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1.
Int J Radiat Oncol Biol Phys ; 105(4): 861-874, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419512

RESUMO

PURPOSE: Telomerase is reactivated in non-small cell lung cancer (NSCLC), and it increases cell resistance to irradiation through protecting damaged telomeres and enhancing DNA damage repair. We investigated the radiosensitizing effect of BIBR1532, a highly selective telomerase inhibitor, and its corresponding mechanism in NSCLC. METHODS AND MATERIALS: Cell proliferation, telomerase activity, and telomere dysfunction-induced foci were measured with CCK-8 assay, real-time fluorescent quantitative polymerase chain reaction, and immunofluorescence. The effect of BIBR1532 on the response of NSCLC cells to radiation was analyzed using clonogenic survival and xenograft tumor assays. Cell death and cell senescence induced by BIBR1532 or ionizing radiation (IR), or both, were detected with western blotting, flow cytometry, and senescence-association ß-galactosidase staining assay. RESULTS: We observed dose-dependent direct cytotoxicity of BIBR1532 at relatively high concentrations in NSCLC cells. Low concentrations of BIBR1532 did not appear toxic to NSCLC cells; however, they substantially increased the therapeutic efficacy of IR in vitro by enhancing IR-induced apoptosis, senescence, and mitotic catastrophe. Moreover, in a mouse xenograft model, BIBR1532 treatment synergized with IR at nontoxic dose levels promoted the antitumor efficacy of IR without toxicity to hematologic and internal organs. Mechanistically, lower concentrations of BIBR1532 effectively inhibited telomerase activity and increased IR-induced telomere dysfunction, resulting in disruption of chromosomal stability and inhibition of the ATM/CHK1 (ataxia-telangiectasia-mutated/Checkpoint kinase 1) pathway, which impaired DNA damage repair. CONCLUSIONS: Our findings demonstrate that disturbances in telomerase function by nontoxic dose levels of BIBR1532 effectively enhance the radiosensitivity of NSCLC cells. This finding provides a rationale for the clinical assessment of BIBR1532 as a radiosensitizer.

2.
Int J Radiat Oncol Biol Phys ; 105(2): 319-328, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31228553

RESUMO

PURPOSE: Clinical tools are unavailable for accurate prediction of pathologic responses to chemoradiation therapy (CRT) among patients with esophageal squamous cell carcinoma (ESCC) before surgery. We evaluated tumor remission and tumor-infiltrating lymphocytes (TILs) during CRT as predictors of pathologic response and prognostic markers for patients with locally advanced ESCC treated with neoadjuvant CRT (neo-CRT) or definitive CRT. METHODS AND MATERIALS: We analyzed patients with locally advanced ESCC (N = 164) who underwent neo-CRT (N = 48) or definitive CRT (N = 116). Patients underwent endoscopic ultrasonography and biopsies when induction CRT finished. Tumor remission characteristics were designated minor (-/+) to excellent remission (ER) (+++). TILs were determined in 10% increments. Tumor remission, TILs, or both were associated with pathologic complete response (pCR) and survival in the neo-CRT group and then analyzed in the definitive CRT group. RESULTS: ER and lymphocyte-predominant ESCC (LPE; ≥60% TILs) were identified according to the pCR rate and disease-free survival. We built a prediction model for pCR incorporating ER and LPE. The area under the receiver operating characteristic curve was 0.877, and sensitivity and specificity were 86.7% and 90.9%, respectively. Furthermore, this model identified pathologic response with an excellent calibration. Disease-free survival of patients with ER and LPE tumors was significantly longer than that of other patients. CONCLUSIONS: When we included tumor remission and TILs during CRT, our model predicted pCR with high probability and helped stratify prognostic subgroups, thereby guiding future therapy decisions for patients with locally advanced ESCC. Validation of this model in larger, prospective, multicenter studies is essential.

3.
BMC Cancer ; 19(1): 397, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036088

RESUMO

BACKGROUND: The importance of definitive radiotherapy for elderly patients with esophageal and esophagogastric-junction cancer is pronounced. However, little is known in terms of the best way to combine radiotherapy with other treatment options. This study aims to compare the efficiency of SIB radiotherapy alone with SIB radiotherapy concurrent and consolidated with S-1 for elderly patients. Comprehensive geriatric assessment is also incorporated in the procedure of treatment. METHODS/DESIGN: The study is a two arm, open, randomized multicenter Phase III trial with patients over 70 years old with stage IIA-IVB (UICC 2002, IVB only with metastasis to supraclavicular or celiac lymph nodes) squamous cell carcinoma or adenocarcinoma of esophagus or gastroesophageal junction. A total of 300 patients will be randomized using a 1:1 allocation ratio stratified by disease stage and study site. Patients allocated to the SIB arm will receive definitive SIB radiotherapy (95%PTV/PGTV 50.4Gy/59.92Gy/28f) while those randomized to SIB + S-1 arm will receive definitive SIB radiotherapy concurrent and consolidated with S-1. The primary endpoint of the trial is 1-year overall survival. Secondary objectives include progression-free survival, recurrence-free survival (local-regional and distant), disease failure pattern, toxicity profile as well as quality of life. Besides, detailed radiotherapy protocol and quality assurance procedure have been incorporated into this trial. DISCUSSION: The proportion of elderly patients in esophageal cancer is now growing, but there is a lack of evidence in term of treatment standard for this group of patients, which is what we aim to obtain through this prospective phase III study. TRIAL REGISTRATION: clinicaltrials.gov NCT02979691 . Registered November 22, 2016.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/terapia , Radioterapia de Intensidade Modulada/métodos , Neoplasias Gástricas/terapia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Combinação de Medicamentos , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/efeitos dos fármacos , Junção Esofagogástrica/patologia , Junção Esofagogástrica/efeitos da radiação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Estadiamento de Neoplasias , Avaliação de Resultados (Cuidados de Saúde)/métodos , Avaliação de Resultados (Cuidados de Saúde)/estatística & dados numéricos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Estudos Prospectivos , Radioterapia de Intensidade Modulada/efeitos adversos , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/efeitos adversos
5.
Radiother Oncol ; 131: 27-34, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30773184

RESUMO

PURPOSE: The prognosis of unresectable stage III non-small cell lung cancer (NSCLC) was poor even after concurrent chemoradiotherapy. There remains a great need to develop novel therapeutic agents in combination with CCRT to improve outcomes. This prospective study sought to evaluate the efficacy and toxicities of the addition of endostar, an anti-angiogenesis agent, to concurrent etoposide, cisplatin (EP) and radiotherapy for treatment of patients with NSCLC. PATIENTS AND METHODS: Patients with untreated pathologically confirmed inoperable stage III NSCLC were eligible. Radiation at doses of 60-66 Gy, four cycles of endostar (7.5 mg/m2/24 h × 120 h, 14 days/cycle), and two cycles of EP (etoposide 50 mg/m2 on days 1-5 and cisplatin 50 mg/m2 on days 1 and 8, 28 days/cycle) were delivered. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate and overall survival (OS), locoregional relapse-free survival (LRFS) distant metastasis-free survival (DMFS) and adverse events (AE). RESULTS: From November 2012 to June 2015, 73 patients were enrolled, and 67 patients were evaluable. The median age was 59 years. Sixty-six percent of the patients had squamous cell carcinoma. Grade ≥3 AEs occurred in 58.2% of the patients. The most common Grade ≥3 AE was leucopenia (44.8%). The response rate was 76.1%. The median times of PFS and OS were 13.3 months and 34.7 months, respectively. The 2-year PFS, OS, LRFS and DMFS rates were 34.8%, 59.9%, 54.7% and 68.5%, respectively. CONCLUSIONS: For patients with unresectable stage III NSCLC, continuous intravenous endostar in combination with concurrent EP and radiotherapy did not prolong median PFS, although it got preferable OS, promising 2-year PFS with tolerable toxicities.

6.
Onco Targets Ther ; 11: 6333-6338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319273

RESUMO

Background: Nab-paclitaxel is produced by the combination of paclitaxel particles with human serum albumin. Encouraging efficacy has been observed with nab-paclitaxel-based chemotherapy in a variety of solid tumors. The aim of the study reported here was to evaluate the efficacy and safety of weekly nab-paclitaxel plus cisplatin with concurrent intensity-modulated radiotherapy in patients with locally advanced esophageal cancer. Methods: Seventeen patients with esophageal cancer were enrolled between July 2014 and December 2015.The treatment included radical radiotherapy (95% planning target volume 60Gy/30f) and concurrent chemotherapy comprising nab-paclitaxel 60mg/m2/week plus cisplatin 25mg/m2/week, administered on days 1, 8, 15, and 22 of each 28-day cycle. The end point of this study included objective response rate (ORR), local-recurrence free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS). Results: All the patients enrolled in the trial had squamous cell carcinoma. The median follow-up duration was 20.47 months. The ORR was 88.2%. LRFS, DMFS, PFS and OS at 3 years were 61%, 40%, 17% and 35%, respectively. The trial regimen was well tolerated, with grade 3-4 myelosupression, grade 3 radioactive esophagitis, and grade 3 radiation pneumonitis rates of 17.6%, 17.6%, and 11.8%, respectively. Conclusion: Weekly nab-paclitaxel plus cisplatin with concurrent intensity-modulated radiotherapy is an effective and well-tolerated treatment option for inoperable, locally advanced squamous cancer of esophageal.

7.
Cell Death Dis ; 9(10): 991, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250224

RESUMO

Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5-fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5-fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients.

8.
J Clin Oncol ; 36(27): 2796-2803, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30089078

RESUMO

Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m2 IV day 1, or 25 mg/m2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.

9.
Cancer Commun (Lond) ; 38(1): 33, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29871674

RESUMO

BACKGROUND: Cisplatin-based chemotherapy with concurrent radiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma (ESCC). NS1-binding protein (NS1-BP), a member of the BTB-kelch protein family, has been shown to inhibit the proliferation of Hela cells by suppressing c-Myc. In the present study, we examined the potential function role of NS1-BP expression in ESCC, and particularly, the sensitivity of ESCC to radiotherapy. METHODS: NS1-BP expression was examined using immunohistochemistry in two cohorts (n = 98 for the training cohort; n = 46 for independent validation cohort) of ESCC patients receiving cisplatin-based chemotherapy and concurrent radiotherapy. Normal esophageal mucosal tissue blocks were used as a control. We also conducted a series of in vitro and in vivo experiments to examine the potential effects of over-expressing NS1-BP on ESCC cells, and particularly their sensitivity to ionizing irradiation. RESULTS: In the training cohort, NS1-BP downregulation was observed in 59% (85/144) of the ESCC specimens. NS1-BP downregulation was associated with chemoradiotherapeutic resistance and shorter disease-specific survival (DSS) in both the training and validation cohorts. Over-expressing NS1-BP in cultured ESCC cells substantially increased the cellular response to irradiation both in vitro and in vivo. NS1-BP also significantly enhanced IR-induced apoptosis, and abrogated IR-induced G2/M cell-cycle arrest and ATM/Chk1 phosphorylation. Immunoprecipitation assays indicated that NS1-BP could interact with c-Myc promoter regions to inhibit its transcription. In ESCC tissues, c-Myc expression was inversely correlated with NS1-BP levels, and was associated with a shorter DSS. CONCLUSIONS: Our findings highlight the role and importance of NS1-BP in radiosensitivity of ESCC. Targeting the NS1-BP/c-Myc pathway may provide a novel therapeutic strategy for ESCC.

10.
Cancer Med ; 7(4): 1326-1337, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29522271

RESUMO

Positive cofactor 4 (PC4) participates in DNA damage repair and involved in nonhomologous end joining (NHEJ). Our previous results demonstrated that knockdown of PC4 downregulated the expression of XRCC4-like factor (XLF) in esophageal squamous cell carcinoma. However, the mechanism how PC4 regulates the expression of XLF remains unclear. Here, we found that knockdown of PC4 increased radiosensitivity of non-small cell lung cancer (NSCLC) both in vivo and in vitro. Furthermore, we found that PC4 knockdown downregulated the expression of XLF, whereas recovering XLF expression restored radioresistance in the PC4-knockdown NSCLC cells. In addition, PC4 knockdown inhibited XLF expression by transcriptionally suppressing of XLF. Moreover, PC4 expression correlated with radiosensitivity and was an independent prognostic factor of progression-free survival (PFS) in patients with NSCLC. These findings suggest that PC4 could be used as a promising therapeutic target for NSCLC.

11.
Cancer Biomark ; 21(2): 489-498, 2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29125483

RESUMO

Epithelia-mesenchymal transition (EMT) is critical for invasion and metastasis of esophageal carcinoma. Gli1, a transcriptional factor in Hedgehog pathway, is correlated with EMT, invasion and metastasis of tumors. However, its role in esophageal cancer is still unknown. Bioinformatics analysis revealed relationship between microRNA (miR)-361 and 3'-UTR of Gli1 gene. This study thus investigated the role of miR-361 and Gli1 in invasion and metastasis of esophageal cancer. Both tumor and adjacent tissues were collected from 58 esophageal cancer patients to test the expressions of miR-361 and Gli1, the relationship of which was confirmed by dual-luciferase reporter gene assay. Cultured esophageal cancer cells EC9706 were transfected with mimic NC, miR-361 mimic, si-NC, si-Gli1, miR-361 mimics+si-Glil, pQC or pQC-FU-Gli1. Transwell and colony formation assays were performed for cell invasion and attachment-independent growth. Expressions of Gli1, Snail, E-cadherin and N-cadherin proteins were revealed by Western blotting. The expression of Gli1 was significantly elevated in esophageal cancer tissues, along with lower miR-361 expression which was correlated with TNM stage. MiR-361 inhibited the expression of Gli1 via targeting on 3'-UTR of Gli1 gene. The transfection of miR-361 mimics and/or si-Gli1 significantly suppressed the growth of malignant cells. The over-expression of miR-361 and/or silencing of Gli1 decreased intracellular expression of Gli1, Snail and N-cadherin, and increased E-cadherin expression to suppress EMT and invasion of tumor cells while the opposite effects were obtained by over-expression of Gli1. Abnormal elevation of Gli1 and decrease of miR-361 were found in esophageal cancer tissues. MiR-361 weakened invasion of cancer cells and impeded EMT process via the inhibition of Gli1.


Assuntos
Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , MicroRNAs/biossíntese , Proteína GLI1 em Dedos de Zinco/biossíntese , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/genética , Feminino , Células HEK293 , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
12.
Radiother Oncol ; 125(2): 331-337, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29079309

RESUMO

BACKGROUND: The importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit. METHODS: 306 patients with ES-SCLC were retrospectively reviewed, of which 170 received IMRT/CRT fractionation RT after ChT, and 136 received chemotherapy (ChT) alone. We adopted the time-adjusted BED (tBED) for effective dose fractionation calculation. Due to the nonrandomized nature of this study, we compared the ChT+RT with ChT groups that matched on possible confounding variables. RESULTS: Patients achieved 2-year OS, PFS and LC rates of 19.7%, 10.7% and 28.4%, respectively. After propensity score matching, (113 cases for each group), the rates of OS, PFS and LC at 2 years were 21.4%, 7.7% and 34.5% for ChT+TRT, and 10.3% (p<0.001), 4.6% (p<0.001) and 6.3% for ChT only (p<0.001), respectively. Among propensity score matching patients, 56 cases for each group received the high dose (tBED>50 Gy) TRT and received low dose (tBED≤50 Gy) TRT. Two-year OS, PFS and LC rates were 32.3%, 15.3% and 47.1% for the high dose compared with 17.0% (p<0.001), 12.9% (p=0.097) and 34.7% (p=0.029) for low dose radiotherapy. CONCLUSIONS: TRT added to ChT improved ES-SCLC patient OS. High dose TRT improved OS over lower doses. Our results suggest that high-dose thoracic radiation therapy may be a reasonable consideration in select patients with ES-SCLC.


Assuntos
Neoplasias Pulmonares/radioterapia , Carcinoma de Pequenas Células do Pulmão/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fracionamento da Dose de Radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Radioterapia Conformacional , Radioterapia de Intensidade Modulada , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Adulto Jovem
13.
Oncotarget ; 8(38): 62998-63013, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28968966

RESUMO

AIMS: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. PATIENTS AND METHODS: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. RESULTS: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. CONCLUSIONS: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

14.
Oncotarget ; 8(39): 65171-65185, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029421

RESUMO

The purpose of this study is to assess the prognostic value of supraclavicular nodes, left gastric nodes, celiac nodes and common hepatic nodes metastasis in esophageal squamous cell carcinoma (ESCC) treated with definitive radiotherapy. A total of 293 ESCC patients treated with radiotherapy or chemoradiotherapy entered the study. The results showed that the presence of supraclavicular nodes (χ2 = 0.075, P = 0.785) and left gastric nodes (χ2 = 3.603, P = 0.058) metastasis had no significant influence on survival, while celiac nodes (χ2 = 33.775, P < 0.001) and common hepatic nodes (χ2 = 42.350, P < 0.001) metastasis were associated with significantly shorter survival, regardless of the sites of primary tumor. Multivariate analysis showed that celiac nodes (HR: 0.457, 95% CI: 0.256-0.816; P = 0.008) and common hepatic nodes (HR: 0.241, 95% CI: 0.092-0.630; P = 0.004) metastasis were independently adverse indicator of survival in upper ESCC. While in the middle and lower ESCC, only the common hepatic nodes (middle ESCC: HR: 0.345, 95% CI: 0.161-0.738, P = 0.006; lower ESCC: HR: 0.377, 95% CI: 0.160-0.890, P = 0.026) metastasis was an independently adverse indicator of survival. In conclusion, our study demonstrated that in ESCC treated with definitive radiotherapy, both of celiac nodes and common hepatic nodes metastasis were adverse indicator of survival in upper ESCC, and common hepatic nodes metastasis were adverse indicator of survival in middle and lower ESCC. Supraclavicular nodes an left gastric nodes metastasis is not associated with patients survival in ESCC.

15.
Sci Rep ; 7(1): 9255, 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28835666

RESUMO

There has been no previous study on the efficacy of the thoracic radiotherapy (TRT) in oligometastatic or polymetastatic extensive stage small-cell lung cancer (ES-SCLC) to the overall survival (OS). In a group of 270 ES-SCLC cases retrospective study, 78 patients (28.9%) had oligometastases and 192 (71.1%) had polymetastases, among which 51 oligometastatic patients (65.4%) and 93 polymetastatic patients (51.6%) received TRT. Propensity score matching (PSM) was utilized. The 2-year OS, progression free survival (PFS) and local control (LC) in oligometastatic and polymetastatic patients were 22.8% and 4.5% (p < 0.001), 12.0% and 3.8% (p < 0.001), and 36.7% and 6.1% (p < 0.001), respectively. The 2-year OS in oligometastatic patients with the chemotherapy + radiotherapy and chemotherapy alone were 25.2% and 12.7% (p = 0.002), in contrast to 10.0% and 6.8% (p = 0.030) in polymetastatic patients. The estimated hazard ratios for survival were 2.9 and 1.7 for both oligometastatic and polymetastatic patients with radiotherapy. The polymetastatic group has a lower LC (6.1% v.s. 36.7%, (p < 0.001)), due to polymetastases patients receiving involved-sites radiotherapy with low dose schemas. TRT improved OS of patients with oligometastases and polymetastases. Our study demonstrated that aggressive TRT might be a suitable addition of chemotherapy when treating ES-SCLC patients with oligometastases and polymetastases.

16.
Cancer Med ; 6(8): 1871-1881, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28719148

RESUMO

FUN14 domain containing 1 (FUNDC1) is an important molecule in receptor-dependent mitophagy. However, the roles of FUNDC1 in human cancer biology remain unknown. The aim of this study was to explore the expression and roles of FUNDC1 in cervical cancer. Immunohistochemistry and Western blotting were applied to detect the expression of FUNDC1, and small-hairpin RNA was applied to inhibit the expression of endogenous FUNDC1 in cervical cancer cells. MTT assays and Flow cytometric analysis were applied to examine cell proliferation and apoptosis. Immunofluorescence was used to detect the formation of γH2AX foci and evaluate the extent of DNA damage. Compared with corresponding adjacent noncancerous cervical tissues, the expression of FUNDC1 in cervical cancer cells was significantly increased. High expression of FUNDC1 and the prognosis of patients with cervical cancer were correlated negatively, which could be used as an independent prognostic factor for overall survival and disease-free survival. Depletion of FUNDC1 significantly inhibited the proliferation of tumor cells, induced apoptosis, and enhanced cell sensitivity to cisplatin and ionizing radiation (IR). Our data suggested that FUNDC1 can be used as a prognostic biomarker in patients with cervical cancer, and may be a new therapeutic target to improve the antitumor effects of chemoradiotherapy.


Assuntos
Biomarcadores Tumorais , Expressão Gênica , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade , Apoptose/genética , Proliferação de Células , Quimiorradioterapia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Tolerância a Radiação/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia
17.
Oncotarget ; 8(25): 40594-40605, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28380449

RESUMO

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein encoded by a gene located in the short arm of chromosome 7. This study aimed to investigate the clinicopathologic characteristics of classic EGFR exon mutation in Chinese patients with TMN stage III lung adenocarcinoma who received radical surgery. A total of 1,801 lung adenocarcinomas were analyzed for mutations in EGFR; 35% exhibited mutation of classic EGFR exons. Clinical and pathologic characteristics of patients with EGFR exon 19 mutation were compared with those who harbored EGFR exon 21 mutation. Patients with EGFR exon 19 mutation had a higher overall survival (OS, p=0.023) than those harboring EGFR exon 21 mutation. Our results demonstrated that patients with a micropapillary pattern (MPP) pathologic type in EGFR exon 19 mutation had a higher OS (p=0.022), and patients with exon 19 mutation were more sensitive to EGFR-tyrosine kinase inhibitors (p=0.032). The results of the current study can be used in decision-making regarding the treatment of patients with classic EGFR exon mutations.


Assuntos
Adenocarcinoma Papilar/genética , Receptores ErbB/genética , Éxons/genética , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma Papilar/etnologia , Adenocarcinoma Papilar/patologia , Grupo com Ancestrais do Continente Asiático/genética , China , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico
18.
Oncotarget ; 8(23): 37208-37216, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28388538

RESUMO

In this retrospective study, we developed nomograms for predicting the efficacy of post-operation radiotherapy (PORT) in IIIA-N2 non-small cell lung cancer (NSCLC) patients. In total, 334 patients received post-operational chemotherapy and were included in the analysis. Of those, 115 also received either concurrent or sequential post-operational radiotherapy (PORT). Nomograms were developed using Cox proportional hazard regression models to identify clinicopathological characteristics that predicted progression free survival (PFS) and overall survival (OS), and subgroup analyses of the effects of PORT were performed using nomogram risk scores. PFS and OS predicted using the nomogram agreed well with actual PFS and OS, and patients with high PFS/OS nomogram scores had poorer prognoses. In subgroup analyses, PORT increased survival more in patients with low PFS nomogram risk scores or high OS nomogram risk scores. Thus, our novel nomogram risk score model predicted PFS, OS, and the efficacy of PORT in IIIA-N2 NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Nomogramas , Período Pós-Operatório , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Risco , Análise de Sobrevida , Resultado do Tratamento
19.
Radiat Oncol ; 12(1): 42, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28245874

RESUMO

BACKGROUND: This study evaluated the prognosis of patients with extensive-stage small-cell lung cancer (ES-SCLC) that may be associated with timing of thoracic radiotherapy (TRT). METHODS: ES-SCLC patients (n = 232) without progression were retrospectively analyzed after first-line induction chemotherapy. Patients in the TRT group were stratified as early-TRT (ERT; ≤3 cycles of induction chemotherapy received prior to TRT, n = 65) or late-TRT (LRT; >3 cycles, n = 122). To avoid selection bias, we conducted Propensity Score Matching (PSM) for patients. Overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRRFS) were assessed and compared. RESULTS: Overall, the median survival time, PFS, and LRRFS were 13.2, 8.7, and 14.6 months, respectively. After matching by PSM, there were 45 patients total in the TRT/non-TRT groups, and 56 patients total in the ERT/LRT groups. OS, PFS, and LRRFS were significantly longer in the TRT group than the non-TRT group (P < 0.001, all). However, between the ERT and LRT groups these survival parameters were similar (P > 0.05, all). CONCLUSION: For ES-SCLC patients without progression, the addition of TRT after first-line chemotherapy benefited survival greatly. Early TRT showed no significant benefit over late TRT.


Assuntos
Neoplasias Pulmonares/radioterapia , Recidiva Local de Neoplasia/radioterapia , Carcinoma de Pequenas Células do Pulmão/radioterapia , Neoplasias Torácicas/radioterapia , Idoso , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Dosagem Radioterapêutica , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/secundário , Taxa de Sobrevida , Neoplasias Torácicas/secundário , Tempo para o Tratamento , Resultado do Tratamento
20.
Onco Targets Ther ; 10: 763-771, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28243112

RESUMO

PURPOSE: The purpose of this study was to investigate the potential effect of activation of epidermal growth factor receptor (EGFR) signaling pathway on the expression of programmed death-ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) cells with EGFR overexpression. METHODS: Flow cytometry and Western blot methods were used to assess PD-L1 expression on ESCC cells when EGFR signaling pathway was activated by epidermal growth factor (EGF) with or without EGFR-specific inhibitor AG-1478, and then EGFR signaling array was applied to analyze the potential signaling pathways involved. RESULTS: This study found that PD-L1 expression increased significantly in an EGFR-dependent manner by the activation of EGFR signaling and decreased sharply when EGFR signaling was blocked. The upregulated expression of PD-L1 was not associated with EGFR-STAT3 signaling pathway, but may be affected by EGFR-PI3K-AKT, EGFR-Ras-Raf-Erk, and EGR-PLC-γ signaling pathways. CONCLUSION: The expression of PD-L1 can be regulated by EGFR signaling activation in ESCC, which indicates an important role for EGFR-mediated immune escape and potential molecular pathways for EGFR-targeted therapy and immunotherapy.

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