RESUMO
BACKGROUND: Aim of the current study was to present the results of the implementation phase of a robotic liver surgery program and to assess the validity of the IWATE difficulty score in predicting difficulty and postoperative complications in robotic liver surgery. METHODS: Based on the prospective database of the Interdisciplinary Robotic Center of Ulm University Hospital, the first 100 robotic liver surgeries were identified and analyzed. Perioperative parameters (duration of surgery and blood loss) and postoperative parameters including morbidity, mortality, and length of hospital stay were assessed and the results were compared between different IWATE difficulty categories. RESULTS: From November 2020 until January 2023, 100 robotic liver surgeries were performed (41 female, 59 male; median age 60.6 years, median BMI 25.9 kg/m2). Median duration of surgery was 180 min (IQR: 128.7), and median blood loss was 300 ml (IQR: 550). Ninety-day mortality was 2%, and overall morbidity was 21%, with major complications occurring in 13% of patients (≥ grade 3 according to Clavien/Dindo). A clinically relevant postoperative biliary leakage was observed in 3 patients. Posthepatectomy liver failure occurred in 7% (4 Grade A, 3 Grade B). Duration of surgery (p < 0.001), blood loss (p < 0.001), CCI (p = 0.004), overall morbidity (p = 0.004), and length of hospital stay (p < 0.001) were significantly increased in the IWATE 'expert' category compared to lower categories. DISCUSSION: Robotic surgery offers a minimally invasive approach for liver surgery with favorable clinical outcomes, even in the implementation phase. In the current study the IWATE difficulty score had the ability to predict both difficulty of surgery as well as postoperative outcomes when assessing the complexity of robotic liver surgery. Therefore, the role of the IWATE score in predicting these outcomes highlights its importance as a tool in surgical planning and decision-making.
Assuntos
Laparoscopia , Neoplasias Hepáticas , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Laparoscopia/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fígado , Estudos Retrospectivos , Tempo de Internação , Hepatectomia/efeitos adversos , Hepatectomia/métodosRESUMO
Nerve tumors in the retroperitoneal space are a rarity. Radical surgery according to soft tissue tumors can lead to persistent pain and neurological deficits. This study aims to evaluate clinical outcomes of patients treated by a visceral- / neurosurgical approach. 33 patients with a retroperitoneal nerve tumor underwent surgery between 01/2002 and 12/2022 at our department. A visceral surgeon provided access to the retroperitoneal space, followed by micro-neurosurgical tumor preparation under neuromonitoring. Clinical examination and MRI were performed 12 weeks after surgery and further 3 months (WHO grade > 1) or 12 months (WHO grade 1). Further examinations were based on MRI findings and residual symptoms with median follow-up time of 24 months. One patient was treated for two distinct masses resulting in a total of 34 histological findings. Schwannomas (n = 15; 44.1%) and neurofibromas (n = 10; 29.4%) were the most common tumors. Long-term improvements were noted in radicular pain (15/18 patients; 83.3%), motor deficits (7/16 patients; 43.8%), abdominal discomfort and pain (5/7 patients; 71.4%). Recurrences were observed in 3/33 (9,1%) patients. This study represents the largest series of retroperitoneal BPNSTs treated with microsurgical techniques. Prospective multicenter studies are warranted to establish standardized treatment guidelines.
Assuntos
Neurilemoma , Procedimentos Neurocirúrgicos , Neoplasias Retroperitoneais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Retroperitoneais/cirurgia , Neoplasias Retroperitoneais/patologia , Adulto , Neurilemoma/cirurgia , Neurilemoma/patologia , Idoso , Seguimentos , Procedimentos Neurocirúrgicos/métodos , Prognóstico , Neurofibroma/cirurgia , Neurofibroma/patologia , Adulto Jovem , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/patologia , Imageamento por Ressonância Magnética/métodos , Espaço Retroperitoneal/cirurgia , Espaço Retroperitoneal/patologiaRESUMO
The epithelial-mesenchymal transition (EMT) is a cellular reprogramming process that occurs during embryonic development and adult tissue homeostasis. This process involves epithelial cells acquiring a mesenchymal phenotype. Through EMT, cancer cells acquire properties associated with a more aggressive phenotype. EMT and its opposite, mesenchymal-epithelial transition (MET), have been described in more tumors over the past ten years, including colorectal cancer (CRC). When EMT is activated, the expression of the epithelial marker E-cadherin is decreased and the expression of the mesenchymal marker vimentin is raised. As a result, cells temporarily take on a mesenchymal phenotype, becoming motile and promoting the spread of tumor cells. Epithelial-mesenchymal plasticity (EMP) has become a hot issue in CRC because strong inducers of EMT (such as transforming growth factor ß, TGF-ß) can initiate EMT and regulate metastasis, microenvironment, and immune system resistance in CRC. In this review, we take into account the significance of EMT-MET in CRC and the impact of the epithelial cells' plasticity on the prognosis of CRC. The analysis of connection between EMT and colorectal cancer stem cells (CCSCs) will help to further clarify the current meager understandings of EMT. Recent advances affecting important EMT transcription factors and EMT and CCSCs are highlighted. We come to the conclusion that the regulatory network for EMT in CRC is complicated, with a great deal of crosstalk and alternate paths. More thorough research is required to more effectively connect the clinical management of CRC with biomarkers and targeted treatments associated with EMT.
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Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Adulto , Humanos , Transição Epitelial-Mesenquimal/genética , Neoplasias Colorretais/patologia , Diferenciação Celular/genética , Caderinas/genética , Fatores de Transcrição , Fator de Crescimento Transformador beta , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
The distinct biology of pancreatic cancer with aggressive and early invasive tumor cells, a tumor promoting microenvironment, late diagnosis, and high therapy resistance poses major challenges on clinicians, researchers, and patients. In current clinical practice, a curative approach for pancreatic cancer can only be offered to a minority of patients and even for those patients, the long-term outcome is grim. This bitter combination will eventually let pancreatic cancer rise to the second leading cause of cancer-related mortalities. With surgery being the only curative option, complete tumor resection still remains the center of pancreatic cancer treatment. In recent years, new developments in neoadjuvant and adjuvant treatment have emerged. Together with improved perioperative care including complication management, an increasing number of patients have become eligible for tumor resection. Basic research aims to further increase these numbers by new methods of early detection, better tumor modelling and personalized treatment options. This review aims to summarize the current knowledge on clinical and biologic features, surgical and non-surgical treatment options, and the improved collaboration of clinicians and basic researchers in pancreatic cancer that will hopefully result in more successful ways of curing pancreatic cancer.
Assuntos
Neoplasias Pancreáticas/terapia , Animais , HumanosRESUMO
In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer.
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Interleucina-13 , Neoplasias Pancreáticas , Apoptose , Citocinas/metabolismo , Humanos , Interleucina-13/farmacologia , Subunidade alfa1 de Receptor de Interleucina-13/genética , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Neoplasias Pancreáticas/genética , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
PURPOSE: Local treatment of small well-differentiated rectal neuroendocrine tumors (NETs) is recommended by current guidelines. However, although several endoscopic methods have been established, the highest R0 rate is achieved by transanal endoscopic microsurgery (TEM). Since a recently published study about endoscopic full thickness resection (eFTR) showed a R0 resection rate of 100%, the aim of this study was to evaluate both methods (eFTR vs. TEM). METHODS: We retrospectively analyzed all patients with rectal NET treated either by TEM (1999-2018) or eFTR (2016-2019) in two tertiary centers (University Hospital Wuerzburg and Ulm). We analyzed clinical, procedural, and histopathological outcomes in both groups. RESULTS: Twenty-eight patients with rectal NET received local treatment (TEM: 13; eFTR: 15). Most tumors were at stage T1a and grade G1 or G2 (in the TEM group two G3 NETs were staged T2 after neoadjuvant chemotherapy). In both groups, similar outcomes for en bloc resection rate, R0 resection rate, tumor size, or specimen size were found. No procedural adverse events were noted. Mean procedure time in the TEM group was 48.9 min and 19.2 min in the eFTR group. CONCLUSION: eFTR is a convincing method for local treatment of small rectal NETs combining high safety and efficacy with short interventional time.
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Tumores Neuroendócrinos , Neoplasias Retais , Microcirurgia Endoscópica Transanal , Humanos , Microcirurgia , Tumores Neuroendócrinos/cirurgia , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages. METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements. RESULTS: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma. CONCLUSION: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Adulto , Preservação da Fertilidade , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Embrionárias de Células Germinativas/terapia , Guias de Prática Clínica como Assunto , Prognóstico , Neoplasias Testiculares/classificação , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/terapiaRESUMO
OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.
Assuntos
Neoplasias Embrionárias de Células Germinativas/terapia , Tumores do Estroma Gonadal e dos Cordões Sexuais/terapia , Neoplasias Testiculares/terapia , Adulto , Assistência ao Convalescente , Humanos , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Cuidados Paliativos , Guias de Prática Clínica como Assunto , Qualidade de Vida , Neoplasias Testiculares/patologiaRESUMO
Interleukin (IL)-4 and -13 are structurally and functionally related cytokines sharing common receptor subunits. They regulate immune responses and, moreover, are involved in the pathogenesis of a variety of human neoplasms. Three different receptors have been described for IL-4, but only IL-4 receptor type II (IL-4Rα/IL-13Rα1) is expressed in solid tumors. While IL-13 can also bind to three different receptors, IL-13 receptor type I (IL-4Rα/IL-13Rα1/IL-13Rα2) and type II (IL-4Rα/IL-13Rα1) are expressed in solid tumors. After receptor binding, IL-4 and IL-13 can mediate tumor cell proliferation, survival, and metastasis in gastric or colon cancer. This review summarizes the results about the role of IL-4/IL-13 and their receptors in gastric and colon cancer.
Assuntos
Neoplasias do Colo/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Interleucina-13/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Receptores de Interleucina-13/genética , Receptores de Interleucina-4/genética , Transdução de Sinais , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologiaRESUMO
Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets.
Assuntos
Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/genética , Interleucina-13/genética , Interleucina-4/genética , Neoplasias Pancreáticas/genética , Carcinogênese/genética , Humanos , Subunidade alfa de Receptor de Interleucina-4/genética , Neoplasias Pancreáticas/patologia , Receptores de Interleucina/genética , Transdução de Sinais/genéticaRESUMO
Protein kinases of the CK1 family can be involved in numerous physiological and pathophysiological processes. Dysregulated expression and/or activity as well as mutation of CK1 isoforms have previously been linked to tumorigenesis. Among all neoplastic diseases, colon and rectal cancer (CRC) represent the fourth leading cause of cancer related deaths. Since mutations in CK1δ previously found in CRC patients exhibited increased oncogenic features, inhibition of CK1δ is supposed to have promising therapeutic potential for tumors, which present overexpression or mutations of this CK1 isoform. Therefore, it is important to develop new small molecule inhibitors exhibiting higher affinity toward CK1δ mutants. In the present study, we first characterized the kinetic properties of CK1δ mutants, which were detected in different tumor entities. Subsequently, we characterized the ability of several newly developed IWP-based inhibitors to inhibit wild type and CK1δ mutants and we furthermore analyzed their effects on growth inhibition of various cultured colon cancer cell lines. Our results indicate, that these compounds represent a promising base for the development of novel CRC therapy concepts.
Assuntos
Caseína Quinase Idelta/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Desenvolvimento de Medicamentos , Proteínas Mutantes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Caseína Quinase Idelta/genética , Caseína Quinase Idelta/metabolismo , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Humanos , Modelos Moleculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Fosforilação , Células Tumorais CultivadasRESUMO
BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.
Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Carcinoma Ductal Pancreático/mortalidade , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Combinação de Medicamentos , Fluoruracila/uso terapêutico , Alemanha/epidemiologia , Humanos , Irinotecano , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante/métodos , Compostos Organometálicos/uso terapêutico , Oxaliplatina , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Adulto Jovem , GencitabinaRESUMO
Colon cancer (CC) and rectal cancer (RC) are synonymously called colorectal cancer (CRC). Based on our experience in basic and clinical research as well as routine work in the field, the term CRC should be abandoned. We analyzed the available data from the literature and results from our multicenter Research Group Oncology of Gastrointestinal Tumors termed FOGT to confirm or reject this hypothesis. Anatomically, the risk of developing RC is four times higher than CC, while physical activity helps to prevent CC but not RC. Obvious differences exist in molecular carcinogenesis, pathology, surgical topography and procedures, and multimodal treatment. Therefore, we conclude that CC is not the same as RC. The term "CRC" should no longer be used as a single entity in basic and clinical research as well as other areas of classification.
Assuntos
Neoplasias do Colo/patologia , Neoplasias Retais/patologia , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Terapia Combinada , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Estudos Multicêntricos como Assunto , Especificidade de Órgãos , Neoplasias Retais/epidemiologia , Neoplasias Retais/genética , Neoplasias Retais/terapia , Fatores de RiscoRESUMO
Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m2) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, <15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (>90%) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.).
Assuntos
Obesidade Mórbida/sangue , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapêutico , Adulto , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Ertapenem , Feminino , Humanos , Laparoscopia , Testes de Sensibilidade Microbiana , Microdiálise , Pessoa de Meia-Idade , Método de Monte Carlo , Obesidade Mórbida/terapiaRESUMO
Exogenous interleukin-4 (IL-4) has been demonstrated to affect the growth of different human malignancies including pancreatic cancer cells. The aim of our study was to determine the role of endogenously expressed IL-4-receptor-α-chain (IL-4Rα) in pancreatic cancer cells. IL-4Rα-suppression was achieved by generating Capan-1 cells stably expressing shRNA targeting IL-4Rα. The malignant phenotype was characterized by assessing growth properties, directional and non-directional cell movement in vitro and tumor growth in vivo. Signaling pathways were analyzed upon IL-4 and IL-13 stimulation of wildtype (WT) and control-transfected cells compared to IL-4Rα-knockdown cells. Silencing of IL-4Rα resulted in reduced anchorage-dependent cell growth (p < 0.05) and reduced anchorage-independent colony size (p < 0.001) in vitro. Moreover, cell movement and migration was inhibited. IL-4 and IL-13 stimulation of Capan-1-WT cells induced activation of similar pathways like stimulation with Insulin-like growth factor (IGF)-I. This activation was reduced after IL-4Rα downregulation while IGF-I signaling seemed to be enhanced in knockdown-clones. Importantly, IL-4Rα silencing also significantly suppressed tumor growth in vivo. The present study indicates that endogenously expressed IL-4 and IL-4Rα contribute to the malignant phenotype of pancreatic cancer cells by activating diverse pro-oncogenic signaling pathways. Addressing these pathways may contribute to the treatment of the disease.
Assuntos
Subunidade alfa de Receptor de Interleucina-4/genética , Interleucina-4/metabolismo , Neoplasias Pancreáticas/patologia , RNA Interferente Pequeno/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Predisposição Genética para Doença , Humanos , Técnicas In Vitro , Interleucina-3/metabolismo , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Camundongos , Transplante de Neoplasias , Neoplasias Pancreáticas/genética , Transdução de SinaisRESUMO
PURPOSE: To establish a chordoma tissue cohort (n = 43) and to correlate localization, size, metastasis, residual disease (R-status), recurrences, histological subtype, matrix content, and Ki-67 proliferation index with patients' overall survival (OS). METHODS AND RESULTS: We used routine histopathology supplemented by immunohistochemistry. In our patient cohort (median age 69 years, range 17 to 84 years) the median OS was 8.25 years. 24 chordomas were localized in the sacrum, 6 in lumbar vertebrae, 7 in thoracic and cervical vertebrae, 5 were limited to the clivus, and one was localized in the nasal septum. Ten patients had metastases, with pulmonary, nodal, and hepatic involvement. 23 patients had recurrent disease. 23 chordomas were classified as 'not otherwise specified' (NOS). Besides NOS, we found the following differentiation patterns: renal cell cancer like in six cases, chondroid in four cases, hepatoid differentiation in three cases, and anaplastic morphology in six cases. Ki-67 index of ≥10 %, presence of metastasis, and the low content of extracellular matrix were statistically linked to poor OS (p < 0.05). The matrix-poor phenotype had a higher Ki-67 index (p < 0.05). Furthermore, presence of metastasis was associated with a higher Ki-67 index in the primary lesion, a positive resection margin, and multiple recurrences (p < 0.05 each). CONCLUSION: We propose to include these parameters in the final pathologic report of the resected chordoma.
Assuntos
Cordoma , Neoplasias da Coluna Vertebral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cordoma/diagnóstico por imagem , Cordoma/epidemiologia , Cordoma/mortalidade , Cordoma/patologia , Humanos , Antígeno Ki-67/sangue , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/epidemiologia , Neoplasias da Coluna Vertebral/mortalidade , Neoplasias da Coluna Vertebral/patologia , Coluna Vertebral/diagnóstico por imagem , Adulto JovemRESUMO
Colorectal cancer (CRC) is the fourth leading cause of cancer related death worldwide due to high apoptotic resistance and metastatic potential. Because mutations as well as deregulation of CK1 isoforms contribute to tumor development and tumor progression, CK1 has become an interesting drug target. In this study we show that CK1 isoforms are differently expressed in colon tumor cell lines and that growth of these cell lines can be inhibited by CK1-specific inhibitors. Furthermore, expression of CK1δ and É is changed in colorectal tumors compared to normal bowel epithelium, and high CK1É expression levels significantly correlate with prolonged patients' survival. In addition to changes in CK1δ and É expression, mutations within exon 3 of CK1δ were detected in colorectal tumors. These mutations influence ATP binding resulting in changes in kinetic parameters of CK1δ. Overexpression of these mutants in HT29 cells alters their ability to grow anchorage independently. Consistent with these results, these CK1δ mutants lead to differences in proliferation rate and tumor size in xenografts due to changes in gene expression, especially in genes involved in regulation of cell proliferation, cell cycle, and apoptosis. In summary, our results provide evidence that changes in the expression levels of CK1 isoforms in colorectal tumors correlate with patients' survival. Furthermore, CK1 mutants affect growth and proliferation of tumor cells and induce tumor growth in xenografts, leading to the assumption that CK1 isoforms provide interesting targets for the development of novel effective therapeutic concepts to treat colorectal cancer.
Assuntos
Caseína Quinase 1 épsilon/genética , Caseína Quinase Idelta/genética , Neoplasias Colorretais/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Idoso , Animais , Western Blotting , Caseína Quinase 1 épsilon/metabolismo , Caseína Quinase Idelta/metabolismo , Adesão Celular/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Perfilação da Expressão Gênica , Células HT29 , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo , Carga Tumoral/genéticaRESUMO
About 10% of all cancer patients will develop brain metastases during advanced disease progression. Interestingly, the vast majority of brain metastases occur in only three types of cancer: Melanoma, lung and breast cancer. In this review, we focus on summarizing the prognosis and impact of surgical resection of brain metastases originating from gastrointestinal cancers such as esophageal, gastric, pancreatic and colorectal cancer. The incidence of brain metastases is <1% in pancreatic and gastric cancer and <4% in esophageal and colorectal cancer. Overall, prognosis of these patients is very poor with a median survival in the range of only months. Interestingly, a substantial number of patients who had received surgical resection of brain metastases showed prolonged survival. However, it should be taken into account that all these studies were not randomized and it is likely that patients selected for surgical treatment presented with other important prognostic factors such as solitary brain metastases and exclusion of extra-cranial disease. Nevertheless, other reports have demonstrated long-term survival of patients upon resection of brain metastases originating from gastrointestinal cancers. Thus, it appears to be justified to consider aggressive surgical approaches for these patients.
Assuntos
Neoplasias Encefálicas/secundário , Carcinoma/secundário , Neoplasias Esofágicas/patologia , Neoplasias Gastrointestinais/patologia , Procedimentos Neurocirúrgicos , Neoplasias Pancreáticas/patologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/cirurgia , Carcinoma/epidemiologia , Carcinoma/cirurgia , Craniotomia , Intervalo Livre de Doença , Neoplasias Esofágicas/epidemiologia , Neoplasias Gastrointestinais/epidemiologia , Humanos , Incidência , Cuidados Paliativos , Neoplasias Pancreáticas/epidemiologia , Seleção de Pacientes , Prognóstico , Qualidade de Vida , Resultado do TratamentoRESUMO
Mediastinal ectopic parathyroid adenomas, a rare cause of primary hyperparathyroidism, has evolved significantly with the advent of robotic-assisted surgery. Traditional surgical approaches, while effective, may be associated with considerable morbidity and extended recovery periods. This study aims to evaluate the effectiveness, precision, and postoperative outcomes of robotic thoracoscopy with parathyroidectomy in the management of mediastinal ectopic parathyroid adenomas. A case of a 70-year-old man with a history of primary hyperparathyroidism underwent a successful left robotic thoracoscopy with parathyroidectomy in an ectopic mediastinal parathyroid adenoma. The robotic approach demonstrated advantages such as enhanced precision and minimal invasiveness. However, the learning curve and cost implications of this technology were identified as considerations. Robotic thoracoscopy with parathyroidectomy underscores the potential of robotic surgery in revolutionizing the management of mediastinal ectopic parathyroid adenomas, offering promising precision, emphasizing the need for ongoing research, and evaluation to optimize this innovative surgical method.