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BACKGROUND: The immunosuppressive tumor microenvironment (TME) of colorectal cancer (CRC) is a major hurdle for immune checkpoint inhibitor-based therapies. Hence characterization of the signaling pathways driving T cell exhaustion within TME is a critical need for the discovery of novel therapeutic targets and the development of effective therapies. We previously showed that (i) the adaptor protein Rai is a negative regulator of T cell receptor signaling and T helper 1 (Th1)/Th17 cell differentiation; and (ii) Rai deficiency is implicated in the hyperactive phenotype of T cells in autoimmune diseases. METHODS: The expression level of Rai was measured by qRT-PCR in paired peripheral blood T cells and T cells infiltrating tumor tissue and the normal adjacent tissue in CRC patients. The impact of hypoxia-inducible factor (HIF)-1α on Rai expression was evaluated in T cells exposed to hypoxia and by performing chromatin immunoprecipitation assays and RNA interference assays. The mechanism by which upregulation of Rai in T cells promotes T cell exhaustion were evaluated by flow cytometric, qRT-PCR and western blot analyses. RESULTS: We show that Rai is a novel HIF-1α-responsive gene that is upregulated in tumor infiltrating lymphocytes of CRC patients compared to patient-matched circulating T cells. Rai upregulation in T cells promoted Programmed cell Death protein (PD)-1 expression and impaired antigen-dependent degranulation of CD8+ T cells by inhibiting phospho-inactivation of glycogen synthase kinase (GSK)-3, a central regulator of PD-1 expression and T cell-mediated anti-tumor immunity. CONCLUSIONS: Our data identify Rai as a hitherto unknown regulator of the TME-induced exhausted phenotype of human T cells.
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Neoplasias Colorretais , Quinase 3 da Glicogênio Sintase , Humanos , Linfócitos T CD8-Positivos , Neoplasias Colorretais/genética , Hipóxia , Linfócitos do Interstício Tumoral , Receptor de Morte Celular Programada 1/genética , Microambiente Tumoral , Regulação para CimaRESUMO
Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms play an essential role in processes connected to tumorigenesis, as they efficiently accelerate the hydration of carbon dioxide to bicarbonate and proton. In this context, examples are CA IX and CA XII, which were proved to be upregulated in many solid malignancies. On the other hand, cancer and the immune system are inextricably linked, and targeting the immune checkpoints recently was shown to efficiently improve the treatment of malignancies. In this study, we have investigated the expression of CA isoforms in tumour-infiltrating lymphocytes (TILs) that, according to the immunosurveillance theory, were suggested to have a crucial role in the development of colorectal cancer (CRC). T lymphocytes isolated from healthy surrounding mucosa showed a higher CA activity compared to those present in tumour and peripheral blood in the same patients. CA I and II were confirmed as enzyme isoforms involved in the process, as determined by proteomic analysis of corresponding TIL samples. These preliminary findings suggest a dysregulation of the local immune response in the CRC tissues and a loss of effective anticancer mechanisms mediated by CAs therein.
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Anidrases Carbônicas , Neoplasias Colorretais , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Humanos , Linfócitos , Proteômica , Relação Estrutura-AtividadeRESUMO
Performing physical exercise after a colorectal cancer diagnosis is associated with lower mortality related to the tumor itself. In order to improve physical recovery after elective surgery, there are no specific exercise protocols after discharge from the hospital. The purpose of this study is to show the preliminary results of an exercise program after colorectal cancer surgery. Six patients with non-metastatic colorectal adenocarcinoma addressed to respective laparoscopic were randomly assigned to a mixed supervised/home-based exercise program for six months and compared to a control group without exercise. To assess the effectiveness of the program, functional and body composition parameters were evaluated. Three months after surgery, the exercise group increased flexibility (p < 0.01, ES = 0.33), strength of lower limbs (p < 0.01, ES = 0.42) and aerobic capacity (p < 0.01, ES = 0.28). After surgery, the six patients experienced a significant reduction in body mass index (BMI) and free fat mass. More specifically, fat mass reached the lowest values, with a concomitant increase in cell mass after six months (p < 0.01, ES = 0.33). This did not occur in the control group. Colorectal cancer treatment induces a reduction in physical function, particularly during the first six months after treatment. A mixed exercise approach appears promising in countering this process after colorectal cancer surgery.
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Neoplasias Colorretais/terapia , Procedimentos Cirúrgicos do Sistema Digestório/reabilitação , Terapia por Exercício/normas , Exercício Físico/psicologia , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias Colorretais/psicologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Exercício Físico/fisiologia , Terapia por Exercício/métodos , Terapia por Exercício/estatística & dados numéricos , Feminino , Humanos , Laparoscopia/métodos , Laparoscopia/reabilitação , Laparoscopia/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
PDAC (pancreatic ductal adenocarcinoma) is the fifth leading cause of cancer-related death. The causes of this cancer remain unknown, but increasing evidence indicates a key role of the host immune response and cytokines in human carcinogenesis. Intra-tumoral IL (interleukin)-22 levels have been shown to be elevated in PDAC patients. However, little is known regarding the expression and clinical relevance of Th22 cells in human PDAC and, furthermore, which TILs (tumour-infiltrating lymphocytes) are the main producers of IL-22 is unknown. In the present study, we characterized the functional proprieties of the different subsets of IL-22-producing TILs and analysed their relationship with the TNM staging system and patient survival. We have demonstrated for the first time that, in PDAC patients, the T-cells co-producing IFN-γ (interferon γ) and exerting perforin-mediated cytotoxicity are the major intra-tumoral source of IL-22. In addition, isolated Th22 cells were able to induce apoptosis, which was antagonized by IL-22. Finally, we observed that the IL-22-producing T-cells were significantly increased in tumour tissue and that this increase was positively correlated with TNM staging of PDAC and poorer patient survival. These novel findings support the dual role of the anti-tumour immune system and that IL-22-producing cells may participate in PDAC pathogenesis. Therefore monitoring Th22 levels could be a good diagnostic parameter, and blocking IL-22 signalling may represent a viable method for anti-PDAC therapies.
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Carcinoma Ductal Pancreático/metabolismo , Interferon gama/metabolismo , Interleucinas/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Pancreáticas/metabolismo , Comunicação Parácrina , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Citotoxicidade Imunológica , Feminino , Granzimas/metabolismo , Humanos , Interferon gama/imunologia , Interleucinas/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Perforina/metabolismo , Fenótipo , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Interleucina 22RESUMO
BACKGROUND: Robotic surgery has been developed with the aim of improving surgical quality and overcoming the limitations of conventional laparoscopy in the performance of complex mini-invasive procedures. The present study was designed to compare robotic and laparoscopic distal gastrectomy in the treatment of gastric cancer. METHODS: Between June 2008 and September 2015, 41 laparoscopic and 30 robotic distal gastrectomies were performed by a single surgeon at the same institution. Clinicopathological characteristics of the patients, surgical performance, postoperative morbidity/mortality and pathologic data were prospectively collected and compared between the laparoscopic and robotic groups by the Chi-square test and the Mann-Whitney test, as indicated. RESULTS: There were no significant differences in patient characteristics between the two groups. Mean tumor size was larger in the laparoscopic than in the robotic patients (5.3 ± 0.5 cm and 3.0 ± 0.4 cm, respectively; P = 0.02). However, tumor stage distribution was similar between the two groups. The mean number of dissected lymph nodes was higher in the robotic than in the laparoscopic patients (39.1 ± 3.7 and 30.5 ± 2.0, respectively; P = 0.02). The mean operative time was 262.6 ± 8.6 min in the laparoscopic group and 312.6 ± 15.7 min in the robotic group (P < 0.001). The incidences of surgery-related and surgery-unrelated complications were similar in the laparoscopic and in the robotic patients. There were no significant differences in short-term clinical outcomes between the two groups. CONCLUSIONS: Within the limitation of a small-sized, non-randomized analysis, our study confirms that robotic distal gastrectomy is a feasible and safe surgical procedure. When compared with conventional laparoscopy, robotic surgery shows evident benefits in the performance of lymphadenectomy with a higher number of retrieved and examined lymph nodes.
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Gastrectomia/métodos , Laparoscopia , Excisão de Linfonodo , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Gastroesophageal reflux (GER) causes injury of the esophageal squamous epithelium, a condition called reflux esophagitis. The sequence reflux-esophagitis-intestinal metaplasia-dysplasia-invasive cancer is widely accepted as the main adenocarcinogenetic pathway in the esophagus; however, the mechanisms of this progression need to be better defined. AIMS: We evaluated COX-2 expression and activity in biopsies from patients affected with GER, and these parameters have been correlated with the stage of the disease, ceramide expression, apoptotic process, and angiogenesis. The effects of celecoxib on bile acid- and EGF-induced mucosal proliferation, apoptosis and angiogenesis have been also investigated. METHODS: Four groups of patients were distinguished: non esophagitis, non erosive esophagitis, erosive esophagitis, and Barrett's esophagus. COX-2 expression, basal PGE2 levels, proliferative activity, VEGF expression and apoptosis were evaluated in esophageal biopsies. RESULTS: COX-2 expression, basal PGE2 levels, proliferative activity, VEGF expression and apoptosis progressively increase from non esophagitis patients to patients with non erosive and erosive esophagitis, to those with BE. Incubation of the cells with DCA/EGF increases PGE2 production, proliferative activity and VEGF production, effects prevented by celecoxib pretreatment. Ceramide expression increased from non esophagitis patients to patients with non erosive and erosive esophagitis, and decreased in BE; caspase-3 activity progressively decreased from non esophagitis to BE patients, suggesting an impairment of the apoptotic process with disease progression. CONCLUSION: These results stand for a close relationship between progression of initial steps of gastroesophageal reflux disease (GERD) and COX-2, proliferative activity and EGF/VEGF expression and could have implications in GERD treatment in order to prevent its neoplastic evolution.
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Esôfago de Barrett/patologia , Ciclo-Oxigenase 2/metabolismo , Esôfago/patologia , Refluxo Gastroesofágico/patologia , Inflamação/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/metabolismo , Biópsia , Caspase 3/genética , Caspase 3/metabolismo , Ceramidas/genética , Ceramidas/metabolismo , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Dinoprostona/metabolismo , Feminino , Refluxo Gastroesofágico/metabolismo , Regulação Enzimológica da Expressão Gênica , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto JovemRESUMO
BACKGROUND: Approximately 95% of Colorectal cancers (CRC) consist of adenocarcinomas originating from colonic Adenomatous polyps (AP). Increasing importance in CRC occurrence and progression has been attributed to the gut microbiota; however, a huge proportion of microorganisms inhabit the human digestive system. So, to comprehensively study the microbial spatial variations and their role in CRC progression, from AP to the different CRC phases, a holistic vision is imperative, including the simultaneous evaluation of multiple niches from the gastrointestinal system. Through an integrated approach, we identified potential microbial and metabolic biomarkers, able to discriminate human CRC from AP and/or also the different Tumor node metastasis (TNM) staging. In addition, as the microbiota contributes to the production of essential metabolic products detectable in fecal samples, we analysed and compared metabolites obtained from CRC and AP patients by using a Nuclear magnetic resonance (NMR) approach. METHODS: In this observational study, saliva, tissue and stool samples from 61 patients, have been collected, including 46 CRC and 15 AP patients, age and sex-matched, undergoing surgery in 2018 at the Careggi University Hospital (Florence, Italy). First, the microbiota in the three-district between CRC and AP patients has been characterized, as well as in different CRC TNM stages. Subsequently, proton NMR spectroscopy has been used in combination with multivariate and univariate statistical approaches, to define the fecal metabolic profile of a restricted group of CRC and AP patients. RESULTS: CRC patients display a different profile of tissue and fecal microbiota with respect to AP patients. Significant differences have been observed in CRC tissue microbial clades, with a rise of the Fusobacterium genus. In addition, significant taxa increase at the genus level has been observed in stool samples of CRC patients. Furthermore, Fusobacterium found in intestinal tissue has been positively correlated with fecal Parvimonas, for the first time. Moreover, as predicted by metagenomics pathway analysis, a significant increase of lactate (p=0.037) has been observed in the CRC fecal metabolic profiles, and positively correlated with Bifidobacterium (p=0.036). Finally, minor bacterial differences in CRC patients at stage T2 (TNM classification) have been detected, with a raise of the Spirochaetota phylum in CRC samples, with a slight increase of the Alphaproteobacteria class in fecal samples. CONCLUSION: Our results suggest the importance of microbiota communities and oncometabolites in CRC development. Further studies on CRC/AP management with a focus on CRC assessment are needed to investigate novel microbial-related diagnostic tools aimed to improve therapeutic interventions.
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Adenoma , Neoplasias Colorretais , Microbioma Gastrointestinal , Microbiota , Neoplasias Retais , Humanos , Neoplasias Colorretais/patologia , Adenoma/diagnóstico , Bactérias , BiomarcadoresRESUMO
The liver is the most common site of colorectal cancer metastasis. Liver surgery is a cornerstone in treatment, with progressive expansion of minimally invasive surgery (MIS). This study aims to compare short- and long-term outcomes of open surgery and MIS for the treatment of colorectal adenocarcinoma liver metastasis during the first three years of increasing caseload and implementation of MIS use in liver surgery. All patients treated between November 2018 and August 2021 at Careggi Teaching Hospital in Florence, Italy, were prospectively entered into a database and retrospectively reviewed. Fifty-one patients were resected (41 open, 10 MIS). Considering that patients with a significantly higher number of lesions underwent open surgery and operative results were similar, postoperative morbidity rate and length of hospital stay were significantly higher in the open group. No differences were found in the pathological specimen. The postoperative mortality rate was 2%. Mean overall survival and disease-free survival were 46 months (95% CI 42-50) and 22 months (95% CI 15.6-29), respectively. The use of minimally invasive techniques in liver surgery is safe and feasible if surgeons have adequate expertise. MIS and parenchymal sparing resections should be preferred whenever technically feasible.
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The microbiota impact on human diseases is well-known, and a growing body of literature is providing evidence about the complex interplay between microbiota-immune system-human physiology/pathology, including cancers. Together with the defined risk factors (e.g., smoke habits, diet, diabetes, and obesity), the oral, gut, biliary, and intrapancreatic microbiota contribute to pancreatic cancer development through different pathways including the interaction with the immune system. Unfortunately, a great majority of the pancreatic cancer patients received a diagnosis in advanced stages not amenable to be radically treated and potentially cured. Given the poor pancreatic cancer prognosis, complete knowledge of these complicated relationships could help researchers better understand the disease pathogenesis and thus provide early potential non-invasive biomarkers, new therapeutic targets, and tools for risk stratification that might result in greater therapeutic possibilities and eventually in a better and longer patient survival.
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Microbiota , Neoplasias Pancreáticas , Biomarcadores , Disbiose , Humanos , Neoplasias Pancreáticas/terapia , Fumar , Neoplasias PancreáticasRESUMO
Surgeons are workers that are particularly prone to the development of musculoskeletal disorders. Recent advances in surgical interventions, such as laparoscopic procedures, have caused a worsening of the scenario, given the harmful static postures that have to be kept for long periods. In this paper, we present a sensor-based platform specifically aimed at monitoring the posture during actual surgical operations. The proposed system adopts a limited number of Inertial Measurement Units (IMUs) to obtain information about spine and neck angles across time. Such a system merges the reliability of sensor-based approaches and the validity of state-of-the-art scoring procedure, such as RULA. Specifically, three IMUs are used to estimate the flexion, lateral bending, and twisting angles of spine and neck. An ergonomic risk index is thus estimated in a time varying fashion borrowing relevant features from the RULA scoring system. The detailed functioning of the proposed systems is introduced, and the assessment results related to a real surgical procedure, consisting of a laparoscopy and mini-laparotomy sections, are shown and discussed. In the exemplary case study introduced, the surgeon kept a high score, indicating the need for an intervention on the working procedures, for a large time fraction. The system allows separately analyzing the contribution of spine and neck, also specifying the angle configuration. It is shown how the proposed approach can provide further information, as related to dynamical analysis, which could be used to enlarge the features taken into account by currently available approaches for ergonomic risk assessment. The proposed system could be adopted both for training purposes, as well as for alerting surgeons during actual surgical operations.
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Doenças Musculoesqueléticas , Doenças Profissionais , Cirurgiões , Dispositivos Eletrônicos Vestíveis , Ergonomia , Humanos , Doenças Musculoesqueléticas/prevenção & controle , Doenças Profissionais/prevenção & controle , Postura , Reprodutibilidade dos TestesRESUMO
Liver cancer is a leading cause of death worldwide, and hepatocellular carcinoma (HCC) is the most frequent primary liver tumour, followed by cholangiocarcinoma. Notably, secondary tumours represent up to 90% of liver tumours. Chronic liver disease is a recognised risk factor for liver cancer development. Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration. The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota, its metabolites and the liver through the portal flow. The interplay between the immune system and gut microbiota is also well-known. Although primarily resulting from experiments in animal models and on HCC, growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours. Despite the curative intent of "traditional" treatments, tumour recurrence remains high. Therefore, microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment. Furthermore, microbiota could represent a non-invasive biomarker for early liver cancer diagnosis. This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development, focusing on the potential therapeutic implications.
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BACKGROUND: Colorectal cancer (CRC), the third most common cause of death in both males and females worldwide, shows a positive response to therapy and usually a better prognosis when detected at an early stage. However, the survival rate declines when the diagnosis is late and the tumor spreads to other organs. Currently, the measures widely used in the clinic are fecal occult blood test and evaluation of serum tumor markers, but the lack of sensitivity and specificity of these markers restricts their use for CRC diagnosis. Due to its high sensitivity and precision, colonoscopy is currently the gold-standard screening technique for CRC, but it is a costly and invasive procedure. Therefore, the implementation of custom-made methodologies including those with minimal invasiveness, protection, and reproducibility is highly desirable. With regard to other screening methods, the screening of fecal samples has several benefits, and metabolomics is a successful method to classify the metabolite shift in living systems as a reaction to pathophysiological influences, genetic modifications, and environmental factors. AIM: To characterize the variation groups and potentially recognize some diagnostic markers, we compared with healthy controls (HCs) the fecal nuclear magnetic resonance (NMR) metabolomic profiles of patients with CRC or adenomatous polyposis (AP). METHODS: Proton nuclear magnetic resonance spectroscopy was used in combination with multivariate and univariate statistical approaches, to define the fecal metabolic profiles of 32 CRC patients, 16 AP patients, and 38 HCs well matched in age, sex, and body mass index. RESULTS: NMR metabolomic analyses revealed that fecal sample profiles differed among CRC patients, AP patients, and HCs, and some discriminatory metabolites including acetate, butyrate, propionate, 3-hydroxyphenylacetic acid, valine, tyrosine and leucine were identified. CONCLUSION: In conclusion, we are confident that our data can be a forerunner for future studies on CRC management, especially the diagnosis and evaluation of the effectiveness of treatments.
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Pólipos Adenomatosos , Neoplasias Colorretais , Biomarcadores Tumorais , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Metabolômica , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Colorectal cancer is a common tumor with a quite high-related mortality. Despite the used curative treatments, patients will develop cancer recurrence in up to 50% of the cases and/or other primary neoplasms. Although most of the recurrences are discovered within 3 years from the first treatment, a small percentage is found after 5 years. The early detection of recurrence is crucial to allow further therapies improving patients' survival. Several follow-up programs have been developed but the optimal one is far from being established. AIM: To evaluation of potential prognostic factors for timing and patterns of recurrence in order to plan tailored follow-up programs. METHODS: Perioperative and long-term data of all consecutive patients surgically treated with curative intent, from January 2006 to June 2009, for colorectal adenocar-cinoma, were retrospectively reviewed to find potential prognostic factors associated with: (1) Recurrence incidence; (2) Incidence of an early (within 3 years from surgery) or late recurrence; and (3) Different sites of recurrence. In addition, the incidence of other primary neoplasms has been evaluated in a cohort of patients with a minimum potential follow-up of 10 years. RESULTS: Our study included 234 patients. The median follow-up period has been 119 ± 46.2 mo. The recurrence rate has been 25.6%. Patients with a higher chance to develop recurrence had also the following characteristics: Higher levels of preoperative glycemia and carcinoembryonic antigen, highest anaesthesiologists Score score, occlusion, received a complex operation performed with an open technique, after a longer hospital stay, and showed advanced tumors. The independent prognostic factors for recurrence were the hospital stay, N stage 2, and M stage 1 (multivariate analysis). Younger ages were significantly associated with an early recurrence onset. Patients that received intermediate colectomies or segmental resections, having an N stage 2 or American Joint Committee on Cancer stage 3 tumors were also associated with a higher risk of liver recurrence, while metastatic diseases at diagnosis were linked with local recurrence. Neoadjuvant treatments showed lung recurrence. Finally, bigger tumors and higher lymph node ratio were associated with peritoneal recurrence (marginally significant). Thirty patients developed a second malignancy during the follow-up time. CONCLUSION: Several prognostic factors should be considered for tailored follow-up programs, eventually, beyond 5 years from the first treatment.
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Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract. These dynamic communities, the environment and their metabolites constitute the microbiota. Growing data suggests a causal role of a dysbiotic microbiota in several pathologies, such as metabolic and neurological disorders, immunity dysregulations and cancer, especially the well-studied colorectal cancer development. However, many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent. The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis. For example, Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins. However, dysbiosis may also cause a pro-inflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity, as demonstrated for Fusobacterium nucleatum. Microbiota has a crucial role in several stages of postoperative course; dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis (and other collagenase-producers microbes) are suggested as a cause of anastomotic leak. Consequently, unbalanced presence of some species, together with altered immune response may also have a prognostic role. Microbiota has also a substantial role in effectiveness of chemotherapy, chemoresistance and in the related side effects. In other words, a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.
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Neoplasias Colorretais/cirurgia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Recidiva Local de Neoplasia/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Colo/imunologia , Colo/microbiologia , Colo/cirurgia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Disbiose/complicações , Disbiose/microbiologia , Disbiose/terapia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/cirurgia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Complicações Pós-Operatórias/etiologia , Prognóstico , Reto/imunologia , Reto/microbiologia , Reto/cirurgia , Fatores de Tempo , Resultado do TratamentoRESUMO
Background Intrahepatic cholangiocarcinoma (ICC) is the second most common liver primary tumour after hepatocellular carcinoma and represents 20% of all the cholangiocarcinomas. Its incidence is increasing and mortality rates are rising. Surgical resection is the only option to cure the disease, despite the high recurrence rates reported to be up to 80%. Intrahepatic recurrences may be still treated with curative intent in a small percentage of the patients. Unfortunately, due to lack of specific symptoms, most patients are diagnosed in a late stage of disease and often unsuitable for resection. Liver transplantation for ICC is still controversial. After the first published poor results, improving outcomes have been reported in highly selected cases, including locally advanced ICC treated with neoadjuvant chemotherapy, when successful in controlling tumour progression. Thus, liver transplantation should be considered a possible option within study protocols. When surgical management is not possible, palliative treatments include chemotherapy, radiotherapy and loco-regional treatments such as radiofrequency ablation, trans-arterial chemoembolization or radioembolization. Conclusions This update on the management of ICC focusses on surgical treatments. Known and potential prognostic factors are highlighted in order to assist in treatment selection.
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Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/terapia , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/cirurgia , Humanos , Transplante de Fígado , Recidiva Local de Neoplasia , Cuidados Paliativos , PrognósticoRESUMO
Background and aim: Gut microbiota (GM) can support colorectal cancer (CRC) progression by modulating immune responses through the production of both immunostimulatory and/or immunosuppressive cytokines. The role of IL-9 is paradigmatic because it can either promote tumor progression in hematological malignancies or inhibit tumorigenesis in solid cancers. Therefore, we investigate the microbiota-immunity axis in healthy and tumor mucosa, focusing on the correlation between cytokine profile and GM signature. Methods: In this observational study, we collected tumor (CRC) and healthy (CRC-S) mucosa samples from 45 CRC patients, who were undergoing surgery in 2018 at the Careggi University Hospital (Florence, Italy). First, we characterized the tissue infiltrating lymphocyte subset profile and the GM composition. Subsequently, we evaluated the CRC and CRC-S molecular inflammatory response and correlated this profile with GM composition, using Dirichlet multinomial regression. Results: CRC samples displayed higher percentages of Th17, Th2, and Tregs. Moreover, CRC tissues showed significantly higher levels of MIP-1α, IL-1α, IL-1ß, IL-2, IP-10, IL-6, IL-8, IL-17A, IFN-γ, TNF-α, MCP-1, P-selectin, and IL-9. Compared to CRC-S, CRC samples also showed significantly higher levels of the following genera: Fusobacteria, Proteobacteria, Fusobacterium, Ruminococcus2, and Ruminococcus. Finally, the abundance of Prevotella spp. in CRC samples negatively correlated with IL-17A and positively with IL-9. On the contrary, Bacteroides spp. presence negatively correlated with IL-9. Conclusions: Our data consolidate antitumor immunity impairment and the presence of a distinct microbiota profile in the tumor microenvironment compared with the healthy mucosa counterpart. Relating the CRC cytokine profile with GM composition, we confirm the presence of bidirectional crosstalk between the immune response and the host's commensal microorganisms. Indeed, we document, for the first time, that Prevotella spp. and Bacteroides spp. are, respectively, positively and negatively correlated with IL-9, whose role in CRC development is still under debate.
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Adenocarcinoma/imunologia , Adenocarcinoma/microbiologia , Bacteroides/isolamento & purificação , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Prevotella/isolamento & purificação , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Interleucina-9/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Ribotipagem , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente TumoralRESUMO
The metabolites produced by the host's gut microbiota have an important role in the maintenance of intestinal homeostasis, but can also act as toxins and induce DNA damage in colorectal epithelial cells increasing the colorectal cancer (CRC) chance. In this scenario, the impact of some of the components of the natural human gastrointestinal microbiota, such as Enterococcus faecalis (E. faecalis), at the onset of CRC progression remains controversial. Since under dysbiotic conditions it could turn into a pathogen, the aim of this study was to compare the effect of E. faecalis' strains (isolated from CRC patients and healthy subjects' stools) on the proliferation of different colorectal cells lines. First, we isolated and genotyping characterized the Enterococcus faecalis' strains. Then, we analyzed the proliferation index (by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay) of three tumor and one normal intestinal cell lines, previously exposed to E. faecalis strains pre-cultured medium. Stool samples of CRC patients demonstrated a reduced frequency of E. faecalis compared to healthy subjects. In addition, the secreted metabolites of E. faecalis' strains, isolated from healthy donors, decreased the human ileocecal adenocarcinoma cell line HCT-8 and human colon carcinoma cell line HCT-116 cell proliferation without effects on human colorectal adenocarcinoma cell line SW620 and on normal human diploid cell line CLR-1790. Notably, the metabolites of the strains isolated from CRC patients did not influence the cell growth of CRC cell lines. Our results demonstrated a new point of view in the investigation of E. faecalis' role in CRC development, which raises awareness of the importance of not only associating the presence/absence of a unique microorganism, but also in defining the specific characteristics of the different investigated strains.
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PURPOSE: Some patients, having undergone sphincter-saving operations for rectal cancer, may suffer from fecal incontinence. This study was designed to evaluate the results of rehabilitative treatment in patients with fecal incontinence after sphincter-saving operations and to identify the negative factors that influence therapeutic success. METHODS: Between January 2000 and June 2007, 88 incontinent patients (54 women; age range, 47-73 years; 69 had received a low anterior rectal resection; 19 a straight coloanal anastomosis) were included in the study. After a preliminary clinical evaluation, including the Wexner Incontinence Scale score, anorectal manometry was performed. All 88 patients underwent rehabilitative treatment according to the "multimodal rehabilitative program" for fecal incontinence. At the end of program, all 88 patients were reassessed by means of a clinical evaluation and anorectal manometry; their results were compared with the clinical and manometric data from ten healthy control subjects. Postrehabilitative Wexner Incontinence Scale scores were used for an arbitrary schedule of patients divided into three classes: Class I, good (score =3); Class II, fair (score >3 to =6); Class III, poor (score >6). RESULTS: After rehabilitation, there was a significant improvement in the overall mean Wexner Incontinence Scale score (P < 0.03) for both surgical operation types (low anterior rectal resection: P < 0.05; coloanal anastomosis: P < 0.02). Only 21 patients (23.8 percent) were symptom-free, and 37 (42 percent) were considered Class III. A significant postrehabilitative direct correlation was found between: 1) Wexner Incontinence Scale score and degree of genital relaxation (rrho (s) 0.78; P < 0.001); 2) Wexner Incontinence Scale score and irradiation (rrho (s) 0.72; P < 0.01); and 3) Wexner Incontinence Scale score and pelvic (rrho (s) 0.65; P < 0.01) or anal surgery (rrho (s) 0.68; P < 0.01). No significant differences were found between prerehabilitative and postrehabilitative anal pressures in low anterior rectal resection and coloanal anastomosis patients. CONCLUSIONS: After rehabilitation, some patients become symptom-free, many patients show an improvement in the Wexner Incontinence Scale score, and others exhibit the highest grades of fecal incontinence. Genital relaxation, radiotherapy, and previous pelvic, and/or anal surgery are impeding factors to rehabilitative success.
Assuntos
Incontinência Fecal/etiologia , Incontinência Fecal/reabilitação , Neoplasias Retais/cirurgia , Idoso , Endossonografia , Feminino , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Incidental diagnosis of pancreatic neuroendocrine tumors (PanNETs) greatly increased in the last years. In particular, more frequent diagnosis of small PanNETs leads to many challenging clinical decisions. These tumors are mostly indolent, although a percentage (up to 39%) may reveal an aggressive behaviour despite the small size. Therefore, there is still no unanimity about the best management of tumor smaller than 2 cm. The risks of under/overtreatment should be carefully evaluated with the patient and balanced with the potential morbidities related to surgery. The importance of the Ki-67 index as a prognostic factor is still debated as well. Whenever technically feasible, parenchyma-sparing surgeries lead to the best chance of organ preservation. Lymphadenectomy seems to be another important prognostic issue and, according to recent findings, should be performed in noninsulinoma patients. In the case of enucleation of the lesion, a lymph nodal sampling should always be considered. The relatively recent introduction of minimally invasive techniques (robotic) is a valuable option to deal with these tumors. The current management of PanNETs is analysed throughout the many available published guidelines and evidences with the aim of helping clinicians in the difficult decision-making process.
RESUMO
BACKGROUND: Although the short-term advantages of laparoscopy for colon cancer (CC) over open surgery have been clearly demonstrated, there is little evidence available concerning the long-term outcomes. This study aimed to compare the long-term results of laparoscopic surgery versus open surgery in a cohort of CC patients from a single center. METHODS: A series of 443 patients consecutively operated on for stage I to III CC between January 2006 and December 2013 were followed up. Patients were divided into two groups according to the surgical technique and were compared for disease-free survival (DFS) and overall survival (OS) before and after 1:1 propensity score matching. RESULTS: Due to exclusions and drop-outs, the statistical analysis of the study is based on 398 patients. Open surgery was performed in 133 patients, and laparoscopic surgery was performed in 265. After propensity score matching, two comparable groups of 89 patients each were obtained. The 5-year DFS was 64.3% and 78.2% for patients in the open and laparoscopic resection groups, respectively [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.33-1.19; Pâ¯=â¯0.148]. A 5-year OS of 72.1% and 86.8% was observed in the open and laparoscopic resection groups, respectively (HR 0.43, 95%CI 0.20-0.94; Pâ¯=â¯0.026). The multivariate survival analysis demonstrated better results of laparoscopy compared with open surgery for both DFS (HR 0.43, 95%CI 0.23-0.78; Pâ¯=â¯0.004) and OS (HR 0.28, 95%CI 0.14-0.59; Pâ¯<â¯0.001). CONCLUSIONS: Despite the limitations of a retrospective analysis, our study confirms better results for laparoscopic surgery in terms of DFS and OS compared with open surgery in CC treatment.