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1.
Langenbecks Arch Surg ; 409(1): 121, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38605271

RESUMO

PURPOSE: The optimal management of colorectal lung metastases (CRLM) is still controversial. The aim of this study was to compare surgical and non-surgical treatment for CRLM regarding the prognostic outcome. METHODS: This retrospective single-center cohort study included 418 patients, who were treated from January 2000 to December 2018 at a German University Hospital due to their colorectal carcinoma and had synchronous or metachronous lung metastases. Patients were stratified according the treatment of the CRLM into two groups: surgical resection of CRLM versus no surgical resection of CRLM. The survival from the time of diagnosis of lung metastasis was compared between the groups. RESULTS: Two- and 5-year overall survival (OS) from the time of diagnosis of lung metastasis was 78.2% and 54.6%, respectively, in our cohort. Patients undergoing pulmonary metastasectomy showed a significantly better 2- and 5-year survival compared to patients with non-surgical treatment (2-year OS: 98.1% vs. 67.9%; 5-year OS: 81.2% vs. 28.8%; p < 0.001). Multivariate Cox regression revealed the surgical treatment (HR 4.51 (95% CI = 2.33-8.75, p < 0.001) and the absence of other metastases (HR 1.79 (95% CI = 1.05-3.04), p = 0.032) as independent prognostic factors in patients with CRLM. CONCLUSION: Our data suggest that patients with CRLM, who qualify for surgery, benefit from surgical treatment. Randomized controlled trials are needed to confirm our findings. CLINICAL TRIAL REGISTRY NUMBER: The work has been retrospectively registrated at the German Clinical Trial Registry (DRKS00032938).


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Estudos Retrospectivos , Estudos de Coortes , Neoplasias Hepáticas/cirurgia , Neoplasias Colorretais/patologia , Prognóstico , Hepatectomia/efeitos adversos , Neoplasias Pulmonares/cirurgia , Resultado do Tratamento
2.
Mol Cancer ; 23(1): 28, 2024 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308296

RESUMO

BACKGROUND: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. METHODS: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. RESULTS: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. CONCLUSIONS: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.


Assuntos
Carcinoma Ductal Pancreático , Ácidos Nucleicos Livres , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Pancreatite , Humanos , Biomarcadores Tumorais/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pancreatite/diagnóstico , Pancreatite/genética , Biópsia Líquida , Carcinoma Ductal Pancreático/patologia
5.
Oncotarget ; 14: 957-969, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38039408

RESUMO

Metastasizing cells display a unique metabolism, which is very different from the Warburg effect that arises in primary tumors. Over short time frames, oxidative phosphorylation and ATP generation are prominent. Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms. Here, we report that autocrine Osteopontin does indeed stimulate an increase in mitochondrial size, with the splice variant -c being more effective than the full-length form -a. Osteopontin-c achieves this via its receptor CD44v, jointly with the upregulation and co-ligation of the chloride-dependent cystine-glutamate transporter SLC7A11. The signaling proceeds through activation of the known mitochondrial biogenesis inducer PGC-1 (which acts as a transcription coactivator). Peroxide is an important intermediate in this cascade, but surprisingly acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation. In vivo, suppression of the biogenesis-inducing mechanisms leads to a reduction in disseminated tumor mass. This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis - both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.


Assuntos
Neoplasias , Biogênese de Organelas , Humanos , Trifosfato de Adenosina/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fatores de Transcrição/metabolismo
6.
Int J Colorectal Dis ; 38(1): 272, 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37991592

RESUMO

INTRODUCTION: Bacteria play an important role not only in pathogenesis of appendicitis but also in the postoperative course of patients. However, the usefulness of an intraoperative swab during appendectomy is controversial. The primary aim of this study was to investigate the impact of intraoperative swab during appendectomy on the postoperative outcome in patients with uncomplicated and complicated appendicitis. METHODS: A retrospective analysis was conducted on a consecutive series of 1570 adult patients who underwent appendectomy for acute appendicitis at the University Hospital Erlangen between 2010 and 2020. Data regarding the intraoperative swab were collected and analyzed for the entire cohort as well as for patients with uncomplicated and complicated appendicitis. RESULTS: An intraoperative swab was taken in 29% of the cohort. The bacterial isolation rate in the obtained intraoperative swabs was 51%, with a significantly higher rate observed in patients with complicated appendicitis compared to those with uncomplicated appendicitis (79% vs. 35%, p < 0.001). The presence of a positive swab was significantly associated with worse postoperative outcomes, including higher morbidity, increased need for re-surgery, and longer hospital stay, when compared to patients without a swab or with a negative swab. A positive swab was an independent risk factor for postoperative morbidity (OR 9.9 (95% CI 1.2-81.9), p = 0.034) and the need for adjustment of postoperative antibiotic therapy (OR 8.8 (95% CI 1.1-72.5), p = 0.043). However, a positive swab resulted in postoperative antibiotic therapy adjustment in only 8% of the patients with bacterial isolation in the swab. CONCLUSION: The analysis of swab samples obtained during appendectomy for acute appendicitis can help identify patients at a higher risk of a worse postoperative outcome. However, the frequency of antibiotic regime changes based on the swab analysis is low.


Assuntos
Apendicectomia , Apendicite , Adulto , Humanos , Apendicectomia/efeitos adversos , Apendicite/complicações , Apendicite/diagnóstico , Apendicite/cirurgia , Estudos Retrospectivos , Antibacterianos/uso terapêutico , Hospitais Universitários
7.
Int J Mol Sci ; 24(19)2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37834391

RESUMO

Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2KO), WTD feeding resulted in reduced body weight gain paralleled by enhanced energy expenditure and uncoupling protein 1 (UCP1) expression, indicative of activated thermogenesis. In human VAT, FHL2 was inversely correlated with UCP1 expression. Furthermore, macrophage infiltration and the expression of the chemokine MCP-1, a known promotor of macrophage accumulation, was significantly reduced in WTD-fed FHL2KO mice compared with wild-type (wt) littermates. While FHL2 depletion did not affect the differentiation or lipid metabolism of adipocytes in vitro, FHL2 depletion in macrophages resulted in reduced expressions of MCP-1 and the neuropeptide Y (NPY). Furthermore, WTD-fed FHL2KO mice showed reduced NPY expression in VAT compared with wt littermates, and NPY expression was enhanced in VAT resident macrophages of obese individuals. Stimulation with recombinant NPY induced not only UCP1 expression and lipid accumulation but also MCP-1 expression in adipocytes. Collectively, these findings indicate that FHL2 is a positive regulator of NPY and MCP-1 expression in macrophages and herewith closely linked to the mechanism of obesity-associated lipid accumulation and inflammation in VAT. Thus, FHL2 appears as a potential novel target to interfere with the macrophage-adipocyte crosstalk in VAT for treating obesity and related metabolic disorders.


Assuntos
Gordura Intra-Abdominal , Neuropeptídeo Y , Animais , Humanos , Camundongos , Tecido Adiposo/metabolismo , Dieta , Dieta Hiperlipídica , Inflamação/metabolismo , Gordura Intra-Abdominal/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Lipídeos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Neuropeptídeo Y/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo
8.
J Clin Med ; 12(19)2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37834943

RESUMO

(1) Background: The aim of the present study was to identify risk factors associated with postoperative morbidity, suture/anastomotic insufficiency, re-surgery, and mortality in patients undergoing surgery for gastroduodenal perforation. (2) Methods: A retrospective analysis of 273 adult patients who received surgical treatment for gastroduodenal perforation from January 2006 to June 2021 at the University Hospital Erlangen was performed. The patient demographics and preoperative, intraoperative, and postoperative parameters were collected and compared among the different outcome groups (in-hospital morbidity, suture/anastomotic insufficiency, re-surgery, and 90-day mortality). (3) Results: In-hospital morbidity, suture/anastomotic insufficiency, need for re-surgery, and 90-day mortality occurred in 71%, 10%, 26%, and 25% of patients, respectively. The independent risk factors for morbidity were a significantly reduced general condition, a lower preoperative hemoglobin level, and a higher preoperative creatinine level. The independent risk factors for suture/anastomotic insufficiency could be identified as an intake of preoperative steroids and a perforation localization in the proximal stomach or duodenum. The four parameters were independent risk factors for the need for re-surgery: a significantly reduced general condition, a perforation localization in the proximal stomach, a higher preoperative creatinine level, and a higher preoperative CRP level. An age over 66 years and a higher preoperative CRP level were independent risk factors for 90-day mortality. (4) Conclusions: Our study could identify relevant risk factors for the postoperative outcome of patients undergoing surgical treatment for gastroduodenal perforation. Patients exhibiting the identified risk factors should receive heightened attention in the postoperative period and may potentially benefit from personalized and tailored therapy.

9.
J Clin Med ; 12(13)2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37445334

RESUMO

(1) Background: Since its introduction in the 1990s, laparoscopic appendectomy has become established over the years and is today considered the standard therapy for acute appendicitis. In some cases, however, a conversion to the open approach is still necessary. The primary aim of this study was to identify risk factors for the need to convert from the laparoscopic to an open approach during appendectomy for acute appendicitis. (2) Methods: A retrospective analysis of 1220 adult patients who underwent laparoscopic appendectomy for acute appendicitis from 2010 to 2020 at the University Hospital Erlangen was performed. Data, including patient demographics and pre-, intra-, and postoperative findings, were collected and compared between patients with and without conversion. (3) Results: The conversion rate in our cohort was 5.5%. A higher preoperative WBC count and CRP (OR 1.9, p = 0.042, and OR 2.3, p = 0.019, respectively), as well as the presence of intraoperative perforation, necrosis or gangrene, perityphlitic abscess and peritonitis (OR 3.2, p = 0.001; OR 2.3, p = 0.023; OR 2.6, p = 0.006 and OR 2.0, p = 0.025, respectively) were identified as independent risk factors for conversion from the laparoscopic to the open approach. Conversion was again independently associated with higher morbidity (OR 2.2, p = 0.043). (4) Conclusion: The laparoscopic approach is feasible and safe in the majority of patients with acute appendicitis. Only increased inflammatory blood markers could be detected as the preoperative risk factors potentially influencing the choice of surgical approach but only with low specificity and sensitivity. For the decision to convert, intraoperative findings are additionally crucial. However, patients with conversion should receive special attention in the postoperative course, as these have an increased risk of developing complications.

10.
Cell Rep ; 42(6): 112637, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37300834

RESUMO

Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis of IBDs has been investigated intensively, the etiology of IBDs remains enigmatic. Here, we report that interleukin-3 (Il-3)-deficient mice are more susceptible and exhibit increased intestinal inflammation during the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesenchymal stem cell phenotype and protects by promoting the early recruitment of splenic neutrophils with high microbicidal capability into the colon. Mechanistically, IL-3-dependent neutrophil recruitment involves CCL5+ PD-1high LAG-3high T cells, STAT5, and CCL20 and is sustained by extramedullary splenic hematopoiesis. During acute colitis, Il-3-/- show, however, increased resistance to the disease as well as reduced intestinal inflammation. Altogether, this study deepens our understanding of IBD pathogenesis, identifies IL-3 as an orchestrator of intestinal inflammation, and reveals the spleen as an emergency reservoir for neutrophils during colonic inflammation.


Assuntos
Colite Ulcerativa , Interleucina-3 , Animais , Camundongos , Colite/patologia , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Neutrófilos/patologia , Baço/patologia
12.
Biomedicines ; 11(5)2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37239137

RESUMO

(1) Background: The intake of aspirin (ASS) has been demonstrated to have a relevant impact on the pathogenesis, incidence and outcome in different solid gastrointestinal tumors. However, data on the effect of ASS on the short-term outcome and the long-term survival in patients with pancreatic carcinoma are still limited. (2) Methods: A total of 213 patients who underwent primary resection of PDAC at the University Hospital of Erlangen from January 2000 to December 2018 were included in this retrospective single-center study in total. Patients were stratified according to the aspirin intake into three groups: continuous aspirin intake (cASS), perioperatively interrupted aspirin intake (iASS) and no aspirin intake (no ASS) at the timepoint of surgery. The postoperative outcome as well as long-term survival were compared between the groups. (3) Results: There were no differences regarding postoperative morbidity (iASS: 54% vs. cASS: 53% vs. no ASS: 64%, p = 0.448) and in-hospital mortality (iASS: 4% vs. cASS: 10% vs. no ASS: 3%, p = 0.198) between the groups. The overall survival (OS) and disease-free survival (DFS) did not differ in the groups when comparing the ASS-intake status (OS: iASS 17.8 months vs. cASS 19.6 months vs. no ASS 21.6 months, p = 0.489; DFS: iASS 14.0 months vs. cASS 18.3 months vs. no ASS 14.7 months, p = 0.957). Multivariate analysis revealed that age (hazard ratio (HR) 2.2, p < 0.001), lymph node-positive status (HR 2.0, p < 0.001), R status 1 or 2 (HR 2.8, p < 0.001) and differentiation with a grading of 3 (HR 1.7, p = 0.005) were significant independent prognostic factors regarding the OS. Moreover, age (HR 1.5, p = 0.040), lymph node-positive status (HR 1.8, p = 0.002) and high-grade (G3) carcinomas (HR 1.5, p = 0.037) could be identified as independent prognostic parameters for DFS. (4) Conclusions: In patients undergoing primary surgery for curative resection of pancreatic carcinoma, the perioperative intake of ASS had no significant impact on postoperative outcome, overall and disease-free survival.

13.
BMC Cancer ; 23(1): 373, 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37095438

RESUMO

BACKGROUND: The cytokine Osteopontin is a mediator of tumor progression and cancer metastasis. In 2006, we reported that (in addition to the full-length form -a) splice variants of Osteopontin (forms -b and -c) are produced selectively by transformed cells. Through June 2021, 36 PubMed-indexed journal articles have studied Osteopontin splice variants in various cancer patients. METHODS: Applying a categorical approach previously developed by us, here we conduct a meta-analysis of the pertinent literature. We supplement this with evaluation of the relevant entries in the TSVdb database, which focusses on splice variant expression, thus including the additional variants -4 and -5. The analysis covers 5886 patients across 15 tumors from the literature and 10,446 patients across 33 tumors from TSVdb. RESULTS: The database yields positive results more frequently than the categorical meta-analysis. The two sources are in agreement on the elevation of OPN-a, OPN-b, and OPN-c in lung cancer and the elevation of OPN-c in breast cancer as compared to healthy tissue. Specific splice variants are associated with grade, stage, or patient survival pertaining to various cancers. CONCLUSIONS: There are cases of persisting discrepancies, which require further investigation to clarify the Osteopontin splice variant utilization, so that their diagnostic, prognostic and potentially predictive potential can be brought to fruition.


Assuntos
Neoplasias da Mama , Osteopontina , Humanos , Feminino , Osteopontina/metabolismo , Neoplasias da Mama/patologia , Prognóstico , Biomarcadores Tumorais
14.
Oncotarget ; 14: 358-362, 2023 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-37096988

RESUMO

Premalignant lesions in the breast pose a difficult decision-making problem, whether to treat proactively and accept the side effects or to engage in watchful waiting and possibly encounter a later diagnosis of invasive cancer. A biomarker or set of biomarkers to inform on the individual progression risk would be beneficial to the patient and cost-effective for the healthcare system. The gene products of tumor progression may be expressed in early non-cancerous ("premalignant") lesions, where they are associated with a high probability for full transformation in breast cancers. One such molecule is the OPN splice variant-c. OPN-c is also present in a fraction of the premalignant lesions, where it reflects an elevated risk for progression to cancer within 5 years, regardless of the lesion's subtype. This marker has the properties needed to facilitate decisions to treat at the premalignant stage.


Assuntos
Neoplasias da Mama , Lesões Pré-Cancerosas , Humanos , Feminino , Mama/patologia , Neoplasias da Mama/patologia , Lesões Pré-Cancerosas/patologia , Biomarcadores
15.
Cancers (Basel) ; 15(7)2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-37046585

RESUMO

Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.

16.
J Clin Med ; 12(8)2023 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-37109136

RESUMO

BACKGROUND: Even if the minimally invasive approach is advancing in pancreatic surgery, the open approach is still the standard for a pancreatoduodenectomy. There are two types of incisions used: the midline incision (MI) and transverse incision (TI). The aim of this study was to compare these two incision types, especially regarding wound complications. METHODS: A retrospective review of 399 patients who underwent a pancreatoduodenectomy at the University Hospital Erlangen between 2012 and 2021 was performed. A total of 169 patients with MIs were compared with 230 patients with TIs, with a focus on postoperative fascial dehiscence, postoperative superficial surgical site infection (SSSI) and the occurrence of incisional hernias during follow-up. RESULTS: Postoperative fascial dehiscence, postoperative SSSI and incisional hernias occurred in 3%, 8% and 5% of patients, respectively. Postoperative SSSI and incisional hernias were significantly less frequent in the TI group (SSI: 5% vs. 12%, p = 0.024; incisional hernia: 2% vs. 8%, p = 0.041). A multivariate analysis confirmed the TI type as an independent protective factor for the occurrence of SSSI and incisional hernias (HR 0.45 (95% CI = 0.20-0.99), p = 0.046 and HR 0.18 (95% CI = 0.04-0.92), p = 0.039, respectively). CONCLUSION: Our data suggest that the transverse incision for pancreatoduodenectomy is associated with reduced wound complications. This finding should be confirmed by a randomized controlled trial.

17.
Front Immunol ; 14: 1140630, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36911737

RESUMO

Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive. Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis. Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections). Measurements and main results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections. Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.


Assuntos
COVID-19 , Sepse , Animais , Camundongos , Antivirais , Células Dendríticas , Interleucina-3 , Pulmão , SARS-CoV-2 , Linfócitos T
18.
J Hematol Oncol ; 16(1): 7, 2023 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-36737824

RESUMO

BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is one of the most dismal of all cancers and the median survival of PDAC patients is only 6-8 months after diagnosis. While decades of research effort have been focused on early diagnosis and understanding of molecular mechanisms, few clinically useful markers have been universally applied. To improve the treatment and management of PDAC, it is equally relevant to identify prognostic factors for optimal therapeutic decision-making and patient survival. Compelling evidence have suggested the potential use of extracellular vesicles (EVs) as non-invasive biomarkers for PDAC. The aim of this study was thus to identify non-invasive plasma-based EV biomarkers for the prediction of PDAC patient survival after surgery. METHODS: Plasma EVs were isolated from a total of 258 PDAC patients divided into three independent cohorts (discovery, training and validation). RNA sequencing was first employed to identify differentially-expressed EV mRNA candidates from the discovery cohort (n = 65) by DESeq2 tool. The candidates were tested in a training cohort (n = 91) by digital droplet polymerase chain reaction (ddPCR). Cox regression models and Kaplan-Meier analyses were used to build an EV signature which was subsequently validated on a multicenter cohort (n = 83) by ddPCR. RESULTS: Transcriptomic profiling of plasma EVs revealed differentially-expressed mRNAs between long-term and short-term PDAC survivors, which led to 10 of the top-ranked candidate EV mRNAs being tested on an independent training cohort with ddPCR. The results of ddPCR enabled an establishment of a novel prognostic EV mRNA signature consisting of PPP1R12A, SCN7A and SGCD for risk stratification of PDAC patients. Based on the EV mRNA signature, PDAC patients with high risk displayed reduced overall survival (OS) rates compared to those with low risk in the training cohort (p = 0.014), which was successfully validated on another independent cohort (p = 0.024). Interestingly, the combination of our signature and tumour stage yielded a superior prognostic performance (p = 0.008) over the signature (p = 0.022) or tumour stage (p = 0.016) alone. It is noteworthy that the EV mRNA signature was demonstrated to be an independent unfavourable predictor for PDAC prognosis. CONCLUSION: This study provides a novel and non-invasive prognostic EV mRNA signature for risk stratification and survival prediction of PDAC patients.


Assuntos
Carcinoma Ductal Pancreático , Vesículas Extracelulares , Neoplasias Pancreáticas , Humanos , Prognóstico , RNA Mensageiro/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Vesículas Extracelulares/patologia , Biomarcadores Tumorais/genética , Medição de Risco , Neoplasias Pancreáticas
19.
Cancers (Basel) ; 15(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36672313

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most fatal cancer diseases, widely accepted to have the most dismal prognoses. Although immunotherapy has broadly revolutionized cancer treatment, its value in PDAC appears to be relatively low. Exhibiting protumoral effects, monocytes have recently been proposed as potential targets of such immunotherapeutic regimens. However, to date, the body of evidence on monocytes' role in PDAC is scarce. Therefore, we analyzed monocytes in the peripheral blood of 58 PDAC patients prior to surgery and compared them to healthy individuals. PDAC patients showed increased levels of monocytes when compared to healthy controls In addition, patients with perineural infiltration demonstrated a higher percentage of monocytes compared to non-infiltrating tumors and PDAC G3 was associated with higher monocyte levels than PDAC G2. Patients with monocyte levels > 5% were found to have an 8.9-fold increased risk for a G3 and perineural infiltrated PDAC resulting in poorer survival compared to patients with <5% monocyte levels. Furthermore, PDAC patients showed increased expressions of CD86 and CD11c and decreased expressions of PD-L1 on monocytes compared to healthy individuals. Finally, levels of monocytes correlated positively with concentrations of IL-6 and TNF-α in plasma of PDAC patients. Based on our findings, we propose monocytes as a novel prognostic biomarker. Large-scale studies are needed to further decipher the role of monocytes in PDAC and investigate their potential as therapeutic targets.

20.
Int J Colorectal Dis ; 37(10): 2245-2253, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36216902

RESUMO

PURPOSE: Intestinal anastomosis is a crucial step in most intestinal resections, as anastomotic leakage is often associated with severe consequences for affected patients. There are especially two different techniques for hand-sewn intestinal anastomosis: the interrupted suture technique (IST) and the continuous suture technique (CST). This study investigated whether one of these two suture techniques is associated with a lower rate of anastomotic leakage. METHODS: A retrospective review of 332 patients with Crohn's disease who received at least one hand-sewn colonic anastomosis at our institution from 2010 to 2020 was performed. Using propensity score matching 183 patients with IST were compared to 96 patients with CST in regard to the impact of the anastomotic technique on patient outcomes. RESULTS: Overall anastomotic leakage rate was 5%. Leakage rate did not differ between the suture technique groups (IST: 6% vs. CST: 3%, p = 0.393). Multivariate analysis revealed the ASA score as only independent risk factor for anastomotic leakage (OR 5.3 (95% CI = 1.2-23.2), p = 0.026). Suture technique also showed no significant influence on morbidity and the re-surgery rate in multivariate analysis. CONCLUSION: Our data suggest that the chosen suture technique (interrupted vs. continuous) has no influence on postoperative outcome, especially on anastomotic leakage rate. This finding should be confirmed by a randomized controlled trial.


Assuntos
Fístula Anastomótica , Doença de Crohn , Anastomose Cirúrgica/efeitos adversos , Anastomose Cirúrgica/métodos , Fístula Anastomótica/etiologia , Fístula Anastomótica/cirurgia , Doença de Crohn/complicações , Humanos , Pontuação de Propensão , Estudos Retrospectivos , Técnicas de Sutura/efeitos adversos
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