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BACKGROUND: Recent work led to recognize sessile serrated adenomas (SSA) as precursor to many of the sporadic colorectal cancers with microsatellite instability (MSI). However, comprehensive analyses of DNA methylation in SSA and MSI cancer have not been conducted. METHODS: With an array-based methylation sensitive amplified fragment length polymorphism (MS-AFLP) method we analyzed 8 tubular (TA) and 19 serrated (SSA) adenomas, and 14 carcinomas with (MSI) and 12 without (MSS) microsatellite instability. MS-AFLP array can survey relative differences in methylation between normal and tumor tissues of 9,654 DNA fragments containing all NotI sequences in the human genome. RESULTS: Unsupervised clustering analysis of the genome-wide hypermethylation alterations revealed no major differences between or within these groups of benign and malignant tumors regardless of their location in intergenic, intragenic, promoter, or 3' end regions. Hypomethylation was less frequent in SSAs compared with MSI or MSS carcinomas. Analysis of variance of DNA methylation between these four subgroups identified 56 probes differentially altered. The hierarchical tree of this subset of probes revealed two distinct clusters: Group 1, mostly composed by TAs and MSS cancers with KRAS mutations; and Group 2 with BRAF mutations, which consisted of cancers with MSI and MLH1 methylation (Group 2A), and SSAs without MLH1 methylation (Group 2B). AXIN2, which cooperates with APC and ß-catenin in Wnt signaling, had more methylation alterations in Group 2, and its expression levels negatively correlated with methylation determined by bisulfite sequencing. Within group 2B, low and high AXIN2 expression levels correlated significantly with differences in size (P = 0.01) location (P = 0.05) and crypt architecture (P = 0.01). CONCLUSIONS: Somatic methylation alterations of AXIN2, associated with changes in its expression, stratify SSAs according to some clinico-pathological differences. We conclude that hypermethylation of MLH1, when occurs in an adenoma cell with BRAF oncogenic mutational activation, drives the pathway for MSI cancer by providing the cells with a mutator phenotype. AXIN2 inactivation may contribute to this tumorigenic pathway either by mutator phenotype driven frameshift mutations or by epigenetic deregulation contemporary with the unfolding of the mutator phenotype.
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Proteínas Adaptadoras Transductoras de Señales/genética , Adenoma/genética , Proteína Axina/genética , Carcinoma/genética , Neoplasias del Colon/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adenoma/patología , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Neoplasias del Colon/patología , Metilación de ADN , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Homólogo 1 de la Proteína MutLRESUMEN
BACKGROUND/AIMS: We investigated the factors associated with a favorable outcome after standard pancreaticoduodenectomy (PD) performed by the less experienced surgeon under expert supervision in a high-volume hospital of PD. METHODOLOGY: Between April 2009 and March 2013, 139 PDs were performed in our hospital, and among them 99 PDs were standard fashion. Two expert surgeons performed 57 of 99 PDs, and the cases were assigned as Group A. Forty-two of 99 PDs were performed by 5 less experienced surgeons under the instruction of expert surgeons, and the cases were assigned as Group B. We compared the intraoperative outcomes and postoperative major complications and mortality between two groups. RESULTS: There was no hospital death in Group B, but one in Group A (1.8%), and the overall mortality rate of 99 patients in this series was 1.0%. In comparison of postoperative major complications, there was no significant difference in the frequencies of patients with all postoperative major complications (Group A; 43.9% vs. Group B 33.3%). CONCLUSIONS: Outcomes after standard PD performed by less experienced surgeons were favorable. The instruction of expert surgeon in a high volume hospital may secure a favorable outcome after standard PD.
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Competencia Clínica , Pancreaticoduodenectomía/educación , Pancreaticoduodenectomía/normas , Anciano , Femenino , Hospitales de Alto Volumen , Humanos , Masculino , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND/AIMS: Postoperative mortality and morbidity after pancreaticoduodenectomy (PD) remain major issues today and we discuss the factors influencing improved patient outcome after PD. METHODOLOGY: Two hundred and nine patients underwent PD between 2001 and 2010 In our hospital. The first 58 cases between 2001 and 2004 were named Group A and the latter 151 cases between 2005 and 2010 were named Group B. Then, we compared the intraoperative outcomes and postoperative mortality and major morbidities between two groups. RESULTS: Between 2005 and 2010, the annual volume of PD has been over 20 continuously. In Group A, 58 PDs were performed by five surgeons but in Group B, the main surgeon performed 131 of 151 (86.8%) PDs. The mortality rate in Group A (1.7%) was not different from that in Group B (1.3%). The frequency of patients with all postoperative morbidities in Group B (43.7%) was significantly lower than that in Group A (70.7%) (p=0.00048). The frequencies of DGE and SSI in Group B (8.6%, 23.8%) were significantly lower than those in Group A (25.8%, 37.9%) (p=0.010, p=0.042). CONCLUSIONS: The increases of surgeon and hospital volume and the change of the mode of PD were factors influencing improved patient outcomes after PD.
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Pancreaticoduodenectomía , Anciano , Distribución de Chi-Cuadrado , Femenino , Hospitales de Alto Volumen , Humanos , Japón , Masculino , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/mortalidad , Complicaciones Posoperatorias/mortalidad , Mejoramiento de la Calidad , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Intra-abdominal infection (IAI) after pancreaticoduodenectomy (PD) is a common cause of prolongation of postoperative hospital stay and readmission to the hospital following discharge. METHODOLOGY: Two hundred and six patients undergoing PD were reviewed to investigate the risk factors for IAI after PD. Patients were separated into two groups: those who developed IAI after PD (Group A; n=44), and those who had not developed IAI after PD (Group B; n=162), the two groups were then compared to identify the risk factors for IAI after PD. A hundred and six patients (51.5%) underwent preoperative biliary drainage (PBD). RESULTS: Multivariate analysis revealed that pancreatic fistula (PF) was an independent risk factor for IAI after PD (p<0.001; odds ratio=9.58; 95% confidence interval=4.37-21.0), but PBD was not a significant risk factor. CONCLUSIONS: We demonstrated that the adequate PBD might not affect IAI after PD. On the other hand, PF was an independent risk factor for IAI after PD. A large randomized controlled trial, which would prove the effect of early removal of a prophylactic placed drain to prevent IAI, should be planned.
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Drenaje , Infecciones Intraabdominales/etiología , Fístula Pancreática/complicaciones , Pancreaticoduodenectomía/efectos adversos , Complicaciones Posoperatorias/etiología , Cuidados Preoperatorios , Anciano , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND/AIMS: Among several kinds of morbidities, pancreatic fistula (PF) is the most common complication of pancreaticoduodenectomy (PD). However, it has not been clarified what kind of perioperative factors are risk factors of PF after PD is performed by a training surgeon. METHODOLOGY: We evaluated the risk factors of PF after PD in which all procedures for 100 consecutive patients were performed by a single training surgeon, retrospectively. The 100 cases were divided into two groups and the first 50 cases were named Group A and the latter 50 cases were named Group B. RESULTS: Multivariate analysis demonstrated that the absence of main pancreatic duct dilatation was an independent risk factor for grade B and grade C PF (p=0.0080; OR=5.311; 95% CI=1.116-7.025). There was no significant difference of the frequencies of grade B and grade C PF between Group A and Group B (p=0.13361). CONCLUSIONS: We demonstrated that the absence of main pancreatic duct dilatation was an independent risk factor for grade B and grade C PF after PD was performed by a training surgeon; for those without pancreatic duct dilatation, PD can be performed by a surgeon in the earlier training period with an acceptable rate of PF.
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Competencia Clínica , Curva de Aprendizaje , Fístula Pancreática/etiología , Pancreaticoduodenectomía/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Dilatación Patológica , Femenino , Humanos , Japón , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Conductos Pancreáticos/patología , Conductos Pancreáticos/cirugía , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Percutaneous radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but delayed thermal damage can cause diaphragmatic hernia (DH). Surgery is recommended for DH, and open surgery is widely accepted. This report presents a case of laparoscopic surgery for strangulated DH that occurred after RFA. CASE PRESENTATION: An 80-year-old woman with a history of hepatitis C-induced liver cirrhosis and HCC was admitted to our institution owing to sudden-onset intense epigastric pain. Twenty-two months earlier, she received RFA treatment for HCC located in segment 6/7. Contrast-enhanced computed tomography revealed herniation of the small intestine into the thoracic cavity, with mesenteric fat haziness. Emergency laparoscopic surgery was performed, and the patient was diagnosed with strangulated DH associated with the prior RFA. The defect was closed using absorbable sutures, and the ischaemic small intestine was resected via mini-laparotomy. The patient was discharged on the 10th postoperative day without complications, and no evidence of DH recurrence 15 months after surgery was noted. CONCLUSIONS: Laparoscopic surgery seems useful and feasible for strangulated DH.
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BACKGROUND AND OBJECTIVES: The predictive value of free cancer cells in the peritoneal fluid of patients with colorectal cancer (CRC) remain to be elucidated. The aim of this study was to determine the prognostic relevance of the methylation of tumor-related genes detected in the peritoneal lavage fluid (PLF) of patients undergoing a resection for CRC. METHODS: The promoter methylation pattern of four target genes, CDH1, CDKN2A (p16), MGMT, and APC, was examined in 51 primary CRC and corresponding matched PLF DNA. The relative methylation levels of these genes in primary CRC tissue and paired PLF were assessed by quantitative methylation-specific polymerase chain reaction (QMSP). RESULTS: An aberrant methylation of at least one gene was found in 45 of 51 (88%) primary tumors. In matched PLF specimens, the frequencies of aberrant promoter methylation detected for each marker were 16% for CDH1, 2% for p16, 4% for MGMT and 24% for APC. Patients with PLF demonstrating the methylation of more than one of these four target genes demonstrated significantly shorter relapse-free survival. CONCLUSIONS: These findings suggest that disseminated tumor cells in PLF detected by QMSP may correlate with the postoperative clinical course of patients undergoing curative surgery for CRC.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Metilación de ADN , Peritoneo/metabolismo , Regiones Promotoras Genéticas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Irrigación TerapéuticaRESUMEN
BACKGROUND: It is important to know when to decide to end palliative chemotherapy (PC) for the quality of life of patients. However, there is currently no clear agreement on when to terminate PC. OBJECTIVES: To determine whether the difference of the period between the completion of PC and death affects patients' trajectory of supportive care near end of life. METHODS: This retrospective study included 52 adult patients with incurable cancer who had received PC and who were referred to our palliative care team and died in our local hospital between July 2011 and June 2014. Group A comprised patients who received anticancer therapy such as surgery and PC only in our hospital and eventually died there. Group B comprised patients who were transitioned to our hospital from tertiary medical centers after cessation of PC. RESULTS: 17 of 22 patients (77%) in Group A conveyed the intention of continuing PC in the first interview with a physician of the palliative care team, whereas 4 of 30 patients (13%) in Group B conveyed a similar intention. The patients in Group B stopped PC a median of 43 days earlier than did the patients in Group A (ð < .0001). CONCLUSIONS: These data showed that more patients in Group A wanted to continue PC and had a shorter interval between last PC and death. Change in the hospital where the patients are given supportive care might contribute to the cessation of futile PC at an appropriate time.
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We report a case of pancreas head carcinoma associated with fat replacement of the body and tail. A 68-year-old man presented with obstructive jaundice and was admitted to our hospital. Ultrasonography and computed tomography showed pancreas head tumor with a neighboring cystic lesion and fatty replacement of parenchyma of the pancreas body and tail. By endoscopic retrograde pancreatography, abruption of the main pancreatic duct and the presence of an accessory duct were detected. After percutaneous transhepatic biliary drainage, pancreatoduodenectomy was successfully performed. At laparotomy, the pancreas head was easily dissected from the replaced fatty tissue of the body and tail without continuity of the ductal system or parenchyma. Microscopic examination revealed the existence of an infiltrating ductal adenocarcinoma and a neighboring. cyst in the pancreas head. The dorsal exocrine pancreas was completely replaced by the fat tissues, in which viable Langerhans' islets were scattered. The patient's postoperative course was uneventful, and exogenous insulin administration was unnecessary for the maintenance of normal blood sugar level. Acquired fat replacement of the body and tail of the pancreas is an uncommon disorder, mimicking congenital agenesis of the dorsal pancreas. Though the mechanism is controversial, obstruction of the main pancreatic duct by a cystic lesion or carcinoma in the pancreas head is a possible cause of fatty degeneration of the pancreatic parenchyma.
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Tejido Adiposo/patología , Carcinoma Ductal Pancreático/patología , Páncreas/patología , Neoplasias Pancreáticas/patología , Anciano , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/cirugía , Colangiopancreatografia Retrógrada Endoscópica , Humanos , Masculino , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía , Tomografía Computarizada por Rayos XRESUMEN
Approximately half of all patients with colorectal cancer develop local recurrence or distant metastasis during the course of their illness. Recently, the molecular detection of metastatic cancer cells in various types of clinical samples, such as lymph nodes, bone marrow, peripheral blood, and peritoneal lavage fluid, has been investigated as a potential prognostic marker. The prognostic value of molecular tumor cell detection was independent of the type of detection method used. As assays become more sensitive and quantitative, a more thorough assessment of the cancer status of patients will be based on molecular markers alone. At present, it is difficult to conclude that one specific molecular marker is superior to others. Comparative analyses are recommended to assess the prognostic impact of molecular analyses in the same patient and determine the biomarkers that provide the most accurate prognostic information.
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Biomarcadores de Tumor , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/secundario , Técnicas de Diagnóstico Molecular , Células Neoplásicas Circulantes/química , Células Neoplásicas Circulantes/patología , Animales , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Médula Ósea/química , Médula Ósea/patología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/química , Neoplasias Colorrectales/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Ganglios Linfáticos/química , Ganglios Linfáticos/patología , Metástasis Linfática , MicroARNs/análisis , Mutación , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Pronóstico , ARN Mensajero/análisisRESUMEN
The Pleckstrin and Sec7 domain-containing (PSD) gene, which regulates skeletal rearrangements, has been found to be more frequently methylated both in ulcerative colitis (UC)-associated colorectal cancer tissues (5 of 7; 71.4%) and matched normal epithelia (4 of 7; 57.1%) compared to non-neoplastic UC epithelia (6 of 22; 27.3%) and sporadic colorectal cancer tissues (6 of 32; 18.8%). The levels of PSD mRNA were positively correlated with the methylation status of PSD, as shown by both MSP and bisulfite sequencing. To determine the potential role of PSD silencing in the mechanisms underlying UC-associated carcinogenesis, the levels of senescence, proliferation and apoptosis were evaluated in a normal human fibroblast cell line (NHDF) in which 93% of PSD expression was knocked down by a small-interfering RNA (si-RNA). Although there were no significant differences in the levels of senescence and proliferation caused by PSD knockdown, the level of apoptosis was significantly decreased by PSD knockdown (5.3% in siControl-treated cells vs. 0.67% in siPSD-treated cells, p=0.0001). In addition, reactive oxygen species inducers accelerated apoptosis in NHDF and a neutrophil-like cell line, which was significantly reduced by PSD knockdown. To verify the effect of PSD methylation in tissue sections including 21 samples from UC patients with or without tumors, we elucidated PSD promoting accumulation of filamentous-actin (F-actin) and apoptosis by immunohistochemistry and TUNEL assay, respectively. Both levels of accumulation of F-actin and apoptosis were significantly decreased in specimens from UC patients with PSD methylation compared to those without PSD methylation (F-actin: 0.69±0.86 with vs. 1.57±0.51 without, p=0.0031, apoptotic index: 0.31±0.63 with vs. 1.0±0.88 without, p=0.0277). In conclusion, our results indicate that PSD methylation plays a significant role in the mechanisms underlying UC-associated carcinogenesis through its inhibitory effect on apoptosis in the interaction between colorectal mucosa and neutrophils.
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Apoptosis/genética , Transformación Celular Neoplásica/genética , Colitis Ulcerosa/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Proteínas del Tejido Nervioso/genética , Actinas/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Procesos de Crecimiento Celular/fisiología , Línea Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Senescencia Celular/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Regulación hacia Abajo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Técnicas de Silenciamiento del Gen/métodos , Silenciador del Gen , Factores de Intercambio de Guanina Nucleótido , Células HL-60 , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Especies Reactivas de Oxígeno/metabolismo , Adulto JovenRESUMEN
Drug resistance remains a major obstacle to successful cancer treatment. Genome-wide comprehensive analysis identified a novel gene, glucocorticoid-induced protein-coding gene (DEXI), which was frequently methylated in colorectal (CRC; 36 of 73 patients; 49%) and gastric (28 of 89 patients; 31%) cancer patients. Here, we show that DEXI methylation is implicated in mechanisms facilitating resistance to camptothecin (CPT) via inhibition of apoptosis. Silencing of DEXI by siRNA significantly reduced CPT-induced apoptosis in a fibroblast cell line (1/6-fold; p<0.01) originally expressing endogenous DEXI. Restored expression of DEXI by 5-aza-2'-deoxycytidine (DAC) significantly enhanced susceptibility to CPT (3-fold; p<0.01) in a colon cancer cell line originally suppressing endogenous DEXI due to almost complete methylation. Exogenous induction of DEXI confirmed that DEXI per se contributed to enhanced susceptibility to CPT. 5-Fluorouracil (5-FU) did not exhibit these synergistic effects by DEXI restoration. Further, to estimate the clinical usefulness of DEXI methylation status as biomarker for drug resistance to irinotecan (CPT-11), 16 CRC patients who underwent FOLFIRI (5-FU + CPT-11) therapy because they were refractory to FOLFOX (5-FU + oxaliplatin) were analyzed. Significantly poor response and outcome were observed in 8 CRC patients harboring DEXI methylation. In 8 CRC patients harboring DEXI methylation disease control rate, progression-free survival and overall survival were 25.0%, 2 and 11.8 months, respectively, whereas in 8 CRC patients without DEXI methylation they were 62.5%, 5.3 and 15 months, respectively (p<0.01). These significant differences were not observed in patients undergoing treatment with FOLFOX. In conclusion, silencing of DEXI leads to resistance, but restored expression enhances susceptibility to CPT in vitro and DEXI methylation results in poor response and outcome to CPT-11-based chemotherapy, suggesting that DEXI is a potent therapeutic target and an epigenetic biomarker for the selection of patients more likely to benefit from CPT-11-based chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Neoplasias del Colon/tratamiento farmacológico , Proteínas de Unión al ADN/genética , Proteínas de la Membrana/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Células CACO-2 , Camptotecina/administración & dosificación , Estudios de Casos y Controles , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Metilación de ADN , Proteínas de Unión al ADN/biosíntesis , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Irinotecán , Masculino , Proteínas de la Membrana/biosíntesis , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/genéticaRESUMEN
We previously reported that the Pleckstrin and Sec7 domain-containing (PSD) gene is preferentially methylated in patients with ulcerative colitis (UC) who developed colorectal cancer (CRC), and is implicated in UC-associated carcinogenesis through its inhibition of apoptosis. This study aimed to determine the potential effect of PSD methylation on its downstream molecule, Ras-related C3 botulinum toxin substrate 1 (Rac1), which governs neutrophil chemotaxis and apoptosis signaling. PSD was knocked down in a normal human fibroblast cell line (HNDF) and a neutrophil-like cell line (HL-60). Both NHDF and HL-60 cells exhibited numerous filamentous-actin (F-actin) rich membrane extensions, resulting in the activation of Rac1; this activation was hampered by PSD silencing. Lipopolysaccharide, a reactive oxygen species (ROS) inducer, stimulated NHDF cells to release ROS and activated caspase3/7 in the presence of neutrophils, which was inhibited by PSD knockdown. Migration assays demonstrated that chemotaxis of HL-60 cells was affected by PSD silencing in NHDF cells. Tissue sections from 6 UC patients with CRC and 15 UC patients without CRC were examined. To verify Rac1-mediated chemotaxis in tissue sections, we evaluated the grade of neutrophil infiltration by histological assessment and assessed F-actin and PSD expression by immunohistochemistry. Neutrophil infiltration, F-actin and PSD expression were significantly decreased in specimens from UC patients with PSD methylation compared with those without. Decreased levels of F-actin expression were observed in colorectal mucosa, as well as in infiltrating cells with PSD methylation. PSD expression was preferentially inhibited in colorectal mucosa by PSD methylation, whereas PSD expression was rarely observed in infiltrating cells, regardless of PSD methylation status. These data indicate that aberrant methylation of PSD occurs in UC-associated colorectal mucosa, enabling circumvention of Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis, and thus plays a pivotal role in the mechanisms underlying UC-associated carcinogenesis.
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Colitis Ulcerosa/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Proteínas del Tejido Nervioso/genética , Neutrófilos/inmunología , Proteína de Unión al GTP rac1/inmunología , Actinas/metabolismo , Adulto , Anciano , Apoptosis/genética , Apoptosis/inmunología , Línea Celular Tumoral , Quimiotaxis de Leucocito/inmunología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Técnicas de Silenciamiento del Gen , Factores de Intercambio de Guanina Nucleótido , Células HL-60 , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/inmunología , Proteínas del Tejido Nervioso/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Especies Reactivas de Oxígeno/metabolismo , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Helicobacter pylori (HP) infection is widely recognized as a risk factor for gastric cancer, but only a minority of infected individuals develop gastric cancer. The aim of this study was to determine whether DNA demethylation in non-cancerous gastric mucosa (NGM) significantly enhances susceptibility to gastric cancer. A total of 165 healthy volunteers, including 83 HP-positive and 82-negative individuals, as well as 83 patients with single and 18 with synchronous double gastric cancer (GC) were enrolled in this study. The relative demethylation levels (RDLs) of repetitive sequences, including Alu, LINE-1 and Sat α, were quantified by real-time methylation-specific polymerase chain reaction. The Alu RDL did not exhibit any differences within each respective group, whereas LINE-1 RDL was significantly elevated in cancer tissues compared with the NGM in the other groups (P<0.001). Our results indicated that a gradual increase in Sat α RDL correlated with HP infection and cancer development. Sat α RDL was significantly elevated in the NGM in HP-positive compared with HP-negative (P<0.001), and significantly elevated in cancer tissues (P<0.001). Although the Sat α RDL of the NGM in the total population increased in an age-dependent manner, it was significantly increased in a fraction of younger GC patients (<45 years) compared with all of the others (45 years or older, P=0.0391). In addition, double GC exhibited a significantly higher Sat α RDL in the NGM compared with single GC (P=0.0014). In these two fractions, Sat α RDL in the NGM exhibited an inverse correlation with age. In conclusion, the present study demonstrated that the accumulation of DNA demethylation in Sat α RDL in the NGM with HP infection potentially renders susceptibility to gastric cancer in a fraction of GC patients younger than 45 years or in patients with multiple cancers.
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Metilación de ADN , ADN Satélite/genética , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/genética , Helicobacter pylori , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiología , Adulto , Factores de Edad , Anciano , Elementos Alu , Femenino , Predisposición Genética a la Enfermedad , Humanos , Elementos de Nucleótido Esparcido Largo , Masculino , Persona de Mediana Edad , Estómago/microbiologíaRESUMEN
A 73-year-old female was referred to our hospital with a diagnosis of advanced transverse colon cancer with severe anemia and body weight loss. Preoperative evaluations, including colonoscopy, gastroduodenoscopy, and computed tomography, revealed not only a transverse colon cancer massively invading the duodenum, but also a non-functioning endocrine tumor in the pancreatic tail. We performed middle-preserving pancreatectomy (MPP) with right hemicolectomy for these tumors with a curative intent. After the resection, about 6 cm of the body of the pancreas was preserved, and signs of diabetes mellitus have not appeared. The postoperative course was complicated by a grade B pancreatic fistula, but this was successfully treated with conservative management. After a 33-day hospital stay, the patient returned to daily life without signs of pancreatic exocrine insufficiency. Although the long-term follow-up of the patient is indispensable, in this case, MPP might be able to lead to the curative resection of transverse colon cancer massively invading the duodenum and non-functioning endocrine tumor in the pancreatic tail with preservation of pancreatic function.
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Genetic and epigenetic features of sessile serrated adenoma (SSA), a precursor lesion to colon cancer with microsatellite instability (MSI), were investigated. The aim of this study was to clarify whether there are location-dependent genetic and epigenetic features in SSA. Twenty-two patients with proximal SSAs and 8 with distal SSAs were recruited. Twenty-two patients with tubular adenoma (TA) and 66 with proximal colon cancer were studied for comparison. Genetic and epigenetic features were evaluated as BRAF and KRAS mutations, MSI, hMLH1 methylation and CpG island methylator phenotype (CIMP). BRAF mutation (p=0.007) and CIMP (p=0.012) were more frequently found in proximal than in distal SSAs. Furthermore, the KRAS mutation was found only in distal SSAs. In TAs, no location-related molecular features were observed. All SSAs, TAs and 42 colon cancer lesions were microsatellite stable (MSS). Twenty-four colon cancer lesions exhibited MSI and had more frequent BRAF mutations (p<0.001), hMLH1 methylation (p<0.001) and CIMP (p<0.001). BRAF mutation occurred in only 9.5% of MSS cancers (p=0.01). In MSI cancers with the BRAF mutation, a higher correlation with CIMP (p=0.032) was observed. We demonstrated the distinct genetic and epigenetic features between proximal and distal SSAs. Similar genetic and epigenetic features were shared between proximal SSAs and proximal MSI cancers harboring the BRAF mutation. By contrast, our results allow the possibility of carcinogenesis in SSAs leading to MSS cancer with the BRAF mutation.
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A 58-year-old female was referred to our hospital with a diagnosis of bowel obstruction due to advanced transverse colon cancer invading the duodenum. Two months after the emergency bypass operation for the bowel obstruction, we performed an en bloc right hemicolectomy with pancreaticoduodenectomy (RHCPD) with a curative intent. During the operation, we could not dissect the tumor from the superior mesenteric vein, so we performed a segmental cylindrical resection of the superior mesenteric vein and its reconstruction. The post-operative course was uneventful, and after a 34-day hospital stay the patient returned to daily life. A histologic examination also revealed a well-differentiated tubular adenocarcinoma invading the duodenum. All the surgical margins were negative and lymph node metastasis was not found. There were no signs of recurrence for 8 months after the operation. Complete resection clearly influences survival time of patients, and surgeons should not hesitate to perform RHCPD.
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PURPOSE: We evaluated the clinical findings of patients with second primary digestive cancers (SPDC) after the resection of lung cancer. METHODS: Among 772 patients who underwent resection of primary lung cancer at Saitama Cardiovascular and Respiratory Center between 1993 and 2002, 10 (1.3%) were diagnosed with SPDC during follow-up. These ten patients were classified into two groups based on whether the SPDC was incidentally (group I) or symptomatically (group S) diagnosed. RESULTS: The median interval to the detection of SPDC was 17 months in group I and 66 months in group S, and the disease was at an earlier stage in group I than in group S ( P = 0.008). Comparing body weight at the time of lung resection to that at the time of abdominal surgery, significant weight loss was evident in group S ( P = 0.009). The postoperative disease-specific survival rate was 100% in group I. No long-term survivor died of lung cancer. CONCLUSION: Special attention must be paid to the possibility of SPDC after the resection of lung cancer to improve the prognosis of patients with lung cancer.
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Adenocarcinoma/cirugía , Carcinoma de Células Escamosas/cirugía , Neoplasias Gastrointestinales/epidemiología , Neoplasias Pulmonares/cirugía , Neoplasias Primarias Secundarias/epidemiología , Neoplasias del Colon/epidemiología , Femenino , Neoplasias Gastrointestinales/cirugía , Humanos , Masculino , Estadificación de Neoplasias , Pronóstico , Neoplasias del Recto/epidemiología , Neoplasias Gástricas/epidemiologíaRESUMEN
We report a successfully managed case of far-advanced hepatocellular carcinoma (HCC) by intraarterial infusion therapy. A 55-year-old man was admitted to our hospital with abdominal pain and subileus. Abdominal ultrasonography, computed tomography, and angiography revealed HCC with obstruction of the main portal vein due to tumor thrombus. Serum levels of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were elevated. Neoadjuvant chemotherapy was tried with a course of low-dose cisplatin (CDDP) +5-fluorouracil (5-FU) intrahepatic arterial infusion through the indwelling catheter via the subcutaneous reservoir port. After 7 weeks of administration (total dose CDDP 370 mg/5-FU 18.5 mg), the main tumor size was effectively reduced. Serum levels of AFP and PIVKA-II decreased markedly. Adverse effects were tolerated. Following the chemoinfusion therapy, posterior segmentectomy and thrombectomy were performed. Reconstruction of the portal vein was not necessary because we removed the tumor thrombus without resecting the portal vein. The postoperative course was uneventful, and the patient has been doing well more than 2 years after surgery, with no evidence of recurrence or metastasis. Preoperative low-dose CDDP +5-FU intrahepatic arterial infusion therapy in combination with hepatic resection may be an effective treatment for advanced HCC with portal vein tumor thrombus.