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1.
BMC Med ; 21(1): 226, 2023 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-37365596

RESUMEN

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC. METHODS: In this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: From November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7-14.0 months). The CBR was 71.7% (95% CI, 57.7-83.2%), and the objective response rate was 64.2% (95% CI, 49.8-76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7-18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event. CONCLUSIONS: Our preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04407988.


Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Letrozol/uso terapéutico , Receptor ErbB-2 , Resultado del Tratamiento
2.
Tohoku J Exp Med ; 254(2): 111-121, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34162779

RESUMEN

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of cancer treatment. The factors influencing CINV in breast cancer patients remain unclear. In this study, we developed a nomogram for predicting the occurrence of CINV in this group using prospective clinical data. We pooled data from multiple studies which focused on the emetogenic chemotherapy. Then, we collected 334 breast cancer patients at Hunan Cancer Hospital (training set) to analyze the demographic and clinical variables. Using multivariate logistic regression, we identified the five significant factors that were associated with CINV: history of CINV, chemotherapy regimen, chemotherapy cycle, metastasis, and symptoms of distress. Then, we construct a prediction nomogram. The external validation set comprised an additional 66 patients. The reliability of the nomogram was assessed by bootstrap resampling. The C-index was 0.78 (95% confidence interval [CI], 0.73-0.85) for the training set and 0.74 (95% CI, 0.62-0.85) for the validation set. Calibration curves showed good concordance between predicted and actual occurrence of CINV. In conclusions, our nomogram model can reliably predict the occurrence of CINV in breast cancer patients based on five significant variables, which might be useful in clinical decision-making.


Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias de la Mama , Náusea , Vómitos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Náusea/inducido químicamente , Náusea/tratamiento farmacológico , Náusea/epidemiología , Nomogramas , Estudios Prospectivos , Reproducibilidad de los Resultados , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico
3.
Cancer Cell Int ; 20: 71, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32165861

RESUMEN

BACKGROUND: Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma. METHODS: To investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model. RESULTS: Skp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo. CONCLUSION: Our data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.

4.
J Transl Med ; 17(1): 27, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30646914

RESUMEN

BACKGROUND: Among breast cancer (BC) patients, near 40% are post-menopause, and 70%-80% are hormone receptor (HR)-positive. About 30%-40% BC patients who are diagnosed as invasive carcinoma HR-positive BC would eventually develop metastatic breast cancers. In 2016, FALCON trial proves Fulvestrant as an effective first-line endocrine therapy for post-menopause HR-positive advanced BC (ABC) patients. But even after FALCON published, Fulvestrant is rarely used as first-line in real world ABC patients in China. METHOD: In this study, 136 Fulvestrant users were enrolled from 2015. To investigate the clinical and genetic risk factors for Fulvestrant treatment response in real world data, biostatistic and bioinformatic analysis tools were adopted. RESULT: KM curves showed that Fulvestrant first-line users had a median progression-free survival (mPFS) of 15.67 months, which was longer than the second-line users and third (or higher)-line users (mPFS = 7.47 and 5.43 months, respectively). 16 s (or higher)-line users were voluntarily received circulating tumor DNA (ctDNA) testing after progression. ctDNA testing results showed that compared to patients with PFS longer than 6 months, Fulvestrant users with PFS less than 6 months had a significantly higher mutation rate of ESR1 or ERBB2 gene (0/6 vs 6/10, Fisher's Exact p-value = 0.03). Multivariate COX regression analysis showed that clinical features, including lymph node metastasis and HER-2 positive, were significant risk factors for poor PFS [hazard ratio (HR) = 2.396 and 2.863, respectively]; high portion of estrogen receptor-positive cells was significant protective factor (HR = 0.663). Propensity-score matching (PMS) analysis suggested that visceral metastasis, prior palliative chemotherapy, and old age at Fulvestrant usage were not significant influential factor for PFS. CONCLUSION: First-line Fulvestrant usage could guarantee a better prognosis than higher-line usage. ESR1 or ERBB2 mutation was found to be related to poor PFS in higher-line Fulvestrant users.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Fulvestrant/uso terapéutico , Predisposición Genética a la Enfermedad , Posmenopausia/genética , Receptores de Estrógenos/genética , Adulto , Neoplasias de la Mama/patología , ADN Tumoral Circulante/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Probabilidad , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/genética , Factores de Riesgo , Resultado del Tratamiento
5.
Pharmacology ; 103(5-6): 282-290, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30808828

RESUMEN

BACKGROUND/AIMS: Hypoxia can induce cell injury in cardiomyocytes and further lead to cardiovascular diseases. Genistein (Gen), the predominant isoflavone found in soy products, has shown protective effects on cardiovascular system. The aim of the present study was to investigate the cardioprotective effect of Gen against chemical hypoxia-induced injury. METHODS: Cobalt chloride (CoCl2) was administrated to trigger chemical hypoxia in H9c2 cardiomyocytes. Cell proliferation was detected by using MTT assay. The expression level of hypoxia-related proteins (hypoxia-inducible factor [HIF]-1α and Notch-1) and apoptosis-related proteins (B cell lymphoma [Bcl]-2, Bax, and caspase-3) were evaluated by Western blot analysis. RESULTS: In response to hypoxia, cell viability was reduced dramatically, whereas the expression of HIF-1α was upregulated. Hypoxia also induced cardiomyocytes apoptosis by reducing the ratio of Bcl-2/Bax and increasing expression of caspase-3. Interestingly, Gen attenuated CoCl2-induced cell death and suppressed HIF-1α expression, as well as upregulated the expression of Notch-1. Furthermore, Gen could antagonize CoCl2-induced apoptosis through upregulating Bcl-2/Bax ratio and inhibiting caspase-3 expression. CONCLUSIONS: Gen prevents chemical hypoxia-induced cell apoptosis through inhibition of the mitochondrial apoptotic pathway, exerting protective effects on H9c2 cardiomyocytes.


Asunto(s)
Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Genisteína/farmacología , Miocitos Cardíacos/efectos de los fármacos , Animales , Western Blotting , Cardiotónicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cobalto/toxicidad , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Miocitos Cardíacos/patología , Ratas , Regulación hacia Arriba/efectos de los fármacos
6.
Front Immunol ; 15: 1337400, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38873609

RESUMEN

Case report: A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed. Conclusion: Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.


Asunto(s)
Antígeno B7-H1 , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Pilomatrixoma , Neoplasias Cutáneas , Humanos , Masculino , Persona de Mediana Edad , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Pilomatrixoma/genética , Pilomatrixoma/patología , Mutación , Enfermedades del Cabello/genética , Enfermedades del Cabello/patología
7.
Breast ; 72: 103597, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37944341

RESUMEN

BACKGROUND: Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for response in HER2-positive metastatic breast cancer (MBC) patients. METHODS: A cohort of HER2-positive MBC patients who received inetetamab-based therapy between June 2020 and August 2021 was evaluated. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 141 patients were included in the final analysis. The median PFS of the entire cohort was 7.1 months. The median number of treatment lines administered was three. The ORR was 36.9 %, and the DCR was 80.9 %. The most frequently employed treatment strategy was inetetamab + chemotherapy (49/141, 34.8 %), followed by inetetamab + HER2-tyrosine kinase inhibitors (HER2-TKIs) + chemotherapy, inetetamab + pertuzumab + chemotherapy, inetetamab + endocrine treatment and inetetamab + HER2-TKIs. Cox multivariate analysis revealed that PFS was associated with liver metastasis (hazard ratio [HR] 2.112, 95 % confidence interval [CI] 1.334-3.343, p = 0.001), previous HER2-TKI treatment (HR 2.019, 95 % CI 1.133-3.597, p = 0.017) and estrogen receptor positivity (HR 0.587, 95 % CI 0.370-0.934, p = 0.024). The toxicity was tolerable, with neutropenia being the most common treatment-related grade 3/4 AE (14.9 %). CONCLUSION: Inetetamab demonstrates effectiveness with a manageable safety profile, offering a promising therapeutic option for HER2-positive breast cancer patients who have shown resistance to prior anti-HER2 treatments.


Asunto(s)
Anticuerpos Monoclonales , Antineoplásicos , Neoplasias de la Mama , Receptor ErbB-2 , Femenino , Humanos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/secundario , Pueblos del Este de Asia , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/uso terapéutico , Resultado del Tratamiento , Anticuerpos Monoclonales/uso terapéutico
8.
Front Endocrinol (Lausanne) ; 13: 1075830, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36518248

RESUMEN

Background: After early-line (first- and second-line) endocrine therapy, hormone-receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (mBCs) become resistant to endocrine therapy. Genetic alterations may underlie resistance to endocrine therapies. This study aims to investigate the circulating tumor DNA (ctDNA) alterations and the clinical implication in hormone-receptor-positive, HER2-negative metastatic breast cancer patients with multiline endocrine therapy failure. Methods: This registered study (NCT05079074, ClinicalTrials.gov) enrolled 104 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer who progressed after the early-line endocrine therapy. ctDNA alterations were analyzed by next generation sequencing (NGS). ctDNA alterations were ranked and clustered by using R 'ComplexHeatmap' and 'hclust' function. ctDNA-guided therapy was administrated. Progression-free survival (PFS) was assessed COX regression analysis, and Kaplan-Meier curves were plotted. Findings: The top ctDNA altered genes were TP53 (39%), PIK3CA (38%), BRCA1/2 (13%), ESR1 (12%), FGFR (11%), ERBB2 (11%), and GATA3 (9%). Among these genes, TP53, PIK3CA helix domain mutation (PIK3CA-HD), FGFR, ESR1 and GATA3 were related to endocrine therapy resistance. The genetic landscapes changed and tumor mutation burden increased in both TP53-altered and PIK3CA-altered patients. Both BRCA1/2 and ERBB2 alterations correlated with TP53 alterations (P=0.02 and P=0.04, respectively). However, while 93% BRCA1/2 alterations concentrated in PIK3CA-wildtype patients, 82% ERBB2 alterations concentrated in PIK3CA-altered patients. Kaplan-Meier curves showed that patients who received druggable ctDNA alteration-guided treatment (DDAT) had significantly longer PFS than those who received physician-chosen therapy, with median PFS of 6.1 months versus 4.6 months (hazard ratio = 0.53, 95% CI: 0.34-0.85, Logrank P = 0.006). Conclusion: Multiple genetic alterations were important reasons for the failure of endocrine therapy for HR-positive and HER2-negative mBC. Targeting these genes might restore the treatment sensitivity and benefit survival.


Asunto(s)
Neoplasias de la Mama , ADN Tumoral Circulante , Femenino , Humanos , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/uso terapéutico , Relevancia Clínica
9.
Ann Transl Med ; 10(17): 924, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36172110

RESUMEN

Background: Maintenance treatment following efficient chemotherapy can improve the treatment outcomes of patients with metastatic breast cancer (MBC). However, there are no studies for identifying the prognostic factors for patients who could benefit from capecitabine maintenance. Therefore, this study aimed to investigate the prognosis and risk factors of capecitabine maintenance therapy and analysed the circulating tumour DNA (ctDNA) markers that may be related to the treatment response. Methods: This study recruited 482 consecutive patients with MBC who achieved clinical benefit from capecitabine-based chemotherapy from 2011 to 2019. A total of 256 patients received subsequent capecitabine maintenance therapy. The baseline clinical factors included age at diagnosis, menopause, neoadjuvant therapy, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and subtypes, prior treatment lines, and prior capecitabine-based treatment response. Treatment outcome (progression-free survival, PFS) was assessed by imaging tools according to RSCIST 1.1 standard during the first two treatment cycles and every 3 weeks thereafter. Univariate and multivariate Cox proportional hazards models were used to analysethe association between capecitabine maintenance treatment and prognosis. Results: The median PFS of patients receiving capecitabine maintenance treatment was 21.7 months [95% confidence interval (CI): 15.1-36.3 months]. Capecitabine maintenance showed similar effects as endocrine maintenance or anti-HER2 therapy in hormone receptor (HR)-positive or HER2-positive patients, with adjusted HR of 1.17 (95% CI: 0.81-1.71, P=0.40). In patients with triple-negative breast cancer (TNBC), capecitabine maintenance showed a marginal benefit in PFS. Compared to late-line (≥2) capecitabine maintenance, first-line capecitabine maintenance significantly prolonged median PFS. Compared to other HR/HER2 subtypes, patients with HR-positive and HER2-positive subtypes significantly benefited from capecitabine maintenance treatment. Analysis of ctDNA revealed that among patients receiving capecitabine maintenance, TP53 aberrations were concentrated in patients with short PFS. Conclusions: Capecitabine maintenance treatment is associated with longer PFS in patients with MBC, especially those receiving first-line capecitabine-based chemotherapy and those with HR positivity/HER2 positivity. TP53 aberrations may be responsible for the poor response to capecitabine maintenance treatment.

10.
EClinicalMedicine ; 51: 101567, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35875816

RESUMEN

Background: After multiple lines of therapies, no guideline or consensus is currently available for the treatment of patients with metastatic breast cancer. This study aims to evaluate the efficacy of a novel re-subtyping and treatment strategy based on ctDNA alterations. Methods: This observational, multicentre study recruited 223 patients with metastatic breast cancer intending to receive late-line therapy from Dec 1, 2016, to June 31, 2019. This study took place in Hunan Cancer Hospital, the Forth Hospital of Changsha and Zhuzhou Central Hospital in China. ctDNA alterations were assessed by next-generation sequencing (NGS). Patients with druggable ctDNA alterations were treated with corresponding targeted drugs which are clinically available. Other patients received physician-chosen treatment. This study was registered with ClinicalTrials.gov, NCT05079074. Findings: The progression-free survival (hazard ratio: 0.45, 95% Confidence Interval (CI): 0.33-0.62, P < 0.0001) and disease control rate (89.4% vs. 65.9%, P < 0.0001) were significantly improved in patients who received druggable ctDNA alteration-guided therapy compared with those of patients who received physician-chosen treatment. ctDNA alterations with top rank and high clustering scores were classified into four subtypes based on their functions as follows: 1) extracellular function (ECF), 2) cell proliferation (CP), 3) nuclear function (NF), and 4) cascade signaling pathway (CSP). A significant benefit from ctDNA alteration-guided treatment was observed in patients with NF and CSP ctDNA alterations, with hazard ratios of 0.39 (95% CI: 0.24-0.65, P = 0.0003) and 0.14 (95% CI: 0.04-0.46, P < 0.0001), respectively. Interpretation: After multiline traditional pathological HR/HER2 subtype-guided therapies, ctDNA testing could identify druggable ctDNA alterations to guide late-line therapy for patients with metastatic breast cancer. Funding: This work was supported by Key Grants of Research and Development in Hunan Province (2018SK2124, 2018SK2120), Natural Science Foundation of Hunan (2019JJ50360), Hunan Provincial Health Commission Project (B2019085, B2019089 and C2019070), and Changsha Science and Technology Project (kq2004125 and kq2004137).

11.
Ann Transl Med ; 10(19): 1067, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36330383

RESUMEN

Background: Ki-67 is a key indicator of the proliferation activity of tumors. However, no standardized criterion has been established for Ki-67 index calculation. Scale-invariant feature transform (SIFT) algorithm can identify the robust invariant features to rotation, translation, scaling and linear intensity changes for matching and registration in computer vision. Thus, this study aimed to develop a SIFT-based computer-aided system for Ki-67 calculation in breast cancer. Methods: Hematoxylin and eosin (HE)-stained and Ki-67-stained slides were scanned and whole slide images (WSIs) were obtained. The regions of breast cancer (BC) tissues and non-BC tissues were labeled by experienced pathologists. All the labeled WSIs were randomly divided into the training set, verification set, and test set according to a fixed ratio of 7:2:1. The algorithm for identification of cancerous regions was developed by a ResNet network. The registration process between paired consecutive HE-stained WSIs and Ki-67-stained WSIs was based on a pyramid model using the feature matching method of SIFT. After registration, we counted the nuclear-stained Ki-67-positive cells in each identified invasive cancerous region using color deconvolution. To assess the accuracy, the AI-assisted result for each slice was compared with the manual diagnosis result of pathologists. If the difference of the two positive rate values is not greater than 10%, it was a consistent result; otherwise, it was an inconsistent result. Results: The accuracy of the AI-based algorithm in identifying breast cancer tissues in HE-stained slides was 93%, with an area under the curve (AUC) of 0.98. After registration, we succeeded in identifying Ki-67-positive cells among cancerous cells across the entire WSIs and calculated the Ki-67 index, with an accuracy rate of 91.5%, compared to the gold standard pathological reports. Using this system, it took about 1 hour to complete the evaluation of all the tested 771 pairs of HE- and Ki-67-stained slides. Each Ki-67 result took less than 2 seconds. Conclusions: Using a pyramid model and the SIFT feature matching method, we developed an AI-based automatic cancer identification and Ki-67 index calculation system, which could improve the accuracy of Ki-67 index calculation and make the data repeatable among different hospitals and centers.

12.
Front Oncol ; 12: 804466, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35280756

RESUMEN

Background: In triple-negative breast cancer (TNBC), PDL1/PD1-directed immunotherapy is effective in less than 20% of patients. In our preliminary study, we have found CSPG4 to be highly expressed together with PDL1 in TNBCs, particularly those harboring TP53 aberrations. However, the clinical implications of co-expressed CSPG4 and PDL1 in TNBCs remain elusive. Methods: A total of 85 advanced TNBC patients treated in the Hunan Cancer Hospital between January 2017 and August 2019 were recruited. The expressions of CSPG4 and PDL1 in TNBC tissues were investigated using immunohistochemistry (IHC). The RNA-seq dataset from the TCGA-BRCA project was further used to analyze the mRNA expression of CSPG4 and PDL1 in TP53-aberrant TNBCs. Cox proportional hazards model and Kaplan-Meier curves with Logrank test was used to analyze the effects of CSPG4 and PDL1 on survival. TNBC cell lines were further used to investigate the molecular mechanism that were involved. Results: TP53 aberrations occurred in more than 50% of metastatic TNBCs and were related to higher tumor mutation burden (TMB). In TCGA-BRCA RNA-seq dataset analysis, both CSPG4 and PDL1 levels were high in TNBCs, especially in TP53-aberrant TNBCs. IHC assay showed nearly 60% of advanced TNBCs to be CSPG4-positive and about 25% to be both CSPG4-positive and PDL1-positive. The levels of CSPG4 and PDL1 were high in TNBC cell lines as revealed by flow cytometry and immunoblotting compared with non-TNBC cells. Univariate Cox regression analysis indicated that CSPG4 positivity was a significant risk factor for progression-free survival in metastatic TNBCs, with a hazard ratio (HR) of 2.26 (P = 0.05). KM curves with Logrank test also identified high level of CSPG4 as a significant risk factor for overall survival in advanced breast cancers in TCGA-BRCA samples (P = 0.02). The immunoblotting assays showed that EMT-related pathways were involved in CSPG4-mediated invasion. Conclusions: CSPG4 expression level is associated with PDL1 positivity in TP53-aberrant TNBC cells. Patients with CSPG4 expression have poor treatment response and poor overall survival. Co-expressed CSPG4 and PDL1 may have an important prognostic value and provide new therapeutic targets in TNBC patients. CSPG4 might mediate tumor invasion and PDL1 overexpression through EMT-related pathway.

13.
BMJ Open ; 12(2): e054135, 2022 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-35105583

RESUMEN

OBJECTIVES: Although primary tumour surgery could prolong survival for patients with stage IV breast cancer, how to select candidates for primary tumour surgery is still a challenging problem for medical oncologists. DESIGN: This study is a retrospective database study. SETTING AND PARTICIPANTS: In this study, we aimed at evaluating the primary site surgery effect and select the beneficial subgroups. 13 618 patients with stage IV breast cancer, diagnosed between 2010 and 2015, were collected from SEER*Stat database. INTERVENTIONS: Based on the local surgery at primary tumour site, patients were categorised into three groups: primary tumour surgery performed group, recommended for primary tumour surgery but refused (RBR) group and surgery not recommended (NR) group. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause survival and breast cancer-specific survival (BCSS). RESULTS: Univariate Cox regression analyses showed that, compared with surgery group, patients in non-surgery (RBR and NR) groups tend to be older, T4, N0/NX, triple-negative and visceral metastatic. For both all-cause survival and BCSS, non-surgery, advanced T stage, triple-negative BC (TNBC) and visceral metastases were significant risk factors. Primary tumour surgery showed benefits for both all-cause survival (HR=0.44, 95% CI=0.39-0.49, p<0.0001) and BCSS (HR=0.43, 95% CI=0.38-0.49, p<0.0001). However, after propensity score matching, primary tumour surgery failed to demonstrate significant benefits for TNBC (HR=0.96, 95% CI=0.60-1.53, p=0.851) and patients with visceral metastases (HR=0.90, 95% CI=0.60-1.36, p=0.62). CONCLUSION: Surgery was associated with prolonged survival in stage IV breast cancers, but not in patients with TNBC and visceral metastases.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Mama/patología , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Estadificación de Neoplasias , Estudios Retrospectivos , Programa de VERF , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/cirugía
14.
Chin J Cancer ; 30(1): 41-53, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21192843

RESUMEN

Apogossypolone (ApoG2), a novel derivative of gossypol, has been shown to be a potent inhibitor of antiapoptotic Bcl-2 family proteins and to have antitumor activity in multiple types of cancer cells. Recent reports suggest that gossypol stimulates the generation of cellular reactive oxygen species (ROS) in leukemia and colorectal carcinoma cells; however, gossypol-mediated cell death in leukemia cells was reported to be ROS-independent. This study was conducted to clarify the effect of ApoG2-induced ROS on mitochondria and cell viability, and to further evaluate its utility as a treatment for nasopharyngeal carcinoma (NPC). We tested the photocytotoxicity of ApoG2 to the poorly differentiated NPC cell line CNE-2 using the ROS-generating TL/10 illumination system. The rapid ApoG2-induced cell death was partially reversed by the antioxidant N-acetyl-L-cysteine (NAC), but the ApoG2-induced reduction of mitochondrial membrane potential (MMP) was not reversed by NAC. In the presence of TL/10 illumination, ApoG2 generated massive amounts of singlet oxygen and was more effective in inhibiting cell growth than in the absence of illumination. We also determined the influence of light on the anti-proliferative activity of ApoG2 using a CNE-2-xenograft mouse model. ApoG2 under TL/10 illumination healed tumor wounds and suppressed tumor growth more effectively than ApoG2 treatment alone. These results indicate that the ApoG2-induced CNE-2 cell death is partly ROS-dependent. ApoG2 may be used with photodynamic therapy (PDT) to treat NPC.


Asunto(s)
Gosipol/análogos & derivados , Luz , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neoplasias Nasofaríngeas/patología , Especies Reactivas de Oxígeno/metabolismo , Oxígeno Singlete/metabolismo , Animales , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Gosipol/farmacología , Humanos , Ratones , Ratones Desnudos , Neoplasias Nasofaríngeas/metabolismo , Trasplante de Neoplasias , Fotoquimioterapia , Carga Tumoral/efectos de los fármacos
15.
Front Genet ; 11: 829, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33193564

RESUMEN

PALB2 is an important BRCAx candidate for familial breast cancers (FBC). PALB2 pathogenic variants (PVs) may not to conform to "two hit" paradigm. However, a recent study demonstrates that in the majority PALB2 germline mutant breast cancers, the loss of heterozygosity (LOH) and somatic point mutations are the "second hit." This study aimed to investigate the second hits in germline PALB2 mutations in breast cancers. We screened out 28 germline PALB2-mutation carriers among 480 familial cancer patients (including 143 FBC patients) in Geneplus database pool. Of the 143 patients with FBC, 10 had mono-allelic PALB2 germline mutations. All these germline PALB2 mutations were high-risk stop-gain, frameshift, or splicing mutations that concentrated in EX5-EX9 and might led to truncated proteins, severe functional defects and malignant phenotype. The hotspots were c.1057A[3 > 2] and c.3114-1G > A. Other mutations included c.389delA, c.2068C > T, c.2167_2168delAT, c.2629delT and c.2968G > T. Only one FBC patient has PALB2 somatic mutation and two patients had LOH of PALB2. All germline PALB2 mutations were high-risk mutations, whereas the somatic PALB2 mutations were moderate-risk missense mutations. We also distinguished PALB2 "novel mutations" from "reported mutations." In conclusion, germline PALB2 mutation should be put into the context of future screening.

16.
Aging (Albany NY) ; 12(12): 11224-11237, 2020 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-32554861

RESUMEN

With the outbreak of coronavirus disease-19 (COVID-19), Changsha faced an increasing burden of treating the Wuhan migrants and their infected patients. This study is a retrospective, single-center case series of the 238 consecutive hospitalized patients with confirmed COVID-19 at the First Hospital of Changsha city, China, from 01/21 to 02/14, 2020; the final date of follow-up was 02/27, 2020. Of 238 patients 43.7% visited Wuhan, 58.4% got in touch with Wuhan people, and 47.5% had contacted with diagnosed patients. 37.8% patients had family members infected. 190 cases had mild / general disease, and 48 cases had severe / critical disease. Compared to mild or general patients, more severe or critical patients visited Wuhan (59.6% vs 40.2%; P=0.02) and contacted with Wuhan people (74.5% vs 55.0%; P=0.02). All patients received antiviral treatment, including Lopinavir / Ritonavir (29.3%), Interferon (14.6%) and their combination (40.6%), Arbidol (6.7%), Xuebijing (7.1%) and Chloroquine phosphate (1.3%). Severe and critical patients received glucocorticoid, Gamma-globulin and oxygen inhalation. Some received mechanic ventilation support. As of 02/27, 161 patients discharged. The median length of hospital stay was 13 days. The 10-, 14-, 20- and 28-day discharge rate was 19.1%, 42.8%, 65.0% and 76.4%, respectively. No hospital-related transmission was observed.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Respiración Artificial , Adulto , Antiinflamatorios no Esteroideos/uso terapéutico , COVID-19 , China/epidemiología , Cloroquina/análogos & derivados , Cloroquina/uso terapéutico , Combinación de Medicamentos , Medicamentos Herbarios Chinos/uso terapéutico , Femenino , Glucocorticoides/uso terapéutico , Hospitalización , Humanos , Factores Inmunológicos/uso terapéutico , Indoles/uso terapéutico , Interferones/uso terapéutico , Lopinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Oxígeno/uso terapéutico , Pandemias , Estudios Retrospectivos , Ritonavir/uso terapéutico , SARS-CoV-2 , gammaglobulinas/uso terapéutico
17.
Aging (Albany NY) ; 12(2): 1577-1590, 2020 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-31980592

RESUMEN

Nearly half of metastatic breast cancers (MBC) have genetic aberrations in the PI3K/AKT pathway. To investigate the distinct effect of these aberrations on MBC, 193 MBC patients who progressed after the early line (≤2) salvage treatment voluntarily received next generation sequencing (NGS) for a panel of 1,021 genes. 93 (48%) patients had genetic aberrations in the PI3K/AKT pathway. The number of patients with PIK3CA mutations in kinase domain (KD), helical domain (HD) and other domain (OD), were 36 (18.7%), 26 (13.5%), 10 (5.2%), respectively. 21 (10.9%) patients had mutations in PI3K/AKT pathway genes other than PIK3CA (P/A). Compared to PI3K/AKT-wild type (WT) patients, PIK3CA-HD patients had a significantly shorter progression-free survival (PFS) (Logrank p-value < 0.0001). PIK3CA-KD, PIK3CA-OD and other P/A mutations showed similar PFS to WT patients (Logrank p-value = 0.63). PIK3CA-HD patients had a distinct ctDNA mutation profile to patients with other PI3K/AKT mutations. PIK3CA-HD patients had a higher rate of FGFR and NF1 aberrations. In addition, more PIK3CA-HD carriers were TMB-high. Cox regression analyses suggested that PIK3CA-HD mutations, FGFR aberrations and high TMB were all significant risk factors for poor PFS. In conclusion, future research needs to focus more on the treatment strategies targeting PIK3CA-HD mutations.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Fosfatidilinositol 3-Quinasa Clase I/química , Fosfatidilinositol 3-Quinasa Clase I/genética , Mutación , Dominios y Motivos de Interacción de Proteínas/genética , Adulto , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , ADN Tumoral Circulante , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Tasa de Mutación , Pronóstico , Transducción de Señal
18.
Artículo en Inglés | MEDLINE | ID: mdl-31678514

RESUMEN

Atherosclerosis (AS) is characterized by lipids metabolism disorder and inflammatory response. Accumulating evidence has demonstrated that Wingless type 5a (Wnt5a) is implicated in cardiovascular diseases through non-canonical Wnt cascades. However, its precise role during the pathogenesis of AS is still unclear. Therefore, the present study aims to investigate the role and the underlying mechanism of Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (Ror2) pathways in the promotion of AS process through affecting lipid accumulation and inflammation. In atherosclerotic clinical samples, Wnt5a levels were measured by using enzyme-linked immunosorbent assay (ELISA) assay. In vivo experiments were conducted by using apolipoprotein E knockout (apoE-/-) mice model. Vascular smooth muscle cells (VSMCs) were applied for in vitro studies. Wnt5a was highly expressed in both of atherosclerotic clinical samples and apoE-/- mice. The knockdown of Wnt5a significantly inhibited cholesterol accumulation and inflammatory response. Additionally, the lipopolysaccharide (LPS)-induced inflammation aggravated the cholesterol accumulation and decreased adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression in VSMCs. Depletion of intracellular cholesterol by ß-cyclodextrin (ß-CD) led to the upregulation of ABCA1 and the inhibition of inflammation. Conversely, the overexpression of Wnt5a inhibited ABCA1 expression, facilitated cholesterol accumulation, impared cholesterol efflux, promoted NF-κB nuclear translocation and the inflammatory cytokines secretion. Moreover, the knockdown of Ror2 increased ABCA1 expression and reduced Wnt5a-induced cholesterol accumulation and inflammatory responses. Furthermore, the knockdown of ABCA1 enhanced cholesterol accumulation and inflammatory response. Therefore, Wnt5a/Ror2 pathway was critical in regulating cholesterol homeostasis and inflammatory response, which might be a promising therapeutic target for AS therapy.


Asunto(s)
Aterosclerosis/metabolismo , Colesterol/metabolismo , Inflamación/metabolismo , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Proteína Wnt-5a/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Aterosclerosis/sangre , Aterosclerosis/inmunología , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Inflamación/sangre , Inflamación/inmunología , Masculino , Ratones , Ratones Noqueados para ApoE , Músculo Liso Vascular/citología , Miocitos del Músculo Liso , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/sangre , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Transducción de Señal/inmunología , Proteína Wnt-5a/sangre , Proteína Wnt-5a/genética
19.
Ther Adv Med Oncol ; 12: 1758835920915305, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32499836

RESUMEN

BACKGROUND: The survival status of patients with breast cancer and brain metastasis (BCBM) receiving current treatments is poor. METHOD: We designed a real-world study to investigate using patients' clinical and genetic aberrations to forecast the prognoses of BCBM patients. We recruited 146 BCBM patients and analyzed their clinical features to evaluate the overall survival (OS). For genetic testing, 30 BCBM and 165 non-brain-metastatic (BM) metastatic breast cancer (MBC) patients from Hunan Cancer Hospital, and 86 BCBM and 1416 non-BM MBC patients from the Geneplus database who received circulating tumor DNA testing, were compared and analyzed. RESULTS: Ki67 >14% and >3 metastatic brain tumors were significant risk factors associated with poor OS, while chemotherapy and brain radiotherapy were beneficial factors for better OS. Compared with non-BM MBC patients, BCBM patients had more fibroblast growth factor receptor (FGFR) aberrations. The combination of FGFR, TP53 and FLT1 aberrations plus immunohistochemistry HER2-positive were associated with an increased risk of brain metastasis (AUC = 77.13%). FGFR aberration alone was not only a predictive factor (AUC = 67.90%), but also a significant risk factor for poor progression-free survival (Logrank p = 0.029). FGFR1 aberration was more frequent than other FGFR family genes in BCBM patients, and FGFR1 aberration was significantly higher in BCBM patients than non-BM MBC patients. Most FGFR1-amplified MBC patients progressed within 3 months of the late-line (>2 lines) treatment. CONCLUSION: A group of genetic events, including FGFR, TP53 and FLT1 genetic aberrations, and HER2-positivity, forecasted the occurrence of BM in breast cancers. FGFR genetic aberration alone predicted poor prognosis.

20.
J Transl Med ; 7: 74, 2009 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-19698176

RESUMEN

BACKGROUND: apogossypolone (ApoG2) is a novel derivate of gossypol. We previously have reported that ApoG2 is a promising compound that kills nasopharyngeal carcinoma (NPC) cells by inhibiting the antiapoptotic function of Bcl-2 proteins. However, some researchers demonstrate that the antiproliferative effect of gossypol on breast cancer cells is mediated by induction of cell cycle arrest. So this study was aimed to investigate the effect of ApoG2 on cell cycle proliferation in NPC cells. RESULTS: We found that ApoG2 significantly suppressed the expression of c-Myc in NPC cells and induced arrest at the DNA synthesis (S) phase in a large percentage of NPC cells. Immunoblot analysis showed that expression of c-Myc protein was significantly downregulated by ApoG2 and that the expression of c-Myc's downstream molecules cyclin D1 and cyclin E were inhibited whereas p21 was induced. To further identify the cause-effect relationship between the suppression of c-Myc signaling pathway and induction of cell cycle arrest, the expression of c-Myc was interfered by siRNA. The results of cell cycle analysis showed that the downregulation of c-Myc signaling pathway by siRNA interference could cause a significant arrest of NPC cell at S phase of the cell cycle. In CNE-2 xenografts, ApoG2 significantly downregulated the expression of c-Myc and suppressed tumor growth in vivo. CONCLUSION: Our findings indicated that ApoG2 could potently disturb the proliferation of NPC cells by suppressing c-Myc signaling pathway. This data suggested that the inhibitory effect of ApoG2 on NPC cell cycle proliferation might contribute to its use in anticancer therapy.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Gosipol/análogos & derivados , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Gosipol/química , Gosipol/farmacología , Gosipol/uso terapéutico , Humanos , Estructura Molecular , Neoplasias Nasofaríngeas/patología , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-myc/genética , Interferencia de ARN , Transducción de Señal/fisiología , Trasplante Heterólogo
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