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OBJECTIVE: This study was conducted to compare the differences between 3D-printed multichannel non-co-planar vaginal applicators and single-channel vaginal applicators in cervical cancer patients with positive or close surgical margins. METHODS: Between January 2015 and June 2023, 104 cervical cancer patients who underwent radical surgery with positive or close surgical margins were enrolled to receive concurrent intensity-modulated chemoradiotherapy combined with 3D-printed multichannel non-co-planar vaginal applicators (3D-printed group, 41 patients) or single-channel vaginal applicators (single-channel group, 63 patients) guided brachytherapy. The dosimetric parameters, 5-year local control (LC), progression-free survival (PFS), overall survival (OS) of two groups were retrospectively analyzed. RESULTS: The high-risk clinical target volume (D90, D100) and high-dose volume fraction (V150) in 3D-printed group were significantly higher than those in single-channel group (p < 0.05), and the homogeneity index (HI) and conformal index (COIN) were equally better in 3D-printed group. In 3D-printed group, the D2cc, D1cc, and D0.1cc of the bladder and rectum were significantly lower than those of the single-channel group (p < 0.05). The 3D-printed group had significantly superior 5-year LC (70.0% vs. 51.3%, pâ¯=â¯0.041) and PFS (63.0% vs. 44.2%, pâ¯=â¯0.045), but OS were not significantly different between treatment groups (75.4% vs. 59.7%, pâ¯=â¯0.112). The incidence of radiation enteritis and cystitis was lower in the 3D-printed group than in the single-channel group, but no statistical difference was noted. CONCLUSIONS: The 3D-printed multichannel non-co-planar vaginal insertion applicators show the advantage of target dose, improve the LC and PFS in patients with positive or close surgical margins after cervical cancer surgery. Thus, the popularization of this method and its application may be of value.
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Background: The comprehensive treatment mode of combining concurrent chemoradiotherapy (CCRT) with adjuvant chemotherapy (AC) is a commonly used mainstream model in the clinical practice of locally advanced cervical cancer (LACC). However, the necessity for AC after CCRT lacks sufficient evidence-based medical support. This study constructs a predictive model for the survival time dependence of CCRT ± AC for LACC based on the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging with internal validation, the prognosis was assessed with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin, and provides guidance for future stratified treatment. Materials and Methods: The retrospective analysis included 482 patients with LACC who CCRT from January 2016 to January 2023. Patients who used the 2009 FIGO staging were all standardized for the 2018 FIGO staging. The 482 patients with LACC were divided into a training set (n = 290) and a validation set (n = 192) at a ratio of 6:4. COX multivariate regression model and LASSO regression were used to screen for independent prognostic factors affecting progression-free survival (PFS) and overall survival (OS), and a nomogram clinical prediction model was constructed based on these factors. Evaluate the effectiveness of the model through the receiver operating characteristic curve, calibration curve, decision curve, risk heat map, and survival curves for risk stratification. Results: The PFS and OS independent prognostic risk factors affecting the 2018 FIGO staging of LACC during CCRT were validated to be similar to the 2009 FIGO staging prediction model reported in previous literature. In the training cohort, area under the curve (AUC) values at 1, 3, and 5 years were 0.941, 0.882, and 0.885 for PFS, and 0.946, 0.946, and 0.969 for OS, respectively. When applied to a test cohort, the model also showed accurate prediction result (AUC at 1, 3, and 5 years were 0.869, 0.891, and 0.899 for PFS, and 0.891, 0.941 and 0.878 for OS, respectively). Subgroup analysis suggests that patients with LACC, adenocarcinoma, stage IVA, pelvic lymph node metastasis, pretreatment hemoglobin ≤100 g/l and residual tumor diameter >2 cm, who received CCRT in the 2018 FIGO stage, may benefit more from adjuvant chemtherapy. Conclusions: Based on the 2018 FIGO staging, a nomogram prediction model for PFS and OS in patients with LACC undergoing CCRT was developed. The model, established by combining weighted clinical and pathological factors, can provide more personalized treatment predictions in clinical practice. For patients with high-risk factors such as residual tumor diameter > 2 cm after CCRT for LACC, AC may bring benefits.
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In order to ascertain the impact of the Tohoku-Oki 3.11 M9.0 earthquake on the stability of the faults in the Beijing Plain, we investigated the adjustment of the in situ stress field of the Beijing Plain after this earthquake based on in situ stress monitoring data. Then, we analyzed the stability of the five main faults in each adjustment stage of the in situ stress field based on the Mohr−Coulomb failure criteria and Byerlee's law. Finally, we studied the fault slip potential (FSP) of the main faults under the current in situ stress field. The research results show that (1) after the Tohoku-Oki 3.11 M9.0 earthquake, the tectonic environment of the Beijing Plain area changed rapidly from nearly EW extrusion to nearly EW extension, and this state was maintained until June 2012. After this, it began to gradually adjust to the state present before the earthquake. As of September 2019, the tectonic environment has not recovered to the state present before the earthquake. (2) The ratios of shear stress to normal stress on the fault plane of the fault subsections in the three time periods before the Tohoku-Oki 3.11 M9.0 earthquake, 6 June 2012 and 8 September 2019 were 0.1−0.34, 0.28−0.52, and 0.06−0.29, respectively. It shows that the stress accumulation level of faults in the Beijing Plain area increased in a short time after the earthquake and then gradually decreased. (3) Under the current in situ stress field, most of the subsections of the five main faults have a low FSP (<5%). The areas with high FSP are mainly concentrated in the central and southeastern parts of the Beijing Plain, including the Nankou-Sunhe fault, the northern section of the Xiadian fault, and the areas where the five faults intersect.
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BACKGROUND: There are obviously ethnic differences between the UGT1A1 gene polymorphisms. Due to the difference of genetic background and environment, the treatment with colorectal cancer patients of Guangxi Zhuang should not completely follow the Euramerican or Chinese han patients. The study aimed to explore the correlation of UGT1A1 gene polymorphism of Guangxi Zhuang metastatic colorectal cancer (mCRC) with irinotecan -based chemotherapy, in order to develop an individualized irinotecan regimen for mCRC patients of Guangxi Zhuang. METHODS: From June 2013 and June 2015, a total of 406 patients of Guangxi who were histologically diagnosed as metastatic colorectal cancer with 102 patients of this cohort with three generations of Zhuang, and 86 patients that conformed to inclusion and exclusion criteria were competitively enrolled. The distribution of UGT1A1 gene polymorphism was analyzed-retrospectively in all patients. Pyrosequencing method was used to detect the UGT1A1*28 and*6 gene polymorphism in the 86 Guangxi Zhuang mCRC patients. After first-line chemotherapy with FOLFIRI regimen, the relationship between gene polymorphism of UGT1A1 and adverse reactions, and efficacy of Irinotecan were analyzed with χ2 test and Kaplan-Meier method. RESULTS: UGT1A1*28 wild-type (TA6/6), heterozygous mutant (TA6/7) and homozygous mutant (TA7/7) accounted for 69.8, 30.2 and 0%, respectively. UGT1A1*6 wild type (G/G), heterozygous mutation type (G/A) and homozygous mutant (A/A) accounted for 76.7%, 20.9 and 2.3%, respectively. UGT1A1*28 TA6/7 type could increase the risk of grade 3~4 diarrhea (p = 0.027), which did not increase the risk of grade 3~4 neutropenia (p = 0.092). UGT1A1*6G/A and A/A type could increase the risk of grade 3~4 diarrhea and neutropenia (p = 0.001; p = 0.017). After chemotherapy with FOLFIRI, there was no significant difference in response rate (RR) (p = 0.729; p = 0.745) or in median progression-free survival (mPFS) between the wild-type, mutant treatment of UGT1A1*28 and UGT1A1*6 (7.0 m vs 7.4 m, p = 0.427; 6.9 m vs 7.0 m p = 0.408). CONCLUSIONS: The distribution of UGT1A1*28 and UGT1A1*6 gene polymorphism in Guangxi Zhuang patients were differed from the existing reported of European people and Chinese Han population. The UGT1A1 gene polymorphism with irinotecan chemotherapy-associated diarrhea and neutropenia were closely related. There was no significant association between UGT1A1 gene polymorphism and therapeutic efficacy of irinotecan.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Glucuronosiltransferasa/genética , Irinotecán/uso terapéutico , Polimorfismo Genético , Adulto , Anciano , Antineoplásicos/efectos adversos , Camptotecina/uso terapéutico , China , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Genotipo , Humanos , Irinotecán/efectos adversos , Estimación de Kaplan-Meier , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Medicina de Precisión , Supervivencia sin Progresión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
TGF-ß signaling plays a critical role in tumor progression and many approaches have been made to inhibit its functions. MicroRNA is one of the approaches that inhibit TGF-ß signaling and can be used as a promising treatment for cancer. This study explored the role of miRNA-145 in pancreatic cancer (PC) development. The expression of miRNA-145 in PC tissues and paired adjacent normal tissues was examined by qRT-PCR. The expression of miRNA-145 in PC cells and the ability of cell migration and invasion were detected both in vivo and in vitro. The results showed that miRNA-145 was down-regulated in PC tissues and PC cells. Increasing the expression of miRNA-145 in PC cells inhibited the TGF-ß signaling pathway and epithelial-mesenchymal transition (EMT) process. Scratch assay and transwell assay showed that miRNA-145 inhibited the migration and invasion in PC cells. In vivo experiments confirmed that miRNA-145 mimics delayed the growth of PC xenografts comparing with miRNA-145 inhibitor. Our results suggested that miRNA-145 can inhibit epithelial to mesenchymal transition (EMT) and tumor growth by suppressing TGF-ß signaling pathway. Thus, miRNA-145 could be a potential therapeutic for targeting TGF-ß signaling in PC treatment.
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PURPOSE: In rectal cancer, the presence of extramesorectal/lateral pelvic lymph node (LPN) is associated with higher risk of locoregional and distant recurrences. LPNs are not typically resected during a standard total mesorectal excision (TME) procedure, and the optimal management for these patients is controversial. We assessed the safety and efficacy of adding a radiation therapy boost to clinically positive LPN during neoadjuvant chemoradiation therapy for rectal cancer. METHODS AND MATERIALS: We analyzed nonmetastatic, lymph node positive rectal adenocarcinoma patients treated with neoadjuvant chemoradiation therapy followed by TME between May 2011 and February 2018. Patients without LPN involvement received external beam radiation therapy (45 Gy in 25 fractions) to the primary tumor and regional draining lymph node basins followed by a boost (5.4 Gy in 3 fractions) to gross disease. Patients with clinically positive LPN that would not be removed during TME received an additional boost (up to a total dose between 54.0 and 59.4 Gy) to the involved LPNs. We compared locoregional control, overall survival, progression-free survival, and treatment-related toxicity between these 2 groups. RESULTS: Fifty-three patients were included in this analysis with median follow-up of 30.6 months for the LPN- group (n = 41) and 19.9 months for the LPN+ group (n = 12). There was no difference in 3-year overall survival (90.04% vs 83.33%, P = .890) and progression-free survival (80.12% vs 80.21%, P = .529) between the 2 groups. We did not observe any LPN recurrences. There were no differences in rates of acute grade 3+ or chronic toxicities. CONCLUSIONS: Despite the well-documented negative prognostic effect of LPN metastasis, we observed promising outcomes for LPN+ patients treated with an additional radiation boost. Our results suggest that radiation therapy boost to clinically involved, unresected LPN is an effective treatment approach with limited toxicity. Additional studies are needed to optimize treatment strategies for this unique patient subset.
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Recurrencia Local de Neoplasia , Neoplasias del Recto , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/patología , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/radioterapia , Estadificación de Neoplasias , Neoplasias del Recto/patología , Neoplasias del Recto/radioterapiaRESUMEN
Non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations and bone metastases are often concurrently administered tyrosine kinase inhibitors (TKIs) and bisphosphonates. Yet, the effects and mechanisms of these agents are unclear. In the present study, we aimed to ascertain whether zoledronic acid (ZA) increases the antitumor effects of gefitinib treatment on NSCLC with EGFR mutations and the related mechanisms of action. The effects of ZA and gefitinib on NSCLC tumor cells with EGFR mutations (HCC827, HCC827 GR and H1975) in regards to proliferation, apoptosis, cell cycle and signaling pathways were detected. ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance in vitro. Gefitinib caused cell cycle arrest in the G0/G1 phase, ZA induced S phase accumulation and the effect of the combined treatment was neutralization. Combined treatment obviously inhibited STAT3 and/or pSTAT3 protein expression compared with treatment with each single drug in vitro and in vivo, and it also significantly inhibited TKI resistance NSCLC tumor growth in vivo. In conclusion, ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance by regulating the cell cycle, inducing caspase-3 expression and inhibiting STAT3 expression.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Difosfonatos/farmacología , Receptores ErbB/genética , Imidazoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Quinazolinas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Factor de Transcripción STAT3/antagonistas & inhibidores , Ácido ZoledrónicoRESUMEN
BACKGROUND: Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations. METHODS: Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed. RESULTS: Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798). CONCLUSIONS: Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Difosfonatos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Éteres Corona/administración & dosificación , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Gefitinib , Humanos , Imidazoles/administración & dosificación , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Pamidronato , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Estudios Retrospectivos , Resultado del Tratamiento , Ácido ZoledrónicoRESUMEN
BACKGROUND: SUMO-activating enzyme subunit 2 (SAE2) is the sole E1-activating enzyme required for numerous important protein SUMOylation, abnormal of which is associated with carcinogenesis. SAE2 inactivation was recently reported to be a therapeutic strategy in cancers with Myc overexpression. However, the roles of SAE2 in small cell lung cancer (SCLC) are largely unknown. METHODS: Stably SAE2 knockdown in H446 cells were established with a lentiviral system. Cell viability, cell cycle, and apoptosis were analyzed using MTT assay and flow cytometric assay. Expression of SAE2 mRNA and protein were detected by qPCR, western blotting, and immunohistochemical staining. Cell invasion and migration assay were determined by transwell chamber assay. H446 cells with or without SAE2 knockdown, nude mice models were established to observe tumorigenesis. RESULTS: SAE2 was highly expressed in SCLC and significantly correlated with tumorigenesis in vivo. Cancer cells with RNAi-mediated reduction of SAE2 expression exhibited growth retardation and apoptosis increasing. Furthermore, down-regulation of SAE2 expression inhibited migration and invasion, simultaneously increased the sensitivity of H446 to etoposide and cisplatin. CONCLUSIONS: SAE2 plays an important role in tumor growth, metastasis, and chemotherapy sensitivity of H446 and is a potential clinical biomarker and therapeutic target in SCLC with high c-Myc expression.
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Transformación Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Humanos , Inmunohistoquímica , RatonesRESUMEN
The echinoderm microtubule-associated protein-like 4(EML4)--anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small-cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation.