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Primary colon cancers arising from the left and right sides exhibit distinct clinical and molecular characteristics. Sidedness-associated heterogeneity relies intricately on the oncogenic properties of cancer cells and multicellular interactions in tumor microenvironments. Here, combining transcriptomic profiling of 426,863 single cells from 105 colon cancer patients and validation with spatial transcriptomics and large-scale histological analysis, we capture common transcriptional heterogeneity patterns between left- and right-sided malignant epithelia through delineating two side-specific expression meta-programs. The proliferation stemness meta-program is notably enriched in left-sided malignant epithelia that colocalize with Mph-PLTP cells, activated regulatory T cells (Tregs), and exhausted CD8-LAYN cells, constituting the glucose metabolism reprogramming niche. The immune secretory (IS) meta-program exhibits specific enrichment in right-sided malignant epithelia, especially in smoking patients with right-sided colon cancer. The IShigh malignant epithelia spatially localize in hypoxic regions and facilitate immune evasion through attenuating Mph-SPP1 cell antigen presentation and recruiting innate-like cytotoxicity-reduced CD8-CD161 cells.
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Neoplasias del Colon , Microambiente Tumoral , Humanos , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/genética , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Linfocitos T Reguladores/inmunología , Perfilación de la Expresión Génica , Transcriptoma/genética , Masculino , FemeninoRESUMEN
In this editorial we comment on the manuscript, describing management and surveillance strategies in synchronous and metachronous, gastric and colon cancers. Synchronous or metachronous primary malignancies at different sites of the gastrointestinal tract pose a unique diagnostic and therapeutic challenge. Multidisciplinary services and strategies are required for the management of multiple site primary malignancies, to provide the best oncological outcomes. Although this study highlights the dual cancers in 76 sporadic cases, the authors excluded 55 patients due to combination of factors which includes; incomplete clinical data, genetic syndrome, gastric stump cancers. In addition, the authors did not elaborate if any patients presented with signet ring cell morphology, E-cadherin mutations or presence of inflammatory bowel disease. Genetic and mutational errors and epithelial field defects from chronic inflammatory diseases of the gastrointestinal tract are important when considering synchronous gastric and colonic cancers. We will briefly discuss these in this editorial.
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BACKGROUND: For high-risk stageIImismatch repair deficient (dMMR) colon cancers, the benefit of adjuvant chemotherapy remains debatable. The principal aim of this study was to evaluate the prognostic value of high-risk factors and the effect of oxaliplatin-based adjuvant chemotherapy among dMMR stageIIcolon cancers. METHODS: Patients with stage II dMMR colon cancers diagnosed between June 2011 and May 2018 were enrolled in the study. Clinicopathological characteristics, treatment, and follow-up data were retrospectively collected. The high-risk group was defined as having one of the following factors: pT4 disease, fewer than twelve lymph nodes harvested (< 12 LNs), poorly differentiated histology, perineural invasion (PNI), lymphatic vascular invasion (LVI), or elevated preoperative carcinoembryonic antigen (CEA). The low-risk group did not have any risk factors above. Factors associated with disease-free survival (DFS) were included in univariate and multivariate Cox analyses. RESULTS: We collected a total of 262 consecutive patients with stage II dMMR colon cancer. 179 patients (68.3%) have at least one high-risk factor. With a median follow-up of 50.1 months, the low-risk group was associated with a tended to have a better 3-year DFS than the high-risk group (96.4% vs 89.4%; P = 0.056). Both elevated preoperative CEA (HR 2.93; 95% CI 1.26-6.82; P = 0.013) and pT4 disease (HR 2.58; 95% CI 1.06-6.25; P = 0.037) were independent risk factors of recurrence. Then, the 3-year DFS was 92.6% for the surgery alone group and 88.1% for the adjuvant chemotherapy group (HR 1.64; 95% CI 0.67-4.02; P = 0.280). Furthermore, no survival benefit from oxaliplatin-based adjuvant chemotherapy was observed in the high-risk group and in the subgroups with pT4 disease or < 12 LNs. CONCLUSIONS: These data suggests that not all high-risk factors have a similar impact on stage II dMMR colon cancers. Elevated preoperative CEA and pT4 tumor stage are associated with increased recurrence risk. However, oxaliplatin-based adjuvant chemotherapy shows no survival benefits in stage II dMMR colon cancers, either with or without high-risk factors.
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Neoplasias Encefálicas , Neoplasias del Colon , Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Síndromes Neoplásicos Hereditarios , Humanos , Estudios Retrospectivos , Oxaliplatino/uso terapéutico , Estadificación de Neoplasias , Antígeno Carcinoembrionario , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/cirugía , Pronóstico , Quimioterapia AdyuvanteRESUMEN
Background: Limited information is currently available on the natural history and prognosis of two distinct histological subtypes of adenocarcinoma (AC) in the colon: mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRCC). Therefore, the aim of this study is to examine the clinicopathological characteristics of colon MAC and SRCC, comparing them to classical AC, using a large cohort of cases from the United States. Methods: Patients diagnosed with colon AC, MAC, or SRCC from the SEER database between 2000 and 2018 were included in our study. Incidence trends, patient demographics, tumor characteristics, treatment, and survival were analyzed. Results: In our study, we analyzed a total of 310,813 patients with colon cancers, including 271,382 cases of classical AC, 34,750 cases of MAC, and 4,681 cases of SRCC. Over the study period, we observed a decline in the age-adjusted incidence rates of colon AC, MAC, and SRCC. Notably, the MAC and SRCC cohorts differed significantly from AC in terms of patient characteristics, tumor locations, and treatment patterns. Patients with MAC and SRCC had poorer survival outcomes compared to those with AC. Factors associated with worse survival included older age, male sex, poorly differentiated tumors, advanced stage, and the presence of MAC or SRCC histology. On the other hand, surgical intervention was associated with improved survival. Conclusion: Our study underscores the significance of recognizing the distinct features and outcomes associated with different histological subtypes of colon cancer. Further research is warranted to delve into the underlying biological traits that contribute to these differences and to develop more tailored treatment strategies.
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Among various routes of metallic nanoparticle (NPs) fabrication, phytosynthesis has significant advantages over other conventional approaches. Plant-mediated synthesis of NPs is a fast, one-step, ecobenign, and inexpensive method with high scalability. Herein, silver (Ag) and gold (Au)-NPs were extracellularly synthesized using aqueous Haloxylon salicornicum (H@Ag-, H@Au-NPs) leaf extracts. GC-MS was performed to analyze the chemical compositions of H. salicornicum extract. H@Ag- and H@Au-NPs were characterized via UV-Vis spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, transmission and scanning electron microscopy, and Zetasizer. H@Ag- and H@Au-NPs have surface plasmon resonance at 435.5 and 530.3 nm, respectively. FTIR and GC-MS data suggest that secondary plant metabolites and hydrocarbons might be responsible for the reduction and stabilization of NPs. XRD demonstrated that both NPs have a crystalline nature. H@Ag-NPs have a uniform spherical shape, whereas H@Au-NPs are spherical with few oval and triangular shapes, and their average nanosizes were 19.1 ± 0.8 and 8.1 ± 0.3 nm, respectively. Hydrodynamic diameters of H@Ag-NPs and H@Au-NPs were 184.7 nm, 56.4, and 295.4 nm, and their potential charges were -24.0 and -24.4 mV, respectively. The inhibitory activity of 500 µg/mL H@Ag- and H@Au-NPs was tested against Sw480, Sw620, HCT-116, and Caco-2 colon cancer cell lines and two normal cell lines, including HFs and Vero. H@Ag-NPs revealed potent anticancer activity against all cancer cells at low concentrations. Sw480 was the most sensitive cell to H@Ag-NPs, whereas Sw620 was the least permeable one. These findings suggested that the antiproliferative activity of H@Ag-NPs is cell-response-dependent and may be influenced by a variety of factors, including the cellular metabolic state, which influences cellular charge and interactions with charged NPs. Although H@Au-NPs were smaller, their reactivity against cancer cells was weak, suggesting that the chemical properties, metal structure, quantity and chemistry of the functional groups on the NP surface may influence their reactivity. The biocidal activity of 1 mg/mL H@Ag- and H@Au-NPs against Staphylococcus aureus, Bacillus cereus, Escherichia coli and Klebsiella pneumoniae was assessed. H@Ag-NPs showed biocidal activity against Gram-positive bacteria compared to Gram-negative bacteria, whereas H@Au-NPs showed no inhibitory activity. FRAP and DPPH assays were used to determine the scavenging activity of the plant extracts and both NPs. H@Ag-NPs (1 mg/mL) had the greatest scavenging activity compared to tested drugs. These findings suggest that H@Ag-NPs are potent anticancer, antibacterial, and antioxidant agents, while H@Au-NPs may be used as a drug vehicle for pharmaceutical applications.
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BACKGROUND: This retrospective cohort study reports on overall survival and short-term complications, comparing laparoscopic to open resection for right-sided colon cancers. It is one of the largest studies in the field with generalizable population-level results. METHOD: This study on right sided colon cancers used prospectively collected administrative data linked to a death registry over 5 years from 2014 to 2018. Exclusion criteria were private patients, patients aged less than 10 years, synchronous and metachronous cancers. Propensity score weighting was used to balance cohorts and Cox proportional hazards regression was used to assess the hazard of death. In addition, logistic regression analysis was used to assess secondary outcomes. For completeness, unweighted data was similarly analysed. RESULTS: There were 3603 patients identified for the analysis: 1729 open patients and 1874 laparoscopic patients. Cox proportional hazards regression analysis of the weighted data showed no evidence of a statistically significant effect of laparoscopic surgery compared to open surgery on overall survival for right-sided colon cancers (HR 0.86, 95% CI 0.71-1.04, P = 0.112). The weighted data showed lower odds of prolonged length of stay, return to theatre and discharge destination other than home in the laparoscopic cohort compared to the open cohort. There was no difference in inpatient mortality. Unweighted results were similar. CONCLUSION: This study validates the use of laparoscopic surgery for right-sided colon cancer, showing similar long-term overall survival and inpatient mortality compared to open surgery. It is superior to open surgery for the short-term outcomes of LOS, return to theatre and discharge destination other than home.
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Neoplasias del Colon , Laparoscopía , Humanos , Puntaje de Propensión , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias del Colon/cirugía , Colectomía/métodos , Laparoscopía/métodosRESUMEN
We report a rare case of multiple primary malignancies, double primary lung cancers, and synchronous colon cancer. Double primary lung cancers were synchronous with adenocarcinoma of the sigmoid (carcinoid tumor and adenocarcinoma). The patient subsequently underwent two surgeries, for lung and colon cancer, followed by four cycles of carboplatin and pemetrexed treatment for the lung adenocarcinoma, with an uneventful chemotherapy course. The patient has been followed up closely for the last 18 months via CT scans and tumor marker tests and has shown no evidence of recurrence or metastasis.
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The aims of this study were to assess the frequency of promoter hypermethylation of the genes encoding the Ras associated domain family (RASSF)/Hippo pathway, as well as the impact on overall (OS) and progression-free survival (PFS) in a single-center retrospective cohort of 229 patients operated on for colon cancers. Hypermethylation status was investigated by methylation-specific PCR on the promoters of the RASSF1/2, STK4/3 (encoding Mammalian Ste20-like protein 1 and 2 (MST1 and 2), respectively), and LATS1/2 genes. Clinicopathological characteristics, recurrence-free survival, and overall survival were analysed. We found the RASSF/Hippo pathway to be highly silenced in colon cancer, and particularly RASSF2 (86%). The other promoters were hypermethylated with a lesser frequency of 16, 3, 1, 10 and 6%, respectively for RASSF1, STK4, STK3, LATS1, and LATS2 genes. As the hypermethylation of one RASSF/Hippo family member was by no means exclusive from the others, 27% of colon cancers displayed the hypermethylation of at least two RASSF/Hippo member promotors. The median overall survival of the cohort was 60.2 months, and the median recurrence-free survival was 46.9 months. Survival analyses showed a significantly poorer overall survival of patients when the RASSF2 promoter was hypermethylated (p = 0.03). The median OS was 53.5 months for patients with colon cancer with a hypermethylated RASSF2 promoter versus still not reached after 80 months follow-up for other patients, upon univariate analysis (HR = 1.86, [95% CI: 1.05-3.3], p < 0.03). Such difference was not significant for relapse-free survival as in multivariate analysis. A logistic regression model showed that RASSF2 hypermethylation was an independent factor. In conclusion, RASSF2 hypermethylation is a frequent event and an independent poor prognostic factor in colon cancer. This biomarker could be investigated in clinical practice.
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Mammalian STE20-like kinase 1 (MST1/STK4/KRS2) encodes a serine/threonine kinase that is the mammalian homolog of Drosophila Hippo. STK4 plays an important role in controlling cell growth, apoptosis, and organ size. STK4 has been studied in many cancers with previous studies indicating an involvement in colon cancer lymph node metastasis and highlighting its potential as a diagnostic marker for colon cancer. However, the role of STK4 defect in promoting colon cancer progression is still understudied. Here, we found that STK4 was significantly downregulated in colon cancer and was associated with distal metastasis and poor survival. Furthermore, STK4 knockdown enhanced sphere formation and metastasis in vitro and promoted tumor development in vivo. We found that STK4 colocalized with ß-catenin and directly phosphorylated ß-catenin resulting in its degradation via the ubiquitin-mediated pathway. This may suggest that STK4 knockdown causes ß-catenin phosphorylation failure and subsequently ß-catenin accumulation, consequently leading to anchorage-independent growth and metastasis in colon cancer. Our results support that STK4 may act as a potential candidate for the assessment of ß-catenin-mediated colon cancer prognosis.
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Movimiento Celular/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Serina-Treonina Quinasas/genética , Proteolisis , beta Catenina/metabolismo , Anciano , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones Endogámicos NOD , Ratones SCID , Modelos Biológicos , Invasividad Neoplásica , Metástasis de la Neoplasia , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fosforilación , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Análisis de Supervivencia , Transcripción GenéticaRESUMEN
The importance of tumour microenvironment in tumour behaviour has now become clearer. This study aimed to determine the prognostic effect of the proportion of tumour-stroma (PTS) in metastatic lymph nodes of advanced-stage colon cancers (CCs). We investigated PTS in positive lymph nodes of stage III-IV CC patients who underwent surgical treatment between 2004 and 2014. We used a standard approach in methodology. PTS was significantly associated with prognostic factors in the metastatic lymph nodes (perineural invasion [p = 0.031], lymphatic invasion [p = 0.032], invasive margin [p = 0.043], advanced pT [p = 0.020], and margin involvement [p = 0.034]). In addition, the correlations between PTS estimates (R = 0.704 to 0.617, p < 0.001), the reproducibility of the research (Κappa = 0.72-0.68) and the usefulness of the cut-off value (ROC: 50.33%; AUC = 0.752 [0.667-0.857]) were successful. In univariate analysis, 5-year survival was poor for RFS (p < 0.001), OS (p = 0.001) and LR (p = 0.013) in high PTS patients. Multivariate analysis confirmed that high PTS was an independent worse parameter for RFS (HR = 1.32, 95% CI: 1.17-2.55, p = 0.001) and OS (HR = 1.37, 95% CI: 1.25-1 - 2.56, p = 0.009). In this study, we showed that high PTS in metastatic lymph nodes was a successful prognostic marker for advanced-stage CCs. Also, the standard approach we used for the methodology was successful.
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Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Ganglios Linfáticos/patología , Células del Estroma/patología , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/inmunología , Neoplasias del Colon/cirugía , Femenino , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios Retrospectivos , Células del Estroma/inmunología , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Cancer-related inflammation (CRI) is thought to be a successful predictor of prognosis in colon cancers (CC), but opinions on how to use it are highly variable. In this study, the role of CRI cells in survival for CC patients was investigated by considering gender and menopausal status. METHODS: 163 stage II/III CC patients who underwent curative surgery between 1995 and 2015 were included in the study. The relationship between CRI cells was examined using a standard methodology. RESULTS: High neutrophil-lymphocyte ratio (NLR) had a better relationship with prognostic factors, especially in postmenopausal women (gender, p = 0.037, positive surgical margin, p = 0.001; MSI, p < 0.001; Crohn's-like reaction, p = 0.001, etc). Also, the reproducibility of the study was better in postmenopausal women (intra-observer agreement = 0.72, intra-class correlation = 0.722, correlation of estimates = 0.718). In univariate analysis, 5-year survival was worse in postmenopausal women with high NLR (OS, p = 0.001; RFS, p < 0.001). In multivariate analysis, high NLR was independently a worse biomarker for OS (hazard ratio [HR], 1.29; 95% CI, 1.18-2.12; p = 0.001) and RFS (HR, 1.30; 95% CI, 1.21-2.59; p < 0.001) in postmenopausal women. CONCLUSIONS: NLR had an independent poor prognostic significance in postmenopausal female patients, and the use of a standard approach for methodology improved successful results.
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Biomarcadores de Tumor/inmunología , Neoplasias del Colon/inmunología , Inflamación/inmunología , Posmenopausia/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Hormonas Esteroides Gonadales/inmunología , Humanos , Inflamación/genética , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neutrófilos/inmunología , Posmenopausia/genética , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores Sexuales , Análisis de SupervivenciaRESUMEN
BACKGROUND: Colon cancer is one of the major causes of morbidity and mortality worldwide. Cycle inhibiting factors (Cifs) have been shown to deamidate Nedd8, resulting in cell cycle arrest. OBJECTIVE: To determine the antitumor effect of Cifs on colon cancer by using attenuated Salmonella typhimurium VNP20009. METHODS: The VNP-SOPE2-cif and VNP-SOPE2-cif-C/A plasmids were transfected into attenuated Salmonella typhimurium VNP20009. The efficiency and specificity of the Cif promoter were validated in colon cancer SW480 cell lines. Western blotting was subsequently performed to evaluate cell cycle regulators, including P21, P27 and Wee1. In vivo, the antitumor effect of VNP20009 was evaluated in a colon cancer xenograft model. RESULTS: Firstly, VNP-SOPE2-cif and VNP-SOPE2-cif-C/A were selectively expressed both in the bacterial and colon cancer cells. Cif expression in SW480 cells via the VNP tumor-targeted expression system induced the accumulation of Wee1, p21 and p27 expression. Moreover, tumor growth was significantly inhibited in the mice with VNP-SOPE2-cif compared to the mice with VNP with the empty construct. CONCLUSION: These results suggest that Cif gene delivered by VNP20009 is a promising approach for the treatment of colon cancer.
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Antineoplásicos/farmacología , Vacunas Bacterianas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Proteínas de Escherichia coli/genética , Salmonella typhimurium/química , Animales , Antineoplásicos/química , Vacunas Bacterianas/química , Línea Celular Tumoral , Neoplasias del Colon/genética , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
PURPOSE: Although local inflammatory response (LIR) is a reliable survival marker in colon cancers (CCs), there is no consensus on its use in daily practice. We investigated the prognostic value of LIR in a highly homogeneous population with a well-designed methodology. METHODS: Eighty stage-IIB CC patients operated between 2002 and 2012 were included in the study. Standardization was investigated for extra-biopsy evaluation methods (magnification, staining, and counting). Model A was used for intra-biopsy evaluation methods (block, section, and focus). So, this study makes important contributions to the standardization of pathological evaluations. RESULTS: In method 1, the following analyzes showed more successful results for LIR: relationship with prognostic factors [tumour deposits (p=0.017), Crohn's-like reaction (p=0.019), advanced grade, (p=0.012), positive surgical margin (p=0.019), perineural invasion (p=0.025), mismatch repair proteins-proficiency (p=0.031)], reproducibility of the study (Kappa=0.49-0.73, Intra-class correlation=0.442-0.724), and correlation of estimates (r=0.704). The cut-off value was also quite useful (area of under ROC=0.820 [0.694-0.920]). In univariate analysis, low LIR was related to poor overall survival (OS; p<0.001) and poor relapse-free survival (RFS, p=0.001) . Multivariate analysis confirmed that low LIR is an independent poor survival marker for OS (Hazard Ratio [HR]=1.32 [1.08-1.61, p=0.005) and RFS (HR=1.50 [1.22-1.85], p<0.001). CONCLUSIONS: Our results showed that low LIR had an independent prognostic significance in stage -IIB CCs. We also recommend using model A and method 1 for successful results and standardization.
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Adenocarcinoma/inmunología , Neoplasias del Colon/inmunología , Inflamación/inmunología , Resultado del Tratamiento , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo , Supervivencia sin Enfermedad , Femenino , Humanos , Inflamación/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Cancer stem cells contribute to tumorigenesis, metastasis, recurrence, and chemoresistance. CD133/prominin-1-a pentaspan membrane glycoprotein-has been used as a stem cell biomarker for the isolation of stem-like cells from a variety of normal and pathological tissues. In our previous studies, we developed several anti-CD133 monoclonal antibodies using Cell-Based Immunization and Screening (CBIS) methods, followed by characterization of their efficacy by flow cytometry, western blotting, and immunohistochemical analyses. One of the 100 clones, CMab-43 (IgG2a, kappa), demonstrated a sensitive and specific reaction against colon cancer cells. This study aimed to investigate the antitumor activity of CMab-43. Caco-2 cells (human colon cancer cell line) were subcutaneously implanted into the flanks of nude mice. CMab-43 and control mouse IgG were injected three times into the peritoneal cavity of mice. Tumor formation was observed in the control and CMab-43-treated mice of Caco-2 xenograft models. CMab-43 significantly reduced tumor development of Caco-2 xenograft in comparison with the control mouse IgG on days 12, 14, and 17. Our results cumulatively suggest that CMab-43 is useful for antibody therapy against CD133-expressing colon cancers.
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Antígeno AC133/inmunología , Anticuerpos Monoclonales/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Neoplasias del Colon/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To investigate whether young patients exhibit different characteristics and survival according to tumor location and stage using data from the Surveillance, Epidemiology, and End Results (SEER) database. PATIENTS AND METHODS: Young patients (20-49 years old) with stage I-III colon cancers were identified from the SEER program from 1990 to 2014. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to analyze the data. Subset analyses were also done among different age and stage subgroups. RESULTS: Of 8197 patients, 3709 (45.2%) had right-sided colon cancers (RCCs). Patients with RCCs were more likely to be male, to be younger, and to have more poorly differentiated and more advanced tumors. The Kaplan-Meier survival curves and univariate survival models revealed that left-sided colon cancers (LCCs) had lower mortality for all stages combined and stage III, but higher mortality for stage II, compared with right-sided tumors. However, multivariate Cox regression models showed no significant survival differences by location for all patients (adjusted hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.86-1.05; P=0.34) or for stage I (adjusted HR, 1.47; 95% CI, 0.82-2.63; P=0.20). Stage II left-sided cancers had higher mortality (adjusted HR, 1.24; 95% CI, 1.00-1.54; P=0.048), whereas stage III left-sided cancers had lower mortality (adjusted HR, 0.86; 95% CI, 0.77-0.97; P=0.01). For 20- to 39-year-old patients, a significant difference was only found in stage II disease, with a higher mortality for left-sided tumors (adjusted HR, 1.82; 95% CI, 1.12-2.97; P=0.02). However, for 40- to 49-year-old patients, a significant difference was only found in stage III disease, with a lower mortality for left-sided tumors (adjusted HR, 0.83; 95% CI, 0.72-0.95; P=0.008). CONCLUSION: In patients younger than 50 years, there were no significant differences in mortality between RCCs and LCCs for all stages combined after adjusting for multiple clinicopathological features. However, RCCs had lower mortality in stage II (especially in 20- to 39-year-old patients) and higher mortality in stage III (especially in 40- to 49-year-old patients).
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BACKGROUND: Folate level was proposed to be a predictor for fluoropyrimidine-related toxicity. We conducted a prospective study to determine the association between serum and red-cell folate and capecitabine-related toxicity in patients with colorectal cancers. MATERIALS AND METHODS: Eligibility criteria included diagnosis of colorectal cancers; eligible patients who were scheduled to undergo capecitabine monotherapy or capecitabine-oxaliplatin (CAPOX) for adjuvant or palliative purposes. Exclusion criteria included concomitant radiotherapy or chemotherapy other than capecitabine or CAPOX and creatinine clearance <30 mL/min. Fasting serum and red-cell folate were measured prior to chemotherapy. Capecitabine was administered at 2,500 mg/m2 per day (monotherapy) or 2,000 mg/m2 per day (CAPOX) for 14 days every 3 weeks. The toxicity of the first four cycles was documented by clinical investigators who were blinded to folate levels. RESULTS: A total of 144 patients were recruited, of whom 126 were eligible; 40 patients had capecitabine alone, and 86 patients received CAPOX. The rates of grade 2 and grade 3 toxicity were 63.5% and 14.3%, respectively. Nausea and vomiting were the most common grade ≥2 adverse event (47.7%), followed by hand-foot syndrome (25.4%), diarrhea (23.1%), and neutropenia (22.3%). Combination with oxaliplatin (odds ratio [OR], 2.77; p = .043) and serum folate (OR, 10.33; p = .002) were independent predictors of grade ≥2 toxicity. Red-cell folate was not predictive of toxicity. For every 10 nmol/L increment in serum folate, the risk of grade ≥2 toxicity increased by 9%. CONCLUSION: Serum folate level, but not red-cell folate, was associated with higher rate of grade ≥2 toxicity during capecitabine-based treatment. Excessive folate intake may be avoided before and during capecitabine-based chemotherapy. IMPLICATIONS FOR PRACTICE: This is the first prospective study to evaluate the association between serum folate level and capecitabine-related toxicity in patients with colon cancers. It shows that higher serum folate level is associated with increased risks of moderate to severe toxicity during capecitabine-based treatment. Excessive folate intake should be avoided before and during capecitabine-based chemotherapy.
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Capecitabina/efectos adversos , Capecitabina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Ácido Fólico/uso terapéutico , Anciano , Capecitabina/farmacología , Neoplasias Colorrectales/patología , Femenino , Ácido Fólico/farmacología , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
A multifunctional albumin/superparamagnetic iron oxide nanoparticle (SPIO) nanocomplex system to deliver IR780, a photothermal agent, for cancer theranostic applications was proposed in this study. Single emulsion method was utilized to fabricate the human albumin/IR780/SPIO (HISP) nanocomplexes with a hydrophobic core (SPIO and IR780) and a hydrophilic shell (human serum albumin (HSA) and poly (ethylene glycol) (PEG)). Effects of PEGylation on the size and surface potential of nanocomplexes were analyzed. Nanospheres containing uniformly dispersed SPIO was observed using Transmission Electron Microscopy (TEM) imaging. As a potential magnetic resonance (MR) imaging agent, the HISP displayed dose-dependent T2-weighted imaging contrast (R2 = 81.6 mM-1s-1). Good colloidal stability was verified from the nanocomplexes under difference circumstances. The nanocomplexes were taken up by cancer cells efficiently and led to significant photothermal-mediated cancer cell death upon short-term near infrared (NIR) irradiation in vitro. Via intravenous injection, PEG-HISP can efficiently deliver IR780 to tumor sites and showed strong photothermal effect compared to free drug on the mice model. Significant tumor suppression by the photothermal treatments using PEG-HISP was demonstrated from the mice CT26 xenograft model. Good safety profile of the PEG-HISP was confirmed from histological examination and liver functional analysis. Taken together, the results suggest that PEG-HISP is a safe and robust nano-theranostic platform for advanced anti-cancer treatment.
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PURPOSE: In this study, we have successfully prepared the hyaluronic acid (HA)-conjugated mesoporous silica nanoparticles loaded with 5-fluorouracil (5-FU) to increase the anticancer efficacy in colon cancers. METHODS: The particles were nanosized and perfectly spherical. In vitro release kinetics clearly showed the enzyme-sensitive release of 5-FU from HA-conjugated 5-FU loaded mesoporous silica nanoparticles (HA/FMSN). RESULTS: The presence of HA on the surface of nanoparticles targeted the CD44 receptors overexpressed in the colon cancer cells In vitro cell viability and apoptosis assay clearly showed the superior anticancer effect of HA/FMSN in HT29 colon cancer cells. HA/FMSN exhibited a remarkably higher 43% of cells in early apoptosis phase and 55% of cells in late apoptosis phase indicating the superior anticancer effect of HA/FMSN. HA/FMSN exhibited a significant reduction in the tumor burden compared to that of any group. HA/FMSN was 3-fold more effective than free drug and 2-fold more effective than -FU loaded mesoporous silica nanoparticles (FMSN). CONCLUSIONS: Overall, results suggest that the novel delivery strategy could hold enormous potential in colon cancer targeting.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Histona Acetiltransferasas/metabolismo , Hialuronoglucosaminidasa/metabolismo , Animales , Antimetabolitos Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Liberación de Fármacos , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Células HT29 , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/metabolismo , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/metabolismo , Silicatos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: According to many Societies' guidelines, patients presenting with clinical T4 colorectal cancer should conventionally be approached by a laparotomy. Results of emerging series are questioning this attitude. METHODS: We retrospectively analysed the oncologic outcomes of 147 patients operated on between June 2008 and September 2015 for histologically proven pT4 colon cancers. All patients were treated with curative intent, either by a laparoscopic or open "en bloc" resection. RESULTS: Median operative time, blood loss and hospital length of stay were significantly reduced in the laparoscopic group. Postoperative surgical complication rate and 30-day mortality did not significantly differ between the two groups ( p = 0.09 and p = 0.99, respectively). R1 resection rate and lymph nodes harvest, as well, did not remarkably differ when comparing the two groups. In the laparoscopic group, conversion rate was 19%. Long-term outcomes were not affected in patients who had undergone conversion. Five-year overall survival and disease-free survival did not significantly differ between the two groups (44.6% and 40.3% vs. 39.4% and 38.9%). Locally advanced stages (IIIB-IIIC) and R1 resections were detected as independent prognostic factors for overall survival. CONCLUSION: Laparoscopic approach might be safe and acceptable for locally advanced colon cancer and does not jeopardize the oncologic results. Conversion to open surgery should be a part of a strategy as it does not seem to adversely affect perioperative and long-term outcomes. We consider laparoscopy, in expert hands, the last diagnostic tool and the first therapeutic approach for well-selected locally advanced colon cancers. Larger prospective studies are needed to widely assess this issue.
Asunto(s)
Colectomía , Neoplasias Colorrectales/cirugía , Anciano , Colectomía/métodos , Colectomía/mortalidad , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
As a result of our efforts to identify bioactive agents from marine algae, we have isolated and identified one new halogenated monoterpene 1 [(-)-(5E,7Z)-348-trichloro-7-dichloromethyl-3-methyl-157-octatriene] in addition to three known compounds (2, 3 and 4) from the red alga Plocamium cartilagineum collected by hand from the eastern coast of South Africa. Compound 1 was found to be active as a cytotoxic agent in human lung cancer (NCI-H460) and mouse neuro-2a cell lines (IC50 4 µg/mL). Two of these compounds (3 and 4) were found to have cytotoxic activity in other cell line assays, especially against human leukaemia and human colon cancers (IC50 1.3 µg/mL). None of these metabolites were active as sodium channel blockers or activators. All structures were determined by spectroscopic methods (UV, IR, LRMS, HRMS, 1D NMR and 2D NMR). 1D and 2D NOE experiments were carried out on these compounds to confirm the geometry of the double bonds.