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1.
Artigo em Inglês | MEDLINE | ID: mdl-36623605

RESUMO

PURPOSE: In the era of immunotherapy, the treatment for bulky locally advanced non-small-cell lung cancer (LA-NSCLC) remains challenging. This study explored the feasibility of induction immune checkpoint inhibitors (ICIs) plus chemotherapy before definitive chemoradiation therapy (CRT) for bulky LA-NSCLC. METHODS AND MATERIALS: Patients with bulky unresectable stage III NSCLC (primary tumor ≥ 5 cm in greatest dimension or metastatic lymph nodes ≥ 2 cm in shortest diameter) receiving ICI and chemotherapy before CRT from 2018 to 2022 were identified. Survival outcomes and toxicity were analyzed. Radiotherapy plans on CT images before and after 2 cycles of induction chemoimmunotherapy were simulated to evaluate dosimetric impact. RESULTS: Seventy-five patients were included. One- and 2-year overall-survival (OS) rates were 91.5% (95% CI, 85.2-98.3) and 75.1% (95% CI, 64.1-88.0), respectively. One- and 2-year progression-free-survival (PFS) rates were 85.8% (95% CI, 78.0-94.4) and 64.2% (95% CI, 52.5-78.6), respectively. Median OS was not reached (NR). Median PFS was 30.6 months (95% CI, 25.9-NR). Grade 2 and ≥ 3 pneumonitis occurred in 26.7% and 9.3%, respectively. Grade ≥ 3 pneumonitis significantly related to poorer OS (P=0.003) and PFS (P=0.018). Treatment discontinuation was significantly associated with shorter OS (P=0.023) and PFS (P=0.047). Patients with consolidation ICI exhibited numerically better OS than those without consolidation ICI (2-year OS 85.8% versus 64.2%, P=0.170). Objective response rate was 76.1% for induction treatment and 86.7% for induction treatment plus CRT. Disease control rate after 2 cycles of induction therapy was significantly greater that after 4 (P=0.046) or more cycles (P=0.025). Simulated radiation plans indicated all target volumes, mean lung dose, lung V5, V20, and V30 significantly decreased after 2 cycles (all P<0.005). CONCLUSIONS: Two cycles of induction ICI plus chemotherapy before definitive CRT are feasible for bulky LA-NSCLC, with significant tumor reduction and normal lung protection. Further investigations on CRT combined with induction and consolidation ICI are warranted.

2.
Front Oncol ; 12: 998238, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439431

RESUMO

Background: It is still uncertain whether the newly released eighth American Joint Committee on Cancer (AJCC) post-neoadjuvant pathologic (yp) tumor-node-metastasis (TNM) stage for esophageal carcinoma can perform well regarding patient stratification. The current study aimed to assess the prognostication ability of the eighth AJCC ypTNM staging system and attempted to explore how to facilitate the staging system for more effective evaluation of prognosis. Materials and methods: A total of 486 patients treated with neoadjuvant radiotherapy/chemoradiotherapy (nRT/CRT) were enrolled. ypN stage was reclassified by recursive partitioning. Prognostic performance, monotonicity, homogeneity, and discriminatory of yp and modified yp (myp) staging systems were assessed by time-dependent receiver operating characteristic (ROC), linear trend log-rank test, likelihood ratio χ2 test, Harrell's c statistic, and Akaike information criterion (AIC). Results: The ypT stage, ypN stage, and pathologic response were significant prognostic factors of overall survival. Survival was not discriminated well using the eighth AJCC ypN stage and ypTNM stage. Recursive partitioning reclassified mypN0-N2 as metastasis in 0, 1-2, and ≥3 regional lymph nodes. Applying the ypT stage, mypN stage, and pathologic response to construct the myp staging system, the myp stage performed better in time-dependent ROC, linear trend log-rank test, likelihood ratio χ2 test, Harrell's c statistic, and AIC. Conclusions: The eighth AJCC ypTNM staging system performed well in differentiating prognosis to some extent. By reclassifying the ypN stage and enrolling pathologic response as a staging element, the myp staging system holds significant potential for prognostic discrimination.

3.
Clin Transl Med ; 12(11): e1116, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36437506

RESUMO

BACKGROUND: The potential of circulating tumour DNA (ctDNA) as a reliable biomarker for relapse/metastasis early detection and prognosis in esophageal squamous cell carcinoma (ESCC) after radiotherapy/chemoradiotherapy (RT/CRT) initiation requires comprehensive investigation. METHODS: Treatment-naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose. Serial plasma samples were collected at baseline (T0 ), week 4 of RT/CRT (T1 ), 1-3 (T2 ) and 3-6 months post-RT/CRT (T3 ). ctDNA was analysed using next-generation sequencing of 474 cancer-relevant genes. RESULTS: A total of 128 plasma samples from 40 eligible patients were analysed (median age: 64 [range: 40-78], 88% males, 95% stage III/IV), and the median follow-up time was 20.6 months (range: 12.2-33.3). During the post-RT/CRT surveillance including 36 patients, radiological progression was observed in 16 patients, and 69% (11/16) had detectable post-RT/CRT ctDNA prior to radiological progression, with a median lead time of 4.4 months compared with radiological imaging. ctDNA positivity at T1 (hazard ratio, HR: 3.60, 95% confidence interval, CI: 1.30-10.01) or T2 (HR: 5.45, 95% CI: 1.72-17.26) indicated inferior progression-free survival (PFS). ctDNA clearance between T0 -T1 (HR: 0.31, 95% CI: 0.08-1.13) or T0 -T2 (HR: 0.11; 95% CI: 0.02-0.61) was associated with relatively favourable PFS. Similar results were obtained when focusing on patients without esophagectomy after RT/CRT. Notably, detectable ctDNA at T1 was a potential indicator of high local recurrence risks (HR: 4.43, 95% CI: 1.31-15.04). CONCLUSIONS: ctDNA was identified as a robust biomarker for early detection of disease progression and post-RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility of ctDNA tests in guiding post-RT/CRT treatments for locoregional control in ESCC.


Assuntos
DNA Tumoral Circulante , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/radioterapia , DNA Tumoral Circulante/genética , Prognóstico , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/radioterapia
4.
Medicine (Baltimore) ; 101(42): e31215, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36281080

RESUMO

Esophageal carcinosarcoma is a rare type of esophageal cancer; however, few studies have investigated the effects of radiotherapy in locally advanced patients. This study aimed to report experience of the safety and efficacy of intensity-modulated radiotherapy for locally advanced esophageal carcinosarcoma and review the literature. By searching the institutional database between January 2010 and December 2020, along with the literature review, 25 patients were eligible for the study. The clinical and radiologic information of all patients with esophageal carcinosarcoma who underwent radiotherapy were collected. Survival outcomes were calculated using Kaplan-Meier plots. In our series, 5 patients were in the curative/neoadjuvant radiotherapy group and 10 patients were in the adjuvant group. Most tumors were protruding (n = 10, 66.7%). All patients underwent intensity-modulated radiotherapy. In the curative/neoadjuvant radiotherapy group, 2 patients underwent concurrent chemoradiotherapy before surgery, and the other three received radiotherapy alone as the initial treatment. The median follow-up time was 43.1 months. All patients showed a partial response at the efficacy evaluation. The median time of overall survival and progression-free survival were 40.2 months (95% confidence interval [CI], 13.1-67.3 months) and 19.0 months (95% CI, 13.9 months-24.1 months) for the entire cohort, but were not reached for curative/neoadjuvant radiotherapy group. Overall survival (hazard ratio [HR] 0.81, 95% CI, 0.15-4.43; P = .805) and progression-free survival (HR 1.68, 95% CI, 0.35-8.19; P = .514) did not differ significantly between the 2 groups. When considering the literature review data in the final analysis, overall survival (HR 0.84, 95% CI, 0.25-2.81; P = .779) and progression-free survival (HR, 0.68; 95% CI, 0.26-1.76; P = .425) were also not different between the 2 groups. Treatment based on intensity-modulated radiotherapy with neoadjuvant or curative intent may be an option for patients with unresectable esophageal carcinosarcoma. Further research with a larger sample size is needed to validate the reliability.


Assuntos
Carcinossarcoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Radioterapia de Intensidade Modulada , Humanos , Intervalo Livre de Doença , Reprodutibilidade dos Testes , Neoplasias Esofágicas/patologia , Carcinossarcoma/radioterapia
5.
Cancers (Basel) ; 14(19)2022 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-36230867

RESUMO

PURPOSE: Thymic neuroendocrine tumors (TNETs) are a collection of slow-progressing neoplasms located in the anterior mediastinum. Relatively few previously published studies have focused on thymic carcinomas. This study investigated the basic clinical characteristics, treatment, and prognosis of TNETs. METHODS: Patients were enrolled in the study from January 2003 to December 2017 who had been diagnosed with TNETs through pathological screening and treated at our institution. Demographic data from each patient, the Masaoka stage, histology and size of the tumor, tumor invasion characteristics, and therapeutic strategies were gathered. The Kaplan-Meier method was used to assess patient survival. In addition, the log-rank test was used to carry out univariate analyses. RESULTS: Twenty-six patients were eligible for inclusion in the study. The median age of the patients was 46.5 (25-69) years. The tumor median maximum diameter was 7.9 cm (from 3 to 19 cm). Twenty-four patients were treated surgically. Nineteen patients completed radiation therapy, and sixteen patients underwent chemotherapy. A median follow-up time of 54.95 months was observed. The survival rate for three years was 75.0% and 70.6% for five years. The corresponding progression-free survival rates for three and five years were 55.7% and 37.7%, respectively. The local, regional recurrence-free survival (LRFS) rates were 87.2% and 81.7%, and the distant metastasis-free survival (DMFS) rates were 55.7% and 37.7%, at three and five years, respectively. Local recurrence (six patients) and bone metastasis (six patients) were observed as the most frequent failures. CONCLUSION: TNET was observed to be an aggressive but rare malignant lesion. While the predominant treatment was complete resection, chemotherapy and radiotherapy were also required due to the high recurrence rate.

7.
Ther Adv Med Oncol ; 14: 17588359221108693, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35923925

RESUMO

Objective: This study aimed to determine the long-term survival of patients with cT4 esophageal cancer (EC) and whether neoadjuvant chemoradiotherapy/radiotherapy plus surgery (nCRT/RT + S) is superior to definitive CRT(dCRT)/RT in terms of survival in cT4 EC downstaged after nCRT/RT. Summary background data: Treatment options for cT4 EC include dCRT/RT and nCRT/RT + S, but it is not clear whether the latter provides survival benefit in patients downstaged after nCRT/RT. Methods: From 2002 to 2017, 726 patients with cT4 esophageal squamous cell carcinoma (ESCC) were retrospectively analyzed. Patients achieving clinical complete response (cCR) or partial response (PR) after 4-week RT (median dose, 40.7 Gy) and considered fit for surgery were offered esophagectomy. Of the 726 patients, 308 (42.4%) achieved cCR/PR, while 74 patients received subsequent surgery (nCRT/RT + S group), 234 patients received dCRT/RT. Results: Median follow-up was 58 months. The 3-year overall survival (OS) and progression-free survival (PFS) rates for all patients were 33.3% and 35.6%, respectively. The corresponding OS and PFS rates were 54.8% and 48.5% in the nCRT/RT + S group versus 30.0% and 22.1% in the dCRT/RT group (both p < 0.0001). After adjusting the confounding variables with inverse probability of treatment weighting, the adjusted 3-year OS rates were 50.4% in the nCRT/RT + S group versus 50.8% in the dCRT/RT group (p = 0.15). However, the adjusted 3-year PFS rates were significantly different between the two groups (49.0% and versus 38.3%, p = 0.004). Postoperative complications occurred in 18 (24.3%) patients. Conclusion: The long-term survival of cT4 ESCC was improved after the use of three-dimensional CRT. In cT4, EC responded to nCRT/RT, surgery improves PFS but not OS.

8.
Front Immunol ; 13: 918787, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35795657

RESUMO

Purpose: Whilst survival benefits of thoracic radiotherapy (TRT) followed by immune checkpoint inhibitor (ICI) have been reported in patients with lung cancer, the potential high risk of treatment-related pneumonitis remains a concern. Asians may be more sensitive to lung toxicity than other races. This retrospective study intended to provide a comprehensive pneumonitis profile of TRT followed by ICI and investigate the risk factors from a Chinese cohort of lung cancer. Methods and Materials: From January 2016 to July 2021, 196 patients with lung cancer who received TRT prior to ICI were retrospectively analyzed. Treatment-related pneumonitis, including checkpoint inhibitor pneumonitis (CIP), radiation pneumonitis (RP), and radiation recall pneumonitis (RRP), were recorded and graded through medical records and chest computed tomography. Characteristics predictive of pneumonitis were assessed using logistic regression models, and the receiver operating characteristic analyses were performed to identify optimal cut points for quantitative variables. Results: With a median follow-up of 18 months, a total of 108 patients (55.1%) developed treatment-related pneumonitis during ICI therapy, with an incidence of 25.5% for grade 2 or higher (G2+) and 4.1% for G3+. The overall rates of CIP, RP and RRP were 8.2% (n=16), 46.9% (n=92) and 7.1% (n=14), respectively. With a total mortality rate of 1.5%, vast majority of the patients recovered from pneumonitis or remained stable. No patients died of RRP. Half of the patients with G2+ RP who withheld ICI therapy restarted ICI safely after resolution of RP. The history of chronic pulmonary diseases (P=0.05), mean lung dose (MLD, P=0.038), percent volume of lung receiving ≥5 Gy (V5, P=0.012) and percent volume of lung receiving ≥20 Gy (V20, P=0.030) predicted the occurrence of RRP in univariate analyses. Interval between TRT and ICI less than 3 months was an independent predictor for G2+ treatment-related pneumonitis in a multivariate model (Odds ratio OR=2.787, P=0.004). Conclusions: Treatment-related pneumonitis, especially RRP, is acceptable and manageable in the setting of TRT followed by ICI in this Asian population. Dosimetric parameters MLD, V5 and V20 may improve the predictions of RRP in clinical practice.


Assuntos
Neoplasias Pulmonares , Pneumonia , Pneumonite por Radiação , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Pneumonia/complicações , Pneumonia/etiologia , Pneumonite por Radiação/diagnóstico , Pneumonite por Radiação/epidemiologia , Pneumonite por Radiação/etiologia , Estudos Retrospectivos , Fatores de Risco
9.
Front Cell Infect Microbiol ; 12: 828605, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719343

RESUMO

Anaplasma phagocytophilum, a tick-borne obligately intracellular bacterium of neutrophils, causes human granulocytic anaplasmosis. Ankyrin A (AnkA), an effector protein with multiple ankyrin repeats (AR) is injected via type IV-secretion into the host neutrophil to gain access to the nucleus where it modifies the epigenome to promote microbial fitness and propagation. AR proteins transported into the host cell nucleus must use at least one of two known eukaryotic pathways, the classical importin ß-dependent pathway, and/or the RanGDP- and AR (ankyrin-repeat)-dependent importin ß-independent (RaDAR) pathway. Truncation of the first four AnkA N-terminal ARs (AR1-4), but not other regions, prevents AnkA nuclear accumulation. To investigate the mechanism of nuclear import, we created point mutations of AnkA N-terminal ARs, predicted to interfere with RaDAR protein import, and used importazole, a specific inhibitor of the importin α/ß, RanGTP-dependent pathway. Nuclear colocalization analysis shows that nuclear localization of AnkA is unaffected by single AR1-4 mutations but is significantly reduced by single mutations in consecutive ARs suggesting RaDAR protein nuclear import. However, AnkA nuclear localization was also decreased with importazole, and with GTPγS. Furthermore, A. phagocytophilum growth in HL-60 cells was completely suppressed with importazole, indicating that A. phagocytophilum propagation requires a ß-importin-dependent pathway. A typical classical NLS overlapping AR4 was subsequently identified suggesting the primacy of the importin-α/ß system in AnkA nuclear localization. Whether the mutational studies of putative key residues support RaDAR NLS function or simply reflect structural changes that diminish engagement of an AR-NLS-importin pathway needs to be resolved through careful structure-function studies.


Assuntos
Anaplasma phagocytophilum , Transporte Ativo do Núcleo Celular , Anaplasma phagocytophilum/genética , Anaplasma phagocytophilum/metabolismo , Animais , Anquirinas/metabolismo , Núcleo Celular/metabolismo , Humanos , Carioferinas/metabolismo , beta Carioferinas/genética , beta Carioferinas/metabolismo
10.
Med Phys ; 49(8): 4971-4979, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35670079

RESUMO

PURPOSE: Fast and accurate delineation of organs on treatment-fraction images is critical in magnetic resonance imaging-guided adaptive radiotherapy (MRIgART). This study proposes a personalized auto-segmentation (AS) framework to assist online delineation of prostate cancer using MRIgART. METHODS: Image data from 26 patients diagnosed with prostate cancer and treated using hypofractionated MRIgART (5 fractions per patient) were collected retrospectively. Daily pretreatment T2-weighted MRI was performed using a 1.5-T MRI system integrated into a Unity MR-linac. First-fraction image and contour data from 16 patients (80 image-sets) were used to train the population AS model, and the remaining 10 patients composed the test set. The proposed personalized AS framework contained two main steps. First, a convolutional neural network was employed to train the population model using the training set. Second, for each test patient, the population model was progressively fine-tuned with manually checked delineations of the patient's current and previous fractions to obtain a personalized model that was applied to the next fraction. RESULTS: Compared with the population model, the personalized models substantially improved the mean Dice similarity coefficient from 0.79 to 0.93 for the prostate clinical target volume (CTV), 0.91 to 0.97 for the bladder, 0.82 to 0.92 for the rectum, and 0.91 to 0.93 for the femoral heads, respectively. CONCLUSIONS: The proposed method can achieve accurate segmentation and potentially shorten the overall online delineation time of MRIgART.


Assuntos
Neoplasias da Próstata , Radioterapia Guiada por Imagem , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Redes Neurais de Computação , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Radioterapia Guiada por Imagem/métodos , Estudos Retrospectivos
12.
Clin Med Insights Oncol ; 16: 11795549221080347, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250326

RESUMO

BACKGROUND: EGFR tyrosine kinase inhibitor (TKI) is recommended as the first-line therapy for patients with EGFR-mutant metastatic non-small cell lung cancer (NSCLC). Yet, resistance often occurs in 1 year after therapy and most progressions occur at the initial sites of disease. Addition of local therapy to the first-line TKI therapy may delay the progression and provide survival benefit to the patients. METHODS: From 2010 to 2017, metastatic NSCLC patients with EGFR activating mutations who received first-line TKI and relatively radical local therapy (RRLT) were reviewed. RRLT was defined as local curative therapy to the main site or any intensity of local therapy to all sites of disease. The Kaplan-Meier method and log-rank test were used for survival estimation and comparison. RESULTS: A total of 45 patients were included in this retrospective study with a median follow-up of 48.0 months. The median progression-free survival (PFS) and overall survival (OS) was 17.0 months (95% confidence interval [CI]: 14.6-19.3) and 55.0 months (95% CI: 49.3-60.6), respectively. Univariate analysis indicated that age ⩽ 60 years (P = .019), first-line TKI duration ⩾ 10 months (P = .028), and accumulated TKI duration ⩾ 20 months (P = .016) were significantly associated with favorable OS. Among the 36 patients who progressed during the follow-up, 55.8% of the progressions occurred at the new sites. RRLT combined with TKI did not show any severe toxicity to the patients. CONCLUSIONS: Combined application of RRLT and first-line TKI may improve the survival and alter the pattern of failure for metastatic NSCLC patients with EGFR activating mutations.

13.
Radiat Oncol ; 17(1): 58, 2022 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-35346279

RESUMO

BACKGROUND: The low incidence of primary mediastinal seminomas has precluded the development of clinical trials on mediastinal seminomas. We investigated the clinicopathologic characteristics, prognosis of patients with primary mediastinal seminomas as well as the efficiency of nonsurgical treatments compared with treatments containing surgery. METHODS: We retrospectively collected data on the clinicopathologic characteristics, treatments, toxicities, and survival of 27 patients from a single center between 2000 and 2018. Patients were divided into two groups according to whether they received operation. Survivals were assessed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test. RESULTS: The median age was 28 (13-63) years. The most common symptoms were chest pain (29.6%), cough (25.9%), and dyspnea (22.2%). There were 13 and 14 patients in surgery and non-surgery group. Patients in the non-surgical group were more likely to be with poor performance scores (100% vs. 76.9%) and disease invaded to adjacent structures (100% vs. 76.9%) especially great vessels (100% vs. 46.2%).The median follow-up period was 32.23 (2.7-198.2) months. There was no significant difference of overall survival (5-year 100% vs. 100%), cancer-specific survival (5-year 100% vs. 100%), local regional survival (5-year 91.7% vs. 90.0%, p = 0.948), distant metastasis survival (5-year 90.9% vs. 100.0%, p = 0.340) and progression-free survival (82.5% vs. 90.0%, p = 0.245) between patients with and without surgery. CONCLUSIONS: Primary mediastinal seminoma was with favorable prognosis, even though frequently invasion into adjacent structures brings difficulties to surgery administration. Chemoradiotherapy is an alternative treatment with both efficacy and safety.


Assuntos
Neoplasias do Mediastino , Seminoma , Neoplasias Testiculares , Adolescente , Adulto , Quimiorradioterapia , Humanos , Masculino , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Seminoma/patologia , Seminoma/radioterapia , Neoplasias Testiculares/terapia , Adulto Jovem
14.
Front Oncol ; 12: 810580, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35155246

RESUMO

PURPOSE: To investigate whether progression-free survival (PFS) or time to progression (TTP) could be a valid surrogate endpoint for overall survival (OS) in patients with limited-stage small-cell lung cancer (LS-SCLC) receiving combined chemoradiotherapy. METHODS: Literature searching was performed in PubMed, Embase, and The Cochrane Library up to 2021. Prediction models were firstly established using data from phase III randomized controlled trials (RCTs) and then externally validated in phase II and retrospective studies. Correlation analysis was evaluated by a weighted linear regression model at both trial and arm levels. Cross-validation was performed to assess the consistency and robustness of the established models. RESULTS: 37 studies, including 15 phase III RCTs, 12 phase II studies, and 10 retrospective studies, were selected in the final analysis. In trial-level surrogacy, a very good correlation was observed between hazard ratios (HRs) of PFS/TTP and OS (R2 = 0.783, 95% CI 0.771-0.794). In arm-level surrogacy, very good correlations were also observed between 2-year (R2 = 0.823, 95% CI 0.814-0.832), 3-year (R2 = 0.843, 95% CI 0.833-0.850), 5-year (R2 = 0.852, 95% CI 0.843-0.859) PFS/TTP, and 5-year OS. An excellent correlation was observed between 4-year PFS/TTP and 5-year OS (R2 = 0.906, 95% CI 0.901-0.910). Cross-validation demonstrated reasonable overall consistency. External validation in phase II and retrospective studies showed good agreement (R2, 0.728-0.824). CONCLUSIONS: PFS/TTP was a valid surrogate endpoint for OS in patients with LS-SCLC receiving combined chemoradiotherapy. The finding provides high-level evidence to support PFS/TTP as the primary endpoint in clinical trials so as to speed up introducing novel agents to the treatment of LS-SCLC.

15.
J Cell Sci ; 135(6)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35142363

RESUMO

TDP-43 (also known as TARDBP) is a nuclear splicing factor functioning in pre-mRNA processing. Its C-terminal 35-kDa fragment (TDP-35) forms inclusions or aggregates in cytoplasm, and sequesters full-length TDP-43 into the inclusions through binding with RNA. We extended the research to investigate whether TDP-35 inclusions sequester other RNA-binding proteins (RBPs) and how RNA-binding specificity has a role in this sequestration process. We have characterized T-cell restricted intracellular antigen-1 (TIA1) and other RBPs that can be sequestered into the TDP-35 inclusions through specific RNA binding, and found that this sequestration leads to the dysfunction of TIA1 in maturation of target pre-mRNA. Moreover, we directly visualized the dynamic sequestration of TDP-43 by the cytoplasmic TDP-35 inclusions by live-cell imaging. Our results demonstrate that TDP-35 sequesters some specific RBPs and this sequestration is assisted by binding with RNA in a sequence-specific manner. This study provides further evidence in supporting the hijacking hypothesis for RNA-assisted sequestration and will be beneficial to further understanding of the TDP-43 proteinopathies.


Assuntos
Esclerose Amiotrófica Lateral , Proteinopatias TDP-43 , Esclerose Amiotrófica Lateral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Corpos de Inclusão/metabolismo , RNA/genética , RNA/metabolismo , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteinopatias TDP-43/metabolismo
16.
J Gastroenterol Hepatol ; 37(4): 734-740, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35102609

RESUMO

BACKGROUND AND AIM: Colonic stem cells play important roles in both normal epithelial turnover and injury repair. Lgr5+ colonic stem cells are highly susceptible to DSS-induced damage. However, it is still unclear how colonic stem cells regenerate injured epithelium during colitis. Here, we explored the functions of a new population of NFATc1+ colonic stem cells in experimental colitis. METHODS: Nfatc1+ colonic stem cells were labeled using Nfatc1CreERT2 ;R26mTmG reporter mice. Immunostaining assays were used to detect Goblet cells, enteroendocrine cells, and intestinal stem/progenitor cells. We performed lineage tracing assay to investigate whether Nfatc1+ cells are real colonic stem cells using Nfatc1CreERT2 ;R26mTmG mice. The contribution of Nfatc1+ stem cells on epithelial regeneration was detected in experimental colitis induced by DSS. RESULTS: Nfatc1-reporter marked cells are enriched for +3 to +5 position in colonic crypts, and they are overlapped with Sox9+ cells and Hopx+ cells that have been identified as stem cells in small intestine. However, Nfatc1-reporter marked cells are not overlapped with Lgr5+ colonic stem cells, as well as differentiated goblet cells and enteroendocrine cells. Furthermore, Nfatc1-reporter marked cells are able to give rise to all lineages of the colonic epithelium, and they preferentially contribute to the regeneration of colonic epithelium in DSS-induced experimental colitis. CONCLUSION: Nfatc1+ cells were identified as a novel population of colonic stem cells that are primarily located at +3 to +5 position and contribute to epithelial regeneration during colitis.


Assuntos
Colite , Fatores de Transcrição NFATC , Células-Tronco , Animais , Colite/induzido quimicamente , Mucosa Intestinal/fisiologia , Camundongos , Fatores de Transcrição NFATC/genética , Regeneração , Células-Tronco/fisiologia
17.
Sci Adv ; 8(5): eabm3629, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35119927

RESUMO

Identifying the dynamic structure of heterogeneous catalysts is crucial for the rational design of new ones. In this contribution, the structural evolution of Fe(0) catalysts during CO2 hydrogenation to hydrocarbons has been investigated by using several (quasi) in situ techniques. Upon initial reduction, Fe species are carburized to Fe3C and then to Fe5C2. The by-product of CO2 hydrogenation, H2O, oxidizes the iron carbide to Fe3O4. The formation of Fe3O4@(Fe5C2+Fe3O4) core-shell structure was observed at steady state, and the surface composition depends on the balance of oxidation and carburization, where water plays a key role in the oxidation. The performance of CO2 hydrogenation was also correlated with the dynamic surface structure. Theoretical calculations and controll experiments reveal the interdependence between the phase transition and reactive environment. We also suggest a practical way to tune the competitive reactions to maintain an Fe5C2-rich surface for a desired C2+ productivity.

18.
J Cancer Res Clin Oncol ; 148(5): 1137-1146, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34255149

RESUMO

OBJECTIVES: To analyze the clinical relevance of heterogeneous phenotypes of peripheral circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: CTCs in 5 mL venous blood were enriched using the Canpatrol™ CTC technique in 82 NSCLC patients. And then, CTCs were subjected to RNA in situ hybridization with a combination of epithelial (EpCAM and CK8/18/19) and mesenchymal (vimentin and TWIST1) markers. RESULTS: According to the fluorescent dots, CTCs were classified into three groups, including epithelial CTCs (E-CTC), hybrid epithelial/mesenchymal phenotypes (E/M-CTCs) and mesenchymal CTCs (M-CTCs). In 82 NSCLC cohort, only 2 patients didn't detect CTCs, the overall CTCs detection rate was 97.5% (80/82). For 60 treatment naïve NSCLC, only one patient didn't detect CTCs. The median number of total CTCs, hybrid E/M phenotype CTCs, E-CTCs and M-CTCs per 5 mL blood was 22 (range 1-90), 13 (range 0-83), 1 (range 0-17 and 0-47), respectively. Hybrid E/M CTCs, especially the e = m-CTCs, significantly differed between patients with and without distant metastasis. M-CTCs in advanced NSCLC patients were significantly more than the numbers observed in early stage patients. Patients with pure hybrid E/M-CTCs showed a lower proportion in distant metastasis positive cohort compared to negative ones (7% vs 22%), while patients with E + E/M CTCs (20% vs 9%) and E/M + M CTCs (33% vs 20%) showed a higher proportion. CTCs dynamic changes after treatment in 12 advanced NSCLC patients suggested that hybrid E/M-CTCs were related to the primary tumor size at baseline, while M-CTCs may suggest the progression of NSCLC. CONCLUSION: We concluded that E-CTCs with a hybrid E/M phenotype are associated to metastasis in therapy-naïve NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/patologia , Transição Epitelial-Mesenquimal/genética , Humanos , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Fenótipo , Prognóstico
19.
Thorac Cancer ; 13(3): 296-307, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34927371

RESUMO

BACKGROUND: This study aimed to establish a predictive nomogram integrating epidermal growth factor receptor (EGFR) mutation status for 3- and 5-year overall survival (OS) in unresectable/inoperable stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. METHODS: A total of 533 stage III NSCLC patients receiving chemoradiotherapy from 2013 to 2017 in our institution were included and divided into training and testing sets (2:1). Significant factors impacting OS were identified in the training set and integrated into the nomogram based on Cox proportional hazards regression. The model was subject to bootstrap internal validation and external validation within the testing set and an independent cohort from a phase III trial. The accuracy and discriminative capacity of the model were examined by calibration plots, C-indexes and risk stratifications. RESULTS: The final multivariate model incorporated sex, smoking history, histology (including EGFR mutation status), TNM stage, planning target volume, chemotherapy sequence and radiation pneumonitis grade. The bootstrapped C-indexes in the training set were 0.688, 0.710 for the 3- and 5-year OS. For external validation, C-indexes for 3- and 5-year OS were 0.717, 0.720 in the testing set and 0.744, 0.699 in the external testing cohort, respectively. The calibration plots presented satisfying accuracy. The derivative risk stratification strategy classified patients into distinct survival subgroups successfully and performed better than the traditional TNM staging. CONCLUSIONS: The nomogram incorporating EGFR mutation status could facilitate survival prediction and risk stratification for individual stage III NSCLC, providing information for enhanced immunotherapy decision and future trial design.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Quimiorradioterapia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estadiamento de Neoplasias , Nomogramas , Prognóstico
20.
Front Oncol ; 12: 955381, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36605447

RESUMO

Purpose: The aim of this study is to evaluate the role of regional nodal irradiation (RNI) in patients with T1-2N1M0 breast cancer and to identify the subgroup that could benefit from RNI. Methods and materials: A total of 4,243 women with pT1-2N1M0 breast cancer treated at two institutions in China were retrospectively reviewed. Survival rates were calculated by the Kaplan-Meier method and compared by the log-rank test. The association of risk factors with survival outcomes was evaluated using multivariable proportional hazards regression. Results: A total of 932 patients (22.0%) received RNI. At a median follow-up of 5.9 years, the 5-year locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) rates were 4.0% and 7.2% (P = 0.001), 13.2% and 10.6% (P = 0.465), 85.0% and 84.7% (P = 0.131), and 93.9% and 92.8% (P = 0.004) in the RNI and non-RNI groups, respectively. Multivariate analysis revealed that RNI was an independent prognostic factor for lower LRR (P = 0.001) and longer DFS (P = 0.013). Patients were stratified into low-, intermediate-, and high-risk groups based on the eight non-therapeutic risk factors. RNI significantly decreased the 5-year LRR (2.2% vs. 7.0%, P = 0.001) and improved the 5-year DFS (88.8% vs. 84.9%, P = 0.015) and OS (95.8% vs. 93.9%, P = 0.010) in the intermediate-risk group. However, neither the low-risk group nor the high-risk group had survival benefit from RNI. Conclusion: T1-2N1M0 breast cancer is a heterogeneous disease. We found that RNI only improved survival in the intermediate-risk group. It might be omitted in low-risk patients, and the role of RNI in high-risk patients needs further study.

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