RESUMO
BACKGROUND: The value of liver resection (LR) for metachronous pancreatic ductal adenocarcinoma (PDAC) metastases remains controversial. However, in light of increasing safety of liver resections, surgery might be a valuable option for metastasized PDAC in selected patients. METHODS: We performed a retrospective, multicenter study including patients undergoing hepatectomy for metachronous PDAC liver metastases between 2004 and 2015 to analyze postoperative outcome and overall survival. All patients were operated with curative intent. Patients with oligometastatic metachronous liver metastasis with definitive chemotherapy (n = 8) served as controls. RESULTS: Overall 25 patients in seven centers were included in this study. The median age at the time of LR was 63.8 years (56.9-69.9) and the median number of metastases in the liver was 1 (IQR 1-2). There were eight non-anatomical resections (32%), 15 anatomical minor (60%) and 2 major LR (8%). Postoperative complications occurred in eleven patients (eight Clavien-Dindo grade I complications (32%) and three grade IIIa complications (12%), respectively). The 30-day mortality was 0%. The median length of stay was 8.6 days (IQR 5-11). Median overall survival following LR was 36.8 months compared to 9.2 months in patients with metachronous liver metastasis with chemotherapy (p = 0007). DISCUSSION: Liver resection for metachronous PDAC metastasis is safe and feasible in selected patients. To address general applicability and to find factors for patient selection, larger trials are urgently warranted.
Assuntos
Carcinoma Ductal Pancreático/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Neoplasias Pancreáticas/cirurgia , Idoso , Áustria/epidemiologia , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante , Feminino , Alemanha/epidemiologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: While the number of laparoscopic liver resections (LLRs) is increasing worldwide, its impact on physical recovery remains unclear. We hypothesized that LLR is associated with better physical recovery than open liver resection (OLR). To address this question, we investigated the impact of laparoscopic liver resection compared to open liver resection on physical recovery in a prospective trial. METHODS: Twenty-one patients who underwent LR were included in this study (11 OLR (52.4%) and 10 LLR (47.6%), respectively). Physical recovery was measured by bicycle stress testing at months 1 and 6 after surgery and compared to preoperative stress testing. Standardized performance for bicycle stress testing was calculated based on age, sex, height and weight. Physical recovery was compared between groups as change of performance (%). RESULTS: Median age was 58 years (Inter Quartile Range (IQR): 44-68), and the main indications for LR were colorectal liver metastases (n = 10; 45%) and hepatocellular carcinoma (n = 6; 27%). The one-month change of performance level was -8% (IQR: -12-1) compared to the preoperative level with no significant difference between open and laparoscopic LR (LLR: -8% (-11 - 1); OLR: -6% (-12 - 4), p = 0.833). Furthermore, 6 months postoperatively, patients in both groups had not reached back their preoperative performance level (LLR: -5.7% (-8.4 - 18.6); OLR -4. 8% (-12.6 - 1.9), p = 0.833). CONCLUSION: In this study, we report an impaired physical recovery after LR that was not fully restored 6 months after surgery. There was no significant difference between open and laparoscopic LR in terms of bicycle stress testing. Limitations of the study include the limited sample size and differences, albeit non-statistically significant, in the baseline characteristics of the two groups. To rule out a possible role of age or underlying indication for liver resection on physical recovery, future randomized controlled trials need to be performed.
Assuntos
Hepatectomia/métodos , Laparoscopia/métodos , Adulto , Idoso , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recuperação de Função FisiológicaRESUMO
INTRODUCTION: Enhanced recovery after surgery (ERAS) for peri-hilar cholangiocarcinoma (pCCA) has not been described in the literature. This study examined patients undergoing pCCA resection within a standard post hepatectomy ERAS pathway to define achievable targets suitable for these patients. METHODS: Patients undergoing pCCA resection at University Hospital Aintree (January 2009-October 2017) were identified. Achievement of key ERAS outcomes was assessed. Patients were stratified on incidence of major complications and pre-operative cardiopulmonary exercise testing. Chi Square and Mann Whitney analyses were undertaken as appropriate. Achievable ERAS targets were derived from patients who did not develop a major complication. RESULTS: 46 patients underwent resection with enhanced recovery. Median age 65 (24 male: 22 female). Key ERAS outcomes in patients who did not experience major complications are described as medians (interquartile range): length of stay 8 days (6-13), duration critical care 2 days (2-4), inotropes 6â¯h (0-24), epidural 3 days (3-4), early mobilization day 1 (1-2), full mobilization day 3 (3-4), urinary catheter removal day 4 (3-5), NGT removal day 1 (1-2) and restoration oral nutrition day 2 (2-4). Patients deemed high risk pre-operatively or those who developed major complications post-operatively required significantly longer critical care (pâ¯=â¯0.008 and pâ¯=â¯0.002 respectively). Other ERAS targets remained achievable in similar timeframes. CONCLUSIONS: ERAS for pCCA is achievable. Applicable ERAS standards are defined which take into account minor complications. High risk patients and those with major complications can be appropriately managed in an ERAS pathway, though there is increased need for critical care support.
Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Deambulação Precoce/métodos , Hepatectomia/métodos , Tumor de Klatskin/mortalidade , Tumor de Klatskin/cirurgia , Idoso , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Hepatectomia/efeitos adversos , Hospitais Universitários , Humanos , Tumor de Klatskin/diagnóstico por imagem , Tumor de Klatskin/patologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Readmissão do Paciente , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/fisiopatologia , Medicina de Precisão/métodos , Prognóstico , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Resultado do Tratamento , Reino UnidoRESUMO
A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P=0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P=0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P=0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.
Assuntos
Fatores de Transcrição Forkhead/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , California/epidemiologia , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Adulto JovemRESUMO
The Hippo pathway is involved in colorectal cancer (CRC) development and progression. The Hippo regulator Rassf1a is also involved in the Ras signaling cascade. In this work, we tested single nucleotide polymorphisms within Hippo components and their association with outcome in CRC patients treated with cetuximab. Two cohorts treated with cetuximab plus chemotherapy were evaluated (198 RAS wild-type (WT) patients treated with first-line FOLFIRI plus Cetuximab within the FIRE-3 trial and 67 Ras WT patients treated either with first-line mFOLFOX6 or SOX plus Cetuximab). In these two populations, Rassf1a rs2236947 was associated with overall survival (OS), as patients with a CC genotype had significantly longer OS compared with those with CA or AA genotypes. This association was stronger in patients with left-side CRC (hazard ratio (HR): 1.79 (1.01-3.14); P=0.044 and HR: 2.83 (1.14-7.03); P=0.025, for Fire 3 and JACCRO cohorts, respectively). Rassf1a rs2236947 is a promising biomarker for patients treated with cetuximab plus chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas Supressoras de Tumor/genética , Idoso , Cetuximab/administração & dosagem , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Colorectal brain metastases (BM) are rare (1-2%) and a late-stage disease manifestation. Molecular mechanisms for BM development are not well understood. We tested whether variants within genes involved in overcoming the blood-brain barrier (BBB) are associated with BM susceptibility and survival in patients with BM. Germline single-nucleotide polymorphisms (SNPs, n=17) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed from germline DNA in patients with resected BM (n=70) or no clinical evidence of BM after at least 24 months from diagnosis (control group, n=45). SNPs were evaluated for association with BM susceptibility and overall survival (OS) from BM diagnosis. ST6GALNAC5 rs17368584 and ITGB3 rs3809865 were significantly associated with BM susceptibility. In multivariable analysis adjusted for patient characteristics, KLF4 rs2236599, ITGAV rs10171481, ST6GALNAC5 rs1883778, CXCR4 rs2680880 and ITGB3 rs5918 were significant for OS. This study shows for the first time that variants within genes involved in breaching the BBB are associated with BM susceptibility and survival. These findings warrant further validation to develop better screening guidelines and to identify novel therapy targets for patients with BM.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/mortalidade , Distribuição de Qui-Quadrado , Neoplasias Colorretais/mortalidade , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Fator 4 Semelhante a Kruppel , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
Estrogen has been shown not only to reduce the incidence of colorectal cancer but also gastric cancer (GC). Polymorphisms in estrogen receptor ß gene, ESR2, correlate with colorectal cancer survival. To better understand the role of ESR2 in GC, genomic DNA extracted from 169 Japanese patients and 172 patients from Los Angeles County (LAC) was analyzed for association of overall survival (OS) with three ESR2 polymorphisms, which are of biological significance using multivariable Cox proportional hazard regression. ESR2 rs1271572 (C>A) and rs3020443 (T>G) had univariate and multivariable associations with OS in the Japanese cohort, whereas the C allele of ESR2 rs2978381 (T>C) predicted favorable OS in the Japanese cohort but worse OS in the LAC cohort. The interaction term of the ESR2 rs2978381 and cohort group reached statistical significance. Our study provides evidence that genetic variations in ESR2 gene are significantly associated with survival in patients with locally advanced GC.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Receptor beta de Estrogênio/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Japão , Estimativa de Kaplan-Meier , Los Angeles , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Fenótipo , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Fatores de Tempo , Resultado do TratamentoRESUMO
We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab- and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P=0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Polimorfismo de Nucleotídeo Único , Receptores CXCR4/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Valor Preditivo dos TestesRESUMO
Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.
Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Imunomodulação/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Adenocarcinoma/terapia , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Intervalo Livre de Doença , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/genética , Neoplasias Gástricas/terapiaRESUMO
PURPOSE: Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM. METHODS: Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival. RESULTS: 40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64-175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively. CONCLUSIONS: Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy. Registered at clinicaltrials.gov (NCT00844233).
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/análogos & derivados , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/terapia , Metastasectomia , Terapia Neoadjuvante , Camptotecina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/secundário , Masculino , Microesferas , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil (5-Fu). In this study, 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56 vs 33%, hazard ratio (HR): 1.87; P=0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28 vs 40%; HR: 0.66; P=0.07). In left-sided tumors, this association was stronger (HR: 0.29; P=0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stages II and III colon cancer.The Pharmacogenomics Journal advance online publication, 15 September 2015; doi:10.1038/tpj.2015.64.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Recidiva Local de Neoplasia , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Aciltransferases , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , California , Quimioterapia Adjuvante , Colectomia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Feminino , Fluoruracila/uso terapêutico , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Tóquio , Resultado do TratamentoRESUMO
BACKGROUND: Tumor-associated macrophages (TAMs) with the M2-like phenotype are regulated by mainly NF-kB pathway including TBK1, which can influence tumor progression by secretion of proangiogenic factors such as vascular endothelial growth factor. The CCL2/CCR2 axis, histidine-rich glycoprotein (HRG), and placenta growth factor (PIGF) play a critical role in the polarization of M1/M2 phenotypes and the recruitment of TAMs to tumor microenvironment. We therefore hypothesized that variations in genes involved in regulating TAMs may predict clinical outcomes of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We analyzed genomic DNA extracted from samples of patients receiving bevacizumab plus FOLFIRI as a first-line treatment using PCR-based direct sequencing. Twelve functional single-nucleotide polymorphisms in eight genes (CCL2, CCR2, HRG, PIGF, NFKB1, TBK1, CCL18, and IRF3) were tested for associations with clinical outcomes in a discovery cohort of 228 participants in TRIBE trial (NCT00719797), then validated in 248 KRAS exon2 (KRAS) wild-type participants in FIRE3 trial (NCT00433927). FIRE3-cetuximab cohort served as a negative control. RESULTS: TBK1 rs7486100 was significantly associated with overall survival in 95 KRAS wild-type patients of TRIBE cohort in univariate analysis and had a strong trend in multivariable analysis; furthermore, the association of the T allele was observed for progression-free survival (PFS) in both univariate and multivariable analyses in FIRE3-bevacizumab but not cetuximab cohort. CCL2 rs4586, CCL18 rs14304, and IRF3 rs2304205 had univariate and multivariable correlations with PFS in KRAS mutant patients of the TRIBE cohort, whereas they had no correlations in KRAS wild-type patients of the TRIBE cohort. No association was seen in control cohort. CONCLUSIONS: Our study demonstrates for the first time that variations in genes regulating TAMs-related functions are significantly associated with clinical outcomes in mCRC patients treated with bevacizumab-containing chemotherapy. These results also suggest that some TAM-related gene variations may predict outcomes of bevacizumab treatment in KRAS status-dependent manner.
Assuntos
Bevacizumab/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Variação Genética/genética , Macrófagos/fisiologia , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Feminino , Variação Genética/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy. PATIENTS AND METHODS: Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns. RESULTS: NME1 rs34214448 C>A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T>C and CD44 rs8193 C>T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C>T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C>G, NME1 rs34214448 C>A and NOTCH3 rs1044009 T>C were the dominant SNPs predicting histological response, RFS and OS, respectively. CONCLUSION: Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.
Assuntos
Carcinoma/genética , Neoplasias Colorretais/genética , Neoplasias Hepáticas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio , Carcinoma/secundário , Carcinoma/cirurgia , Neoplasias Colorretais/patologia , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Receptores de Hialuronatos/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Metastasectomia , Pessoa de Meia-Idade , Nucleosídeo NM23 Difosfato Quinases/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor Notch3 , Receptores Notch/genéticaRESUMO
AIM: We investigated whether the type of antibody [bevacizumab (bev) or cetuximab (cet)] added to neoadjuvant combination chemotherapy before curative liver resection was associated with histological response, the pattern of tumor destruction and clinical outcome in patients with colorectal liver metastases (CLM). METHODS: We investigated 138 patients with KRAS wild-type status (codon 12, 13 and 61) who received neoadjuvant chemotherapy including bev (n = 101) or cet (n = 37). The primary endpoint was histological response. Secondary endpoints were necrosis and fibrosis of metastases, radiological response, recurrence-free survival (RFS) and overall survival (OS). RESULTS: Histological response was not significantly different between the two groups (P = 0.19). A significantly higher fraction of patients in the bev group showed necrosis of the metastases of ≥ 50% (P < 0.001), while a higher fraction of patients in the cet group showed fibrosis of ≥ 40% (P = 0.030). Radiological response was not significantly different (P = 0.17). Median RFS was significantly shorter in the cet group in univariable analysis (HR 1.59 (95% CI 1.00, 2.51), P = 0.049), but this difference did not remain significant in multivariable analysis (P = 0.45). The 3-year OS rate was not significantly different (P = 0.73). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy showed more necrosis but less fibrosis of metastases compared to cetuximab and a trend towards higher histological and radiological response and longer RFS. Further investigations of biological tumor characteristics are required to individualize treatment combinations.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/tratamento farmacológico , Fígado/patologia , Terapia Neoadjuvante/métodos , Adulto , Idoso , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Quimioterapia Adjuvante , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Necrose/prevenção & controle , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Proteínas ras/genéticaRESUMO
In patients with colorectal liver metastases (CLM), liver resection offers the possibility of cure and long-term survival. The liver is a highly immunogenic organ harboring ~80% of the body's tissue macrophages. Emerging data demonstrate a critical role of the immune response for cancer treatment. We investigated variations within genes involved in immune response checkpoints and their association with outcomes in patients with CLM who underwent neoadjuvant chemotherapy including bevacizumab and liver resection. Single-nucleotide polymorphisms (SNPs) in nine genes (CCL2, CCR2, LAG3, NT5E, PDCD1, CD274, IDO1, CTLA4 and CD24) were analyzed in genomic DNA from 149 patients with resected bevacizumab-pretreated CLM by direct Sanger DNA sequencing, and correlated with response, recurrence-free survival (RFS), overall survival (OS), probability of cure and recurrence patterns. IDO1 (indoleamine 2, 3-dioxygenase) rs3739319 G>A and CD24 rs8734 G>A showed a significant difference in 3-year OS rates. In addition, IDO1 rs3739319 G>A was significantly associated with extrahepatic recurrence. Recursive partitioning analyses revealed that IDO1 rs3739319 G>A was the dominant SNP predicting RFS and OS. Our data suggest that variants within genes involved in immune response checkpoints are associated with outcomes in patients with resected CLM and might lead to improved treatment strategies modulating anti-tumor immune response by targeting novel immune checkpoints.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Genes MHC da Classe II/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Hepatectomia/métodos , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Nuclear factor-kappaB (NF-κB) and CCL2/CCR2 chemokine axis play a central role in tumor progression such as stimulation of angiogenesis, acceleration of tumor invasion and migration, and suppression of innate immunosurveillance in the macrophage-related functions. There have been few reports regarding association of the macrophage function-related genes with the clinical outcome in gastric cancer. We hypothesized that variants in genes encoding for NF-κB and CCL2/CCR2 axis may predict prognosis in gastric cancer and tested whether the functional single-nucleotide polymorphisms (SNPs) will be associated with clinical outcome in patients with gastric cancer across two independent groups. PATIENTS AND METHODS: This study enrolled two cohorts which consisted of 160 Japanese patients and 104 US patients with locoregional gastric cancer. Genomic DNA was analyzed for association of 11 SNPs in NFKB1, RELA, CCL2, and CCR2 with clinical outcome using PCR-based direct DNA sequencing. RESULTS: The univariable analysis showed four SNPs had significant association with clinical outcome in the Japanese cohort, NFKB1 rs230510 remained significant upon multivariable analysis. The patients with the A allele of the NFKB1 rs230510 had significantly longer overall survival (OS) compared with those with the T/T genotype in both the Japanese and US cohort in the univariable analysis. In contrast, genotypes with the T allele of CCL2 rs4586 were significantly associated with shorter OS compared with the C/C genotype in the US cohort [hazard ratio (HR) 2.43; P = 0.015] but longer OS in the Japanese cohort (HR 0.58; P = 0.021), resulting in the statistically significant opposite impact on OS (P = 0.001). CONCLUSIONS: Our study provides the first evidence that the NFKB1 rs230510 and CCL2 rs4586 are significantly associated with the clinical outcome in patients with locoregional gastric cancer. These results also suggest that the genetic predisposition of the host may dictate the immune-related component of the tumor for progression in gastric cancer.
Assuntos
Quimiocina CCL2/genética , Macrófagos/imunologia , NF-kappa B/genética , Receptores CCR2/genética , Neoplasias Gástricas/genética , Fator de Transcrição RelA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidadeRESUMO
BACKGROUND: The prognostic value of KRAS mutation in patients with colorectal cancer liver metastases (CLM) receiving neoadjuvant chemotherapy including bevacizumab before liver resection is unclear. METHODS: The KRAS and BRAF status of resected CLM was assessed in prospectively studied patients. Mutations were correlated with recurrence-free and overall survival. Only patients with remaining vital tumour cells in the resected specimen and those without disease progression were analysed; those with progressive disease did not undergo resection. RESULTS: A total of 60 patients were enrolled. Fifteen (25 per cent) had a KRAS mutation, but none of the 60 patients had a BRAF mutation. The radiological response to neoadjuvant chemotherapy including bevacizumab, assessed according to the Response Evaluation Criteria In Solid Tumours, was partial in 52 patients (87 per cent) and the remaining eight had stable disease. The partial response rate was similar in patients with a KRAS mutation and those with the wild-type gene (12 of 15 versus 40 of 45 patients; P = 0·400). KRAS mutation had a negative prognostic effect on recurrence-free survival (hazard ratio (HR) 2·48, 95 per cent confidence interval 1·26 to 4·89; P = 0·009) and overall survival (HR 3·51, 1·30 to 9·45; P = 0·013). CONCLUSION: This study provided further evidence for the prognostic importance of KRAS status in terms of recurrence-free and overall survival. Neoadjuvant chemotherapy including bevacizumab elicited a response, irrespective of KRAS status, in this selected group of patients with CLM.
Assuntos
Neoplasias Colorretais/genética , Genes ras/genética , Neoplasias Hepáticas/secundário , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Quimioterapia Adjuvante , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estudos ProspectivosRESUMO
AIM: Endorectal advancement flaps are an established treatment for high transsphincteric and suprasphincteric fistulae. The outcome of a repeat procedure in the case of flap breakdown and fistula recurrence remains unclear. The aim of the study was to analyse the outcome of repeat endorectal advancement flaps. METHODS: We retrospectively analysed patients with a repeat endorectal advancement flap procedure after flap breakdown and recurrence of fistula-in-ano of cryptoglandular origin who had been treated in our unit between 1994 and 2010. RESULTS: In all, 97 patients underwent an endorectal advancement flap procedure for fistula-in-ano and, of these, nine patients (five men, four women, 9.3%) subsequently underwent a repeat procedure due to flap breakdown. Median age was 40 years (range 25-60). Median follow-up time was 85 months (range 26-136). Seven full-thickness and two mucosal flap repeat procedures were performed because of eight transsphincteric and one suprasphincteric fistulae. The repeat procedure was successful in seven (78%) patients. In one of the two patients with repeat flap failure, a third flap procedure failed again. Disturbances of postoperative faecal incontinence were observed in five (55%) patients. Overall, the median postoperative Vaizey faecal incontinence score was 1 (range 0-4). CONCLUSION: Repeat endorectal advancement flap procedures are feasible and associated with a low recurrence rate and mild postoperative faecal incontinence. Therefore, a repeat procedure is a viable option in the case of a flap breakdown and fistula recurrence.
Assuntos
Incontinência Fecal/cirurgia , Fístula Retal/cirurgia , Reto/cirurgia , Retalhos Cirúrgicos , Adulto , Áustria , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Incontinência Fecal/etiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Fístula Retal/complicações , Recidiva , Estudos Retrospectivos , Falha de TratamentoRESUMO
BACKGROUND: Portal hypertension associated with liver cirrhosis increases the risk of postoperative complications after liver resection for hepatocellular carcinoma (HCC). This study assessed the role of preoperative hepatic venous pressure gradient (HVPG) assessment in identifying portal hypertension. METHODS: All patients who underwent liver resection for HCC between January 2000 and December 2009 at the Department of General Surgery, Medical University Vienna, were analysed retrospectively. HVPG was assessed prospectively in a subset of patients before liver resection. The influence of this assessment on postoperative complications was investigated. RESULTS: A total of 132 patients were enrolled, of whom 39 underwent HVPG measurement. Mean(s.d.) HVPG was 6·4(3·0) and 4·3(1·4) mmHg in patients with and without postoperative complications respectively (P = 0·028). Complication rates differed significantly at a cut-off HVPG value of 5 mmHg: 11 of 21 patients with a gradient of 1-5 mmHg developed complications versus 12 of 14 patients with a higher value (P = 0·045). HVPG exceeding 5 mmHg was associated with worse liver fibrosis (P = 0·004), higher rates of postoperative liver dysfunction (5 of 13 versus 1 of 18; P = 0·022) and ascites (7 of 14 versus 3 of 21; P = 0·022), and a longer hospital stay (median (range) 11 (7-26) versus 8 (4-20) days; P = 0·034). Overall postoperative morbidity did not differ between patients who had preoperative HVPG assessment and those who did not (P = 0·142). CONCLUSION: Preoperative HVPG assessment predicted liver fibrosis and postoperative complications.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hipertensão Portal/diagnóstico , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/etiologia , Idoso , Determinação da Pressão Arterial/métodos , Carcinoma Hepatocelular/fisiopatologia , Feminino , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Reoperação , Estudos Retrospectivos , Fatores de Risco , Pressão Venosa/fisiologiaRESUMO
AIM: The study investigated the fate of patients with perianal sepsis of cryptoglandular origin. METHOD: All patients treated for perianal sepsis between January 1994 and December 2000 were retrospectively analysed regarding recurrence and faecal incontinence. Data collection was conducted by chart review and by telephone questionnaire using the Vaizey incontinence score. RESULTS: One hundred seventy-three (58%) of 300 patients were available for follow-up at a median period of 121 (77-171) months. Fistula-in-ano was diagnosed in 156 (90%) patients. After a single surgical procedure, 55 (32%) patients had no recurrence of perianal sepsis. In 118 (68%), recurrence required multiple procedures (median 3, range 2-19). If only a single incision and drainage was performed (n = 10, 6%), no faecal incontinence occurred. Drainage with fistulotomy (n = 45, 26%) induced mild incontinence in 9% and severe incontinence in 4%. After multiple procedures that were required in 118 (68%) patients, mild and severe faecal incontinence was found in 16% and 4% of them, respectively. CONCLUSION: Treatment of anal sepsis is associated with a high recurrence rate and a substantial risk of faecal incontinence.