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1.
SAGE Open Med ; 12: 20503121241241936, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38623475

RESUMO

Background: The scope and number of disasters have increased over the years. This has called for more robust disaster preparedness training and plans. The use of virtual reality exercises in addition to tabletop exercises is considered a new approach to the preparation of disaster preparedness plans. Virtual reality exercises are being developed to either replace or complement current traditional approaches to disaster preparedness training. Objectives: To review and summarize the current existing literature regarding the effectiveness, advantages and limitations of using virtual reality exercises in disaster preparedness as a complementary/replacement mechanism for real-time drills and tabletop exercises. Methods: In this scoping review, we searched PubMed, Cochrane, EMBASE, PLOS, and Google Scholar for research publications involving virtual reality exercises in disaster training from 2008 to 2022 using "AND" and "OR" operators for the keywords "disaster," "preparedness," "virtual reality," and "tabletop." From a total of 333 articles that resulted in our search and were then evaluated by the authors, 55 articles were finally included in this review. Results: Virtual reality exercises are found to be better in the formulation of disaster preparedness plans compared to tabletop exercises. Virtual reality exercises can be used as the primary means of creating a real-life-like experience in disaster preparedness training and proved at least as better complementary to tabletop exercises. Virtual reality exercises have many advantages over traditional real-life or tabletop exercises and are more cost-effective, but some drawbacks are still identified. Conclusion: The advantages of virtual reality exercises are remarkable and underline their benefits and uses versus costs. We highly encourage decision-makers and institutions dealing in disaster preparedness to adopt using virtual reality exercises in training for disaster preparedness.

2.
Am J Disaster Med ; 19(1): 71-77, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38597649

RESUMO

OBJECTIVE: This study aimed to assist governments and organizers of mass gathering events in reviewing existing preventive measures for disease outbreaks to inform the adoption of enhanced strategies for risk reduction and impacts on public health. DESIGN: A cross-sectional, quantitative, descriptive study. SETTING: This study was conducted in a mass gathering of Hajj, an annual religious event in Mecca, Saudi Arabia. PARTICIPANTS: A convenience sample of 70 personnel working in government ministries of Saudi Arabia (Ministry of Health, Ministry of Hajj, and Ministry of Interior) and the Saudi Red Crescent Authority involved in health management in Hajj, including policy formulation and implementation. MAIN OUTCOME MEASURES: Perception and knowledge of health risks and outbreaks associated with Hajj. RESULTS: The majority of the respondents (60 percent) expressed concern about the potential for infection transmission during Hajj. The respondents also reported having or knowing a colleague, a friend, or a family member with a history of infection during or after Hajj. However, the respondents' knowledge of the possible modes of infection of various diseases was limited. CONCLUSIONS: Hajj is associated with various risks of outbreaks, and thus, better protection-enhancing measures are required. Training personnel involved in health management, including planners, coordinators, and healthcare providers, can help reduce the risks and prevent potential outbreaks.


Assuntos
Surtos de Doenças , Saúde Pública , Humanos , Estudos Transversais , Surtos de Doenças/prevenção & controle , Arábia Saudita/epidemiologia , Pessoal de Saúde , Islamismo , Viagem
3.
Pharmaceuticals (Basel) ; 16(4)2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-37111311

RESUMO

KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRASG12C inhibitors in KRASG12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRASG12C-driven NSCLC cells, enhance KRASG12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRASG12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRASG12C and TEAD leads to a specific dual cell cycle arrest in KRASG12C NSCLC cells.

4.
Sci Rep ; 12(1): 20435, 2022 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-36443381

RESUMO

Despite beneficial effects in acute heart failure, the full therapeutic potential of recombinant relaxin-2 has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. A multiparametric optimization of the relaxin B-chain led to the identification of single chain lipidated peptide agonists of RXFP1 like SA10SC-RLX with subcutaneous bioavailability and extended half-life. SA10SC-RLX has sub nanomolar activity on cells expressing human RXFP1 and molecular modeling associated with the study of different RXFP1 mutants was used to decipher the mechanism of SA10SC-RLX interaction with RXFP1. Telemetry was performed in rat where SA10SC-RLX was able to engage RXFP1 after subcutaneous administration without tachyphylaxis after repeated dosing. Renal blood flow was then used as a translational model to evaluate RXFP1 activation. SA10SC-RLX increased renal blood flow and decreased renal vascular resistance in rats as reported for relaxin in humans. In conclusion, SA10SC-RLX mimics relaxin activity in in vitro and in vivo models of acute RXFP1 engagement. SA10SC-RLX represents a new class of long-lasting RXFP1 agonist, suitable for once daily subcutaneous administration in patients and potentially paving the way to new treatments for chronic fibrotic and cardiovascular diseases.


Assuntos
Relaxina , Humanos , Animais , Ratos , Relaxina/farmacologia , Meia-Vida , Circulação Renal , Modelos Moleculares , Administração Intravenosa , Receptores de Peptídeos/genética , Receptores Acoplados a Proteínas G
5.
BMC Cancer ; 22(1): 639, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35689194

RESUMO

Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.


Assuntos
Mesotelioma Maligno , Mesotelioma , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Mesotelioma/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas de Sinalização YAP
7.
J Med Chem ; 64(15): 10834-10848, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34266235

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9), identified as a regulator of low-density lipoprotein receptor (LDLR), plays a major role in cardiovascular diseases (CVD). Recently, Pep2-8, a small peptide with discrete three-dimensional structure, was found to inhibit the PCSK9/LDLR interaction. In this paper, we describe the modification of this peptide using stapled peptide and SIP technologies. Their combination yielded potent compounds such as 18 that potently inhibited the binding of PCSK9 to LDLR (KD = 6 ± 1 nM) and restored in vitro LDL uptake by HepG2 cells in the presence of PCSK9 (EC50 = 175 ± 40 nM). The three-dimensional structures of key peptides were extensively studied by circular dichroism and nuclear magnetic resonance, and molecular dynamics simulations allowed us to compare their binding mode to tentatively rationalize structure-activity relationships (SAR).


Assuntos
Lisina/farmacologia , Inibidores de PCSK9 , Peptídeos/farmacologia , Inibidores de Serino Proteinase/farmacologia , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Lisina/química , Modelos Moleculares , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Pró-Proteína Convertase 9/metabolismo , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade
8.
Front Physiol ; 12: 665994, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149446

RESUMO

BACKGROUND AND AIMS: The YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Moreover, YAP/TAZ signaling plays a role in the progression of cancers and renal damage associated with diabetes. However, whether YAP/TAZ signaling is also implicated in diabetes-associated vascular complications is not known. METHODS: The effect of high glucose on YAP/TAZ signaling was firstly evaluated in vitro on endothelial cells cultured under static conditions or subjected to shear stress (either laminar or oscillatory flow). The impact of diabetes on YAP/TAZ signaling was additionally assessed in vivo in db/db mice. RESULTS: In vitro, we found that YAP was dephosphorylated/activated by high glucose in endothelial cells, thus leading to increased endothelial inflammation and monocyte attachment. Moreover, YAP was further activated when high glucose was combined to laminar flow conditions. YAP was also activated by oscillatory flow conditions but, in contrast, high glucose did not exert any additional effect. Interestingly, inhibition of YAP reduced endothelial inflammation and monocyte attachment. Finally, we found that YAP is also activated in the vascular wall of diabetic mice, where inflammatory markers are also increased. CONCLUSION: With the current study we demonstrated that YAP signaling is activated by high glucose in endothelial cells in vitro and in the vasculature of diabetic mice, and we pinpointed YAP as a regulator of high glucose-mediated endothelial inflammation and monocyte attachment. YAP inhibition may represent a potential therapeutic opportunity to improve diabetes-associated vascular complications.

9.
Ann Surg Oncol ; 28(11): 6294-6306, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33839975

RESUMO

BACKGROUND: The optimal surgical procedure for duodenal gastrointestinal stromal tumors (D-GISTs) remains poorly defined. Pancreaticoduodenectomy (PD) allows for a wide resection but is associated with a high morbidity rate. OBJECTIVES: The aim of this study was to compare the short- and long-term outcomes of PD versus limited resection (LR) for D-GISTs and to evaluate the role of tumor enucleation (EN). METHODS: In this retrospective European multicenter cohort study, 100 patients who underwent resection for D-GIST between 2001 and 2013 were compared between PD (n = 19) and LR (n = 81). LR included segmental duodenectomy (n = 47), wedge resection (n = 21), or EN (n = 13). The primary objective was to evaluate disease-free survival (DFS) between the groups, while the secondary objectives were to analyze the overall morbidity and mortality, radicality of resection, and 5-year overall survival (OS) and recurrence rates between groups. Furthermore, the short- and long-term outcomes of EN were evaluated. RESULTS: Baseline characteristics were comparable between the PD and LR groups, except for a more frequent D2 tumor location in the PD group (68.3% vs. 29.6%; p = 0.016). Postoperative morbidity was higher after PD (68.4% vs. 23.5%; p < 0.001). OS (p = 0.70) and DFS (p = 0.64) were comparable after adjustment for D2 location and adjuvant therapy rate. EN was performed more in American Society of Anesthesiologists (ASA) stage III/IV patients with tumors < 5 cm and was associated with a 5-year OS rate of 84.6%, without any disease recurrences. CONCLUSIONS: For D-GISTs, LR should be the procedure of choice due to lower morbidity and similar oncological outcomes compared with PD. In selected patients, EN appears to be associated with equivalent short- and long-term outcomes. Based on these results, a surgical treatment algorithm is proposed.


Assuntos
Neoplasias Duodenais , Tumores do Estroma Gastrointestinal , Estudos de Coortes , Neoplasias Duodenais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Recidiva Local de Neoplasia/cirurgia , Pancreaticoduodenectomia/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
11.
JACC Basic Transl Sci ; 5(6): 549-557, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32613143

RESUMO

Lipoprotein(a) (Lp[a]) is the most common genetically inherited risk factor for cardiovascular disease. Many aspects of Lp(a) metabolism remain unknown. We assessed the uptake of fluorescent Lp(a) in primary human lymphocytes as well as Lp(a) hepatic capture in a mouse model in which endogenous hepatocytes have been ablated and replaced with human ones. Modulation of LDLR expression with the PCSK9 inhibitor alirocumab did not alter the cellular or the hepatic uptake of Lp(a), demonstrating that the LDL receptor is not a major route for Lp(a) plasma clearance. These results have clinical implications because they underpin why statins are not efficient at reducing Lp(a).

12.
J Pharmacol Exp Ther ; 374(2): 283-294, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32409422

RESUMO

Lysophosphatidic acid (LPA) is the natural ligand for two phylogenetically distinct families of receptors (LPA1-3, LPA4-6) whose pathways control a variety of physiologic and pathophysiological responses. Identifying the benefit of balanced activation/repression of LPA receptors has always been a challenge because of the high lability of LPA and the limited availability of selective and/or stable agonists. In this study, we document the discovery of small benzofuran ethanolamine derivatives (called CpX and CpY) behaving as LPA1-3 agonists. Initially found as rabbit urethra contracting agents, their elusive receptors were identified from [35S]GTPγS-binding and ß-arrestin2 recruitment investigations and then confirmed by [3H]CpX binding studies (urethra, hLPA1-2 membranes). Both compounds induced a calcium response in hLPA1-3 cells within a range of 0.4-1.5-log lower potency as compared with LPA. The contractions of rabbit urethra strips induced by these compounds perfectly matched binding affinities with values reaching the two-digit nanomolar level. The antagonist, KI16425, dose-dependently antagonized CpX-induced contractions in agreement with its affinity profile (LPA1≥LPA3>>LPA2). The most potent agonist, CpY, doubled intraurethral pressure in anesthetized female rats at 3 µg/kg i.v. Alternatively, CpX was shown to inhibit human preadipocyte differentiation, a process totally reversed by KI16425. Together with original molecular docking data, these findings clearly established these molecules as potent agonists of LPA1-3 and consolidated the pivotal role of LPA1 in urethra/prostate contraction as well as in fat cell development. The discovery of these unique and less labile LPA1-3 agonists would offer new avenues to investigate the roles of LPA receptors. SIGNIFICANCE STATEMENT: We report the identification of benzofuran ethanolamine derivatives behaving as potent selective nonlipid LPA1-3 agonists and shown to alter urethra muscle contraction or preadipocyte differentiation. Unique at this level of potency, selectivity, and especially stability, compared with lysophosphatidic acid, they represent more appropriate tools for investigating the physiological roles of lysophosphatidic acid receptors and starting point for optimization of drug candidates for therapeutic applications.


Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Descoberta de Drogas , Etanolamina/química , Receptores de Ácidos Lisofosfatídicos/agonistas , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Benzofuranos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Diferenciação Celular/efeitos dos fármacos , Cricetulus , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Simulação de Acoplamento Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Conformação Proteica , Coelhos , Ratos , Receptores de Ácidos Lisofosfatídicos/química , Receptores de Ácidos Lisofosfatídicos/metabolismo , beta-Arrestina 2/metabolismo
13.
Sci Rep ; 9(1): 8342, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171832

RESUMO

The therapeutic management of patients with endoscopic resection of colorectal cancer invading the submucosa (i.e. pT1 CRC) depends on the balance between the risk of cancer relapse and the risk of surgery-related morbidity and mortality. The aim of our study was to report on the histopathological risk factors predicting lymph node metastases and recurrences in an exhaustive case series comprising every pT1 CRC (of adenocarcinoma subtype only) diagnosed in Finistère (France) during 5-years. For 312 patients with at least 46 months follow-up included in the digestive cancers registry database, histopathological factors required for risk stratification in pT1 CRC were reviewed. Patients were treated by endoscopic resection only (51 cases), surgery only (138 cases), endoscopic resection followed by surgery (102 cases) or transanal resection (21 cases). Lymph node metastases were diagnosed in 19 patients whereas 15 patients had an extra-nodal recurrence (7 local recurrences only, 4 distant metastases only and 4 combining local and distant recurrences). Four patients with distant metastases died of their cancer. Poor tumor differentiation, vascular invasion and high grade tumor budding on HES slides were notably identified as strong risk-factors of lymph node metastases but the prediction of extra-nodal recurrences (local, distant and sometimes fatal) was less obvious, albeit it was more frequent in patients treated by transanal resection than with other treatment strategies. Beyond good performances in predicting lymph node metastases and guiding therapeutic decision in patients with pT1 CRC, our study points that extra-nodal recurrence of cancer is more difficult to predict and requires further investigations.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Metástase Linfática/diagnóstico , Recidiva Local de Neoplasia , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/metabolismo , Bases de Dados Factuais , Endoscopia , Feminino , Seguimentos , França , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Distribuição Tecidual
14.
Pathology ; 51(1): 46-54, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30477880

RESUMO

Assessment of the risk of lymph node invasion and tumour recurrence is critical to determine whether additional surgery is required in patients with endoscopically-removed pT1 colorectal cancer (CRC). A reproducible assessment of this risk of recurrence based on histopathological parameters is crucial for relevant therapeutic decisions. The inter-observer reproducibility of these parameters was the subject of our study. Two pathologists independently analysed 163 endoscopically-removed pT1 CRC recorded in a local digestive cancer registry database (Finistère, France). Using haematoxylin-eosin-saffron (HES) and immunohistochemistry slides, they evaluated several parameters related to the risk of tumour recurrence according to the international pT1 CRC-dedicated guidelines. Based on Kappa and intra-class correlation coefficients, good to very good inter-observer agreement was obtained by analysing vertical and lateral margins, submucosal invasion, tumour differentiation and lymphovascular invasion. The reproducibility of tumour budding quantification was only fair on the basis of HES slides but reached a very good agreement using cytokeratin immunohistochemistry. Dual colour cytokeratin and podoplanin immunohistochemistry also improved inter-observer agreement for the detection of lymphovascular invasion. All patients with loco-regional nodal metastases (7 of 101 who underwent complementary surgery) or distant metastases (3 patients) were diagnosed as having a high risk of recurrence and requiring an additional surgery by the two observers. Our study showed that good to very good inter-observer agreement is achievable in evaluating the pathological parameters of recurrence risk in endoscopically-removed pT1 CRC. In addition to HES slides, the detection of lymphovascular invasion and tumour budding can benefit with more reproducible immunohistochemical analyses.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Linfonodos/patologia , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
15.
Clin Sci (Lond) ; 132(10): 1075-1083, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29724769

RESUMO

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivoSix nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [2H3]-leucine was assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (-28%), LDL-C (-67%), Lp(a) (-56%), apolipoprotein B100 (apoB100) (-53%), and apo(a) (-53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (-42%), but not significantly that of apoB100, compared with IgG1, respectively.In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , Lipoproteína(a)/sangue , Inibidores de PCSK9 , Animais , Anticorpos Monoclonais Humanizados , Apoproteína(a)/biossíntese , Colesterol/sangue , Estudos Cross-Over , Feminino , Lipídeos/sangue , Macaca fascicularis , Masculino
16.
Int J Surg ; 53: 257-261, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29621656

RESUMO

PURPOSE: Surgery remains the mainstay of gastrointestinal stromal tumors (GISTs) treatment. The aim of our study was to compare postoperative outcomes and long term oncologic results of GISTs resection. An analysis of laparoscopic versus open surgery for GISTs and a subgroup analysis of lesions larger than 5 cm were realized. MATERIALS AND METHODS: Between January 2005 and December 2014, 143 patients with primary GISTs were treated with radical resection in two tertiary centers. Eight patients with metastatic disease were excluded. The remaining patients were assigned to 2 groups: laparoscopy and open surgery. A separate analysis of tumors larger than 5 cm was realized for the laparoscopy group. Long-term follow-up was used to analyze the oncologic and surgical results. Relevant clinical variables were evaluated using univariate and multivariate analyses. RESULTS: With similar oncological outcomes(p = 0.09) and morbidity(p = 0.56), laparoscopy compared to open surgery significantly reduced length of hospitalization (p = 0.01). For lesions >5 cm laparoscopic resection is associated with similar short-term outcomes with resection for small tumors without compromising oncological outcomes (p = 0.89). For all patients, the probability of remaining disease free at 3 years, and 5 years was 97, 6% and 95%, respectively. CONCLUSION: Laparoscopic resection is a technically and oncologically safe and feasible approach for GISTs compared with open resection. Resection of lesions superior of 5 cm by laparoscopy has efficacy and recurrence rates similar to open surgical controls. Large tumor resection should only be attempted by surgeons with a large experience with minimally invasive surgery in order to avoid operative complications and unfavorable long term outcome.


Assuntos
Gastrectomia/métodos , Tumores do Estroma Gastrointestinal/cirurgia , Laparoscopia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Hospitalização , Humanos , Laparoscopia/métodos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Segunda Neoplasia Primária/cirurgia , Estudos Retrospectivos
17.
Int J Surg ; 52: 1-6, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29427749

RESUMO

PURPOSE: The treatment of rectal cancer could be complex and the long term complications have the potential to greatly impact the quality of life. The aim of this study was to evaluate the long term functional and oncological results after sphincter-saving resection for rectal cancer. METHODS: Between January 2005 and December 2013, a total of 187 rectal resections with total mesorectal excision (TME) for cancer were performed. The data of 72 (38.5%) patients were available for analysis. Long-term follow-up was used to analyze the oncologic and functional results. Standardized questionnaires were used to determine fecal incontinence and urinary function. Relevant clinical variables were evaluated using univariate and multivariate analyses. RESULTS: The overall survival rate was 71% and the distribution of the International Union against Cancer (UICC) stages was 48.6% stage 1, 18% stage 2, and 33.3% stage 3. In univariate analysis, neoadjuvant radiotherapy (P < 0.01), rectal pouch (P < 0.01) and hand-sewn anastomosis (P = 0.02) was found to adversely affect fecal continence. On multivariate analysis fecal incontinence was significantly correlated with neoadjuvant radiochemotherapy (P < 0.05) and low rectal resection (P < 0.01). Urinary function was not statistically significant affected by preoperative treatment (P = 0.48) or surgical procedure (P = 0.45). CONCLUSION: Tumor location, surgical technique and neoadjuvant treatment had an impact on long term oncologic and functional results after sphincter-saving resection for rectal cancer. Urinary dysfunction occurs less frequently than anal disorders. These results highlight the importance of functional evaluation before and after rectal cancer resection in daily clinical practice and the necessity to tailor treatment to each patient.


Assuntos
Canal Anal/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Neoplasias Retais/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/efeitos adversos , Estudos de Coortes , Defecação , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Incontinência Fecal/etiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Neoplasias Retais/mortalidade , Reto/patologia , Reto/cirurgia , Estudos Retrospectivos , Inquéritos e Questionários , Taxa de Sobrevida , Resultado do Tratamento
18.
Hum Pathol ; 72: 135-143, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29208565

RESUMO

Mismatch repair-deficient (dMMR) colorectal cancers (CRCs) are good responders to anti-programmed cell death ligand-1 (PD-L1) immunotherapy, but the value of PD-L1 testing remains unclear. We studied PD-L1 expression and the tumor immune microenvironment in dMMR CRC as a model of good responders to immunotherapy. We examined 35 dMMR and 34 mismatch repair-proficient (pMMR) CRCs using immune cell markers (CD3, CD4, CD8, CD20, CD68, and FOXP3) as well as programmed cell death receptor-1 (PD-1) and PD-L1 immunohistochemistry staining in whole tumor specimens and tissue microarray slides to compare 4 PD-L1 immunohistochemistry clones (SP142, E1L3N, 22C3, and 28.8). We observed no significant difference in PD-L1 expression between dMMR and pMMR CRCs. Only 2 dMMR tumors had membranous PD-L1 staining. Expression of PD-L1 was greater in stromal immune cells of dMMR CRC, which also contained more numerous intraepithelial (CD3+, CD8+, FOXP3+, and PD-1+) and stromal (CD8+, PD-1+) lymphocytes than did pMMR tumors. Immune cell quantification discriminated better between dMMR and pMMR tumors than did PD-L1 expression. Tumor heterogeneity and variations in PD-L1 expression were noted with different antibodies, especially for PD-L1+ immune cells, which were more numerous at the invasion margin. Given the poor correlation with mismatch repair status and technical limitations, the value of PD-L1 testing to accompany the development of anti-PD-1/PD-L1 immunotherapy remains unclear. Further clinical trials are required to determine which parameters are valuable predictive biomarkers of the response to immunotherapy among mismatch repair status, PD-L1 expression, and immune cell quantification in CRC.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Microambiente Tumoral/imunologia
19.
J Emerg Manag ; 16(6): 405-411, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30667042

RESUMO

Every disaster often holds a potential for significant impacts on human health and life. Every new threat presents new challenges to health risk management. However, family medicine faces an uncertainty on the specific roles it can assume to support urgent efforts at disaster surge response. Its preparedness level remains unknown. This research project, designed to explore issues of family medicine competency in this changed disaster response environment, conducted a disaster preparedness and response workshop among 28 family medicine physicians, testing their learning rate using a pre-test-post-test data collection method. Pre-test results (38.11 percent, x = 10.67) indicate that family medicine practitioners as a group were not ready by competency to respond to a disaster event and may instead increase the life risks of disaster victims. Post-test results (x = 21.67, 77.39 percent) showed an average doubling of their learning levels, indicating the workshop effectiveness in improving their disaster preparedness and response competency.


Assuntos
Medicina de Desastres , Planejamento em Desastres , Desastres , Medicina de Família e Comunidade/organização & administração , Humanos
20.
Surg Laparosc Endosc Percutan Tech ; 27(2): 94-97, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28368961

RESUMO

OBJECTIVE: Colovesical fistulas (CVF) constitute the most common type of spontaneously occurring fistulas associated with diverticular disease. One-stage laparoscopic resection has been shown to be feasible, but studies comparing this approach to open surgery are scarce. The aim of this study was to compare the clinical outcomes of open and laparoscopic surgery for CVF of diverticular origin. MATERIALS AND METHODS: From January 2000 to July 2014, 37 colectomies were performed for diverticular disease-related CVF. Twenty-eight patients who underwent resection and primary anastomosis were divided in 2 groups: the laparoscopic surgery group (group A) and the open surgery group (group B). We have analyzed the following parameters: operative time, complication rate, hospital stay, recurrence, and early mortality rate. RESULTS: Groups A and B were comparable in terms of age, sex, diverticulitis episodes, previous abdominal surgery, and body mass index.The mean duration of surgery was significantly shorter in group B: 175 versus 237 minutes (P=0.011). There was a faster recovery of gastrointestinal transit in group A (2 vs. 13; P=0, 0002). However, there were no significant differences between the groups with respect to serious postoperative morbidity [(Clavien-Dindo scores of 3, 4, and 5) 4 vs. 0; P=0.098)] and with respect to hospital stay (10.5 vs. 9.5 d; P=0.537). There was no recurrence during a median follow-up of 12 months. CONCLUSIONS: Laparoscopic resection and primary anastomosis should be considered a safe and feasible option for the management of diverticular CVF. Despite progresses in minimally invasive colorectal surgery, the conversion rate and morbidity are still high.


Assuntos
Divertículo do Colo/cirurgia , Fístula Intestinal/cirurgia , Laparoscopia/métodos , Idoso , Colectomia/métodos , Divertículo do Colo/complicações , Feminino , Humanos , Fístula Intestinal/complicações , Tempo de Internação/estatística & dados numéricos , Masculino , Duração da Cirurgia , Recidiva , Resultado do Tratamento
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