and stroke-to-SE time <90 days (p < 0.0001) were independent predictors of functional decline. At long-term follow-up, SE occurring within 72 h after stroke (p = 0.0001), SE duration (p = 0.004), and baseline mSTESS score (p = 0.012) remained as predictive of mortality. CONCLUSIONS: The timing of SE after stroke is associated with different consequences: mortality was higher when SE occurred within the first 72 h after stroke and this risk persisted at follow-up, whereas risk of functional decline was higher when SE occurred during the first 3 months. Other factors such as the mSTESS score and SE duration were associated with outcome at both discharge and long-term follow-up.

Prognosis of status epilepticus in patients requiring intravenous anesthetic drugs (a single center experience).

PURPOSE: There is concern about the safety of anesthetic drugs (IVADs) in the management of status epilepticus (SE). To clarify this aspect, we aimed to assess the factors associated with a poor prognosis in SE requiring anesthetics. METHOD: We analyzed all SE requiring IVADs between October 2011 and December 2015. Demographics, clinical data, etiology, SE duration, indications for sedation, electroencephalography features, complications and the prognosis at discharge were collected. Hypoxic etiology was ruled out. RESULTS: 73 patients needed IVADs. These were indicated as third-line treatment for SE in 58.9%, for decreased level of consciousness resulting from previous treatments in 27.4%, and for the underlying etiology in 13.7%. At discharge 41(56.2%) patients showed a bad outcome and 32 a good outcome. Outcome was poorer in patients with higher STESS (p=0.003), lower level of consciousness (p=0.025), non-convulsive SE in coma (p=0.040), potentially fatal etiology-PFE (p=0.006), longer duration (p=0.026), presence of complications (p=0.022), use of IVADs due to the underlying etiology (p=0.020), and periodic epileptiform discharges on electroencephalography (p=0.032). Following multivariate analysis, SE duration >12h (OR=3.266; 95%CI=1.077-9.908; p=0.037), STESS ≥3 (OR=4.816; 95%CI=1.435-16.165; p=0.011), and PFE (OR=3.526; 95%CI=1.184-10.506; p=0.024) were independently associated with a poor functional prognosis. Regarding mortality, duration >12h (OR=7.07; 95%CI=1.836-27.220; p=0.004), low level of consciousness (OR=6.97; 95%CI=1.194-40.718; p=0.031), and presence of complications (OR=21.32; 95%CI=2.440-186.295; p=0.006) were independent predictors of death. CONCLUSIONS: Lengthy duration of SE in patients requiring IVADs is associated with a poorer prognosis and death. A STESS ≥3 and the etiology seem mainly related to the functional status at discharge, whereas more severely impaired consciousness and complications during sedation are related to mortality.

Exogenous Calreticulin, incorporated onto non-infective Trypanosoma cruzi epimastigotes, promotes their internalization into mammal host cells.

Chagas disease is an endemic pathology in Latin America, now emerging in developed countries, caused by the intracellular protozoan Trypanosoma cruzi, whose life cycle involves three stages: amastigotes, epimastigotes, and trypomastigotes. T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum resident chaperone, translocates to the external cellular membrane, where it captures complement component C1, ficolins and MBL, thus inactivating the classical and lectin pathways. Trypomastigote-bound C1 is detected as an "eat me" signal by macrophages and promotes the infective process. Unlike infective trypomastigotes, non-infective epimastigotes either do not express or express only marginal levels of TcCRT on their external membrane. We show that epimastigotes bind exogenous rTcCRT to their cellular membrane and, in the presence of C1q, this parasite form is internalized into normal fibroblasts. On the other hand, Calreticulin (CRT)-deficient fibroblasts show impaired parasite internalization. In synthesis, CRT from both parasite and host cell origin is important in the establishment of C1q-dependent first contacts between parasites and host cells.

Molluskan Hemocyanins Activate the Classical Pathway of the Human Complement System through Natural Antibodies.

Molluskan hemocyanins are enormous oxygen-carrier glycoproteins that show remarkable immunostimulatory properties when inoculated in mammals, such as the generation of high levels of antibodies, a strong cellular reaction, and generation of non-specific antitumor immune responses in some types of cancer, particularly for superficial bladder cancer. These proteins have the ability to bias the immune response toward a Th1 phenotype. However, despite all their current uses with beneficial clinical outcomes, a clear mechanism explaining these properties is not available. Taking into account reports of natural antibodies against the hemocyanin of the gastropod Megathura crenulata [keyhole limpet hemocyanin (KLH)] in humans as well as other vertebrate species, we report here for the first time, the presence, in sera from unimmunized healthy donors, of antibodies recognizing, in addition to KLH, two other hemocyanins from gastropods with documented immunomodulatory capacities: Fisurella latimarginata hemocyanin (FLH) and Concholepas concholepas hemocyanin (CCH). Through an ELISA screening, we found IgM and IgG antibodies reactive with these hemocyanins. When the capacity of these antibodies to bind deglycosylated hemocyanins was studied, no decreased interaction was detected. Moreover, in the case of FLH, deglycosylation increased antibody binding. We evaluated through an in vitro complement deposition assay whether these antibodies activated the classical pathway of the human complement system. The results showed that all three hemocyanins and their deglycosylated counterparts elicited this activation, mediated by C1 binding to immunoglobulins. Thus, this work contributes to the understanding on how the complement system could participate in the immunostimulatory properties of hemocyanins, through natural, complement-activating antibodies reacting with these proteins. Although a role for carbohydrates cannot be completely ruled out, in our experimental setting, glycosylation status had a limited effect. Finally, our data open possibilities for further studies leading to the design of improved hemocyanin-based research tools for diagnosis and immunotherapy.

Use of perampanel in one case of super-refractory hypoxic myoclonic status: Case report.

UNLABELLED: Proper treatment of hypoxic myoclonic status is not clearly determined. Induced hypothermia is improving prognosis and a more aggressive treatment might be beneficial in some patients. Among the new options of antiepileptic drugs, perampanel (PER) is a drug with a novel mechanism, and it might be a promising drug for myoclonic status or as an antimyoclonic drug. We describe the use of PER in one patient with hypoxic super-refractory myoclonic status. DESCRIPTION: A 51-year-old patient presented after an out-of-hospital cardiac arrest due to an acute myocardial infarction. The patient was diagnosed with clinical and electrical (EEG) myoclonic status at the rewarming phase. Several treatments were used, starting with clonazepam, valproate, sedation (midazolam, propofol), and subsequently barbiturate-induced coma with persistent myoclonic status. Finally, we decided to try PER (dose: 6-8 mg) through a nasogastric tube, resulting in a marked improvement of EEG activity and myoclonus decrease. The patient had a progressive clinical improvement, with a CPC (Cerebral Performance Category) scale score of 1. CONCLUSION: This case shows the potential utility of PER as a therapeutic option in super-refractory hypoxic status and even its potential use before other aggressive alternatives considering their greater morbidity.

Is it all That Bad When Living with an Intracellular Protozoan? The Role of Trypanosoma cruzi Calreticulin in Angiogenesis and Tumor Growth.

The immune system protects against disease, but may aberrantly silence immunity against "altered self," with consequent development of malignancies. Among the components of the endoplasmic reticulum (ER), important in immunity, is calreticulin (CRT) that, in spite of its residence in the ER, can be translocated to the exterior. Trypanosoma cruzi is the agent of Chagas disease, one of the most important global neglected infections, affecting several hundred thousand people. The syndrome, mainly digestive and circulatory, affects only one-third of those infected. The anti-tumor effects of the infection are known for several decades, but advances in the identification of responsible T. cruzi molecules are scarce. We have shown that T. cruzi CRT (TcCRT) better executes the antiangiogenic and anti-tumor effects of mammal CRT and its N-terminus vasostatin. In this regard, recombinant TcCRT (rTcCRT) and/or its N-terminus inhibit angiogenesis in vitro, ex vivo, and in vivo. TcCRT also inhibits the growth of murine adenocarcinomas and melanomas. Finally, rTcCRT fully reproduces the anti-tumor effect of T. cruzi infection in mice. Thus, we hypothesize that, the long reported anti-tumor effect of T. cruzi infection is mediated at least in part by TcCRT.

Human survivin and Trypanosoma cruzi calreticulin act in synergy against a murine melanoma in vivo.

Immune-based anti-tumor or anti-angiogenic therapies hold considerable promise for the treatment of cancer. The first approach seeks to activate tumor antigen-specific T lymphocytes while, the second, delays tumor growth by interfering with blood supply. Tumor Associated Antigens are often employed to target tumors with therapeutic drugs, but some are also essential for tumor viability. Survivin (Surv) is a member of the inhibitor of apoptosis protein family that is considered a Tumor Associated Antigen important for cancer cell viability and proliferation. On the other hand, Trypanosoma cruzi (the agent of Chagas' disease) calreticulin (TcCRT) displays remarkable anti-angiogenic properties. Because these molecules are associated with different tumor targets, we reasoned that immunization with a Surv-encoding plasmid (pSurv) and concomitant TcCRT administration should generate a stronger anti-tumor response than application of either treatment separately. To evaluate this possibility, C57BL/6 mice were immunized with pSurv and challenged with an isogenic melanoma cell line that had been pre-incubated with recombinant TcCRT (rTcCRT). Following tumor cell inoculation, mice were injected with additional doses of rTcCRT. For the combined regimen we observed in mice that: i). Tumor growth was impaired, ii). Humoral anti-rTcCRT immunity was induced and, iii). In vitro rTcCRT bound to melanocytes, thereby promoting the incorporation of human C1q and subsequent macrophage phagocytosis of tumor cells. These observations are interpreted to reflect the consequence of the following sequence of events: rTcCRT anti-angiogenic activity leads to stress in tumor cells. Murine CRT is then translocated to the external membrane where, together with rTcCRT, complement C1 is captured, thus promoting tumor phagocytosis. Presentation of the Tumor Associated Antigen Surv induces the adaptive anti-tumor immunity and, independently, mediates anti-endothelial cell immunity leading to an important delay in tumor growth.

Caveolin-1 is a risk factor for postsurgery metastasis in preclinical melanoma models.

Melanomas are highly lethal skin tumours that are frequently treated by surgical resection. However, the efficacy of such procedures is often limited by tumour recurrence and metastasis. Caveolin-1 (CAV1) has been attributed roles as a tumour suppressor, although in late-stage tumours, its presence is associated with enhanced metastasis. The expression of this protein in human melanoma development and particularly how the presence of CAV1 affects metastasis after surgery has not been defined. CAV1 expression in human melanocytes and melanomas increases with disease progression and is highest in metastatic melanomas. The effect of increased CAV1 expression can then be evaluated using B16F10 murine melanoma cells injected into syngenic immunocompetent C57BL/6 mice or human A375 melanoma cells injected into immunodeficient B6Rag1-/- mice. Augmented CAV1 expression suppresses tumour formation upon a subcutaneous injection, but enhances lung metastasis of cells injected into the tail vein in both models. A procedure was initially developed using B16F10 melanoma cells in C57BL/6 mice to mimic better the situation in patients undergoing surgery. Subcutaneous tumours of a defined size were removed surgically and local tumour recurrence and lung metastasis were evaluated after another 14 days. In this postsurgery setting, CAV1 presence in B16F10 melanomas favoured metastasis to the lung, although tumour suppression at the initial site was still evident. Similar results were obtained when evaluating A375 cells in B6Rag1-/- mice. These results implicate CAV1 expression in melanomas as a marker of poor prognosis for patients undergoing surgery as CAV1 expression promotes experimental lung metastasis in two different preclinical models.