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1.
ANZ J Surg ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32407000

RESUMO

Bleeding related to rectal varices associated with portal hypertension is rare but life-threatening, and requires prompt treatment. We reviewed the literature for patients with this complex presentation and current recommendations, and commented on a case at our institution of a 68-year-old man with Child-Pugh B alcoholic liver cirrhosis and hepatic encephalopathy who presented with profuse life-threatening rectal variceal bleeding. Treatment options for rectal varices in patients with hepatic encephalopathy were reviewed and a management algorithm was devised from current knowledge in the literature. We suggest endoscopic management, and if unsuccessful then to proceed to angioembolization and/or balloon-occluded retrograde transvenous obliteration, which may be used in conjunction with surgical management. The chosen therapeutic option may depend on the clinical condition of the patient, the cause of portal hypertension and clinical expertise or facilities available. Given that transjugular intra-hepatic portosystemic shunting is contraindicated in patients with hepatic encephalopathy, management of life-threatening rectal variceal bleeding should be multimodal.

2.
Int J Colorectal Dis ; 35(4): 665-674, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32020266

RESUMO

BACKGROUND: Pouch prolapse is a rare pouch complication which often leads to pouch failure in inflammatory bowel disease (IBD) patients. Its exact cause remains unknown. Floppy pouch complex (FPC) was defined as the presence of any one of the following pouch disorders: pouch prolapse, afferent limb syndrome (ALS), redundant loop, and pouch folding. We aimed to explore the role of peripouch fat area in the occurrence of pouch prolapse and FPC. METHODS: Pouch patients with available pouchoscopy and abdominal CT scans who were followed up between 2011 and 2017 in Cleveland Clinic were reviewed. Peripouch fat was measured on CT images. RESULTS: Of the 93 included patients, 31 were females; 87 had J pouches and 6 had S pouches. The median duration of pouch was 8.0 (interquartile range [IQR] 5.0-16.5) years. A total of 18 cases (19.4%, 18/93) were identified as FPC, including 12 pouch prolapse, 5 ALS, 1 redundant loop, and 3 pouch folding. Patients with pouch prolapse had lower peripouch fat area (13.6 (9.3-18.5) vs. 27.6 (11.0-46.2)cm2, P = 0.022) than those without. Patients with FPC had lower peripouch fat area (15.4 (11.4-20.6) vs. 27.6 (11.0-46.9)cm2, P = 0.040) than those without. Univariate and multivariate analyses demonstrated that lower peripouch fat area, lower weight, and family history of IBD were independent predictors of pouch prolapse and FPC. CONCLUSIONS: A lower peripouch fat area was observed in inflammatory bowel disease patients with pouch prolapse and FPC. Longitudinal studies are needed to further elucidate the role of peripouch fat in the pathogenesis of pouch prolapse and FPC.

3.
Cancer Res ; 80(2): 334-346, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31704889

RESUMO

Neoadjuvant radiation is standard of care for locally advanced rectal cancer. Response to radiation is highly variable and directly linked with survival. However, there currently are no validated biomarkers or molecular targets to predict or improve radiation response, which would help develop personalized treatment and ideally targeted therapies. Here, we identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines. Importantly, genetic overexpression and knockdown yielded radioresistant and sensitive phenotypes, respectively, in vitro and in vivo. COASY-knockdown xenografts were more vulnerable to radiation, showing delayed tumor growth, decreased proliferation, and increased apoptosis. Mechanistically, COASY protein directly interacted with the PI3K regulatory subunit PI3K-P85α, which increased AKT and mTOR phosphorylation, enhancing cell survival. Furthermore, shRNA COASY knockdown disrupted downstream PI3K pathway activation and also hindered DNA double-strand break repair, which both led to improved radiosensitivity. Collectively, this work reveals for the first time the biological relevance of COASY as a predictive rectal cancer biomarker for radiation response and offers mechanistic evidence to support COASY as a potential therapeutic target. SIGNIFICANCE: COASY is a novel radiotherapy response modulator in rectal cancer that regulates PI3K activation and DNA repair. Furthermore, COASY levels directly correlate with radiation response and serve as a predictive biomarker.

5.
Int J Clin Oncol ; 24(2): 141-152, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30612269

RESUMO

BACKGROUND: Simultaneous detection of multiple molecular biomarkers is helpful in the prediction of treatment response and prognosis for colorectal cancer (CRC) patients. METHODS: A 22-gene panel consisting of 103 hotspot regions was utilized in the formalin-fixed paraffin-embedded (FFPE) tissue samples of 207 CRC patients, using the next-generation sequencing (NGS)-based multiplex PCR technique. Those 22 genes included AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53. RESULTS: Of the 207 patients, 193 had one or more variants, with 170, 20, and 3 having one, two, and three mutated genes, respectively. Of the total 414 variants identified in this study, 384, 25, and 5 were single-nucleotide variants, deletion, and insertion. The top four frequently mutated genes were TP53, KRAS, PIK3CA, and FBXW7. There was high consistency between the results of NGS-PCR technique and routine ARMS-PCR in KRAS and BRAF mutation detection. Univariate and multivariate analyses demonstrated that advanced TNM stage, elevated serum CEA, total variants number ≥ 2, AKT1 and PTEN mutation were independent predictors of shorter DFS; poor differentiation, advanced TNM stage, total variants number ≥ 2, BRAF, CTNNB1 and NRAS mutation were independent predictors of shorter OS. CONCLUSIONS: It is feasible to detect multiple gene mutations with a 22-gene panel in FFPE CRC specimens. TNM stage and total variants number ≥ 2 were independent predictors of DFS and OS. Detection of multiple gene mutations may provide additional prognostic information to TNM stage in CRC patients.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Inclusão em Parafina , Transcriptoma , Idoso , Neoplasias Colorretais/genética , Feminino , Formaldeído , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Dis Colon Rectum ; 62(1): 21-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30394984

RESUMO

BACKGROUND: The methylator pathway of colorectal carcinogenesis, characterized by CpG island hypermethylation and BRAF mutations, accounts for ≈25% of colorectal cancers. Because these cancers tend to be right sided and because DNA methylation in the right colon increases with age, we expect an increasing proportion of right-sided cancer over time. Conversely, we expect young patients (age <50 y) to have less methylated and fewer right-sided cancers OBJECTIVE:: The purpose of this study was to analyze the distribution and genetic traits of colorectal cancer from different age groups. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a high-volume tertiary referral center. PATIENTS: Patient samples included those from our colorectal cancer biobank of resected colorectal cancer specimens. MAIN OUTCOME MEASURES: Tumor CpG island hypermethylation, microsatellite instability, and mutations in KRAS and BRAF oncogenes were analyzed in resected specimens and stratified by age and tumor location. Comparisons included age >50 or <50 years and decade of diagnosis (≤50, 51-60, 61-70, 71-80, and >81 y). Patients with IBD or hereditary syndromes were excluded. RESULTS: A total of 497 colorectal cancers were analyzed (266 men and 231 women); 57 patients (11.5%) were ≤50 years of age. No young cancers (0/57) were hypermethylated compared with 97 (22%) of 440 cancers of patients aged >50 years (p < 0.001). An increasing percentage of tumors were CpG island phenotype high with each decade of age at diagnosis. No cancers in patients <50 years of age were microsatellite unstable compared with 91 (23.6%) of 346 for those >50 years of age. No young cancers contained a BRAF mutation compared with 46 (10.6%) of 434 in older cancers (p < 0.001). KRAS mutations were less common in young cancers compared with older cancers (13/57 (22.8%) vs 126/410 (30.7%); p < 0.01). Eleven (19.3%) of 57 young cancers were proximal compared with 228 (51.8%) of 440 (p < 0.001) older cancers. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: The lack of CpG island methylator phenotype tumors in young patients is consistent with the dominant left-sided cancer distribution seen in the young and focuses efforts to understand and prevent cancer in this age group on causes of chromosomal instability. See Video Abstract at http://links.lww.com/DCR/A709.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Ilhas de CpG , Metilação de DNA , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos
7.
Asia Pac J Clin Oncol ; 15(1): 69-74, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30421554

RESUMO

PURPOSE: The prognostic significance of biomarkers in colorectal cancer is still being defined. This study aimed to determine the prognostic significance of BRAF mutation alone and in combination with microsatellite instability (MSI), in stage III colon cancer. METHODS: Curatively resected stage III colon cancers were studied from a 33-year period. Clinicopathological data were collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumour location, grade, presence of mucin, nodal stage, extramural vascular, and perineural invasion). MSI status was established and molecular testing for BRAF (V600E) was performed. Four mutation categories were examined: "traditional" (microsatellite stable [MSS]/BRAF -ve), "presumed Lynch" (MSI/BRAF -ve), "sporadic MSI" (MSI/BRAF +ve), and "other BRAF" (MSS/BRAF +ve). These factors were correlated with cancer-specific survival. RESULTS: In total, 686 unselected cases met our inclusion criteria, of which 15.7% had a BRAF mutation and 13.8% showed MSI. In the adjusted analysis, neither BRAF mutation nor MSI mutation were independently prognostic. On univariate analysis, survival in presumed Lynch cancers was similar to traditional cancers (5-year survival: 62% and 61%, respectively). While there was no difference in cancer-specific survival between sporadic MSI and other BRAF, both these tumour group had poorer outcome when compared to traditional or presumed Lynch cancers. Adjusted analysis of the four groups, however, showed that none of the subgroups were independently prognostic. CONCLUSION: BRAF-mutated cancers demonstrated a trend toward poorer outcomes, however, when adjusted for clinicopathological factors and chemotherapy, BRAF mutation was not found to be an independent prognostic biomarker in stage III colon cancer, even when combined with MSI.


Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Feminino , Humanos , Masculino , Prognóstico , Taxa de Sobrevida
8.
J Surg Oncol ; 118(8): 1311-1317, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30399198

RESUMO

PURPOSE: The predictive role of biomarkers in colon cancer is still being defined. The aim of this study is to determine the interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival benefit after adjuvant 5-FU based chemotherapy in stage III colon cancer. METHODS: We performed a retrospective cohort study including all curatively resected stage III colon cancer cases over a 33-year period. A clinicopathological database was collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumor location, grade, mucin, nodal stage, extramural vascular, and perineural invasion). BRAF (V600E) mutation testing was performed and MSI status established by immunohistochemistry for mismatch repair proteins and molecular testing for National Cancer Institute panel markers. Patients were categorized into four groups for comparison: MSS and BRAF-ve (termed " traditional"), MSI and BRAF-ve (termed " presumed Lynch"), MSI and BRAF+ve (termed " sporadic MSI"), and MSS and BRAF+ve (termed " other BRAF"). The primary endpoint was cancer specific survival. Interaction testing was conducted to determine whether there were different responses to chemotherapy between groups. RESULTS: A total of 686 unselected cases met inclusion criteria and had tissue available, of which 15.7% had BRAF mutation (BRAF+ve) and 13.8% had MSI. Thirty-nine percent received chemotherapy. Overall, adjuvant chemotherapy produced a cancer specific survival benefit (HR 0.66, 95% CI, 0.49-0.88, P < 0.01). On adjusted analysis, neither BRAF nor MSI status were individually predictive of survival benefit. On adjusted analysis specifically of the chemotherapy effect in each subgroup, only patients in the presumed Lynch (HR 0.260, 95% CI, 0.09-0.80, P < 0.01) and other BRAF groups (HR 0.45, 95% CI, 0.23-0.87, P < 0.01) had a significant survival benefit from chemotherapy. On interaction testing of subgroups, adjusting for all the clinicopathological parameters, only patients in the presumed Lynch group (HR 0.277, 95% CI, 0.10-0.75, P < 0.01) gained a differentially greater benefit from chemotherapy than other groups. CONCLUSIONS: In this historical cohort, MSI testing is predictive of response to adjuvant chemotherapy in stage III colon cancer, but only when results are interpreted in combination with BRAF. This supports the role of routine testing for these biomarkers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Austrália/epidemiologia , Quimioterapia Adjuvante , Estudos de Coortes , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos
9.
Int J Colorectal Dis ; 33(11): 1617-1625, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29679151

RESUMO

PURPOSE: Intestinal obstruction is a leading cause of patient mortality and the most common reason for emergent operation in colorectal surgery. The influence of inter-hospital transfer on patients' outcomes varies greatly in different diseases. We aimed to compare the surgical outcomes and medical costs between transferred and directly admitted patients diagnosed with intestinal obstruction in an American tertiary referral center. METHODS: All intestinal obstruction patients operated in Cleveland Clinic from Jan 2012 to Dec 2016 were collected from a prospectively maintained database. Preoperative characteristics; surgical outcomes, including intraoperative complication, postoperative complication, readmission, reoperation, and postoperative 30-day mortality; and medical cost were collected. All parameters were compared between two groups before and after propensity score match. Multivariate logistic analysis was used to explore risk factors of surgical outcomes. RESULTS: A total of 576 patients were included, with 75 in the transferred group and 501 in the directly admitted group. Before match, the transferred patients had longer waiting interval from admission to surgery (p < 0.001), more contaminated or infected wounds (p = 0.02), different surgical procedures (p = 0.02), and similar surgical outcomes and total medical cost (all p > 0.05), compared with the directly admitted group. Multivariate analysis showed that inter-hospital transfer was not an independent predictor of any surgical outcome. After matching to balance the preoperative characteristics between two groups, no significant differences were identified in all surgical outcomes and total medical cost between two groups (all p > 0.05). CONCLUSIONS: Compared with directly admitted patients, transferred intestinal obstruction patients are associated with similar surgical outcomes and similar medical costs.


Assuntos
Custos Hospitalares , Hospitalização/economia , Obstrução Intestinal/economia , Obstrução Intestinal/cirurgia , Transferência de Pacientes/economia , Encaminhamento e Consulta/economia , Centros de Atenção Terciária/economia , Feminino , Humanos , Obstrução Intestinal/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Resultado do Tratamento , Estados Unidos
10.
Inflamm Bowel Dis ; 24(4): 806-817, 2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29506071

RESUMO

Background: There are no published studies on the impact of peripouch fat on pouch outcomes in inflammatory bowel disease (IBD) patients. Methods: Patients with pelvic MRI-DIXON scans from our prospectively maintained Pouch Database between 2002 and 2016 were evaluated. Peripouch fat area was measured on MRI-DIXON-F images at the middle height level of the pouch (area M) and the highest level of the pouch (area H). Results: Of all 1863 patients in the database, 197 eligible patients were included in this study. The median of area M was 52.4 cm2, so the 197 patients were classified into 2 groups: group 1 (Area-M <52.4 cm2) and group 2 (Area-M ≥52.4 cm2). Compared with group 1, group 2 was found to have thicker perianal fat, more Caucasian and more males. Group 2 also had a higher Area-H, more weight, height, and body mass index, along with greater age at IBD diagnosis, age at pouch construction and pouch age, and a higher frequency of total pouch complication (86.7% versus 66.7%, P = 0.001), chronic pouch complication (68.4% versus 51.5%, P = 0.016), and chronic antibiotic-refractory pouchitis (16.3% versus 7.1%, P = 0.043). Multivariate logistic analysis showed that Area-M was an independent risk factor for chronic antibiotic-refractory pouchitis (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.007-1.042, P = 0.005). The 22 patients with 2 or more pelvic MRI-DIXON scans were further classified into 2 groups by the change from the initial to latest MRI-DIXON scans. Patients with Area-M increase ≥10% and Area-M/height increase ≥10% were found to have shorter pouch survivals than those with increase <10%. Conclusions: A new method was established for measuring peripouch fat using pelvic MRI-DIXON-F image. Our study suggests that accumulation of peripouch fat may be associated with poor outcomes in selected IBD patients suspected of inflammatory or mechanical disorders of the pouch. Whether this association is causal warrants further investigation.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Doenças Inflamatórias Intestinais/cirurgia , Imagem por Ressonância Magnética , Pouchite/diagnóstico por imagem , Proctocolectomia Restauradora/efeitos adversos , Adulto , Bolsas Cólicas/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Pouchite/etiologia , Fatores de Risco , Adulto Jovem
11.
Sci Rep ; 7(1): 12443, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963558

RESUMO

A total of 27 pouch patients with inflammatory bowel diseases, who underwent pelvic MRI-DIXON and CT scan within one year, were included. Peripouch fat areas were measured at the middle height level of pouch (AreaM) and the highest level of pouch (AreaH). Our results demonstrated that measurements of perianal fat thickness, AreaM and AreaH based on MRI image were accurate and reproducible (correlation efficiency(r): intraobserver: 0.984-0.991; interobserver: 0.969-0.971; all P < 0.001). Bland-Altman analysis showed that more than 92.593% (25/27) of dots fell within the limits of agreement. We also identified strong agreements between CT and MRI image in measuring perianal fat thickness(r = 0.823, P < 0.001), AreaM (r = 0.773, P < 0.001) and AreaH (r = 0.862, P < 0.001). Interchangeable calculating formula to normalize measurements between CT and MRI images were created: Thickness_CT = 0.610 × Thickness_MRI + 0.853; AreaM_CT = 0.865 × AreaM_MRI + 1.392; AreaH_CT = 0.508 × AreaH_MRI + 15.001. In conclusion, pelvic MRI image is a feasible and reproducible method for quantifying peripouch fat. Pelvic MRI and CT images are interchangeable in retrospective measurements of peripouch fat, which will foster future investigation of the role of mesentery fat in colorectal diseases.


Assuntos
Colite Ulcerativa/diagnóstico por imagem , Doença de Crohn/diagnóstico por imagem , Gordura Intra-Abdominal/diagnóstico por imagem , Mesentério/diagnóstico por imagem , Pelve/diagnóstico por imagem , Proctocolectomia Restauradora/métodos , Adolescente , Adulto , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Doença de Crohn/patologia , Doença de Crohn/cirurgia , Feminino , Humanos , Gordura Intra-Abdominal/patologia , Imagem por Ressonância Magnética , Masculino , Mesentério/patologia , Pessoa de Meia-Idade , Pelve/patologia , Estudos Prospectivos , Tomografia Computadorizada por Raios X
12.
ANZ J Surg ; 82(6): 408-11, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22548742

RESUMO

BACKGROUND: A substantial percentage of patients with colorectal cancer present with obstructive symptoms. In such patients, surgery is often required and is associated with significant morbidity and mortality. Colorectal stenting is an increasingly commonplace alternative with potentially fewer risks than open surgery. We present our clinical experience over an 8-year period with colorectal stenting in a major tertiary Australian hospital. METHODS: From 2000 to 2008, patients undergoing colorectal stenting were identified via medical records. Clinical data collected included patient demographics, tumour type, extent of metastatic disease, stent characteristics, technical and clinical success, acute and chronic complications, and long-term follow-up status. RESULTS: Thirty-five patients (69 ± 13 years, 25 male) received a total of 39 stents. Technical success was achieved in 37 (95%), and clinical relief of obstruction was achieved in 34 (89%). One case was complicated by perforation at the time of procedure and three cases experienced delayed perforation. Reintervention was required in 17% of patients, all of whom had less than 50% hepatic volume replacement by metastatic disease. CONCLUSIONS: Colorectal stenting is a feasible and safe alternative for patients presenting with obstructive symptoms but the benefit may be restricted to patients with a short expected survival.


Assuntos
Colonoscopia/instrumentação , Neoplasias Colorretais/complicações , Obstrução Intestinal/cirurgia , Stents , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Feminino , Seguimentos , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/mortalidade , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento
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