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1.
Surg Oncol ; 31: 46-53, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31536927

RESUMO

Acetylcholine (ACh) was first identified as a classic neuromodulator and transmit signals through two subgroups of receptors, namely muscarinic receptors (mAChRs) and nicotinic receptors (nAChRs). Apart from its well-established physiological role in central nervous system (CNS) and peripheral nervous system (PNS), autonomic nervous system and neuromuscular junction, the widely distributed expression of AChRs in different human organs suggests roles in other biological processes in addition to synaptic transmission. Accumulating evidence revealed that cancer cell processes such as proliferation, apoptosis, angiogenesis and even epithelial-mesenchymal transition (EMT) are mediated by overexpression of AChRs in different kinds of tumors. In breast cancer, α7-nAChR and α9-nAChR were reported to be oncogenic. On the other hand, research on the role of mAChRs in breast cancer tumorgenesis is limited and confined to M3 receptor only. Since AChRs distributed in both CNS and PNS even non-neuronal tissues, there is an urgent need for the development of subtype-specific AChR antagonist which inhibits cancer cell progression with minimal intervention on the normal acetylcholine-regulated system within human body.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31474444

RESUMO

BACKGROUND: Survival of patients with breast cancer liver metastasis is very poor. This study aimed to analyze the survival outcome of hepatectomy for this patient population. METHODS: From January 1995 to December 2014, 2522 patients with liver cancer received hepatectomy at our hospital. Twenty-one of them, all female, received the operation for breast cancer liver metastasis. Performance was compared with patients with colorectal liver metastasis treated with hepatectomy after propensity score analysis in a ratio of 1:3. RESULTS: Twenty-one patients received hepatectomy for breast cancer. After propensity score matching, 63 patients who had hepatectomy for colorectal cancer were selected for comparison. There was no significant difference in immediate or short-term outcomes between the two groups of patients in terms of operative time, blood loss and surgical morbidities. All patients with breast cancer had R0 resection. No hospital death occurred. After hepatectomy, the 1-, 3- and 5-year overall survival rates were 100.0%, 58.9% and 58.9% respectively in patients with breast cancer. The 1-, 3- and 5-year overall survival rates were 95.0%, 57.2% and 39.7% respectively in patients with colorectal cancer (P = 0.572). On multivariate analysis, triple negative status was the only independent poor prognostic factor in breast cancer liver metastasis (OR = 6.411; 95% CI: 1.351-30.435; P = 0.019). CONCLUSIONS: Hepatectomy is a safe and effective way of treating breast cancer liver metastasis at experienced centers where multidisciplinary adjuvant treatments are available. It can be considered more frequently as part of the multidisciplinary care for this patient population.

3.
Int J Cancer ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31396961

RESUMO

Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole-exome sequencing (WES) included 186 familial ESCC patients from high-risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate-risk Hong Kong Chinese. A WES approach identified BRCA2 loss-of-function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10-10 ). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild-type somatic allelic loss via loss of heterozygosity. Gene-based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10-5 ), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.

5.
Sci Rep ; 9(1): 10326, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316143

RESUMO

With the increasing incidence and mortality of colorectal cancer (CRC), early and accurate diagnosis is of paramount priority to combat this cancer. Epigenetic alterations such as DNA methylation are innovative biomarkers for CRC, due to their stability, frequency, and accessibility in bodily fluids. In this study, blood samples were prospectively collected from patients before and after operation for CRC for determination of methylated septin 9 (mSEPT9) and compared to carcinoembryonic antigen (CEA). The sensitivity of using mSEPT9 methylation status for diagnosing CRC was significantly higher than using elevated CEA levels (73.2% vs 48.2%; p value < 0.001). The sensitivities of both tests increased with higher tumor staging (P = 0.004 and 0.04 respectively). Combined mSEPT9 and CEA had higher accuracy than single CEA or mSEPT9 (P = 0.009 and 0.532 separately). An increase in the methylation level of mSEPT9 detected in the post-operative samples was associated with a higher mortality rate (15.2% vs 1.8%; P = 0.024) and the presence of metastasis (27.3% vs 7.0%; P = 0.013). mSEPT9 was more sensitive than CEA for diagnosing CRC, and combined mSEPT9 and CEA was more accurate. After curative resection, detection of increased mSEPT9 methylation level may indicate adverse outcomes.

6.
Int J Epidemiol ; 48(3): 781-794, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243447

RESUMO

BACKGROUND: Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk. METHODS: Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results. RESULTS: The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P = 1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P = 9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050). CONCLUSION: Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.

7.
Mol Genet Genomic Med ; 7(6): e707, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066241

RESUMO

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

8.
J Natl Cancer Inst ; 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31093668

RESUMO

BACKGROUND: The incidence of breast cancer among younger East Asian women has been increasing rapidly over recent decades. This international collaborative study systemically compared the differences in age-specific incidences and pathological characteristics of breast cancer in women between East Asian and predominantly European ancestry. METHODS: We excerpted analytic data from six national cancer registries (979,675 cases) and eight hospitals (18,008 cases) in East Asian countries/regions and, for comparisons, from the United States Surveillance, Epidemiology, and End Results (SEER) program database. Linear regression analyses of age-specific incidences of female breast cancer and logistic regression analyses of age-specific pathological characteristics of breast cancer were performed. All statistical tests were two-sided. RESULTS: Unlike female colorectal cancer, the age-specific incidences of breast cancer among East Asian women aged ≤ 59 years increased disproportionally over recent decades relative to rates in United States contemporaries. For years 2010 - 2014, the estimated age-specific probability of estrogen receptor (ER) positivity increased with age in American patients, whereas that of triple negative breast cancer (TNBC) declined with age. No similar trends were evident in East Asian patients: their probability of ER positivity at age 40-49 years was statistically significantly higher (odd ratio [OR] = 1.50, 95% confidence interval [CI]: 1.36-1.67, P < .001) and of TNBC was statistically significantly lower (OR = 0.79, 95% CI: 0.71-0.88, P < .001), whereas the probability of ER positivity at age 50-59 years was statistically significantly lower (OR = 0.88, 95% CI: 0.828-0.95, P < .001). Subgroup analyses of SEER data showed similarly distinct patterns between East Asian American and white American patients. CONCLUSION: Contrasting age-specific incidences and pathological characteristics of breast cancer between East Asian and American women, as well as between East Asian Americans and white Americans, suggests racial differences in the biology.

9.
Ann Surg Oncol ; 26(9): 2747-2758, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31111353

RESUMO

BACKGROUND: Phyllodes tumors (PTs) of the breast are uncommon fibroepithelial neoplasms. Most behave in a benign fashion but they also have the potential to recur locally or to metastasize. METHODS: In the current study involving 290 PTs (181 benign, 76 borderline, and 33 malignant) from three hospitals over an 11-year period, we assessed the relationship between histologic parameters (including histologic features affecting grade and surgical margin status), postoperative adjuvant treatment, and local recurrences and distant metastases. RESULTS: An involved surgical margin was the only factor associated with increased risk of local recurrences (hazard ratio [HR] 4.673, p = 0.003), but not for distant metastases. For local recurrences, a wider margin did not confer additional benefits. None of the histologic factors were predictive for local recurrences. In contrast, distant metastases were correlated with histologic parameters, particularly an infiltrative border (HR 10.935, p = 0.012) and the presence of necrosis (HR 15.311, p = 0.007). In this series, all local recurrences were found in patients without radiotherapy, regardless of surgical margin status. CONCLUSION: A negative surgical margin is mandatory for the effective local control of PT recurrence, and a minimal margin clearance may be sufficient. For distant metastases, the inherent characteristics of PTs are important, thus it may be prudent to evaluate additional histologic features, including necrosis, for patients' prognostication.

10.
Hum Mutat ; 40(10): 1781-1796, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31112363

RESUMO

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.

11.
Asian J Surg ; 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31130499

RESUMO

BACKGROUND: Atypical ductal hyperplasia (ADH) is known to be associated with underlying malignant breast conditions. Previous studies have shown that up to 40% of ADH found in core needle biopsy of the breasts had undiagnosed malignant lesions after excision. METHODS: This is a retrospective study on a prospectively maintained database. From 1st January 2005 to 31st December 2014, a total of 262 excision or mastectomy specimens were identified to contain ADH. Clinical, radiological and pathological data were retrieved and analyzed. Correlating factors for the presence of co-existing pre-malignant or malignant conditions were analyzed. Overall survival in patients with or without co-existing malignant breast lesions were evaluated. RESULTS: 95 (36.3%) had co-existing malignant breast lesions within the same specimen. The median age at diagnosis was 49 (Range 17-85). Suspicious breast imaging features (BIRADS 4 or above) and lesions larger than 10 mm on breast imaging were independent risk factor for co-existing malignant pathology (p < 0.001 and 0.005 respectively). After median follow-up interval of 60 months (6-120 months), the overall survival was comparable between the groups of patients having ADH with or without co-existing malignant pathologies (98.2% and 97.9% respectively). CONCLUSION: Co-existing malignant lesions were present in up to 36.3% of the pathology specimens containing ADH, in which its presence could be predicted by pre-operative breast imaging.

12.
Psychooncology ; 28(6): 1243-1251, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30932279

RESUMO

OBJECTIVE: Fear of cancer recurrence (FCR) represents a chronic burden for many cancer survivors. We determined FCR prevalence and potential correlates, specifically metacognitive styles and neuroticism among Chinese cancer survivors with breast or colorectal cancer. METHODS: This study included 285 Chinese patients with breast (N = 173) and colorectal (N = 112) cancers at 8-week postsurgery. Participants completed a set of baseline questionnaires evaluating FCR (Fear of Cancer Recurrence Inventory-Short Form [FCRI-SF]), metacognition (Metacognitions Questionnaire-30), and neuroticism (Eysenck Personality Questionnaire). Scores of 13 to 21 were indicative of subclinical FCR on the FCRI-SF. Scores greater than or equal to 22 indicated clinically significant levels of FCR. Fully adjusted multinomial logistic regressions identified correlates of subclinical and clinically significant FCR. RESULTS: Respectively, 26.0% (n = 74) and 11.2% (n = 32) achieved scores indicating subclinical and clinically significant FCR. Expressing significantly more positive (OR = 1.21, P = .003) and negative (OR = 1.19, P = .005) beliefs about worry was associated with a higher likelihood of reporting subclinical FCR. Both higher neuroticism (OR = 1.28, P = .003) and more negative beliefs about worry (OR = 1.19, P = 0.035) were associated with an increased likelihood of experiencing clinically significant FCR. CONCLUSIONS: Positive and negative metacognitions may play an important role in the development of subclinical FCR. In particular, negative metacognition and neuroticism may elevate FCR from subclinical to a clinical level. The findings give insight into the identification of cancer survivors with subclinical or clinical FCR and aid the development of interventions aimed at changing metacognitive beliefs in order to manage FCR.

13.
Postgrad Med J ; 95(1121): 155-161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31004045

RESUMO

BACKGROUND: Over the last 10 years, there has been a major treatment revolution for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to explore the outcome of different neoadjuvant chemotherapy in a tertiary breast cancer centre with early HER2-positive breast cancer as well as factors associated with pathological complete response (pCR) and recurrence-free survival (RFS). The pattern of recurrence was also studied. METHODS: This retrospective study analysed the outcome of neoadjuvant chemotherapy during the period 2005 to 2016 in a tertiary referral centre in Hong Kong. Patients were divided into three groups according to the neoadjuvant chemotherapy they received: chemotherapy only (Chemo), chemotherapy plus trastuzumab (Chemo-H) and chemotherapy plus double anti-HER2 therapy (Chemo-DH). RESULTS: There were 226 cases analysed during the study period. The rate of pCR was 5%, 26% and 60% in Chemo, Chemo-H and Chemo-DH groups, respectively (Chemo vs pooled Chemo-H/DH: p<0.0001; Chemo-H vs Chemo-DH: p<0.0001). This was accompanied by a trend of increased rate of breast conservation therapy in Chemo-DH cohort (p=0.046). Use of double anti-HER2 therapy, older age (>50 years) and hormone receptor negativity were associated with more pCR. pCR was associated with better RFS. Among those with recurrence, the proportion of patients with brain as the only site of recurrence increased remarkably with more efficacious anti-HER2 treatment (0% in Chemo, 8% in Chemo-H, 67% in Chemo-DH). CONCLUSION: pCR remains an important predictive factor for improved RFS. In the era of dual anti-HER2 neoadjuvant therapy, brain-only recurrence poses a challenge to disease surveillance and treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/genética , Feminino , Hong Kong , Humanos , Lapatinib/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2 , Estudos Retrospectivos , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Resultado do Tratamento
14.
Br J Cancer ; 121(1): 15-21, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30971774

RESUMO

BACKGROUND: Women with a BRCA1 or BRCA2 mutation face high risks of breast and ovarian cancer. In the current study, we report on uptake of cancer screening and risk-reduction options in a cohort of BRCA mutation carriers from ten countries over two time periods (1995 to 2008 and 2009 to 2017). METHODS: Eligible subjects were identified from an international database of female BRCA mutation carriers and included women from 59 centres from ten countries. Subjects completed a questionnaire at the time of genetic testing, which included past use of cancer prevention options and screening tests. Biennial follow-up questionnaires were administered. RESULTS: Six-thousand two-hundred and twenty-three women were followed for a mean of 7.5 years. The mean age at last follow-up was 52.1 years (27-96 years) and 42.3% of the women had a prior diagnosis of breast cancer. In all, 27.8% had a prophylactic bilateral mastectomy and  64.7% had a BSO. Screening with breast MRI increased from 70% before 2009 to 81% at or after 2009. There were significant differences in uptake of all options by country. CONCLUSION: For women who received genetic testing more recently, uptake of prophylactic mastectomy and breast MRI is significantly higher than those who received genetic testing more than 10 years ago. However, uptake of both BSO and breast MRI is not optimal, and interventions to increase uptake are needed.

15.
World J Surg ; 43(8): 1991-1996, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30888473

RESUMO

BACKGROUND: The combined use of radioisotope and blue dye is the gold standard in sentinel lymph node (SLN) localization in early breast cancer. Superparamagnetic iron oxide (SPIO) has recently emerged as a non-inferior new tracer in sentinel lymph node mapping with fewer disadvantages. This study represents the first and the largest cohort of superparamagnetic iron oxide application in Asian population. METHODS: Retrospective analysis of a prospectively maintained database was performed from August 2016 to December 2017. All patients with SLN localization by SPIO were included in this study. RESULTS: A total of 328 breast cancer patients with 333 SLNB procedures were included in this study. Median age was 54 years (range 32-86). Median tumor size was 1.9 cm (range 0.1-12 cm).There were 138 breast-conserving surgeries and 195 mastectomies. All patients received injection of SPIO 1 day prior to operation. A total of 329 successful sentinel lymph node biopsy (SLNB) procedures were undertaken with 1514 sentinel lymph nodes (SLNs) identified. One hundred and fifty-three (10.1%) of the SLNs were positive for malignancy. There were 54 patients with macrometastases, 26 with micrometastases and 24 with isolated tumor cells. Sixty-seven patients underwent subsequent axillary dissection. Four patients failed sentinel lymph node identification with SPIO. The success rate of SPIO in sentinel lymph node localization was 98.8%. CONCLUSION: SPIO represents a feasible alternative in sentinel lymph node mapping with comparably high nodal detection rate.

16.
Asia Pac J Clin Oncol ; 15 Suppl 2: 20-31, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30838787

RESUMO

AIMS: BRCA mutation (BRCAmut) testing is an important tool for the risk assessment, prevention and early diagnosis of breast cancer (BC) and ovarian cancer (OC), and more recently, for determining patient susceptibility to targeted therapy. This study assessed the current BRCAmut testing patterns and explored physicians' perspectives on the utilities and optimal sequencing of the testing, in order to facilitate and standardize testing practices. METHODS: Medical specialists in BC and OC in Hong Kong were invited to complete a questionnaire on BRCAmut testing practices. A panel of specialists with extensive BRCAmut testing experience was also convened to develop consensus statements on testing, using the Delphi method and an anonymous electronic voting system. RESULTS: The survey respondents (n = 71) recognized family history (FH) of BC and/or OC and an early age of onset as key factors for referring BRCAmut testing. The proportion of respondents who would test all OCs regardless of FH or age, as per the recent international guideline, was low (28.2%). The largest hurdles to testing were the cost, as well as the availability of next-generation sequencing-accredited testing and genetic counseling facilities. The panelists suggested that the sequence of somatic testing followed by germline testing may help address both the imminent need of treatment planning and longer term hereditary implications. The potential emotional and financial burdens of BRCAmut testing should be weighed against the potential therapeutic benefits, and the type and timing of testing personalized. CONCLUSIONS: Accessibility of BRCAmut testing to all at-risk individuals will be achievable through improvements in testing affordability, as well as widened availability of accredited testing and genetic counseling facilities.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Testes Genéticos , Terapia de Alvo Molecular , Mutação , Neoplasias Ovarianas/genética , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Adulto , Consenso , Feminino , Hong Kong , Humanos , Neoplasias Ovarianas/terapia , Especialização , Adulto Jovem
17.
Cell Death Dis ; 10(4): 270, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894512

RESUMO

Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer with the absence of targeted therapy, resulting in poor prognosis in patients. Chemotherapy remains the mainstay of treatment for TNBC; however, development of drug resistance is the main obstacle for successful treatments. In recent years, long non-coding RNA (lncRNA) has been implicated in multiple biological functions in various diseases, particularly cancers. Accumulating evidence suggested that lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression is dysregulated in many human cancers and thus is a useful prognostic marker for cancer patients. Nevertheless, the mechanism of how NEAT1 confers drug resistance in TNBC is still largely unknown. We performed lncRNA profiling by the LncRNA Profiler qPCR Array Kit in normal control (NC) and breast cancers (BC) blood samples and further validated in a larger cohort of samples by qRT-PCR. Gene expression level and localization were investigated by qRT-PCR, western blotting, and immunofluorescence staining. Flow cytometric analysis was carried out to detect cancer stem cells. Functional studies were performed both in vitro and in vivo xenograft model. Among 90 lncRNAs, NEAT1 was highly expressed in the blood samples of breast cancer patients than in NC. In particular, the expression of NEAT1 was higher in TNBC tissues than other subgroups. Functional studies revealed that NEAT1 conferred oncogenic role by regulating apoptosis and cell cycle progression in TNBC cells. We identified that knockdown of NEAT1 sensitized cells to chemotherapy, indicating the involvement in chemoresistance. Importantly, shNEAT1 reduced stem cell populations such as CD44+/CD24-, ALDH+, and SOX2+, implicating that NEAT1 was closely related to cancer stemness in TNBC. Our data highlighted the roles of NEAT1 chemoresistance and cancer stemness, suggesting that it could be used as a new clinical therapeutic target for treating TNBC patients especially those with drug resistance.

18.
Cancer Treat Res Commun ; 19: 100118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825858

RESUMO

BACKGROUND: Treatment of de novo metastatic breast cancer is usually palliative with systemic treatment; surgical excision of the primary tumour is reserved in patients with significant symptoms from the primary tumour. Survival benefit of surgical removal of the primary tumour remains controversial. METHODS: All patients treated with de novo metastatic breast cancer (MBC) between 2007 and 2016 were retrieved from a prospectively-maintained database. Demographic and tumour characteristics were compared. Overall survival (OS) was analysed using Kaplan-Meier Method and log rank tests. Multivariate analysis was performed to evaluate the prognosticators of OS in de novo MBC. RESULTS: Median age of diagnosis was 53 years old (Range 24-91 years old). 91 patients received resection of the primary tumour, including 86 mastectomies and 5 breast conserving surgeries (surgical group). 81 patients were never treated surgically (non-surgical group). Baseline demographic data were comparable apart from being younger age in the surgical group. 5-year OS in surgical group was significantly better than non-surgical group (43.9% vs. 33.9%, p = 0.026). Multivariate analysis found that advanced age (Hazard ratio: 1.034, p = 0.005, 95% CI 1.010-1.058) and presence of visceral metastasis (Hazard ratio: 1.672, p = 0.038, 95% CI 1.028-2.719) were significant adverse prognosticators through multivariate analysis; while positive oestrogen receptor (ER) status was the only positive prognosticator in the analysis (Hazard ratio: 0.42, p = 0.001, 95% CI 0.256-0.688). CONCLUSION: Surgical excision of primary breast tumour may confer survival benefit in de novo MBC.


Assuntos
Neoplasias da Mama/mortalidade , Mastectomia Segmentar/mortalidade , Mastectomia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/secundário , Neoplasias da Mama/cirurgia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
19.
Pathology ; 50(7): 742-747, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30389215

RESUMO

Idiopathic granulomatous mastitis (IGM) is an uncommon, chronic inflammatory breast disease with elusive aetiology, simulating malignancy clinically and radiologically. Here we present our 10-year review on a region-wide multicentre IGM database. A retrospective study was performed on a prospectively maintained database from three University affiliated hospitals in Hong Kong and Shenzhen, China. All patients with biopsy proven IGM were included while patients with positive culture of Mycobacterium tuberculosis were excluded. Disease recurrence rate and its prognosticators were evaluated. A total of 102 patients were included between January 2007 and December 2017. Median age was 33 years (range 20-54). Most patients presented with painful inflammatory mass (n = 57); median size at presentation was 37 mm (6-92 mm). Sixty-three patients had bacterial culture performed on the pus sample: eight patients had Corynebacterium kroppenstedtii while four had Corynebacterium species not otherwise specified. Seventy-seven (75.5%) patients received conservative treatment with oral corticosteroid (±antibiotics) and drainage only, while 25 (24.5%) patients received breast lump excision after initial medical treatment. Twelve (11.8%) patients developed recurrence after a median follow-up interval of 14 months (4-51 months). Univariate analysis revealed that abscess on presentation, history of smoking, and presence of C. kroppenstedtii were significant prognosticators for recurrence. Subsequent multivariate analysis with logistic regression revealed cigarette smoking and isolation of C. kroppenstedtii as independent risk factors for disease recurrence (p < 0.05). In conclusion, IGM is uncommon with a recurrence rate of 12%, especially in patients with history of smoking and isolation of C. kroppenstedtii.

20.
Hum Genomics ; 12(1): 40, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30134973

RESUMO

BACKGROUND: Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. METHODS: In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published "nontumor"-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. RESULTS: Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in "nontumor" tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in "paratumor" tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from "nontumor" to "paratumor" and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. CONCLUSIONS: These findings suggest that developing cancer cells undergo sequential changes that enable the "nontumor" cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the "paratumor" cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

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