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BACKGROUND: Anastomotic leakage following colorectal surgery remains a significant complication despite advances in surgical techniques. Recent findings on serosal injury repair in coelomic cavities, such as the peritoneum, challenge the current understanding of the cellular origins and mechanisms underlying intestinal anastomotic healing. Understanding the contribution of each layer of the intestinal wall during anastomotic healing is needed to find new therapeutic strategies to prevent anastomotic leakage. The aim of this experimental study was to investigate the role of the serosal layer of the intestinal wall in anastomotic healing. MATERIALS AND METHODS: Comprehensive histologic analysis of human and murine anastomoses was performed to elucidate histologic changes in the different intestinal layers during anastomotic healing. In vivo staining of the extracellular matrix (ECM) in the serosal layer was performed using a fluorophore-conjugated N-hydroxysuccinimide-ester before anastomosis surgery in a murine model. RESULTS: Histological examination of both human and murine anastomoses revealed that closure of the serosal layer occurred first during the healing process. In vivo serosal ECM staining demonstrated that a significant portion of the newly formed ECM within the anastomosis was indeed deposited onto the serosal layer. Furthermore, mesenchymal cells within the anastomotic scar were positive for mesothelial cell markers, podoplanin and Wilms tumour protein. CONCLUSIONS: In this experimental study, the results suggest that serosal scar formation is an important mechanism for anastomotic integrity in intestinal anastomoses. Mesothelial cells may significantly contribute to scar formation during anastomotic healing through epithelial-to-mesenchymal transition, potentially suggesting a novel therapeutic target to prevent anastomotic leakage by enhancing physiological healing processes.
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Anastomosis Quirúrgica , Fuga Anastomótica , Membrana Serosa , Cicatrización de Heridas , Animales , Anastomosis Quirúrgica/efectos adversos , Humanos , Ratones , Cicatrización de Heridas/fisiología , Fuga Anastomótica/prevención & control , Fuga Anastomótica/etiología , Membrana Serosa/patología , Masculino , Matriz Extracelular/metabolismo , Femenino , Ratones Endogámicos C57BL , Colon/cirugía , Colon/patologíaRESUMEN
Many pancreatic neuroendocrine tumors (PanNETs) fall into 2 major prognostic subtypes based on DAXX/ATRX-induced alternative lengthening of telomerase phenotype and alpha- and beta-cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well-characterized in terms of their histologic and hormonal phenotypes. We aimed to identify new subgroups of PanNETs by extending the currently used transcription factor signatures and investigating their correlation with histologic, hormonal, molecular, and prognostic findings. One hundred eighty-five PanNETs (nonfunctioning 165 and functioning 20), resected between 1996 and 2023, were classified into 5 subgroups (A1, A2, B, C, and D) by cluster analysis based on ARX, PDX1, islet-1 (ISL1), and CDX2 expressions and correlated with trabecular vs solid histology, expression of insulin, glucagon, polypeptide (PP), somatostatin, serotonin, gastrin, calcitonin, adrenocorticotropic hormone (ACTH), DAXX/ATRX, MEN1, and alternative lengthening of telomerase status by fluorescence in situ hybridization, and disease-free survival. A1 (46%, ARX+/ISL1+/PDX1-/CDX2-) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2-) showed trabecular histology and glucagon/PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX-/CDX2-) showed solid histology, insulin, and somatostatin expression (P < .001). It included all insulinomas and had the best outcome (P < .01). C (15%, ARX-/PDX1-/ISL1-/CDX2-) showed solid histology and frequent expression of serotonin, calcitonin, and ACTH. D (5%, PDX1+/CDX2+/ISL1-/ARX-) showed solid histology, expressed ACTH/serotonin, and was an independent poor prognosticator (P < .01). Differential expressions of ARX, PDX1, ISL1, and CDX2 stratified PanNETs into 5 subgroups with different histologies, hormone expressions, and outcomes. Subgroups A1 and A2 resembled the alpha-cell-like type, and subgroup B, the beta-cell-like type. Subgroup C with almost no transcription factor signature was unclear in cell lineage, whereas the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the subgroups may help establish the diagnosis, predict the outcome, and guide the treatment.
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BACKGROUND: Pancreatic cancer is often accompanied by wasting conditions. While surgery is the primary curative approach, it poses a substantial risk of postoperative complications, hindering subsequent treatments. Therefore, identifying patients at high risk for complications and optimizing their perioperative general condition is crucial. Sarcopenia and other body composition abnormalities have shown to adversely affect surgical and oncological outcomes in various cancer patients. As most pancreatic tumours are located close to the neuronal control centre for the digestive tract, it is possible that neural infiltration in this area deranges bowel functions and contributes to malabsorption and malnutrition and ultimately worsen sarcopenia and weight loss. METHODS: A retrospective analysis of CT scans was performed for pancreatic cancer patients who underwent surgical tumour resection at a single high-volume centre from 2007 to 2023. Sarcopenia prevalence was assessed by skeletal muscle index (SMI), and visceral obesity was determined by the visceral adipose tissue area (VAT). Obesity and malnutrition were determined by the GLIM criteria. Sarcopenic obesity was defined as simultaneous sarcopenia and obesity. Postoperative complications, mortality and perineural tumour invasion, were compared among patients with body composition abnormalities. RESULTS: Of 437 patients studied, 46% were female, the median age was 69 (61;74) years. CT analysis revealed 54.9% of patients with sarcopenia, 23.7% with sarcopenic obesity and 45.9% with visceral obesity. Sarcopenia and sarcopenic obesity were more prevalent in elderly and male patients. Postoperative surgical complications occurred in 67.7% of patients, most of which were mild (41.6%). Severe complications occurred in 22.7% of cases and the mortality rate was 3.4%. Severe postoperative complications were significantly more common in patients with sarcopenia or sarcopenic obesity. Visceral obesity or malnutrition based on BMI alone, did not significantly impact complications. Perineural invasion was found in 80.1% of patients and was unrelated to malnutrition or body composition parameters. CONCLUSIONS: This is the first and largest study evaluating the associations of CT-based body mass analysis with surgical outcome and histopathological perineural tumour invasion in pancreatic cancer patients. The results suggest that elderly and male patients are at high risk for sarcopenia and should be routinely evaluated by CT before undergoing pancreatic surgery, irrespective of their BMI. Confirmation of the results in prospective studies is needed to assess if pancreatic cancer patients with radiographic sarcopenia benefit from preoperative amelioration of muscle mass and function by exercise and nutritional interventions.
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Composición Corporal , Pancreatectomía , Neoplasias Pancreáticas , Complicaciones Posoperatorias , Sarcopenia , Humanos , Masculino , Femenino , Anciano , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Persona de Mediana Edad , Sarcopenia/epidemiología , Sarcopenia/etiología , Sarcopenia/complicaciones , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Pancreatectomía/métodos , Invasividad Neoplásica , Obesidad/complicaciones , Tomografía Computarizada por Rayos XRESUMEN
Background: Arterial resection (AR) during pancreatectomy for curative R0 resection of pancreatic ductal adenocarcinoma (PDAC) remains a controversial procedure with high morbidity. Objective: To investigate the feasibility and oncological outcomes of pancreatectomy combined with AR at a high-volume center for pancreatic surgery. Methods: We retrospectively analyzed our experience in PDAC patients, who underwent pancreatic resection with AR and/or venous resection (VR) between 2007 and 2021. Results: In total 259 PDAC patients with borderline resectable (n = 138) or locally advanced (n = 121) PDAC underwent vascular resection during tumor resection. From these, 23 patients had AR (n = 4 due to intraoperative injury, n = 19 due to suspected arterial infiltration). However, 12 out of 23 patients (52.2%) underwent simultaneous VR including 1 case with intraoperative arterial injury. In comparison, 11 patients (47.8%) underwent AR only including 3 intraoperative arterial injury patients. Although the operation time and bleeding rate of patients with AR were respectively longer and higher than in VR, no significant difference was detected in postoperative complications between VR and AR (P = 0.11). The final histopathological findings of PDAC patients were similar, including M stage, regional lymph node metastases, and R0 margin resection. The mortality of the entire cohort was 6.2% (16/259), with a tendency to increase mortality in the AR cohort, yet without statistical significance (VR: 5% vs AR: 21.1%; P = 0.05). Although 19 (82.6%) patients had PDAC in the final histopathology, only 6 were confirmed to have infiltrated arteria. The microscopic distribution of PDAC in these infiltrated arterial walls on hematoxylin-eosin staining was classified into 3 patterns. Strikingly, the perivascular nerves frequently exhibited perineural invasion. Conclusions: AR can be performed in high-volume centers for pancreatic surgery with an acceptable morbidity, which is comparable to that of VR. However, the likelihood of arterial infiltration seems to be rather overestimated, and as such, AR might be avoidable or replaced by less invasive techniques such as divestment during PDAC surgery.
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OBJECTIVES: Cancer is considered an emerging diabetes complication, with higher incidence and worse prognosis in patients with diabetes. Cancer is frequently associated with cachexia, a systemic metabolic disease causing wasting. It is currently unclear how diabetes affects the development and progression of cachexia. METHODS: We investigated the interplay between diabetes and cancer cachexia retrospectively in a cohort of 345 patients with colorectal and pancreatic cancer. We recorded body weight, fat mass, muscle mass, clinical serum values, and survival of these patients. Patients were grouped either into diabetic/non-diabetic groups based on previous diagnosis, or into obese/non-obese groups based on body mass index (BMI ≥30 kg/m2 was considered obese). RESULTS: The pre-existence of type 2 diabetes, but not obesity, in patients with cancer led to increased cachexia incidence (80%, compared to 61% without diabetes, p ≤ 0.05), higher weight loss (8.9% vs. 6.0%, p ≤ 0.001), and reduced survival probability (median survival days: 689 vs. 538, Chi square = 4.96, p ≤ 0.05) irrespective of the initial body weight or tumor progression. Patients with diabetes and cancer showed higher serum levels of C-reactive protein (0.919 µg/mL vs. 0.551 µg/mL, p ≤ 0.01) and interleukin 6 (5.98 pg/mL vs. 3.75 pg/mL, p ≤ 0.05) as well as lower serum albumin levels (3.98 g/dL vs. 4.18 g/dL, p ≤ 0.05) than patients with cancer without diabetes. In a sub-analysis of patients with pancreatic cancer, pre-existing diabetes worsened weight loss (9.95% vs. 6.93%, p ≤ 0.01), and increased the duration of hospitalization (24.41 days vs. 15.85 days, p ≤ 0.001). Further, diabetes aggravated clinical manifestations of cachexia, as changes in the aforementioned biomarkers were more pronounced in patients with diabetes and cachexia co-existence, compared to cachectic patients without diabetes (C-reactive protein: 2.300 µg/mL vs. 0.571 µg/mL, p ≤ 0.0001; hemoglobin: 11.24 g/dL vs. 12.52 g/dL, p ≤ 0.05). CONCLUSIONS: We show for the first time that pre-existing diabetes aggravates cachexia development in patients with colorectal and pancreatic cancer. This is important when considering cachexia biomarkers and weight management in patients with co-existing diabetes and cancer.
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Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Neoplasias Pancreáticas , Humanos , Caquexia/metabolismo , Estudios Retrospectivos , Proteína C-Reactiva , Diabetes Mellitus Tipo 2/complicaciones , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/metabolismo , Peso Corporal , Obesidad/complicaciones , Biomarcadores , Neoplasias Colorrectales/complicaciones , Neoplasias PancreáticasRESUMEN
BACKGROUND: Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans. METHODS: miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (N ≤ 12) and cachectic patients (N ≤ 23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using in silico prediction, related genes were identified and evaluated. The findings were confirmed in vitro by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses. RESULTS: Validating the results of the array, a 2-fold down-regulation of miR-122-5p (P = 0.0396) and a 4.5-fold down-regulation of miR-194-5p (P < 0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (P = 0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (P = 0.0386, P = 0.0112 and P = 0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the in silico predicted atrophy-related target genes IL-15 and TRIM63. Both were up-regulated in miR-27b-3p knock-down cells (P < 0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of IL-15 (P = 0.0237) and TRIM63 (P = 0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes LIPE, PNPLA2, MGLL and LPL (P < 0.01). CONCLUSIONS: The identified miRNAs, in particular miR-122-5p, miR-27b-3p, miR-375 and miR-424-5p, represent features of human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the regulation of catabolic signals. Further studies are needed to explore the potential of the identified miRNAs as a screening tool for early detection of cancer cachexia.
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MicroARNs , Neoplasias , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Interleucina-15 , Caquexia/genética , Neoplasias/complicaciones , Neoplasias/genética , Pérdida de PesoRESUMEN
Background: Pancreatic fistula/PF is a challenging surgical complication. We could recently show that intestinal bacteria such as Enterobacterales colonize the PF fluid even after a "sterile" operation like distal pancreatectomy/DP. Therefore, we explored the bacterial flora of the human pancreatic duct in a patient collective undergoing pancreatic surgery. Methods: In this observational study, upon transection of the pancreas during surgery, a swab was inserted into the main duct, and the micro-organismal content was correlated with clinical characteristics. Results: Between February 2017 and February 2020, an intraoperative swab from the pancreatic duct was obtained from a total of 54 patients who underwent pancreatico-duodenectomy/PD or DP. The swabs were sterile in 39 cases (72.2%), detected intestinal bacteria in 10 cases (18.5%), and other bacteria in 5 cases (9.3%). There was no correlation of the micro-organismal content of the pancreatic duct swab with bacteria detected in the PF fluid or bile. Preoperative ERCP was associated with a higher frequency of bacterial colonization of the pancreatic duct (33.3% vs. 6.7%, p = 0.005). There was no correlation of the pancreatic duct swabs with postoperative complications. Discussion: The human main pancreatic duct is usually sterile, and its bacterial colonization does not correlate with the occurrence of PF. Therefore, the mechanisms leading to infection of PF warrant in-depth, mechanistic investigation.
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BACKGROUND: Malignant tumors of the esophagus are the sixth leading cause of cancer-related deaths worldwide. Postoperative leakage of the esophago-gastrostomy leads to mediastinal sepsis, which is still associated with a high morbidity and mortality rate. The aim of this study was to describe the endoscopic view of the different severity grades of an anastomotic leakage. METHODS: Patients Between June 2016 and September 2018, 144 patients were operated upon in the Department of Surgery, University of Munich, Germany. Among these patients, 34 (23.6%) presented with a leakage of the anastomosis. Endoscopy In this retrospective analysis, the focus is to describe different patterns of leakage of the anastomosis. RESULTS: We studied 34 patients in whom post-esophagectomy leakage of the anastomosis was detected and treated with an endoluminal vacuum sponge system. The leakage healed in 26 of 29 patients (success rate 89.7%). With the increasing severity of leakage, the treatment time and the in-hospital mortality correspondingly increased. Furthermore, the incidence of the development of a fistula to the tracheobronchial system increased with higher grades of leakage. CONCLUSIONS: Exact descriptions of leakage are necessary to compare the cases and to prove post-treatment improvement. This is, to our knowledge, the first publication to present a leakage grading score in patients after esophagectomy including reconstruction with a gastric tube. This new grading system needs to be tested in further analyses, with a special focus on prospective analysis.
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Fuga Anastomótica , Esófago , Fuga Anastomótica/etiología , Endoscopía Gastrointestinal , Esofagectomía/efectos adversos , Esófago/cirugía , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: Cachexia, a devastating syndrome in cancer patients, critically determines survival and life quality. It is characterized by impaired homeostasis of multiple organs including the liver, involves tissue wasting, and is conventionally diagnosed and classified by weight loss (WL). However, recent studies pointed at the problem that WL is not sufficient for precise classification of cancer patients according to disease severity (i.e. prognosis). Tissue inhibitor of metalloproteinases-1 (TIMP-1) is an easily accessible cachexia-associated biomarker in the blood, known to alter liver homeostasis. Here, we investigated the value of combining blood levels of TIMP-1 with parameters of liver functionality towards establishment of a cachexia-associated clinical score, which predicts survival of cancer patients, reflects the clinical manifestation of cachexia, and is easily accessible in the clinic. METHODS: The TIMP-1/liver cachexia (TLC) score, expressed as numerical value ranging from 0 to 1, was calculated by categorizing the blood levels of TIMP-1 and parameters of liver functionality (C-reactive protein, ferritin, gamma-glutamyl transferase, albumin, and total protein) for each patient as below/above a certain risk threshold. The TLC score was tested in a cohort of colorectal cancer (CRC) patients (n = 82, 35.4% women, 64.6% men, median age: 70 years) and validated in a cohort of pancreatic cancer (PC) patients (n = 84, 54.8% women, 45.2% men, median age: 69 years). RESULTS: In CRC patients, the TLC score positively correlated with presence of cachexia-related symptoms (WL, impaired liver function), predicted survival [P < 0.001, hazard ratio (HR): 96.91 (9.85-953.90)], and allowed classification of three prognostically distinct patient subpopulations [low (LO)-risk, intermediate (IM)-risk, and high (HI)-risk groups; LO vs. IM: P = 0.003, LO vs. HI: P < 0.001, IM vs. HI: P = 0.029]. The prognostic power of the cachexia-associated TLC score [P < 0.001, HR: 7.37 (2.80-19.49)] and its application to define risk groups (LO vs. IM: P = 0.032, LO vs. HI: P < 0.001, IM vs. HI: P = 0.014) was confirmed in a cohort of PC patients. The prognostic power of the TLC score was independent of presence of liver metastases in CRC or PC patients and was superior to clinically established staging classifications. CONCLUSIONS: The TLC score, a result of straightforward determination of blood parameters, is an objective cachexia-associated clinical tool for precise survival prediction of gastrointestinal cancer patients.
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Caquexia , Neoplasias Gastrointestinales , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Anciano , Caquexia/diagnóstico , Caquexia/etiología , Femenino , Neoplasias Gastrointestinales/complicaciones , Humanos , Hígado , Masculino , Neoplasias Pancreáticas , PronósticoRESUMEN
Malnutrition and cachexia affects the majority of cancer patients and significantly worsens their quality of life and prognosis. However, the diagnostic criteria of malnutrition and cachexia remain a topic under constant debate. To overcome this hurdle, diagnostic tools to objectively detect and quantify the loss of muscle and fat mass are needed. Computed tomography (CT)-based measurement is currently considered the golden standard. Bioelectrical impedance analysis (BIA) is an economical, non-invasive tool but it is seen controversial in patients with cancer and malnutrition because of possible estimation errors.BIA and CT-based analysis of body mass compartments were performed 172 times in 118 cancer patients, within the nutrition program of our institution. Prevalence of malnutrition was determined according to the global leadership initiative on malnutrition criteria. Data obtained for muscle and fat mass from both BIA and CT were correlated using Pearson's ρ. All analyses were performed with an explorative significance level of 5%.45.7% of the cohort were classified as "malnourished." No significant differences were observed between the 2 groups regarding demographic data. Median body mass index, Karnofsky performance status, and nutritional risk score were lower in the malnourished group. Values for muscle and fat mass by BIA and CT were significantly lower in malnourished patients. Correlation of the measured parameters were highly significant between CT-based and BIA measurement. In the overall cohort, correlation of measured muscle mass values by CT and BIA was significant with Pearson's ρâ=â0.794 (Pâ<â.01). Looking at patients without malnutrition only, Pearson's ρ was 0.754 (Pâ<â.01). The correlation of measured fat mass values was equally significant, with Pearson's ρ of 0.748 (Pâ<â.01) in the overall cohort and 0.771 (Pâ<â.01) in patients with malnutrition.To our knowledge, this is the first study comparing BIA to CT-based body mass analysis in a large cohort of cancer patients with malnutrition. The results suggest that BIA is a valid diagnostic tool for the assessment of muscle and fat mass, even in patients with malnutrition, and could be implemented for the early detection and short-term follow-up of malnutrition and cachexia.
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Índice de Masa Corporal , Caquexia/diagnóstico , Impedancia Eléctrica , Desnutrición/diagnóstico , Neoplasias/complicaciones , Tomografía Computarizada por Rayos X/normas , Adulto , Factores de Edad , Anciano , Composición Corporal/fisiología , Caquexia/etiología , Caquexia/patología , Estudios Transversales , Femenino , Humanos , Masculino , Desnutrición/etiología , Desnutrición/patología , Persona de Mediana Edad , Estado Nutricional , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
One of the major challenges in using pancreatic cancer patient-derived organoids (PDOs) in precision oncology is the time from biopsy to functional characterization. This is particularly true for endoscopic ultrasound-guided fine-needle aspiration biopsies, typically resulting in specimens with limited tumor cell yield. Here, we tested conditioned media of individual PDOs for cell-free DNA to detect driver mutations already early on during the expansion process to accelerate the genetic characterization of PDOs as well as subsequent functional testing. Importantly, genetic alterations detected in the PDO supernatant, collected as early as 72 hours after biopsy, recapitulate the mutational profile of the primary tumor, indicating suitability of this approach to subject PDOs to drug testing in a reduced time frame. In addition, we demonstrated that this workflow was practicable, even in patients for whom the amount of tumor material was not sufficient for molecular characterization by established means. Together, our findings demonstrate that generating PDOs from very limited biopsy material permits molecular profiling and drug testing. With our approach, this can be achieved in a rapid and feasible fashion with broad implications in clinical practice.
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Biomarcadores de Tumor/genética , Ácidos Nucleicos Libres de Células/análisis , Ácidos Nucleicos Libres de Células/genética , Organoides/patología , Neoplasias Pancreáticas/patología , Medicina de Precisión , Animales , Apoptosis , Biomarcadores de Tumor/análisis , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Desnudos , Organoides/metabolismo , Neoplasias Pancreáticas/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Cachexia is the direct cause of at least 20% of cancer-associated deaths. Muscle wasting in skeletal muscle results in weakness, immobility, and death secondary to impaired respiratory muscle function. Muscle proteins are massively degraded in cachexia; nevertheless, the molecular mechanisms related to this process are poorly understood. Previous studies have reported conflicting results regarding the amino acid abundances in cachectic skeletal muscle tissues. There is a clear need to identify the molecular processes of muscle metabolism in the context of cachexia, especially how different types of molecules are involved in the muscle wasting process. METHODS: New in situ -omics techniques were used to produce a more comprehensive picture of amino acid metabolism in cachectic muscles by determining the quantities of amino acids, proteins, and cellular metabolites. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging, we determined the in situ concentrations of amino acids and proteins, as well as energy and other cellular metabolites, in skeletal muscle tissues from genetic mouse cancer models (n = 21) and from patients with cancer (n = 6). Combined results from three individual MALDI mass spectrometry imaging methods were obtained and interpreted. Immunohistochemistry staining for mitochondrial proteins and myosin heavy chain expression, digital image analysis, and transmission electron microscopy complemented the MALDI mass spectrometry imaging results. RESULTS: Metabolic derangements in cachectic mouse muscle tissues were detected, with significantly increased quantities of lysine, arginine, proline, and tyrosine (P = 0.0037, P = 0.0048, P = 0.0430, and P = 0.0357, respectively) and significantly reduced quantities of glutamate and aspartate (P = 0.0008 and P = 0.0124). Human skeletal muscle tissues revealed similar tendencies. A majority of altered amino acids were released by the breakdown of proteins involved in oxidative phosphorylation. Decreased energy charge was observed in cachectic muscle tissues (P = 0.0101), which was related to the breakdown of specific proteins. Additionally, expression of the cationic amino acid transporter CAT1 was significantly decreased in the mitochondria of cachectic mouse muscles (P = 0.0133); this decrease may play an important role in the alterations of cationic amino acid metabolism and decreased quantity of glutamate observed in cachexia. CONCLUSIONS: Our results suggest that mitochondrial dysfunction has a substantial influence on amino acid metabolism in cachectic skeletal muscles, which appears to be triggered by diminished CAT1 expression, as well as the degradation of mitochondrial proteins. These findings provide new insights into the pathobiochemistry of muscle wasting.
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Aminoácidos/metabolismo , Caquexia/fisiopatología , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/fisiopatología , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: The nutritional status of patients with tumor diseases in German out-patient clinics is largely unknown. This cross-sectional survey on patients with tumor diseases aimed to assess the prevalence of the risk of malnutrition in this group. METHODS: In out-patient clinics of oncologists, patients with a diagnosed cancer disease were consecutively interrogated between June 2017 and May 2018 using a standardized questionnaire. In addition to questions on the health status and dietary habits, the validated screening questionnaires Malnutrition Universal Screening Tool (MUST) and the Nutrition Risk Screening Tool-2002 (NRS-2002) were used to assess the risk of malnutrition of these patients (primary endpoint). A descriptive statistical analysis was performed. RESULTS: In total, data from 765 patients with a diagnosed tumor (60.9â% female) were analyzed. The participants had a mean age of 63.1â±â13.1 years and a mean body mass index (BMI) of 25.2â±â5.1âkg/m². Using the MUST questionnaire 15.4â% of participants had a moderately increased risk and 19.5â% a high risk of malnutrition. Of those, patients with tumors of the gastrointestinal tract showed the highest rate of malnutrition risk (46.6â%). The criteria for a nutrition risk based on the NRS-2002 questionnaire (score ≥â3) were fulfilled by 29.1â% of the patients. Less than one third of the patients reported to have received dietary counselling after cancer diagnosis (29.9â%). CONCLUSION: Every third patient with a diagnosed tumor disease in out-patient care exhibits an increased risk of malnutrition. The results of this survey clearly indicate the need for a systematic screening for malnutrition and an evidence-based nutrition management of tumor patients under ambulatory care.
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Atención Ambulatoria , Desnutrición , Neoplasias , Anciano , Atención Ambulatoria/estadística & datos numéricos , Estudios Transversales , Femenino , Humanos , Masculino , Desnutrición/epidemiología , Desnutrición/etiología , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/epidemiología , Neoplasias/terapia , Estado Nutricional/fisiología , Prevalencia , Encuestas y CuestionariosRESUMEN
In previous experiments, human and rat small bowel samples have been successfully used to study the spasmolytic effect of (potential) therapeutics in carbamate-constricted bowel specimens. Additionally, transferability from rat to human data was shown in the previous study. In the present study, the effects of atropine, scopolamine, MB327, HI-6 as well as obidoxime were examined in organophosphorus-poisoned human small bowel specimens. All substances were tested with at least seven concentrations in samples previously exposed to the nerve agent sarin. Furthermore, the cholinesterase reactivation potential of all substances was investigated. The test substances displayed a spasmolytic effect allowing the calculation of dose-response curves and EC50s. The parasympatholytic compound scopolamine had the strongest relaxing effect (EC50â¯=â¯0.05⯵M) followed by atropine (EC50â¯=â¯0.07⯵M). HI-6 and obidoxime were capable to reactivate the sarin-inhibited cholinesterase activity in small bowel samples. Both substances restored AChE activity in a dose-dependent way, with HI-6 being more potent (HI-6 EC50â¯=â¯3.8⯵M vs obidoxime EC50â¯=â¯197.8⯵M). Summarizing, our isolated human small bowel setup is a suitable tool to investigate the smooth muscle relaxing effect of (candidate) therapeutics for organophosphorus compound poisoning i.e. sarin exposure in a complex 3D tissue model.
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Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/farmacología , Intestino Delgado/efectos de los fármacos , Intoxicación por Organofosfatos , Sarín/toxicidad , Adulto , Anciano , Anciano de 80 o más Años , Colinesterasas/metabolismo , Femenino , Humanos , Intestino Delgado/fisiología , Masculino , Persona de Mediana Edad , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Adulto JovenRESUMEN
BACKGROUND: The optimal nutritional therapy in the field of pancreatic surgery is still debated. METHODS: An international panel of recognized pancreatic surgeons and pancreatologists decided that the topic of nutritional support was of importance in pancreatic surgery. Thus, they reviewed the best contemporary literature and worked to develop a position paper to provide evidence supporting the integration of appropriate nutritional support into the overall management of patients undergoing pancreatic resection. Strength of recommendation and quality of evidence were based on the approach of the grading of recommendations assessment, development and evaluation Working Group. RESULTS: The measurement of nutritional status should be part of routine preoperative assessment because malnutrition is a recognized risk factor for surgery-related complications. In addition to patient's weight loss and body mass index, measurement of sarcopenia and sarcopenic obesity should be considered in the preoperative evaluation because they are strong predictors of poor short-term and long-term outcomes. The available data do not show any definitive nutritional advantages for one specific type of gastrointestinal reconstruction technique after pancreatoduodenectomy over the others. Postoperative early resumption of oral intake is safe and should be encouraged within enhanced recovery protocols, but in the case of severe postoperative complications or poor tolerance of oral food after the operation, supplementary artificial nutrition should be started at once. At present, there is not enough evidence to show the benefit of avoiding oral intake in clinically stable patients who are complicated by a clinically irrelevant postoperative pancreatic fistula (a so-called biochemical leak), while special caution should be given to feeding patients with clinically relevant postoperative pancreatic fistula orally. When an artificial nutritional support is needed, enteral nutrition is preferred whenever possible over parenteral nutrition. After the operation, regardless of the type of pancreatic resection or technique of reconstruction, patients should be monitored carefully to assess for the presence of endocrine and exocrine pancreatic insufficiency. Although fecal elastase-1 is the most readily available clinical test for detection of pancreatic exocrine insufficiency, its sensitivity and specificity are low. Pancreatic enzyme replacement therapy should be initiated routinely after pancreatoduodenectomy and in patients with locally advanced disease and continued for at least 6 months after surgery, because untreated pancreatic exocrine insufficiency may result in severe nutritional derangement. CONCLUSION: The importance of this position paper is the consensus reached on the topic. Concentrating on nutritional support and therapy is of utmost value in pancreatic surgery for both short- and long-term outcomes.
Asunto(s)
Insuficiencia Pancreática Exocrina/terapia , Desnutrición/terapia , Apoyo Nutricional/métodos , Pancreaticoduodenectomía/efectos adversos , Complicaciones Posoperatorias/terapia , Consenso , Terapia de Reemplazo Enzimático/métodos , Medicina Basada en la Evidencia/métodos , Medicina Basada en la Evidencia/normas , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/etiología , Insuficiencia Pancreática Exocrina/metabolismo , Heces/química , Humanos , Desnutrición/diagnóstico , Desnutrición/etiología , Desnutrición/metabolismo , Estado Nutricional , Apoyo Nutricional/normas , Elastasa Pancreática/análisis , Fístula Pancreática/diagnóstico , Fístula Pancreática/etiología , Fístula Pancreática/metabolismo , Fístula Pancreática/terapia , Atención Perioperativa/métodos , Atención Perioperativa/normas , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions. METHODS: Plasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC (n = 36) and chronic pancreatitis (CP) (n = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls (n = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters. RESULTS: TIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed. CONCLUSION: This retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/sangre , Neoplasias Pancreáticas/sangre , Pancreatitis Crónica/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/complicaciones , Pancreatitis Crónica/complicaciones , Estudios Retrospectivos , Adulto JovenRESUMEN
Isolated organs proofed to be a robust tool to study effects of (potential) therapeutics in organophosphate poisoning. Small bowel samples have been successfully used to reveal smooth muscle relaxing effects. In the present study, the effects of obidoxime, TMB-4, HI-6 and MB 327 were investigated on human small bowel tissue and compared with rat data. Hereby, the substances were tested in at least seven different concentrations in the jejunum or ileum both pre-contracted with carbamoylcholine. Additionally, the cholinesterase activity of native tissue was determined. Human small intestine specimens showed classical dose response-curves, similar to rat tissue, with MB 327 exerting the most potent smooth muscle relaxant effect in both species (human EC50=0.7×10-5M and rat EC50=0.7×10-5M). The AChE activity for human and rat samples did not differ significantly (rat jejunum=1351±166 mU/mg wet weight; rat ileum=1078±123 mU/mg wet weight; human jejunum=1030±258 mU/mg wet weight; human ileum=1293±243 mU/mg wet weight). Summarizing, our isolated small bowel setup seems to be a solid tool to investigate the effects of (potential) therapeutics on pre-contracted smooth muscle, with data being transferable between rat and humans.
Asunto(s)
Antídotos/uso terapéutico , Intestino Delgado/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Intoxicación por Organofosfatos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Animales , Carbacol/farmacología , Reactivadores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Íleon/efectos de los fármacos , Técnicas In Vitro , Yeyuno/efectos de los fármacos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Agonistas Muscarínicos/farmacología , Contracción Muscular/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Peri- and postoperative nutrition in colorectal cancer patients Abstract. The long multimodal therapy regimens for colorectal cancer require a sufficient nutritional status of the patient. The "Enhanced Recovery After Surgery" concept aims for minimization of the interruption of nutrient intake and has been validated prospectively. Preoperative malnutrition as a strong risk factor for complications should be detected and treated early after cancer diagnosis by screening tools as the "Nutritional Risk Screening" (NRS-2002) or the "Malnutrition Universal Screening Tool" (MUST). High-caloric oral supplementation, enteral nutrition and parenteral nutrition are possible measures, which should be escalated stepwise. The recent concept of "prehabilitation" additionally includes shortterm optimization of the physical and psychological status. Postoperative attention should be paid to possible deficiency syndromes of single nutrients due to reduced resorption after bowel segment resection or stoma creation. Risk- and preventive factors in primary prevention of colorectal carcinoma are well-known, in secondary prevention knowledge is less clear. There is only low evidence for a positive effect of omega-3 fatty acids, coffee, high-fiber diet and vitamin D in secondary prevention of colorectal carcinoma, requiring further studies.
Asunto(s)
Neoplasias Colorrectales , Estado Nutricional , Cuidados Posoperatorios , Neoplasias Colorrectales/cirugía , Ingestión de Energía , Nutrición Enteral , Humanos , Nutrición Parenteral Total , Complicaciones PosoperatoriasRESUMEN
BACKGROUND: The majority of patients with gastric or esophago-gastric cancer are at risk for malnutrition. Preoperative malnutrition was shown to increase the incidence of postoperative complications following abdominal surgery. However, it remains unclear if preoperative parenteral nutritional support during neoadjuvant chemotherapy (NACT) may be effective to reduce the rate of postoperative complications in these patients. METHODS/DESIGN: The PERCOG trial is a randomized controlled multicenter observer-blinded trial, investigating if the improvement of the general condition of patients with non-metastasized gastric cancer or cancer of the esophago-gastric junction during NACT by supplemental parenteral nutrition can decrease the postoperative Comprehensive Complication Index (CCI). Statistical analysis of the primary endpoint measure (CCI on postoperative day 30) will be based on the intention-to-treat population. The global level of significance is set at 5% and the sample size (n = 150) is determined to assure a power of 80%. DISCUSSION: The results of the PERCOG trial will provide high-level evidence for clinical recommendations regarding the administration of preoperative supportive parenteral nutrition and provide all participating patients the opportunity of an improved treatment. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00009451 . Registered on 3 July 2017.