RESUMO
BACKGROUND: Ramucirumab is indicated for salvage treatment after failure of first-line treatment for metastatic colorectal cancer (mCRC). However, the application of ramucirumab at later-line treatment in real-world practice has not received much discussion. METHODS: In this retrospective study, we enrolled 70 patients with mCRC who received ramucirumab plus chemotherapy at National Taiwan University Hospital between 2018 and 2019. RESULTS: Compared with those who received third- or later-line ramucirumab treatment, patients who received second-line ramucirumab treatment had significantly longer median time to treatment discontinuation (mTTD; 6.7 vs 3.6 months, P = .004) and median overall survival (mOS; not reached vs 7.6 months, P = .009). Multivariate analyses revealed that second-line ramucirumab and triplet chemotherapy backbone were the only independent predictive factors for long mTTD and mOS. Patients who received ramucirumab with triplet chemotherapy had a significantly longer mOS than did patients who received ramucirumab with doublet chemotherapy (not reached vs 5.6 months, P = .002). Among those receiving second-line ramucirumab treatment, combination with triplet chemotherapy led to a longer mTTD than did combination with doublet chemotherapy, but the difference was non-significant (not reached vs 4.4 months, P = .108). By contrast, in patients receiving fourth- or later-line ramucirumab, combination with triplet chemotherapy led to significantly longer mTTD than did combination with doublet chemotherapy (8.0 vs 2.9 months, P = .032). CONCLUSION: Ramucirumab plus triplet chemotherapy may be an alternative regimen in patients with mCRC, particularly as a later-line treatment modality.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais/etiologia , Fluoruracila , Humanos , Estudos Retrospectivos , Terapia de Salvação , RamucirumabRESUMO
BACKGROUND: The aim of this study was to determine if robotic surgery can reproduce the technical advantages and oncologic outcomes of laparoscopic surgery for the treatment of locally advanced colorectal cancer invading the urinary bladder. METHODS: We retrospectively reviewed the prospectively maintained data of patients with locally advanced colorectal cancer invading the urinary bladder undergoing robotic or laparoscopic surgery between June 2006 and November 2020. Clinicopathologic features, surgical outcomes, and oncologic efficacy were compared between patient groups of robotic or laparoscopic surgery. All patients underwent surgery with the intent of R0 resection for the primary tumor. Major surgical complications were defined as Clavien-Dindo grade ≥ III. Multivariate regression analysis was performed to identify risk factors. RESULTS: A total of 41 patients (M:F = 32:9; median age: 63 [42-88] years) were analysed; 32 underwent laparoscopic surgery and 9 underwent robotic surgery. There was no statistically significant difference between the two groups in baseline demographic and clinicopathologic features. There were no significant differences in terms of mean operative time (353.24 vs. 387.33 min), mean blood loss (315.00 vs. 171.11 mL), mean number of lymph nodes harvested (27.16 vs. 23.50), R0 resection (89.7 vs. 66.7%), conversion (12.5 vs. 11.1%), major complication rate (9.4 vs. 22.2%), mean time to flatus passage (4.8 vs. 4.1 days), mean postoperative length of hospital stay (18.9 vs. 19.8 days), 5-year disease-free survival rate (64.6 vs. 62.5%) and overall survival rate (75.3 vs. 83.3%). Multivariate analysis showed that R1 resection was the only independent prognostic factor for reduced disease-free survival (hazard ratio 21.386; 95% confidence interval 1.991-229.723; p = 0.0115). CONCLUSIONS: Robotic surgery can reproduce the technical advantages and oncologic outcomes of laparoscopic surgery for the treatment of locally advanced colorectal cancer invading the urinary bladder. However, larger studies are mandatory to clarify the role of robotic surgery in such a scenario.
Assuntos
Neoplasias Colorretais , Laparoscopia , Procedimentos Cirúrgicos Robóticos , Bexiga Urinária , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Estudos de Viabilidade , Humanos , Laparoscopia/efeitos adversos , Tempo de Internação , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Resultado do Tratamento , Bexiga Urinária/patologia , Bexiga Urinária/cirurgiaRESUMO
PURPOSE: Current guidelines suggest that adjuvant chemotherapy (AC) be administered to all locally advanced (clinically T3-4 or N-positivity) rectal cancer patients undergoing neoadjuvant chemoradiotherapy (nCRT) and radical surgical resection regardless of the final pathological staging (yp staging). This study aimed to evaluate the necessity of AC for ypT0-2N0 rectal cancer. METHODS: Patients with ypT0-2N0 rectal cancer, who received nCRT and radical surgical resection, were recruited retrospectively at a university hospital. The main outcome was to evaluate the 5-year overall survival (OS) and disease-free survival (DFS) between ypT0-2N0 rectal cancer patients with AC and those without AC. We also identified potential independent prognostic factors associated with poor outcomes. RESULTS: One hundred and ten ypT0-2N0 rectal cancer patients (ypT0: n = 6; ypT1: n = 44; ypT2: n = 60) were followed up for a median of 60 months. No significant difference was observed in DFS and 5-year OS between patients with AC and those without AC. The risk of recurrence was associated with the postoperative pathological staging (0% with ypT0, 2.4% with ypT1, and 10% with ypT2). In the multivariate analysis, retrieval of < 12 lymph nodes was an independent favorable prognostic factor, which correlated with a higher OS (HR: 2.263; 95% CI: 1.093-4.687, P = 0.028). Intra-tumor lymphovascular and perineural invasion were poor prognostic markers for shorter DFS (HR: 5.940; 95% CI: 1.150-30.696, P = 0.033). CONCLUSION: Postoperative AC is not required for patients with ypT0-2N0 rectal cancer downstaged by nCRT, especially in those without poor prognostic factors.
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Terapia Neoadjuvante , Neoplasias Retais , Quimiorradioterapia , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Intervalo Livre de Doença , Humanos , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Retais/patologia , Estudos RetrospectivosRESUMO
Metastasis often occurs in colorectal cancer (CRC) patients and is the main difficulty in cancer treatment. The upregulation of poly-N-acetyllactosamine-related glycosylation is found in CRC patients and is associated with progression and metastasis in cancer. ß-1,4-Galactosyltransferase III (B4GALT3) is an enzyme responsible for poly-N-acetyllactosamine synthesis, and therefore, we investigated its expression in CRC patients. We found that B4GALT3 negatively correlated with poorly differentiated histology (P < 0.001), advanced stages (P = 0.0052), regional lymph node metastasis (P = 0.0018) and distant metastasis (P = 0.0463) in CRC patients. B4GALT3 overexpression in CRC cells suppressed cell migration, invasion and adhesion, whereas B4GALT3 knockdown enhanced malignant cell phenotypes. The ß1 integrin-blocking antibody reversed the B4GALT3-mediated increase in cell invasion. B4GALT3 expression altered glycosylation on the N-glycan of ß1 integrin probably through changes in poly-N-acetyllactosamine expression. Furthermore, more activated ß1 integrin along with the activation of its downstream signaling transduction were found in B4GALT3 knockdown cells, whereas overexpression of B4GALT3 suppressed the expression of active ß1 integrin and inhibited its downstream signaling. Our results suggest that B4GALT3 is negatively associated with CRC metastasis and suppresses cell invasiveness through inhibiting activation of ß1 integrin.
Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Galactosiltransferases/metabolismo , Integrina beta1/metabolismo , Fenótipo , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Neoplasias Colorretais/genética , Matriz Extracelular/metabolismo , Feminino , Galactosiltransferases/genética , Expressão Gênica , Glicosilação , Humanos , Imuno-Histoquímica , Integrina beta1/genética , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Transdução de SinaisRESUMO
Expression of T antigen (Galbeta1, 3GalNAc) is associated with enhanced metastatic potential and poor prognosis in colorectal cancer. Cosmc is a molecular chaperone required for the formation of an active T-synthase, which catalyzes the synthesis of T antigen. However, the expression and role of Cosmc in colorectal cancer are still unclear. Here, real-time PCR showed that overexpression of Cosmc mRNA in colorectal tumors compared with paired non-tumorous tissues was associated with increased American Joint Committee on Cancer (AJCC) tumor stage. Forced expression of Cosmc in HCT116 cells significantly increased T antigen expression and enhanced cell growth, migration, and invasion, which was associated with increased phosphorylation of focal adhesion kinase (FAK), ERK, and Akt. These Cosmc-enhanced malignant phenotypes were significantly suppressed by specific inhibitor of MEK or PI3K. We also found that Cosmc overexpression increased tumor growth and decreased survival of tumor-bearing SCID mice. Conversely, knockdown of Cosmc with siRNA in SW480 cells decreased malignant behaviors and the signaling pathways, which were substantially reversed by constitutively active Akt or MEK. Taken together, these results suggest that Cosmc promotes malignant phenotypes of colon cancer cells mainly via activation of MEK/ERK and PI3K/Akt signaling pathways, and that Cosmc may serve as a potential target for colorectal cancer treatment.
Assuntos
Neoplasias Colorretais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Chaperonas Moleculares/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Western Blotting , Adesão Celular , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Citometria de Fluxo , Quinase 1 de Adesão Focal/metabolismo , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos SCID , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais CultivadasRESUMO
BACKGROUND: The effect of positron emission tomography (PET) on the surgical treatment of locoregionally recurrent colorectal cancer (LRRCRC) remains unclear and warrants further investigation. MATERIAL AND METHODS: A total of 193 patients with LRRCRC were identified from a prospectively maintained institutional database, of whom 134 LRRCRCs were deemed resectable and underwent resection with curative intent, whereas the remaining 59 LRRCRCs were unresectable. Patients with resectable LRRCRC were further classified according to whether recurrence was detected solely by PET (n = 35, PET-only group) or by a combination of computed tomography (CT)/magnetic resonance imaging (MRI) and PET (n = 99, CT/MRI/PET group). Clinicopathologic features, operative morbidity/mortality, and overall survival were compared between the patient groups based on long-term follow-up for at least 5 years. RESULTS: Patients in the PET-only group tended to have less extensive organ resection (p = 0.0074), less blood loss (p < 0.0001), and shorter operation time and hospitalization (p < 0.0001), but surgical complication and readmission rates were not significantly different (p > 0.05) compared with the CT/MRI/PET group. Although the PET-only group had significantly higher R0 resection rate (80 % vs. 54.55 %, p = 0.0079), they also had a higher risk (17.14 % vs. 2.02 %, p = 0.0011) of sham operation. The estimated 5-year and 10-year survival rates significantly decreased in order (p < 0.0001) from PET-only (85.71 % and 57.98 %) and CT/MRI/PET (41.41 % and 15.93 %) to unresectable group of patients (16.95 % and 1.88 %). Subset analysis of the CT/MRI/PET group indicated that PET improved surgical decision-making because 24 (24.2 %) LRRCRCs that manifested on CT/MRI as equivocal lesions were later confirmed by PET as resectable recurrences, while 18 (19.4 %) LRRCRCs that manifested on CT/MRI as resectable lesions were later diagnosed by PET as more disseminated unresectable recurrences and precluded futile surgery. CONCLUSION: PET alone can identify a subset (20.9 %) of LRRCRCs with less tumor burden for timely surgery; PET in combination with CT/MRI can better define the resectability of LRRCRCs. The positive impacts of PET can translate into better surgical outcomes, with enhanced safety and patient survival.
Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Humanos , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Imageamento por Ressonância Magnética , Neoplasias Colorretais/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
INTRODUCTION: This study aimed to investigate whether the incidence, patterns, and surgical outcomes of small bowel obstruction (SBO) have changed in the era of minimally invasive surgery (MIS) for primary colorectal cancer (CRC). METHODS: Consecutive patients who underwent laparotomy for SBO were divided into MIS and traditional open surgery (TOS) groups based on the previous colorectal cancer operation technique used. The MIS group was selected from 1544 consecutive patients who underwent MIS as a treatment for primary CRCs between 2014 and 2022, while the TOS group was selected from 1604 consecutive patients who underwent TOS as a treatment for primary CRCs between 2004 and 2013. The demographics, clinicopathological features, and surgical outcomes were compared between the two groups. RESULTS: The SBO incidence in patients who underwent MIS for primary CRC was significantly lower than that in patients who underwent TOS (4.4%, n =68/1544 vs. 9.7%, n =156/1604, P <0.0001). Compared with the TOS group, the MIS group had significantly different ( P <0.0001) SBO patterns: adhesion (48.5 vs. 91.7%), internal herniation (23.5 vs. 2.6%), external herniation (11.8 vs. 1.9%), twisted bowel limbs (4.4 vs. 0.6%), ileal volvulus with pelvic floor adhesion (5.9 vs. 1.9%), and nonspecific external compression (5.9 vs. 1.3%). A subset analysis of patients with adhesive SBO (ASBO) showed that the MIS group tended to ( P <0.0001) have bands or simple adhesions (75.8%), whereas the TOS group predominantly had matted-type adhesions (59.4%). Furthermore, SBO in the MIS group had an acute (<3 months) or early (3-12 months) onset (64.7%), while that in the TOS group ( P <0.0001) had an intermediate or a late onset. When the surgical outcomes of SBO were evaluated, the TOS group had significantly more ( P <0.0001) blood loss and longer operation time; however, no significant difference was observed in the surgical morbidity/mortality (Clavien-Dindo classification â§3, 11.8 vs. 14.1%, P =0.6367), hospitalization, and readmission rates between the two groups. Postoperative follow-up showed that the estimated 3-year (11.37 vs. 18.8%) and 6-year (25.54 vs. 67.4%) recurrence rates of SBO were significantly lower ( P =0.016) in the MIS group than in the TOS group. CONCLUSIONS: The wide adoption of MIS to treat primary CRC has led to a lower incidence, altered patterns, and reduced recurrence rates of SBO. Awareness of this new trend will help develop surgical techniques to prevent incomplete restoration of anatomical defects and bowel malalignments specifically associated with MIS for CRC, as well as facilitate timely and appropriate management of SBO complications whenever they occur.
Assuntos
Neoplasias Colorretais , Obstrução Intestinal , Humanos , Estudos Retrospectivos , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Obstrução Intestinal/epidemiologia , Aderências Teciduais/cirurgia , Aderências Teciduais/complicações , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Resultado do Tratamento , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: The territory of D3-D4 lymphadenectomy for upper rectal and sigmoid colon cancer varies, and its oncological efficacy is unclear. This prospective study aimed to standardize the surgical technique of robotic D3-D4 lymphadenectomy and clarify its oncologic significance. METHODS: Patients with upper rectal or sigmoid colon cancer with clinically suspected more than N2 lymph node metastasis were prospectively recruited to undergo standardized robotic D3-D4 lymphadenectomy. Immediately postsurgery, the retrieved lymph nodes were mapped to five N3-N4 nodal stations: the inferior mesenteric artery, para-aorta, inferior vena cava, infra-renal vein, and common iliac vessels. Patients were stratified according to their nodal metastasis status to compare their clinicopathological data and overall survival. Univariate and multivariate analyses were performed to determine the relative prognostic significance of the five specific nodal stations. Surgical outcomes and functional recovery of the patients were assessed using the appropriate variables. RESULTS: A total of 104 patients who successfully completed the treatment protocol were assessed. The standardized D3-D4 lymph node dissection harvested sufficient lymph nodes (34.4±7.2) for a precise pathologic staging. Based on histopathological analysis, 28 patients were included in the N3-N4 nodal metastasis-negative group and 33, 34, and nine patients in the single-station, double-station, and triple-station nodal metastasis-positive groups, respectively. Survival analysis indicated no significant difference between the single-station nodal metastasis-positive and N3-N4 nodal metastasis-negative groups in the estimated 5-year survival rate [53.6% (95% CI: 0.3353-0.7000) vs. 71.18% (95% CI: 0.4863-0.8518), P=0.563], whereas patients with double-station or triple-station nodal metastatic disease had poor 5-year survival rates (24.76 and 22.22%), which were comparable to those of AJCC/UICC stage IV disease than those with single-station metastasis-positive disease. Univariate analysis showed that the metastatic status of the five nodal stations was comparable in predicting the overall survival; in contrast, multivariate analysis indicated that common iliac vessels and infra-renal vein were the only two statistically significant predictors (P<0.05) for overall survival. CONCLUSIONS: Using a robotic approach, D3-D4 lymph node dissection could be safely performed in a standardized manner to remove the relevant N3-N4 lymphatic basin en bloc, thereby providing significant survival benefits and precise pathological staging for patients. This study encourages further international prospective clinical trials to provide more solid evidence that would facilitate the optimization of surgery and revision of the current treatment guidelines for such a clinical conundrum.
Assuntos
Excisão de Linfonodo , Metástase Linfática , Procedimentos Cirúrgicos Robóticos , Neoplasias do Colo Sigmoide , Humanos , Excisão de Linfonodo/normas , Excisão de Linfonodo/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Robóticos/normas , Procedimentos Cirúrgicos Robóticos/métodos , Idoso , Estudos Prospectivos , Neoplasias do Colo Sigmoide/cirurgia , Neoplasias do Colo Sigmoide/patologia , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , Linfonodos/patologia , Linfonodos/cirurgia , AdultoRESUMO
OBJECTIVE: Mucins play a critical role in the malignancy of various tumors and have been identified as diagnostic markers and as attractive therapeutic targets. However, the role of mucin (MUC) 20 in endometrial cancer (EC) is still unknown. METHODS: The relationship between MUC20 expression and clinical characteristics of EC was analyzed in 97 EC tumors and 16 normal tissues by immunohistochemistry. Effects of MUC20 on EC cells, HEC-1A and RL95-2, were examined by in vitro cell growth, migration, and invasion assays, as well as in vivo tumor growth in SCID mouse model. Western blotting was performed to analyze signaling pathways modulated by MUC20. RESULTS: MUC20 expression was significantly higher in EC tumors compared with the normal tissue. High levels of MUC20 expression in EC tumors were correlated with an unfavorable histologic subtype. Furthermore, MUC20 was an independent prognostic factor for poor survival as evaluated by multivariate analyses. Overexpression of MUC20 in EC cells significantly enhanced cell growth, migration, and invasion, as well as tumor growth in vivo. The MUC20-enhanced invasive behavior was significantly blocked by erlotinib, an EGFR inhibitor. Moreover, MUC20 overexpression enhanced EGF-mediated migration and invasion, suggesting a critical role of EGFR in MUC20-mediated effects. We found that MUC20 overexpression could enhance EGF-induced phosphorylation of EGFR and STAT3. Inhibition of the STAT3 activity by its inhibitor Stattic significantly suppressed the MUC20-enhanced invasive behavior. CONCLUSIONS: MUC20 is novel prognostic factor for EC and its overexpression enhances EGF-triggered invasive behavior through activation of EGFR-STAT3 pathway.
Assuntos
Neoplasias do Endométrio/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Mucinas/biossíntese , Fator de Transcrição STAT3/metabolismo , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Fator de Crescimento Epidérmico/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Mucinas/genética , Mucinas/metabolismo , Estadiamento de Neoplasias , Fenótipo , Fosforilação , Prognóstico , Fator de Transcrição STAT3/genética , Transdução de Sinais , TransfecçãoRESUMO
Crohn's disease (CD) is a chronic inflammatory disease mainly affecting the gastrointestinal tract. With the increased availability of modalities in the last two decades, the treatment of CD has advanced remarkably. Although medical treatment is the mainstay of therapy, most patients require surgery during the course of their illness, especially those who experience complications. Nutritional optimization and ERAS implementation are crucial for patients with CD who require surgical intervention to reduce postoperative complications. The increased surgical risk was found to be associated with the use of corticosteroids, but the association of surgical risk with immunomodulators, biologic therapy, such as anti-TNF mediations, anti-integrin medications, and anti-IL 12/23 was low in certainty. Decisions about preoperative medication must be made on an individual case-dependent basis. Preoperative imaging studies can assist in the planning of appropriate surgical strategies and approaches. However, patients must be informed of any alterations to their treatment. In summary, the management of perioperative medications and surgery-related decision-making should be individualized and patient-centered based on a multidisciplinary approach.
RESUMO
GalNAc-type O-glycosylation and its initiating GalNAc transferases (GALNTs) play crucial roles in a wide range of cellular behaviors. Among 20 GALNT members, GALNT2 is consistently associated with poor survival of patients with colorectal cancer in public databases. However, its clinicopathological significance in colorectal cancer remains unclear. In this study, immunohistochemistry showed that GALNT2 was overexpressed in colorectal tumors compared with the adjacent nontumor tissues. GALNT2 overexpression was associated with poor survival of colorectal cancer patients. Forced expression of GALNT2 promoted migration and invasion as well as peritoneal metastasis of colorectal cancer cells. In contrast, GALNT2 knockdown with siRNAs or knockout with CRISPR/Cas9 system suppressed these malignant properties. Interestingly, we found that GALNT2 modified O-glycans on AXL and determined AXL levels via the proteasome-dependent pathway. In addition, the GALNT2-promoted invasiveness was significantly reversed by AXL siRNAs. These findings suggest that GALNT2 promotes colorectal cancer invasion at least partly through AXL.
Assuntos
Neoplasias Colorretais , N-Acetilgalactosaminiltransferases , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Glicosilação , Invasividade Neoplásica , N-Acetilgalactosaminiltransferases/genética , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
The outcome of radiofrequency ablation (RFA) for liver metastases from colorectal cancer (CRLM) has been thought to be inferior to metastasectomy. However, the recent development of multielectrode RFA (multi-RFA) systems has made the ablation zone larger and more complete. Thus, we assessed the survival benefits of this modality in cases of metachronous CRLM. This retrospective study assessed patients diagnosed with resectable metachronous CRLM between 2013 and 2016; 132 patients were categorized by treatment for liver metastases: multi-RFA (n = 68), hepatectomy (n = 34), or systemic treatment only (n = 30). Therapeutic effectiveness, outcomes, and intervention-related complications were compared between groups. Median overall survival (OS), recurrence-free survival (RFS), and intrahepatic recurrence-free survival (IHRFS) were 69.8, 85.2, and 59.7 months for the hepatectomy group; 53.4, 41.3, and 32.3 months for the multi-RFA group; and 19.1, 7.1, and 7.1 months for the systemic treatment group. No significant differences were observed between the multi-RFA and hepatectomy groups after a median follow-up of 59.8 months. This study demonstrated that multi-RFA and hepatectomy provide similar survival benefits for patients with resectable CRLM. Multi-RFA may represent a reliable treatment option for the management of resectable liver metastases.
RESUMO
C1GALT1 controls the crucial step of GalNAc-type O-glycosylation and is associated with both physiologic and pathologic conditions, including cancers. EPH receptors comprise the largest family of receptor tyrosine kinases (RTKs) and modulate a diverse range of developmental processes and human diseases. However, the role of C1GALT1 in the signaling of EPH receptors remains largely overlooked. Here, we showed that C1GALT1 high expression in gastric adenocarcinomas correlated with adverse clinicopathologic features and is an independent prognostic factor for poor overall survival. Silencing or loss of C1GALT1 inhibited cell viability, migration, invasion, tumor growth and metastasis, as well as increased apoptosis and cytotoxicity of 5-fluorouracil in AGS and MKN45 cells. Phospho-RTK array and western blot analysis showed that C1GALT1 depletion suppressed tyrosine phosphorylation of EPHA2 induced by soluble Ephrin A1-Fc. O-glycans on EPHA2 were modified by C1GALT1 and both S277A and T429A mutants, which are O-glycosites on EPHA2, dramatically enhanced phosphorylation of Y588, suggesting that not only overall O-glycan structures but also site-specific O-glycosylation can regulate EPHA2 activity. Furthermore, depletion of C1GALT1 decreased Ephrin A1-Fc induced migration and reduced Ephrin A1 binding to cell surfaces. The effects of C1GALT1 knockdown or knockout on cell invasiveness in vitro and in vivo were phenocopied by EPHA2 knockdown in gastric cancer cells. These results suggest that C1GALT1 promotes phosphorylation of EPHA2 and enhances soluble Ephrin A1-mediated migration primarily by modifying EPHA2 O-glycosylation. Our study highlights the importance of GalNAc-type O-glycosylation in EPH receptor-regulated diseases and identifies C1GALT1 as a potential therapeutic target for gastric cancer.
Assuntos
Adenocarcinoma/patologia , Efrina-A1/metabolismo , Efrina-A2/metabolismo , Galactosiltransferases/metabolismo , Neoplasias Gástricas/patologia , Acetilgalactosamina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Galactosiltransferases/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Glicosilação , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Estadiamento de Neoplasias , Fosforilação , Receptor EphA2 , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To clarify the anatomic concept of Toldt fascia, based on the literature review and the surgical anatomic dissection using laparoscopic or robotic approach. We undertook review of the historic literature and surgical videos from 250 patients with colorectal cancer operated on laparoscopically or robotically to discuss the surgical implications of Toldt fascia in complete mesocolic excision for colon cancer. Toldt fascia, sandwiched by the overlying mesothelial layer of the mesocolon and underlying mesothelial layer of the retroperitoneum, comprised loose fibrous tissues with minute vessels inside, and was contiguous from the ileocecal mesentery radix to the upper rectum. Surgical dissection plane is readily developed within the Toldt fascia; however, any attempt to dissect along the interface between Toldt fascia and the overlying mesocolon or underlying retroperitoneum failed. Within the anatomic territory of kidney, Toldt fascia fused with Gerota fascia, and then extended in all directions: upward to the dosal surface of the duodenum, liver and pancreas; medially to fuse with the adventitia layer of the abdominal aorta; laterally, it tapered at the area below the reflection of visceral and parietal peritoneum; and downward, it became a thin membranous structure covering the gonadal vessels, ureters and retroperitoneal structures and ended at the upper rectum, where it met the junction of endopelvic fascia and proper fascia of the rectum. The present study demonstrated that Toldt fascia is a natural embryonic dissection plane for the precise conduction of complete mesocolic excision for colon cancer.
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Neoplasias do Colo/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Fáscia/anatomia & histologia , Mesocolo/cirurgia , Humanos , Laparoscopia , Procedimentos Cirúrgicos RobóticosRESUMO
BACKGROUND: Appropriate management of cystic lesions of the pancreas is controversial. Major pancreatectomies (pancreaticoduodenectomy or distal pancreatectomy with splenectomy) are the commonly used procedures, even though most cystic lesions are noninvasive neoplasms. We tested the adequacy of limited pancreatectomies in the treatment of pancreatic cystic lesions. METHODS: Data from 109 patients who underwent surgical resection of a pancreatic cystic lesion at National Taiwan University Hospital from 2001 to 2007 were retrospectively reviewed. Major pancreatomies (n = 79) constituted pancreaticoduodenectomy and total/distal pancreatectomies, while other resection procedures (n = 30) represented limited pancreatectomies. Clinicopathologic features were compared between the major and limited groups. RESULTS: There were no statistically significant differences in sex, age, presence of symptoms, cyst diameter, minor or major treatment complications, or pancreatic leakage between the two groups. Cystic lesions located in the neck/body/tail rather than in the head/uncinate process were significantly more often treated with limited pancreatectomy (P = .02). Both groups had similar pathologic distribution of cystic lesions, with the exception of nine invasive neoplasms. The latter were treated with major pancreatectomy. No recurrence was noted in 100 patients with noninvasive cystic neoplasms after major or limited pancreatectomy. CONCLUSIONS: Noninvasive pancreatic cystic neoplasms can be safely and effectively treated by limited pancreatectomy.
Assuntos
Cistadenocarcinoma Seroso/cirurgia , Cistadenoma Seroso/cirurgia , Pancreatectomia , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Adulto , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Cistadenocarcinoma Mucinoso/patologia , Cistadenocarcinoma Mucinoso/cirurgia , Cistadenocarcinoma Seroso/patologia , Cistadenoma Seroso/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Cisto Pancreático/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos RetrospectivosRESUMO
The prognostic implication of BRAF mutant colorectal cancer remains paradoxical. Records of BRAF mutant and wild-type colorectal cancer patients at all stages were reviewed. Clinicopathologic features, including microsatellite instability, CpG islands methylator phenotype, and overall survival, of these patients were analyzed. Between 2005 and 2013, 428 colorectal cancer patients were enrolled in this study. The overall survival between BRAF mutant and wild-type patients with early-stage (stages I and II) colorectal cancer differed nonsignificantly (P = 0.99). By contrast, in late-stage (stages III and IV) patients, the median overall survival of BRAF mutant patients (N = 25) was significantly poorer than that of BRAF wild-type (N = 207) patients (BRAF mutant: 21.3 months (95% confidence interval [CI] 7.1-35.5); BRAF wild-type: 53.5 months (95% CI 37.5-69.5), P < 0.0001). In early-stage patients, we found that BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P < 0.001), and microsatellite instability-high status (P = 0.0013). Conversely, in late-stage patients, BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P = 0.0015) and the right-side colon (P = 0.014). BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Neoplasias Colorretais/mortalidade , Ilhas de CpG , Metilação de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Análise Multivariada , PrognósticoRESUMO
Aberrant glycosylation is frequently observed in cancers. Core 1 ß1,3-galactosyltransferase (C1GALT1) is an exclusive enzyme in humans that catalyzes the biosynthesis of core 1 O-glycan structure, Gal-GalNAc-O-Ser/Thr, whose expression is commonly up-regulated during tumorigenesis. Little is known about the function of C1GALT1 in breast cancer. This study aims to determine the correlation between C1GALT1 expression and breast cancer clinicopathological features and roles of C1GALT1 in breast cancer malignant phenotypes. Public databases and our data showed that C1GALT1 mRNA and C1GALT1 protein are frequently up-regulated in breast cancer; and increased C1GALT1 expression correlates with higher histological grade and advanced tumor stage. Overexpression of C1GALT1 enhanced breast cancer cell growth, migration, and invasion in vitro as well as tumor growth in vivo. Conversely, C1GALT1 knockdown suppressed these malignant phenotypes. Furthermore, C1GALT1 modulates O-glycan structures on Mucin (MUC) 1 and promotes MUC1-C/ß-catenin signaling in breast cancer cells. These findings suggest that C1GALT1 enhances breast cancer malignant progression through promoting MUC1-C/ß-catenin signaling pathway. Unveiling the function of C1GALT1 in breast cancer opens new insights to the roles of C1GALT1 and O-glycosylation in tumorigenesis and renders the potential of C1GALT1 as a target of novel therapeutic agent development.
Assuntos
Neoplasias da Mama/metabolismo , Galactosiltransferases/metabolismo , Mucina-1/metabolismo , beta Catenina/metabolismo , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Galactosiltransferases/genética , Xenoenxertos , Humanos , Camundongos , Camundongos SCID , Mucina-1/genética , Transdução de Sinais , Transfecção , Regulação para CimaRESUMO
O-glycosylation is a common protein modification. Aberrant O-glycosylation is associated with many cancers. GALNT1 is a GalNAc-transferase that initiates protein O-glycosylation. We found that GALNT1 is frequently up-regulated in hepatocellular carcinoma (HCC) and is associated with poor patient survival. Overexpression of GALNT1 increased and knockdown decreased HCC cell migration and invasion. Knockdown of GALNT1 inhibited EGF-induced migration and invasion. Knockdown of GALNT1 decreased EGFR activation and increased EGFR degradation, by decreasing EGFR O-glycosylation. This study demonstrates that down-regulation of GALNT1 is sufficient to suppress malignant phenotype of HCC cells by decreasing EGFR signaling. Thus, GALNT1 is a potential target in HCC.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Receptores ErbB/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , N-Acetilgalactosaminiltransferases/deficiência , N-Acetilgalactosaminiltransferases/genética , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação para Baixo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Técnicas de Silenciamento de Genes , Glicosilação , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , N-Acetilgalactosaminiltransferases/metabolismo , Fenótipo , Transdução de Sinais , Transfecção , Regulação para Cima , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
BACKGROUND: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies benefit patients with wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). However, their effect in KRAS-mutant mCRC remains unclear. PATIENTS AND METHODS: This was a retrospective study enrolling 163 patients with unresectable KRAS-mutant mCRC diagnosed at the National Taiwan University Hospital between 2007 and 2011. RESULTS: The median overall survival (mOS) was 29.5 months in patients who had never used cetuximab and 19.0 months in those who had (p=0.040). The mOS was 32.0 months in patients with mutant KRAS codon 12 who had never used cetuximab and 17.5 months in those who had (p=0.017). In patients with mutant KRAS codon 13, the mOS was not significantly different. Univariate and multivariate Cox proportional hazards analysis revealed that absence of cetuximab treatment was an independent prognostic factor for longer mOS in patients with unresectable KRAS-mutant mCRC. CONCLUSION: Cetuximab usage might be detrimental to patients with mCRC with mutant KRAS codon 12.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Códon/genética , Neoplasias Colorretais/tratamento farmacológico , Mutação/genética , Metástase Neoplásica/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cetuximab , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Taiwan , Adulto JovemRESUMO
Core 1 ß1,3-galactosyltransferase (C1GALT1) transfers galactose (Gal) to N-acetylgalactosamine (GalNAc) to form Galß1,3GalNAc (T antigen). Aberrant O-glycans, such as T antigen, are commonly found in colorectal cancer. However, the role of C1GALT1 in colorectal cancer remains unclear. Here we showed that C1GALT1 was frequently overexpressed in colorectal tumors and is associated with poor survival. C1GALT1 overexpression promoted cell survival, migration, invasion, and sphere formation as well as tumor growth and metastasis of colon cancer cells. Conversely, knockdown of C1GALT1 with small interference (si) RNA was sufficient to suppress these malignant phenotypes in vitro and in vivo. Moreover, we are the first to show that fibroblast growth factor receptor (FGFR) 2 carried O-glycans in colon cancer cells. Mechanistic investigations showed that C1GALT1 modified the O-glycans on FGFR2 and enhanced bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. In addition, BGJ398, a selective inhibitor of FGFR, blocked the effects of C1GALT1. These findings suggest that C1GALT1 overexpression modifies O-glycans on FGFR2 and enhances its phosphorylation to promote the invasive behavior and cancer stem-like property in colon cancer cells, indicating a critical role of O-glycosylation in the pathogenesis of colorectal cancer.