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1.
Orphanet J Rare Dis ; 14(1): 292, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842933

RESUMO

BACKGROUND: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are two kinds of diseases caused by inborn errors of metabolism. So far, the epidemiological data on them are limited in China. The aim of our study is to investigate the proportion and characteristics of hospitalized pediatric patients with MMA and PA in China. METHODS: The data in this study were obtained from the Hospital Quality Monitoring System, a national inpatient database in China, with information on the patients hospitalized during the period from 2013 to 2017. We identified the data related to the patients who were under 18 years old and were diagnosed with MMA/PA, and extracted the information on demographic characteristics, hospital location, total cost and other related clinical presentations from the data. RESULTS: Among all hospitalized pediatric patients with liver diseases, there were increasing trends in the proportion of individuals diagnosed with MMA or PA during the period from 2013 (0.76% for MMA; 0.13% for PA) to 2017 (1.61% for MMA; 0.32% for PA). For both MMA and PA, children under 2-year-old accounted for the highest proportion. The median of total cost per hospitalization was relatively high (RMB 7388.53 for MMA; RMB 4999.66 for PA). Moreover, most patients hospitalized in tertiary class A hospitals (MMA: 80.96%, PA: 76.21%); and a majority of pediatric patients admitted in the hospitals in Shanghai and Beijing are from outside districts. Manifestations of nervous system-related symptoms, and metabolic acidosis or anemia in laboratory findings were more common during hospitalization. CONCLUSIONS: The study is the first nationwide one in providing epidemiological and clinical information on hospitalized pediatric patients with MMA/PA. An increasing hospitalization with various presentations and a heavy financial burden were observed. In addition, geographically, the medical resources in China have been unevenly distributed.

2.
Hepatobiliary Surg Nutr ; 8(5): 470-479, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31673536

RESUMO

Background: There are few detailed consensus and guidelines on perioperative clinical characteristics of liver transplantation (LT) in patients with methylmalonic acidemia (MMA). This retrospective study investigated details of the clinical course and individualized treatment plan of the center with largest experience in China. Methods: A total of 7 MMA patients undergoing LT in Beijing Friendship Hospital from June 2013 to December 2017 were enrolled in the study, whose clinical data (clinical characteristics, laboratory findings, chronological changes in urine MMA levels, treatment, etc.) during perioperative period were analyzed retrospectively. All the patients received strict postoperative management. Results: All the 7 cases were confirmed to have isolated MMA, among which, 3 cases received living donor liver transplantation (LDLT), 4 cases received deceased donor liver transplantation (DDLT). A wild fluctuate of metabolic condition was observed within the first few days after surgery and two weeks after LT, the mean base excess of blood value (BE-B) restored to normal whereas plasma bicarbonate (HCO3 -) was still below normal value even with intermittent sodium bicarbonate correction. It also showed marked reduction in propionylcarnitine (C3) and C3/C2 level and the mean urine MMA by gas chromatography-mass spectrometry (GC-MS) was reduced by 81.7% (P<0.01) but remained >72× higher than upper limit of normal. The metabolism-correcting medications were administered as before. The renal function of one case with renal insufficiency before LT (serum creatinine rising) maintained stable by adjusting the immunosuppressive regimen during the observation period. All patients survive to date. Conclusions: LT is an effective treatment to prevent metabolic crisis, but patients with MMA tend to be metabolically fragile even after surgery. During perioperative period, close monitoring should be given for acidosis episodes so as to implement sodium bicarbonate correction. Metabolism-correcting medications are still needed. Special immunosuppressive regimen is an effective way of maintaining renal function for those with kidney dysfunction.

3.
Nat Protoc ; 14(11): 3220-3242, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31619810

RESUMO

Precise identification of sites of RNA modification is key to studying the functional role of such modifications in the regulation of gene expression and for elucidating relevance to diverse physiological processes. tRNA reduction and cleavage sequencing (TRAC-Seq) is a chemically based approach for the unbiased global mapping of 7-methylguansine (m7G) modification of tRNAs at single-nucleotide resolution throughout the tRNA transcriptome. m7G TRAC-Seq involves the treatment of size-selected (<200 nt) RNAs with the demethylase AlkB to remove major tRNA modifications, followed by sodium borohydride (NaBH4) reduction of m7G sites and subsequent aniline-mediated cleavage of the RNA chain at the resulting abasic sites. The cleaved sites are subsequently ligated with adaptors for the construction of libraries for high-throughput sequencing. The m7G modification sites are identified using a bioinformatic pipeline that calculates the cleavage scores at individual sites on all tRNAs. Unlike antibody-based methods, such as methylated RNA immunoprecipitation and sequencing (meRIP-Seq) for enrichment of methylated RNA sequences, chemically based approaches, including TRAC-Seq, can provide nucleotide-level resolution of modification sites. Compared to the related method AlkAniline-Seq (alkaline hydrolysis and aniline cleavage sequencing), TRAC-Seq incorporates small RNA selection, AlkB demethylation, and sodium borohydride reduction steps to achieve specific and efficient single-nucleotide resolution profiling of m7G sites in tRNAs. The m7G TRAC-Seq protocol could be adapted to chemical cleavage-mediated detection of other RNA modifications. The protocol can be completed within ~9 d for four biological replicates of input and treated samples.


Assuntos
Guanosina/análogos & derivados , RNA de Transferência/química , Análise de Sequência de RNA/métodos , Animais , Genômica , Guanosina/análise , Guanosina/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Metilação , Camundongos , RNA de Transferência/genética , Software , Transcriptoma
4.
J Biol Inorg Chem ; 24(7): 1023-1033, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31506822

RESUMO

In the present work, we performed Density Functional Theory calculations to explore the bioactivation mechanism of thiophene-containing molecules mediated by P450s. For this purpose, relatively large size compounds, 2,5-diaminothiophene derivatives were selected particularly for this investigation. Here we found the successive regio-selectivity triggered by conformational turn played a significant role in the occurrence of bioactivation. 2,5-Diaminothiophene was oxidized to a 2,5-diimine thiophene-reactive intermediate by Compound I (Cpd I) through successive activations of two N-H bonds (H3-N11 and H1-N6). This reaction exhibited three special characteristics: (1) self-controlled regio-selectivity during the oxidation process. There was a large scale of conformational turn in the abstraction of the first H atom which triggers the selection of the second H for abstraction. (2) Proton-shuttle mechanism. In high spin (HS) state, proton-shuttle mechanism was observed for the abstraction of the second H atom. (3) Spin-selective manner. In protein environment, the energy barrier in HS state was much lower than that in low spin state. The novel proposed bioactivation mechanism of 2,5-diaminothiophene compounds can help us in rational design of thiophene-contained drugs avoiding the occurrence of bioactivation.

5.
Theranostics ; 9(17): 4935-4945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410192

RESUMO

Background: Estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancers (triple-positive breast cancers, TPBCs) account for 5% to 10% of all breast cancers. The clinical and molecular features of TPBCs remain elusive. In this study, we aim to analyze the multiomics landscape and responsiveness of TPBCs to trastuzumab. Methods: We employed five cohorts. The first cohort was from the Surveillance, Epidemiology, and End Results database (n=32,056) and was used to determine the clinical characteristics of TPBC. The second, third and fourth cohorts were from The Cancer Genome Atlas (n=162), GSE2603 (n=37) and GSE2109 (n=30) datasets, respectively, and were used to examine the genomic features and molecular classification of TPBC. The fifth cohort comprised TPBC patients treated at Fudan University Shanghai Cancer Center (FUSCC, n=171) and was used to investigate an immunohistochemistry-defined luminal A-like subgroup of TPBC. Results: Patients with TPBC had a significantly better prognosis than those with ER-PR-HER2+ breast cancer. Genomic analysis revealed that TPBCs showed a lower TP53 mutation rate (30% vs. 69%, P < 0.001) and lower levels of HER2 mRNA and protein expression than ER-PR-HER2+ breast cancers. More than 40% of TPBCs were classified as the luminal A intrinsic subtype, with an even lower HER2 expression level. Based on the immunohistochemical detection of CDCA8, BCL2 and STC2, we identified a luminal A-like subgroup of TPBCs in the FUSCC cohort (CDCA8-negative, BCL2- and/or STC2-positive). Patients with luminal A-like TPBC had a better prognosis and benefited less from trastuzumab than those with TPBC of other subtypes. Conclusions: TPBCs consist of clinically and genomically heterogeneous subgroups that may require different therapeutic strategies. The luminal A-like subgroup of TPBCs is associated with a better prognosis and reduced benefit from trastuzumab.

6.
Cancer Med ; 8(14): 6212-6220, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373147

RESUMO

BACKGROUND: Endocrine therapy is the preferred treatment for patients with hormone receptor -positive metastatic breast cancer (MBC). While visceral metastasis is a negative prognostic factor, few studies have distinguished between the prognoses of patients with metastases at different visceral sites. PATIENTS AND METHODS: In total, 398 patients receiving fulvestrant 500 mg at a single center over a 6-year period were analyzed. Logistic regression models were used to identify the prognostic factors associated with progression-free survival (PFS). Kaplan-Meier analysis was used to compare the PFS of patients with lung and liver metastases. RESULTS: Baseline visceral metastases were present in 233 patients, including 138 with lungw/o liver metastases (lung metastases without liver involvement), 51 with liverw/o lung metastases (liver metastases without lung involvement) and 41 with lung and liver metastases. The median PFS was 6.8 months (5.6 and 9.2 months for visceral and nonvisceral metastases, respectively, P = .028). PFS was longer in patients with lungw/o liver metastases than in those with liverw/o lung metastases or lung and liver metastases (9.6, 3.7 and 3.2 months, respectively, P < .001; liverw/o lung vs. lungw/o liver hazard ratio (HR) 1.70; lung and liver vs. lungw/o liver HR 2.85). Patients with liver metastases experienced significantly worse PFS than those without liver involvement (3.7 vs. 9.2 months, P < .001). PFS benefits were observed in patients with longer disease-free intervals, no liver metastases, and no previous chemotherapy. CONCLUSION: Fulvestrant treatment benefited patients with lungw/o liver or nonvisceral metastases. When treating hormone receptor-positive/HER2-negative MBC patients with endocrine therapy, it is important to differentiate patients with lung metastases from those with liver metastases.

7.
J Cancer ; 10(11): 2443-2449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258749

RESUMO

Background: Patients with early stage breast cancer with lymph nodes metastasis were proven to have more aggressive biologically phenotypes. This study aimed to build a nomogram to predict lymph node metastasis in patients with T1 breast cancer. Methods: We identified female patients with T1 breast cancer diagnosed between 2010 and 2014 in the Surveillance, Epidemiology and End Results database. The patients were randomized into training and validation sets. Univariate and multivariate logistic regressions were carried out to assess the relationships between lymph node metastasis and clinicopathological characteristics. A nomogram was developed and validated by a calibration curve and receptor operating characteristic curve analysis. Result: Age, race, tumour size, tumour primary site, pathological grade, oestrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status were independent predictive factors of positive lymph node metastasis in T1 breast cancer. Increasing age, tumour size and pathological grade were positively correlated with the risk of lymph node metastasis. We developed a nomogram to predict lymph node metastasis and further validated it in a validation set, with areas under the receiver operating characteristic curves of 0.733 and 0.741 in the training and validation sets, respectively. Conclusions: A better understanding of the clinicopathological characteristics of T1 breast cancer patients might important for assessing their lymph node status. The nomogram developed here, if further validated in other large cohorts, might provide additional information regarding lymph node metastasis. Together with sentinel lymph node biopsy, this nomogram can help comprehensively predict lymph node metastasis.

8.
Front Pediatr ; 7: 87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949461

RESUMO

Introduction: MMA is a rare autosomal recessive disorder with the manifestation of recurrent and severe episodes of acute metabolic decompensation or a variety of long-term complications that require timely treatment. While conventional long-term medical and dietary management cannot prevent rapid progression of conditions in patients with severe complications, LT, or CKLT has become an option. Methods: We reviewed the literature for MMA patients undergoing LT/CKLT published since 2006, and data on metabolic decompensation status, protein dietary, neurological damage, renal insufficiency, and developmental delay before and after transplantations were compared to evaluate the clinical value of the procedure in the treatment of MMA. Results: To date, some successful LTs/CKLT procedures have prolonged survival and resulted in better quality of life in patients (lowered urine/plasma MMA levels but still much higher than normal, reduced onset of metabolic stroke, occasional improved developmental delay, and relaxed protein diet), although these procedures cannot reverse neurological damage or thoroughly stop the progress of complications, such as renal dysfunction. Conclusion: LT is the only effective treatment for MMA patients with recurrent metabolic decompensation. However, it is still possible that neurological and renal damage remains irreversible. Metabolism-correcting medications should be administered even after surgery.

9.
Int J Cancer ; 145(10): 2850-2860, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30977117

RESUMO

Lung metastasis is one of the leading causes of death for triple-negative breast cancer (TNBC). We sought to characterize the genetic alterations underlying TNBC lung metastases by integrating whole-genome sequencing and functional screening. Furthermore, we aimed to develop a metastasis-related gene signature for TNBC patients to improve risk stratification. In this prospective observational study, we first conducted whole-genome sequencing of paired primary tumor and lung metastasis from one TNBC patient to identify potential genetic driver alterations. An in vivo gain-of-function screening using an amplified open reading frame library was then employed to screen candidate genes promoting lung metastasis. Finally, we applied Cox proportional hazard regression modeling to develop a prognostic gene signature from 14 candidate genes in TNBC. Compared to the primary tumor, copy number amplifications of chromosomes 3q and 8q were identified in the lung metastasis. We discovered an enrichment of 14 genes from chromosomes 3q and 8q in mouse lung metastases model. We further developed and validated a four-gene signature (ENY2, KCNK9, TNFRSF11B and KCNMB2) that predicts recurrence-free survival and lung metastasis in TNBC. Our data also demonstrated that upregulated expression of ENY2 could promote invasion and lung metastasis of TNBC cells both in vitro and in vivo. In conclusion, our study reveals functional genes with copy number amplifications among chromosome 3q and 8q in lung metastasis of TNBC. And we develop a functional gene signature that can effectively stratify patients into low- and high-risk subgroups of recurrence, helping frame personalized treatments for TNBC.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Animais , Linhagem Celular Tumoral , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Feminino , Seguimentos , Mutação com Ganho de Função , Perfilação da Expressão Gênica , Biblioteca Gênica , Células HEK293 , Humanos , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Osteoprotegerina/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Prognóstico , Estudos Prospectivos , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Clin Cancer Res ; 25(16): 5002-5014, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30837276

RESUMO

PURPOSE: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. EXPERIMENTAL DESIGN: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. RESULTS: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the "immune-desert" cluster, with low microenvironment cell infiltration; cluster 2, the "innate immune-inactivated" cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the "immune-inflamed" cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathologic sections and externally with The Cancer Genome Atlas and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. CONCLUSIONS: Our study represents a step toward personalized immunotherapy for patients with TNBC. Immune checkpoint inhibitors might be effective for "immune-inflamed" cluster, and the transformation of "cold tumors" into "hot tumors" should be considered for "immune-desert" and "innate immune-inactivated" clusters.

11.
Chin Med J (Engl) ; 132(9): 1087-1099, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30913064

RESUMO

BACKGROUND: Portosystemic shunts, including surgical portosystemic shunts and transjugular intra-hepatic portosystemic shunt (TIPS), may have benefit over endoscopic therapy (ET) for treatment of variceal bleeding in patients with cirrhotic portal hypertension; however, whether there being a survival benefit among them remains unclear. This study was to compare the effect of three above-mentioned therapies on the short-term and long-term survival in patient with cirrhosis. METHODS: Using the terms "variceal hemorrhage or variceal bleeding or variceal re-bleeding" OR "esophageal and gastric varices" OR "portal hypertension" and "liver cirrhosis," the Cochrane Central Register of Controlled Trials, PubMed, Embase, and the references of identified trials were searched for human randomized controlled trials (RCTs) published in any language with full texts or abstracts (last search June 2017). Risk ratio (RR) estimates with 95% confidence interval (CI) were calculated using random effects model by Review Manager. The quality of the included studies was evaluated using the Cochrane Collaboration's tool for the assessment of the risk of bias. RESULTS: Twenty-six publications comprising 28 RCTs were included in this analysis. These studies included a total of 2845 patients: 496 (4 RCTs) underwent either surgical portosystemic shunts or TIPS, 1244 (9 RCTs) underwent either surgical portosystemic shunts or ET, and 1105 (15 RCTs) underwent either TIPS or ET. There was no significant difference in overall mortality and 30-day or 6-week survival among three interventions. Compared with TIPS and ET, separately, surgical portosystemic shunts were both associated with a lower bleeding-related mortality (RR = 0.07, 95% CI = 0.01-0.32; P < 0.001; RR = 0.17, 95% CI = 0.06-0.51, P < 0.005) and rate of variceal re-bleeding (RR = 0.23, 95% CI = 0.10-0.51, P < 0.001; RR = 0.10, 95% CI = 0.04-0.24, P < 0.001), without a significant difference in the rate of postoperative hepatic encephalopathy (RR = 0.52, 95% CI = 0.25-1.00, P = 0.14; RR = 1.09, 95% CI = 0.59-2.01, P = 0.78). TIPS showed a trend toward lower variceal re-bleeding (RR = 0.46, 95% CI = 0.36-0.58, P < 0.001), but a higher incidence of hepatic encephalopathy than ET (RR = 1.78, 95% CI = 1.34-2.36, P < 0.001). CONCLUSIONS: The overall analysis revealed that there seem to be no short-term and long-term survival advantage, but surgical portosystemic shunts are with the lowest bleeding-related mortality among the three therapies. Surgical portosystemic shunts may be the most effective without an increased risk of hepatic encephalopathy and TIPS is superior to ET but at the cost of a higher incidence of hepatic encephalopathy. However, some of findings should be interpreted with caution due to the lower level of evidence and the existence of significant heterogeneity.


Assuntos
Varizes Esofágicas e Gástricas/patologia , Hemorragia Gastrointestinal/prevenção & controle , Intervalos de Confiança , Humanos , Derivação Portossistêmica Transjugular Intra-Hepática , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Cancer Cell ; 35(3): 428-440.e5, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30853353

RESUMO

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/classificação , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 22/genética , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Metástase Neoplásica , Prognóstico , Neoplasias de Mama Triplo Negativas/genética
13.
Sci Adv ; 5(3): eaat9820, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30854423

RESUMO

Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. Here, our genome-wide transcriptome analysis of HERVs revealed that a primate long noncoding RNA, which we dubbed TROJAN, was highly expressed in human triple-negative breast cancer (TNBC). TROJAN promoted TNBC proliferation and invasion and indicated poor patient outcomes. We further confirmed that TROJAN could bind to ZMYND8, a metastasis-repressing factor, and increase its degradation through the ubiquitin-proteasome pathway by repelling ZNF592. TROJAN also epigenetically up-regulated metastasis-related genes in multiple cell lines. Correlations between TROJAN and ZMYND8 were subsequently confirmed in clinical samples. Furthermore, our study verified that antisense oligonucleotide therapy targeting TROJAN substantially suppressed TNBC progression in vivo. In conclusion, the long noncoding RNA TROJAN promotes TNBC progression and serves as a potential therapeutic target.

14.
Int J Clin Oncol ; 24(8): 934-940, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30888527

RESUMO

BACKGROUND: With the improvement in the survival of breast cancer, developing second primary malignancy becomes a serious health issue. The aim of this study was to explore the survival of breast cancer patients with second primary malignancy, and to evaluate the impact of chemotherapy on the risk of different cancer sites. METHOD: Obtaining data from the Surveillance, Epidemiology, and End Results database, we calculated the standardized incidence ratio (SIR) for second primary malignancy in breast cancer survivors between 2000 and 2014. Overall survival and cancer-specific survival were analyzed with Kaplan-Meier method. Then, we further conducted stratified sub-analyses according to chemotherapy. RESULTS: The overall risk of second primary cancer for all sites was significantly elevated in breast cancer patients (SIR = 1.15, 95% CI 1.14-1.16). Overall survival and cancer-specific survival of the patients with breast cancer only were significantly better than the patients with multiple primary cancers (both P < 0.001). Chemotherapy was associated with increased incidences for all sites, except lymphoma, myeloma, and chronic lymphocytic leukemia (SIR = 0.80, 95% CI 0.72-0.88; SIR = 0.85, 95% CI 0.71-1.01; SIR = 0.57, 95% CI 0.43-0.74, respectively). The risk for developing second acute myeloid leukemia after chemotherapy in breast cancer patients varied with age and latency. CONCLUSION: Female breast cancer patients showed higher incidence of second primary malignancy, which was associated with poorer prognosis. Chemotherapy benefits should be weighed against the risks of second primary malignancy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/mortalidade , Segunda Neoplasia Primária/induzido quimicamente , Programa de SEER , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segunda Neoplasia Primária/patologia , Estudos Retrospectivos , Risco , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
15.
Cancer Cell ; 35(1): 64-80.e7, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30612941

RESUMO

Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5ß1, αvß1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.


Assuntos
Proteínas da Matriz Extracelular/genética , Integrina alfa5beta1/metabolismo , Lipocalinas/genética , Neoplasias Pulmonares/terapia , Receptores de Vitronectina/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Receptores ErbB/metabolismo , Proteínas da Matriz Extracelular/administração & dosagem , Proteínas da Matriz Extracelular/metabolismo , Feminino , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Lipocalinas/administração & dosagem , Lipocalinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Prognóstico , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
16.
J Ultrasound Med ; 38(7): 1747-1755, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30480341

RESUMO

OBJECTIVES: To identify clinicopathologic and ultrasound (US) variables that were associated with a heavy nodal tumor burden, which was defined as 3 or more lymph nodes involved with metastasis to the axilla after invasive breast carcinoma. METHODS: With ethical approval, 621 patients with a pathologic diagnosis of invasive breast carcinoma were retrospectively analyzed for clinical, pathologic, and US data. Pathologic findings were ascertained by the final paraffin pathologic analysis. Ultrasound characteristics were evaluated on the basis of the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS). Univariate and multivariate logistic regression analyses were used to assess the clinicopathologic and US variables that were associated with a heavy nodal tumor burden at the axilla. RESULTS: There were 107 cases (17.2%) of invasive breast carcinoma with a heavy tumor burden at the axilla. The independent clinicopathologic variables for a heavy tumor burden at the axilla included a tumor size of 2 to 5 cm (odds ratio [OR], 1.86; P = .036), the presence of lymphovascular invasion (OR, 23.52; P < .001), the presence of papillary invasion (OR, 2.93; P = .043), and a non-triple-negative subtype (OR, 2.34; P = .04). The independent US features of breast tumors that were associated with a heavy tumor burden at the axilla included BI-RADS category 5 (OR, 5.50; P = .024) and a posterior acoustic shadow (OR, 1.94; P = .024). CONCLUSIONS: A large tumor size, lymphovascular invasion, papillary invasion, and a non-triple-negative subtype on the pathologic analysis as well as BI-RADS category 5 and a posterior acoustic shadow on a US assessment were associated with a heavy nodal tumor burden at the axilla. These US characteristics of the primary breast carcinoma might provide additional information to axillary US for the prediction of axillary nodal tumor loads.


Assuntos
Axila/diagnóstico por imagem , Axila/patologia , Neoplasias da Mama/patologia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Invasividade Neoplásica/diagnóstico por imagem , Invasividade Neoplásica/patologia , Ultrassonografia/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Carga Tumoral
17.
Breast ; 43: 97-104, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30529406

RESUMO

OBJECTIVES: Patients with T1N0M0 breast cancers are considered to have an excellent prognosis, even in triple-negative breast cancer (TNBC), which is often associated with diminished recurrence-free survival (RFS) and overall survival. Chemotherapy remains the only adjuvant treatment for TNBC, but evidence that adjuvant chemotherapy is beneficial for stage T1N0M0 TNBC patients is limited. In this study, we aimed to evaluate the effect of adjuvant chemotherapy and the benefit of taxanes in T1N0M0 TNBC patients. MATERIAL AND METHODS: A cohort of 354 consecutive patients with newly diagnosed T1N0M0 TNBC between January 2008 and December 2015 were included from the Fudan University Shanghai Cancer Center. Univariate and multivariate survival analyses were performed to compare patients treated with adjuvant chemotherapy with/without taxane addition. RESULTS: Median follow-up was 45 months. Chemotherapy was used in 92.4% of patients. The 5-year estimated RFS rates of patients with and without adjuvant chemotherapy were 94.5% and 83.6%, respectively. In multivariate analysis, adjuvant chemotherapy and a lack of lymphovascular invasion were associated with a significant benefit for RFS. A significant RFS benefit from adjuvant chemotherapy was observed in T1c (hazard ratio, HR = 0.24, 95% CI [0.08-0.76], P = 0.014) but not in T1b (HR = 0.32, 95% CI [0.03-3.18], P = 0.330) subgroups. Addition of taxane to an anthracycline-based regimen was not significantly associated with improved RFS in T1N0M0 TNBC patients. CONCLUSION: Adjuvant chemotherapy improves recurrence-free survival in T1c TNBC patients but not in T1b. Anthracycline-based taxane-free regimens might be sufficient to achieve RFS benefits in T1N0M0 TNBC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Mastectomia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas , Carcinoma/patologia , Quimiorradioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Radioterapia Adjuvante , Estudos Retrospectivos , Taxoides , Neoplasias de Mama Triplo Negativas/patologia
18.
Cancer Med ; 7(12): 6137-6146, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30430768

RESUMO

DSCAM-AS1 is one of the few intensively studied lncRNAs with high specific expression in luminal breast cancer. It is directly regulated by estrogen receptor α (ERα) and plays vital roles in tumor proliferation, invasion, and tamoxifen resistance. However, the detailed function of DSCAM-AS1 in tumor progression and its clinical significance remain unclear. We reveal that DSCAM-AS1 regulates cell proliferation and colony formation by inducing the G1/S transition. RNA-seq analysis demonstrated that DSCAM-AS1 participates in crucial biological processes, including DNA replication, the G1/S phase transition, sister chromatid cohesion, chromosome segregation, protein localization to the chromosome and DNA recombination. Most importantly, in the retrospectively registered clinical analysis, high expression of DSCAM-AS1 is a poor prognostic factor in patients with luminal breast cancer treated with endocrine therapy. In conclusion, DSCAM-AS1 is a promising clinical therapeutic target that may prolong survival of luminal breast cancer patients treated with endocrine therapy.


Assuntos
Neoplasias da Mama/genética , RNA Longo não Codificante , Adulto , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Tamoxifeno/uso terapêutico
19.
Cancer Manag Res ; 10: 4381-4391, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349371

RESUMO

Background: Occult breast cancer (OBC) is a rare type of breast cancer that has not been well studied. The clinicopathological characteristics and treatment recommendations for OBC are based on a limited number of retrospective studies and thus remain controversial. Patients and methods: We identified 479 OBC patients and 115,739 non-OBC patients from 2004 to 2014 in and the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological characteristics and survival outcomes were compared between OBC and non-OBC patients. We used the propensity score 1:1 matching analysis to evaluate OBC vs non-OBC comparison using balanced groups with respect to the observed covariates. We further divided the OBC population into four groups based on different treatment strategies. Univariable and multivariable analyses were used to calculate and compare the four treatment outcomes within the OBC population. Results: OBC patients were older, exhibited a more advanced stage, a higher rate of negative estrogen receptor and progesterone receptor status, a higher rate of HER2-positive status, and a higher rate of ≥10 positive lymph nodes, and were less likely to undergo surgical treatment than non-OBC patients. After adjustments for clinicopathological factors, the OBC patients exhibited a significantly better survival than the non-OBC patients (P<0.001). This result was confirmed in a 1:1 matched case-control analysis. Within the four OBC treatment groups, we observed no difference in survival among the mastectomy group, the breast-conserving surgery (BCS) group, and the axillary lymph node dissection (ALND)-only group. The multivariable analysis revealed that the sentinel lymph node dissection-only group had the worst prognosis (P<0.001). Conclusion: OBC has unique clinicopathological characteristics and a favorable prognosis compared with non-OBC. BCS plus ALND and radiotherapy showed a survival benefit that was similar to that of mastectomy for OBC patients.

20.
Transl Oncol ; 11(6): 1334-1342, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30189361

RESUMO

INTRODUCTION: The objective of current study was to develop and validate comprehensive nomograms for predicting the survival of young women with breast cancer. METHODS: Women aged <40 years diagnosed with invasive breast cancer between 1990 and 2010 were selected from the Surveillance, Epidemiology, and End Results database and randomly divided into training (n = 12,465) and validation (n = 12,424) cohorts. A competing-risks model was used to estimate the probability of breast cancer-specific survival (BCSS). We identified and integrated significant prognostic factors for overall survival (OS) and BCSS to construct nomograms. The performance of the nomograms was assessed with respect to calibration, discrimination, and risk group stratification. RESULTS: The entire cohort comprised 24,889 patients. The 5- and 10-year probabilities of breast cancer-specific mortality were 11.6% and 20.5%, respectively. Eight independent prognostic factors for both OS and BCSS were identified and integrated for the construction of the nomograms. The calibration curves showed optimal agreement between the predicted and observed probabilities. The C-indexes of the nomograms in the training cohort were higher than those of the TNM staging system for predicting OS (0.724 vs 0.694; P < .001) and BCSS (0.733 vs 0.702; P < .001). Additionally, significant differences in survival were observed in patients stratified into different risk groups within respective TNM categories. CONCLUSIONS: We developed and validated novel nomograms that can accurately predict OS and BCSS in young women with breast cancer. These nomograms may help clinicians in making decisions on an individualized basis.

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