RESUMO
Non-ampullary duodenal adenocarcinoma (DAC) is a rare malignancy. Little information is available concerning the histopathological prognostic factors associated with DAC. Carbonic anhydrases (CAs) are metalloenzymes catalyzing the universal reaction of CO2 hydration. Isozymes CAII, CAIX, and CAXII are associated with prognosis in various cancers. Our aim was to analyze the immunohistochemical expressions of CAII, CAIX, and CAXII in normal duodenal epithelium, duodenal adenomas, and adenocarcinoma and their associations with clinicopathological variables and survival. Our retrospective study included all 27 DACs treated in Oulu University Hospital during years 2000-2020. For comparison, samples of 42 non-ampullary adenomas were collected. CAII expression was low in duodenal adenomas and adenocarcinoma. CAIX expression in adenomas and adenocarcinoma was comparable with the high expression of normal duodenal crypts. Expression patterns in carcinomas were largely not related to clinicopathological features. However, low expression of CAII associated with poorer differentiation of the tumor (p=0.049) and low expression of CAIX showed a trend for association with nodal spread, although statistical significance was not reached (p=0.091). CAII and CAIX lost their epithelial polarization and staining intensity in adenomas. CAXII expression was not detected in the studied samples. CAs were not associated with survival. The prognostic value of CAII and CAIX downregulation should be further investigated. Both isozymes may serve as biomarkers of epithelial dysplasia in the duodenum.
Assuntos
Adenocarcinoma/enzimologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Neoplasias Duodenais/enzimologia , Adenocarcinoma/patologia , Adulto , Idoso , Antígenos de Neoplasias/genética , Anidrase Carbônica II/genética , Anidrase Carbônica IX/genética , Diferenciação Celular , Estudos de Coortes , Neoplasias Duodenais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Extrapulmonary neuroendocrine carcinoma (EPNEC) is a lethal disease with a poor prognosis. Platinum-based chemotherapy is used as the standard first-line treatment for unresectable EPNEC. Several retrospective studies have reported the results of the utilization of temozolomide (TMZ) as a drug for the second-line treatment for EPNEC. Patients with unresectable EPNEC that were resistant to platinum-based combination chemotherapy were recruited for a prospective phase II study of TMZ monotherapy. A 200 mg/m2 dose of TMZ was given from day 1 to day 5, every 4 weeks. Response rate (RR) was evaluated as the primary end-point. The presence of O6 -methylguanine DNA methyltransferase (MGMT) in EPNEC patients was also evaluated as exploratory research. Thirteen patients were enrolled in this study. Primary lesions were pancreas (n = 3), stomach (n = 3), duodenum (n = 1), colon (n = 1), gallbladder (n = 1), liver (n = 1), uterus (n = 1), bladder (n = 1), and primary unknown (n = 1). Each case was defined as pathological poorly differentiated neuroendocrine carcinoma from surgically resected and/or biopsied specimens. The median Ki-67 labeling index was 60% (range, 22%-90%). The RR was 15.4%, progression-free survival was 1.8 months (95% confidence interval [CI], 1.0-2.7), overall survival (OS) was 7.8 months (95% CI, 6.0-9.5), and OS from first-line treatment was 19.2 months (95% CI, 15.1-23.3). No grade 3 or 4 hematological toxicity had occurred and there was one case of grade 3 nausea. One case presented MGMT deficiency and this case showed partial response. Temozolomide monotherapy is a feasible, modestly effective, and safe treatment for patients with unresectable EPNEC following platinum-based chemotherapy, especially those with MGMT deficiency.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Temozolomida/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/enzimologia , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Esquema de Medicação , Neoplasias Duodenais/tratamento farmacológico , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/patologia , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/enzimologia , Neoplasias da Vesícula Biliar/patologia , Humanos , Antígeno Ki-67/análise , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , O(6)-Metilguanina-DNA Metiltransferase/análise , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Estudos Prospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/patologiaRESUMO
Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of pTyr105-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, pTyr105-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended in vivo, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear pTyr105-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer.
Assuntos
Neoplasias Duodenais/enzimologia , Indóis/farmacologia , Nitrobenzenos/farmacologia , Piruvato Quinase/antagonistas & inibidores , Piruvato Quinase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/enzimologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Neoplasias Duodenais/tratamento farmacológico , Humanos , Indóis/uso terapêutico , Masculino , Metanol/análogos & derivados , Camundongos , Camundongos Nus , Nitrobenzenos/uso terapêutico , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Neoplasias Gástricas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BACKGROUND & AIMS: The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia. METHODS: Primary enteric glial cultures were generated from the VillinCre:Men1FL/FL:Sst-/- mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from C57BL/6 mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom. RESULTS: Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas. CONCLUSIONS: MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.
Assuntos
Duodeno/metabolismo , Gastrinas/metabolismo , Neuroglia/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/genética , Neoplasias Duodenais/patologia , Duodeno/efeitos dos fármacos , Duodeno/patologia , Gastrinoma/enzimologia , Gastrinoma/genética , Gastrinoma/patologia , Gastrinas/genética , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Hiperplasia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroglia/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Proteólise , Proteínas Proto-Oncogênicas/genética , Inibidores da Bomba de Prótons/farmacologia , Receptor de Colecistocinina B/metabolismo , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Fatores de Tempo , UbiquitinaçãoRESUMO
BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA. METHODS: Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations. RESULTS: MGMT methylation was detected in 17 of 64 (26.6%) patients, and was not correlated with sex, age, tumor differentiation, CIMP, MSI, or KRAS mutations. MGMT methylation was the only one factor associated with both overall survival (OS) and disease-free survival (DFS) on both univariate and multivariate analyses. In patients treated with surgery alone, MGMT-methylated group had worse OS and DFS when compared with MGMT-unmethylated group. However, in patients treated with chemotherapy/radiotherapy, outcomes became comparable between the two groups. CONCLUSIONS: Our results demonstrate MGMT methylation is a reliable and independent prognostic factor in DAs. Methylation of MGMT is associated with poor prognosis in patients with stage III DAs.
Assuntos
Adenocarcinoma/patologia , Metilação de DNA , Neoplasias Duodenais/patologia , O(6)-Metilguanina-DNA Metiltransferase/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Antineoplásicos/uso terapêutico , Quimiorradioterapia , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Others and we have demonstrated that hypoxia-inducible factor 1α (HIF-1α) and transcriptionally upregulated Aurora-A are required for disease progression in several tumors. We investigated the clinicopathological value of HIF-1α and Aurora-A in primary duodenal adenocarcinoma (PDA). Using immunohistochemistry, we evaluated Aurora-A and HIF-1α expression semiquantitatively in 140 PDA cases. There were 76 cases from one institute that formed the training set; 64 cases from another two institutes were used as the testing set to validate the prognostic value of Aurora-A and HIF-1α expression. Aurora-A expression was high or sufficient in the tumor zone, whereas expression was low in the adjacent normal epithelia. High Aurora-A expression, identified using the training set receiver operator characteristic (ROC) analysis-generated cutoff score, predicted poorer overall survival both in the testing set (18.0 vs. 45.1 %, P = 0.001) and training set (23.1 vs. 53.9 %, P = 0.011). Multivariate Cox regression confirmed that Aurora-A was an independent prognostic factor. Contrary to previous studies, we did not detect any correlation between Aurora-A and HIF-1α. Survival analysis showed that HIF-1α level was not correlated with patient outcome (P = 0.466). Activation of Aurora-A, an independent negative prognostic biomarker, might be used to identify particular PDA patients for more selective therapy.
Assuntos
Adenocarcinoma/enzimologia , Aurora Quinase A/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Duodenais/enzimologia , Adenocarcinoma/diagnóstico , Western Blotting , Neoplasias Duodenais/diagnóstico , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica/estatística & dados numéricos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Curva ROCAssuntos
Biomarcadores Tumorais/análise , Neoplasias Duodenais/diagnóstico , Linfoma Anaplásico de Células Grandes/diagnóstico , Receptores Proteína Tirosina Quinases/análise , Neoplasias Gástricas/diagnóstico , Quinase do Linfoma Anaplásico , Biomarcadores Tumorais/genética , Biópsia , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/genética , Duodenoscopia , Gastroscopia , Humanos , Imuno-Histoquímica , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Masculino , Receptores Proteína Tirosina Quinases/genética , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Adulto JovemRESUMO
AIM: To investigate whether Recql5, a DNA helicase that plays an important role in the maintenance of genome integrity, is a tumor suppressor in the gastrointestinal tract in mice. METHODS: We generated cohorts of both Recql5-proficient and Recql5-deficient Apc(min/+) mice and compared the tumor susceptibility in their gastrointestinal tracts. RESULTS: Recql5 deficiency in Apc(min/+) mice resulted in a significant increase in the tumor incidence in both the colon (P = 0.0162) and the small intestine (P < 0.01). These findings have provided the first genetic evidence for a tumor suppression role of Recql5 in the gastrointestinal tract of mice. Importantly, since mouse Recql5 and human RECQL5 are highly conserved, these findings also suggest that RECQL5 may be a tumor suppressor for human colon cancer. CONCLUSION: Recql5 has a tumor suppression role in the mouse gastrointestinal tract.
Assuntos
Adenoma/genética , Genes APC , Neoplasias Intestinais/genética , RecQ Helicases/deficiência , Proteínas Supressoras de Tumor/deficiência , Adenoma/enzimologia , Adenoma/patologia , Adenoma/prevenção & controle , Animais , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias do Íleo/enzimologia , Neoplasias do Íleo/genética , Neoplasias Intestinais/enzimologia , Neoplasias Intestinais/patologia , Neoplasias Intestinais/prevenção & controle , Neoplasias do Jejuno/enzimologia , Neoplasias do Jejuno/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RecQ Helicases/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Carbamoyl phosphate synthetase I (CPS1), normally found in hepatocytes and small-intestine (SI) enterocytes, is the antigen of Hep Par 1 antibody. Expression of CPS1 in invasive SI adenocarcinoma seems to be lost. We retrospectively collected 36 total specimens, which included 31 SI adenomas and 21 adenocarcinomas. We used 34 cases of duodenitis as a control group. Immunohistochemical and Western blot analyses were performed to determine CPS1 expression. The normal SI mucosa, all 34 cases of duodenitis, and all 29 adenomas with low-grade dysplasia demonstrated diffuse Hep Par 1 expression. Of the 21 invasive adenocarcinomas, 15 lost antigen expression (71%). These data are statistically significant (P < .05). Western blot analysis confirmed the immunohistochemical findings, with strong CPS1 expression within the normal mucosa and adenoma and complete loss in the invasive tumor. The differential expression of Hep Par 1 in dysplastic vs malignant tumors of the SI may be diagnostically useful in difficult cases.
Assuntos
Adenocarcinoma/enzimologia , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Neoplasias Duodenais/enzimologia , Duodeno/enzimologia , Adenocarcinoma/patologia , Adenoma/enzimologia , Adenoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Duodenais/patologia , Duodenite/enzimologia , Duodenite/patologia , Duodeno/patologia , Humanos , Imuno-Histoquímica , Mucosa Intestinal/enzimologia , Mucosa Intestinal/patologia , Invasividade Neoplásica , Estudos RetrospectivosRESUMO
BACKGROUND: Elevated serum concentrations of M2-pyruvate kinase (M2-PK) correlate with poor prognosis in patients with pancreaticobiliary and duodenal cancer, but the expression of M2-PK in formalin-fixed pancreatic tissue is unknown. We aimed to characterise the immunohistochemical expression of M2-PK in archived specimens of pancreaticobiliary and duodenal cancers, premalignant lesions, chronic pancreatitis, and normal pancreas. METHODS: Immunohistochemical staining was performed with mouse anti-M2-PK monoclonal antibody (clone DF-4) at an optimal dilution of 1:25 on tissue microarrays constructed from formalin-fixed paraffin-embedded pancreatic tissue of 126 consecutive patients undergoing pancreatic resections between June 2001 and June 2006. 104 underwent resection for cancer and 22 for chronic pancreatitis. 78 specimens of chronic pancreatitis tissue were obtained adjacent to areas of cancer. Normal pancreatic tissue was obtained from the resection specimens in a total of 30 patients. Metastatic tumours in 61 regional lymph nodes from 61 patients were also studied. A further 11 premalignant pancreaticobiliary and duodenal lesions were studied. M2-PK expression was quantified with the immunohistochemical score (IHS; Range 0-12). RESULTS: Benign non-ductal tissue in chronic pancreatitis and normal pancreas showed variable expression of M2-PK (IHS = 1 in 25%, IHS = 2-3 in 40%, IHS>3 in 40%). Benign pancreatic ductal epithelium, all primary pancreaticobiliary and duodenal premalignant lesions and cancers (and lymph node metastasis) showed complete lack of expression (IHS = 0). CONCLUSION: Complete lack of M2-PK expression was observed in benign pancreatic ducts, premalignant lesions and cancer. M2-PK is present only in benign non-ductal epithelium in normal pancreas and peri-tumoural tissue.
Assuntos
Carcinoma Ductal Pancreático/enzimologia , Neoplasias Duodenais/enzimologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/enzimologia , Piruvato Quinase/genética , Idoso , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Neoplasias Duodenais/genética , Neoplasias Duodenais/patologia , Epitélio/enzimologia , Epitélio/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/citologia , Pâncreas/enzimologia , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Piruvato Quinase/metabolismoRESUMO
BACKGROUND: In the normal duodenal mucosa, differentiated cells (enterocytes, goblet cells and endocrine cells) migrate from stem cells to the tip of the villi, but the lysozyme-producing Paneth cells migrate to the bottom of the crypts. The position of the Paneth cells within duodenal adenomas was investigated. PATIENTS AND METHODS: Sections from 83 duodenal adenomas were stained with hematoxylin-eosin (H&E) and with anti-lysozyme. Mature Paneth cells were those showing coarse brightly red cytoplasmic granules in H&E stain whereas their precursors were the lysozyme-positive cells that were undetected by H&E. RESULTS: The number of mature Paneth cells/high power field (x 40) varied in adenomas from 4 to 12 (mean 65) in H&E stain, while 32 to 62 cells/field (mean 46.5) were positive in anti-lysozyme immunostain (p < 0.05). The lysozyme-expressing cells were randomly distributed within the adenoma including the superficial cell layers. DISCUSSION AND CONCLUSION: Since mature Paneth cells and their precursors are positioned underneath stem cells, the presence of mature Paneth cells and their lysozyme-positive precursors in the surface epithelium of duodenal adenomas would imply that stem cells might have already exfoliated. An alternative explanation would mean that mutated stem cells, anchored in the bottom of the crypts of the adenoma would redirect, in an unparalleled fashion, the ontogenetic logistics of migration for Paneth cells. This stochastic molecular behaviour would require a reversal from the pre-determined migratory flow for Paneth cells to a paradoxical migration mode for these cells (from stem cells vertically along the villus, before exfoliation). Consequently, it is not inconceivable that stem cells might participate, together with other mature cells, in the cellular turnover of duodenal adenomas. If that is the case, the duodenal adenoma emerges as a suitable model to monitor the actual fate of mutated stem cells.
Assuntos
Adenoma/patologia , Neoplasias Duodenais/patologia , Células-Tronco Neoplásicas/patologia , Adenoma/enzimologia , Polipose Adenomatosa do Colo/enzimologia , Polipose Adenomatosa do Colo/patologia , Neoplasias Duodenais/enzimologia , Amarelo de Eosina-(YS) , Hematoxilina , Humanos , Mucosa Intestinal/patologia , Muramidase/biossíntese , Células-Tronco Neoplásicas/enzimologia , Celulas de Paneth/enzimologia , Celulas de Paneth/patologia , Coloração e Rotulagem/métodosRESUMO
Individual differences in 5-FU metabolism are mainly attributed to individual differences in the activity of DPD, an enzyme that can metabolize more than 85% of 5-FU. Because urinary uracil is a reflection of DPD activity, it is measured to predict and prevent the occurrence of side effects caused by pyrimidine-type chemotherapeutic agents. From urinary uracil values measured in 84 gastrointestinal cancer patients, 0-60 mmol/g.creatinine was set as a standard. In patients whose urinary uracil values exceeded the standard, 5-FU tended to be accumulated when S-1, a DIF product, was administered and side effects, such as anorexia, vomiting and diarrhea occurred immediately after the start of S-1 administration. If an appropriate DIF product is selected and its dosage set based on the patient's urinary uracil value, the occurrence of side effects would be reduced. Subsequently, a continuation of medication would be possible.
Assuntos
Antineoplásicos/urina , Di-Hidrouracila Desidrogenase (NADP)/antagonistas & inibidores , Neoplasias Duodenais/tratamento farmacológico , Inibidores Enzimáticos/urina , Compostos de Flúor/urina , Neoplasias Gástricas/tratamento farmacológico , Uracila/urina , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/urina , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Feminino , Compostos de Flúor/administração & dosagem , Compostos de Flúor/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/urinaRESUMO
Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas.
Assuntos
Citidina Desaminase/metabolismo , Células Dendríticas Foliculares/patologia , Neoplasias Duodenais/patologia , Linfonodos/patologia , Linfoma Folicular/patologia , Hipermutação Somática de Imunoglobulina , Idoso , Biomarcadores Tumorais/metabolismo , DNA de Neoplasias/análise , Células Dendríticas Foliculares/enzimologia , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/genética , Feminino , Genes de Cadeia Pesada de Imunoglobulina , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Antígeno Ki-67/metabolismo , Linfonodos/embriologia , Linfoma Folicular/enzimologia , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Translocação GenéticaRESUMO
Accumulating evidence suggests that grape seed and wine polyphenol extracts possess a diverse array of actions and may be beneficial in the prevention of inflammatory-mediated disease such as cardiovascular disease and cancer. This study aimed to determine whether the reported pleiotropic effects of several polyphenolic extracts from grape seed products or red wine would also include inhibition of cholesterol uptake and cell proliferation, and inhibit a known specific target of the inflammatory process, that is, 5-lipoxygenase (5-LOX). Incubation of HT29, Caco2, HepG2, or HuTu80 cells in a medium containing [(3)H]cholesterol in the presence of a grape seed extract (GSE) or red wine polyphenolic compounds (RWPCs) inhibited [(3)H]cholesterol uptake by up to 66% (which appeared maximal). The estimated IC(50) values were 60 and 83 microg/mL for RWPC and GSE, respectively. Similar cholesterol uptake inhibitory effects were observed using the fluorescent cholesterol analogue NBD cholesterol. The inhibition of cholesterol uptake was independent of the sample's (GSE and RWPC) potent antioxidative capacity. Red wine polyphenolic compound and GSE dose dependently inhibited HT29 colon adenocarcinoma cell proliferation, which was accompanied by an increase in apoptosis. In addition, RWPC and GSE inhibited 5-LOX activity with the IC(50) values being 35 and 13 microg/mL, respectively. Two of 3 other GSEs tested also significantly inhibited 5-LOX activity. Inhibition of cholesterol uptake and proinflammatory 5-LOX activity may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease and cancer.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Colesterol/metabolismo , Flavonoides/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Sementes , Vitis , Vinho , Adenocarcinoma/enzimologia , Adenocarcinoma/metabolismo , Adenoma/enzimologia , Adenoma/metabolismo , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Doenças Cardiovasculares/prevenção & controle , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/enzimologia , Neoplasias do Colo/metabolismo , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/metabolismo , Flavonoides/uso terapêutico , Humanos , Inibidores de Lipoxigenase , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Fenóis/uso terapêutico , Extratos Vegetais/uso terapêutico , PolifenóisRESUMO
BACKGROUND: In the normal duodenum, Paneth cells migrate from the stem cells downwards, towards the bottom of the crypts of Lieberkuhn. MATERIALS AND METHODS: The spatial position of Paneth cells within the profile of histological sections was investigated with hematoxilin and eosin (H&E) in 6 duodenal adenomas; 2 of them were also immonostained with lysozyme, an enzyme present in Paneth cells. RESULTS: In H&E stain sections, the numbers of mature Paneth cells/high power field varied from 2 to 7 (mean 4.5). In the two immunostained adenomas, the numbers of lysozyme-expressing cells/high power field were 15 and 42, respectively. The lysozyme-stained cells were present at all levels in the adenomas, including the luminal epithelial layer. CONCLUSION: In duodenal adenomas, not all Paneth cells detected by lysozyme immunostain are apparent in H&E-stained sections, suggesting that lysozyme immunostain also detects Paneth cells precursors. Since mature Paneth cells and their precursors are positioned underneath the stem cells, it is conceivable that the Paneth cells that had reached the luminal aspect of the adenomas, were preceded by stem cells. This possibility would imply that in duodenal adenomas, the stem cells would be subjected to the same laws that orchestrate the turnover of epithelial duodenal cells, including Paneth cells and their precursors.
Assuntos
Adenoma/patologia , Neoplasias Duodenais/patologia , Células-Tronco Neoplásicas/patologia , Adenoma/enzimologia , Neoplasias Duodenais/enzimologia , Humanos , Muramidase/análise , Células-Tronco Neoplásicas/enzimologia , Coloração e Rotulagem/métodosRESUMO
BACKGROUND: Patients with familial adenomatous polyposis (FAP) are at high risk of developing duodenal adenomas and carcinomas. Besides germline mutations in the adenomatous polyposis coli (APC) gene, additional factors may influence the age of onset and number of duodenal adenomas. This study compared the genotype distributions of duodenal detoxification enzyme isoforms in patients with FAP and controls. METHODS: The study included 85 patients with FAP and 218 healthy age- and sex-matched controls. Genotyping of all participants using polymerase chain reaction was performed to detect polymorphisms in isoforms of uridine 5'-diphosphate glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs): UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A10, UGT2B4, UGT2B7, UGT2B15, GSTA1, GSTP1, GSTM1 and GSTT1. RESULTS: The variant genotypes of UGT1A3 were less common in patients with FAP than in controls (odds ratio 0.39 (95 per cent confidence interval 0.22 to 0.67)). There were no associations between FAP and the other polymorphic genes. The polymorphisms investigated had no predictive value for the severity of duodenal adenomatosis in patients with FAP. CONCLUSION: Although the variant genotypes of UGT1A3 were less common in patients with FAP than in those without, this did not modulate the severity of duodenal adenomatosis.
Assuntos
Polipose Adenomatosa do Colo/enzimologia , Neoplasias Duodenais/enzimologia , Genes APC , Glucuronosiltransferase/genética , Glutationa Transferase/genética , Polimorfismo Genético/genética , Adulto , Feminino , Genótipo , Humanos , MasculinoRESUMO
BACKGROUND AND AIM: The impact of obstructive jaundice (OJ) complicated by primary duodenal adenocarcinoma (PDA) on survival, and its treatment options, has rarely been mentioned in literature. The aim of the present study was to review the clinical features of PDA patients in an attempt to determine the prognostic factors and the influence of OJ on survival. METHODS: From May 1994 to February 2005, all duodenal malignancies treated at Kaohsiung Chang Gung Memorial Hospital were reviewed. Preliminary findings were made on a total of 116 duodenal adenocarcinoma (DA) cases. After excluding metastatic DA and the papilla of Vater cancer, 23 patients (19.8%), confirmed as having PDA, were enrolled. RESULTS: Among the 23 predominantly male patients with a mean age of 68 years, abdominal pain was the most common symptom. Major tumor origin was the second portion, and the predominantly cytological feature was moderate differentiation. Tumor-node-metastasis (TNM) cancer stage IV accounted for 47.8% of the patients, and cancer-directed surgeries (CDS) were performed on 11 patients. Seven patients experienced complications due to OJ, which could be a sign of grave prognosis predicting survival of less than 1 year. Four of the patients received internal or external biliary drainage before CDS or palliative surgeries. Cigarette smoking, cytology, TNM stage, aspartate aminotransferase (AST), OJ, and CDS were significant factors of overall survival in a univariate analysis. The independent predictors of long-term survival were CDS, TNM stage, cytology, cigarette smoking, and AST using the Cox proportional hazard model. CONCLUSION: PDA patients who did not smoke and who were eligible for and received CDS had better prognostic outcomes.
Assuntos
Adenocarcinoma/complicações , Adenocarcinoma/mortalidade , Neoplasias Duodenais/complicações , Neoplasias Duodenais/mortalidade , Icterícia Obstrutiva/complicações , Complicações Pós-Operatórias/etiologia , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspartato Aminotransferases/sangue , Procedimentos Cirúrgicos do Sistema Biliar , Diferenciação Celular , Bases de Dados como Assunto , Procedimentos Cirúrgicos do Sistema Digestório , Drenagem , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Feminino , Seguimentos , Humanos , Icterícia Obstrutiva/cirurgia , Estimativa de Kaplan-Meier , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Colorectal cancers arising in patients with familial adenomatous polyposis (FAP) can be largely prevented by polyp surveillance and prophylactic colectomy. As a result, duodenal adenocarcinoma has become a leading cause of death in patients with FAP. Cyclooxygenase 2 (COX-2) inhibition is effective against colorectal polyposis in FAP, but is less effective in treating duodenal polyps. We compared the expression of COX-2 in duodenal and colorectal adenomas from patients with FAP and from patients with sporadic neoplasms and correlated expression to a COX-2 promoter polymorphism (-765G/-->C) that is reported to influence COX-2 expression. METHODS: The study population included 36 FAP patients with colonic adenomas, 22 FAP patients with duodenal adenomas, 22 patients with sporadic duodenal adenomas, and 17 patients with sporadic duodenal adenocarcinoma. Neoplastic and corresponding normal tissue COX-2 expressions were determined using immunohistochemistry on tissue microarrays. The prevalence and ethnic distribution of a polymorphism in the COX-2 promoter that influences COX-2 expression (-765G --> C) were determined in DNA from 274 individuals by real-time quantitative PCR. RESULTS: Among patients with FAP, histologically normal duodenal mucosa showed higher COX-2 expression than normal colonic mucosa (P < 0.02), and duodenal adenomas had higher COX-2 expression than colonic adenomas (P = 0.01). In addition, the normal duodenum of patients with FAP showed higher COX-2 expression than the normal duodenal mucosa of patients with sporadic adenomas (P < 0.05). COX-2 expression was significantly higher in the normal-appearing (P < 0.01) mucosa of patients with FAP carrying the -765GG genotype compared with those carrying the -765GC or -765CC genotypes. The -765C genotype was more common in African Americans than in Caucasians (52% versus 33%, P < 0.01). CONCLUSIONS: High COX-2 expression in the normal and adenomatous duodenal mucosa of patients with FAP may explain the poorer response of these neoplasms to chemoprevention with COX-2 inhibitors.
Assuntos
Adenoma/patologia , Polipose Adenomatosa do Colo/patologia , Neoplasias do Colo/patologia , Neoplasias Duodenais/patologia , Polimorfismo de Nucleotídeo Único , Prostaglandina-Endoperóxido Sintases/genética , Adenoma/enzimologia , Adenoma/genética , Polipose Adenomatosa do Colo/enzimologia , Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Ciclo-Oxigenase 2 , Análise Mutacional de DNA , Neoplasias Duodenais/enzimologia , Neoplasias Duodenais/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Prostaglandina-Endoperóxido Sintases/metabolismoRESUMO
Enteropeptidase (EP) is a serine proteinase and activates trypsinogen to trypsin, thus playing an important role in food digestion. Nevertheless, the localization of EP is still controversial, likely due to a lack of studies using specific antibodies against EP. The aim of this study was to define cellular localization of EP in human duodenum and expression in tumor cells at the duodenal region. Immunohistochemical staining for resected tissues was performed with two antibodies against recombinant EP light and heavy chains, respectively. In situ hybridization was done with two RNA probes that include either the light or the heavy chain sequences of proEP, respectively. The two antibodies reacted with enterocytes, accentuated on the brush border, and goblet cells, with increasing intensity from the bottom of crypts to the top of villi. Paneth cells, neuroendocrine cells, Brunner's glands, lymphocytes, smooth muscle, or connective tissue did not react with the antibodies. The two RNA probes detected EP mRNA expression only in enterocytes and goblet cells. EP is produced in enterocytes and goblet cells, and the localization on the brush border of the cells is reasonable for the physiological activation of digestive enzymes. Interestingly, the antibodies reacted with tumor cells in duodenal polyps and adenocarcinoma at the duodenum but not in Brunner's gland adenoma. EP seems to be a marker of differentiated enterocytes and goblet cells, which suggests the existence of a common progenitor of these cells. Furthermore, EP may be a useful marker of tumor cells originating from these cells.
Assuntos
Neoplasias Duodenais/enzimologia , Duodeno/enzimologia , Enterócitos/enzimologia , Enteropeptidase/metabolismo , Células Caliciformes/enzimologia , Neoplasias Duodenais/patologia , Duodeno/citologia , Enteropeptidase/genética , Humanos , Imuno-Histoquímica/métodos , RNA Mensageiro/metabolismo , Coloração e RotulagemRESUMO
OBJECTIVE: To determine the presence of telomerase activity in a variety of periampullary malignancies and pancreatic diseases and quantify its activity to establish any association with the stage or aggressiveness of malignancy. SUMMARY BACKGROUND DATA: Progressive shortening of telomeres, repetitive DNA sequences at the ends of chromosomes, plays a role in cell senescence. Telomerase catalyzes conservation of telomeric repeats and may promote cell immortality and hence malignancy. It is absent in normal tissues but upregulated in more than 80% of cancers. METHODS: Fresh specimens of 62 periampullary tumors were snap-frozen in liquid nitrogen and adjacent tissue was formalin-fixed for histopathology. The telomerase repeat amplification protocol (TRAP) was used to obtain telomerase DNA products. These were separated with gel electrophoresis, stained with SYBR green, and quantified by densitometry. Findings were confirmed with a fluorometric TRAP assay in which fluorescent primers specific for telomerase were selectively amplified in its presence. RESULTS: Telomerase activity was upregulated in 26 of 33 periampullary malignancies (79%): 17 of 21 pancreatic adenocarcinomas (81%), 2 of 2 cholangiocarcinomas, 2 of 2 duodenal carcinomas, and 5 of 8 ampullary carcinomas (63%). Poorly differentiated periampullary tumors had significantly higher telomerase activity than well-differentiated tumors, and tumors larger than 2 cm had significantly higher telomerase activity than those 2 cm or smaller. Pancreatic ductal adenocarcinomas with lymph node metastases had significantly greater activity than node-negative cancers. Two of 11 intraductal papillary mucinous tumors were positive for telomerase activity, but only in foci of invasive carcinoma. Chronic pancreatitis (n = 7), serous cystadenomas (n = 5), benign mucinous cystic neoplasms (n = 4), neuroendocrine cancer (n = 1), and acinar cell carcinoma (n = 1) had no detectable telomerase activity. CONCLUSION: Telomerase activity is common in periampullary carcinomas. The magnitude of activity correlates with aggressiveness in pancreatic adenocarcinoma and may prove useful as a molecular index for biologic staging.