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PURPOSE: Receptor and subtype discordance between primary breast tumours and metastases is a frequently reported phenomenon. The aim of this article is to review the current evidence on receptor discordance in metastatic breast cancer and to explore the benefit of performing a repeat biopsy in this context. METHODS: Searches were undertaken on PubMed and Clinicaltrials.gov for relevant publications and trials. CONCLUSION: The current guidelines recommend offering to perform a biopsy of a metastatic lesion to evaluate receptor status. The choice of systemic therapy in metastatic disease is often based on the receptor status of the primary lesion. As therapeutic decision making is guided by subtype, biopsy of the metastatic lesion to determine receptor status may alter treatment. This article discusses discordance rates, the mechanisms of receptor discordance, the effect of discordance on treatment and survival outcomes, as well as highlighting some ongoing clinical trials in patients with metastatic breast cancer.
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BACKGROUND: Systemic inflammatory response markers have been found to have a prognostic role in several cancers, but their value in predicting the response to neoadjuvant chemotherapy in breast cancer is uncertain. A systematic review and meta-analysis of the literature was carried out to investigate this. METHODS: A systematic search of electronic databases was conducted to identify studies that explored the predictive value of circulating systemic inflammatory response markers in patients with breast cancer before commencing neoadjuvant therapy. A meta-analysis was undertaken for each inflammatory marker where three or more studies reported pCR rates in relation to the inflammatory marker. Outcome data are reported as ORs and 95% confidence intervals. RESULTS: A total of 49 studies were included, of which 42 were suitable for meta-analysis. A lower pretreatment neutrophil-to-lymphocyte ratio was associated with an increased pCR rate (pooled OR 1.66 (95% c.i. 1.32 to 2.09); P < 0.001). A lower white cell count (OR 1.96 (95% c.i. 1.29 to 2.97); P = 0.002) and a lower monocyte count (OR 3.20 (95% c.i. 1.71 to 5.97); P < 0.001) were also associated with a pCR. A higher lymphocyte count was associated with an increased pCR rate (OR 0.44 (95% c.i. 0.30 to 0.64); P < 0.001). CONCLUSION: The present study found the pretreatment neutrophil-to-lymphocyte ratio, white cell count, lymphocyte count, and monocyte count of value in the prediction of a pCR in the neoadjuvant treatment of breast cancer. Further research is required to determine their value in specific breast cancer subtypes and to establish optimal cut-off values, before their adoption in clinical practice.
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Neoplasias da Mama , Terapia Neoadjuvante , Feminino , Humanos , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/terapia , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Contagem de Leucócitos , Contagem de Linfócitos , Neutrófilos , Valor Preditivo dos Testes , PrognósticoRESUMO
BACKGROUND: Electrosurgical devices are commonly used during mastectomy for simultaneous dissection and haemostasis, and can provide potential benefits regarding vessel and lymphatic ligation. The aim of this prospective RCT was to assess whether using a vessel-sealing device (LigaSure™) improves perioperative outcomes compared with monopolar diathermy when performing simple mastectomy. METHODS: Patients were recruited prospectively and randomized in a 1 : 1 manner to undergo simple mastectomy using either LigaSure™ or conventional monopolar diathermy at a single centre. The primary outcome was the number of days the drain remained in situ after surgery. Secondary outcomes of interest included operating time and complications. RESULTS: A total of 86 patients were recruited (42 were randomized to the monopolar diathermy group and 44 were randomized to the LigaSure™ group). There was no significant difference in the mean number of days the drain remained in situ between the monopolar diathermy group and the LigaSure™ group (7.75 days versus 8.23 days; P = 0.613) and there was no significant difference in the mean total drain output between the monopolar diathermy group and the LigaSure™ group (523.50â ml versus 572.80â ml; P = 0.694). In addition, there was no significant difference in the mean operating time between the groups, for simple mastectomy alone (88.25â min for the monopolar diathermy group versus 107.20â min for the LigaSure™ group; P = 0.078) and simple mastectomy with sentinel lymph node biopsy (107.20â min for the monopolar diathermy group versus 114.40â min for the LigaSure™ group; P = 0.440). CONCLUSION: In this double-blinded single-centre RCT, there was no difference in the total drain output or the number of days the drain remained in situ between the monopolar diathermy group and the LigaSure™ group. REGISTRATION NUMBER: EudraCT 2018-003191-13 BEAUMONT HOSPITAL REC 18/66.
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Neoplasias da Mama , Diatermia , Humanos , Feminino , Mastectomia Simples , Neoplasias da Mama/cirurgia , Estudos Prospectivos , MastectomiaRESUMO
BACKGROUND: The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). METHODS: A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. RESULTS: A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. CONCLUSION: The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Biópsia de Linfonodo Sentinela , Excisão de Linfonodo , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Hormônios/uso terapêutico , Axila/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologiaRESUMO
BACKGROUND: The current standard of care in the neoadjuvant setting for high-risk HER2-positive (HER2 +) breast cancer is to combine systemic chemotherapy with dual HER2 blockade, trastuzumab and pertuzumab. Targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer. To improve treatment-associated toxicity, chemotherapy-sparing approaches are currently being investigated. Trastuzumab deruxtecan (T-DXd) is an HER2-directed antibody-drug-conjugate (ADC) with promising results in the metastatic setting for HER2-positive breast cancer. The SHAMROCK study investigates neoadjuvant T-DXd in early stage HER2-positive breast cancer, using pathological complete response (pCR) rate as the primary endpoint. METHODS: This is a phase II open-label, single arm, adaptive multi-centre trial of T-DXd in the neoadjuvant setting in stage 2-3 HER2-positive breast cancer. Eligible patients will receive 5.4 mg/kg of T-DXd intravenously every 3 weeks for up to 6 cycles. A repeat biopsy will performed after 2 cycles for the RNA disruption index (RDI) score assessment. According to their likelihood of pCR, as determined by the RDI score, patients will either undergo 4 or 6 cycles of T-DXd prior to imaging. Patients with imaging complete response (iCR) after either 4 or 6 cycles will proceed to surgery. Patients who do not achieve iCR will either undergo further systemic therapy or proceed to surgery. DISCUSSION: The SHAMROCK study is a chemotherapy-sparing approach to curative intent treatment, investigating neoadjuvant T-DXd. We hypothesise that neoadjuvant T-DXd will have a high pCR rate and be associated low toxicity in early stage HER2-positive breast cancer. TRIAL REGISTRATION: EudraCT Number: 2022-002485-32; ClinicalTrials.gov identifier: NCT05710666; Cancer Trials Ireland study number: CTRIAL-IE 22-01.
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Neoplasias da Mama , Camptotecina/análogos & derivados , Imunoconjugados , Humanos , Feminino , Neoplasias da Mama/patologia , Terapia Neoadjuvante/efeitos adversos , Receptor ErbB-2/análise , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Trastuzumab/uso terapêutico , Imunoconjugados/uso terapêutico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
PURPOSE OF REVIEW: In the last decade, poly (ADP-ribose) polymerase (PARP) inhibitors have been approved in the treatment of several cancers, such as breast and ovarian cancer. This article aims to discuss the current uses, limitations, and future directions for PARP inhibitors (PARPis) in the treatment of breast cancer. RECENT FINDINGS: Following the results of the OlympiAD and EMBRACA trials, PARPis were approved in HER2-negative breast cancer with a germline BRCA mutation. We reviewed this class of drugs' mechanism of action, efficacy, and limitations, as well as further studies that discussed resistance, impaired homologous recombination repair (HRR), and the combination of PARPis with other drugs. Improving understanding of HRR, increasing the ability to target resistance, and combining PARPis with other novel agents are continuing to increase the clinical utility of PARPis.
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Neoplasias da Mama , Neoplasias Ovarianas , Feminino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Poli(ADP-Ribose) Polimerases/genética , Reparo do DNA , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
PURPOSE OF REVIEW: Homologous recombination repair deficiency (HRD) increases breast cancer susceptibility and influences both prophylactic and active management of breast cancer. This review evaluates HRD testing and the therapeutic implications of HRD in a global context. RECENT FINDINGS: Ongoing research efforts have highlighted the importance of HRD beyond BRCA1/2 as a potential therapeutic target in breast cancer. However, despite the improved affordability of next-generation sequencing (NGS) and the discovery of PARP inhibitors, economic and geographical barriers in access to HRD testing and breast cancer screening do not allow all patients to benefit from the personalized treatment approach they provide. Advancements in HRD testing modalities and targeted therapeutics enable tailored breast cancer management. However, inequalities in access to testing and optimized treatments are contributing to widening health disparities globally.
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Neoplasias da Mama , Reparo de DNA por Recombinação , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/diagnóstico , Feminino , Reparo de DNA por Recombinação/genética , Testes Genéticos/métodos , Detecção Precoce de Câncer/métodos , Predisposição Genética para Doença , Proteína BRCA2/genética , Proteína BRCA1/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
BACKGROUND: Breast cancer surveillance programmes ensure early identification of recurrence which maximises overall survival. Programmes include annual clinical examination and radiological assessment. There remains debate around the value of annual clinical exam in diagnosing recurrent disease/second primaries. The aim was to assess diagnostic modalities for recurrent breast cancer with a focus on evaluating the role of annual clinical examination. PATIENTS AND METHODS: A prospectively maintained database from a symptomatic breast cancer service between 2010-2020 was reviewed. Patients with biopsy-proven recurrence/second breast primary were included. The primary outcome was the diagnostic modality by which recurrences/secondary breast cancers were observed. Diagnostic modalities included (i) self-detection by the patient, (ii) clinical examination by a breast surgeon or (iii) radiological assessment. RESULTS: A total of 233 patients were identified and, following application of exclusion criteria, a total of 140 patients were included. A total of 65/140 (46%) patients were diagnosed clinically, either by self-detection or clinical examination, while 75/140 (54%) were diagnosed radiologically. A total of 59/65 (91%) of patients clinically diagnosed with recurrence presented to the breast clinic after self-detection of an abnormality. Four (6%) patients had cognitive impairment and recurrence was diagnosed by a carer. Two (3%) patients were diagnosed with recurrence by a breast surgeon at clinical examination. The median time to recurrence in all patients was 48 months (range 2-263 months). CONCLUSION: Clinical examination provides little value in diagnosing recurrence (< 5%) and surveillance programmes may benefit from reduced focus on such a modality. Regular radiological assessment and ensuring patients have urgent/easy access to a breast clinic if they develop new symptoms/signs should be the focus of surveillance programmes.
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Neoplasias da Mama , Feminino , Humanos , Instituições de Assistência Ambulatorial , Biópsia , Neoplasias da Mama/diagnóstico , Doença Crônica , SeguimentosRESUMO
BACKGROUND: Sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NACT) in patients with breast cancer who are initially node-positive but convert to clinically/radiologically node-negative remains controversial. The primary aim was to assess pooled 5-year disease-free (DFS) and overall (OS) survival for patients who are initially node-positive but have a negative SLNB after NACT, and do not proceed to axillary lymph node dissection (ALND). METHODS: The study was performed using PRISMA guidelines. A systematic literature search of relevant databases was conducted. The Der Simonian-Laird and Cochran-Mantel-Haenszel methods were used to calculate weighted pooled estimates for OS and DFS for this group compared with patients who had NACT and proceeded to ALND after a negative or positive SLNB. RESULTS: Seven studies involving 915 patients who had a negative SLNB after NACT were included. Pooled estimates of 5-year DFS and OS in patients with a negative SLNB after NACT were 86 (95 per cent c.i. 82.1 to 90.3) and 93.1 (87.8 to 97.0) per cent respectively. Patients with a positive SLNB who underwent ALND had reduced 5-year DFS (OR 0.49, 95 per cent c.i. 0.35 to 0.69; P < 0.001) and OS (OR 0.41, 0.16 to 1.02; P = 0.06) compared with those who had a negative SLNB after NACT. There were no differences in DFS for patients who had a negative SLNB only compared with those undergoing ALND with a pCR (OR 1.65, 0.71 to 3.79; P = 0.24). CONCLUSION: Patients who are initially node-positive and who achieve a complete clinical/radiological axillary response after NACT with a subsequent negative SLNB have high rates of DFS and OS after 5 years. Patients with residual disease have significantly reduced DFS and further axillary treatment may still be warranted.
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Neoplasias da Mama , Linfonodo Sentinela , Humanos , Feminino , Biópsia de Linfonodo Sentinela/métodos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Terapia Neoadjuvante , Excisão de Linfonodo/métodos , Axila/patologia , Linfonodos/patologia , Linfonodo Sentinela/cirurgia , Linfonodo Sentinela/patologiaRESUMO
BACKGROUND: Clinical acumen and experience are critical in the diagnosis of the commonest surgical emergency, acute appendicitis. However, there is an increasing focus on haematological and radiological parameters in reaching the diagnosis of appendicitis, which can negate the importance of clinical findings. The aim was to assess the accuracy of each grade of the surgical team in diagnosing acute appendicitis using clinical acuity alone and compare them to each other as well as validated predictive scores. METHODS: A prospective single-centre study was performed over a six-month period (Dec 2020-May 2021). All patients presenting to the emergency department with right iliac fossa pain were included. RESULTS: A total of 180 patients were included of whom 35% were male. Mean age was 36.2 years (range 16-91). 51.1% had a final diagnosis of appendicitis, of which 91.3% were managed surgically and 8.7% were treated conservatively with antibiotics. Consultants were correct in their prediction of appendicitis in 84.6% of cases (females-83.4%, males-86.6%). Registrars accurately predicted appendicitis in 82.2% of patients (females-80.3%, males-85.7%), whilst house officers (SHOs) and interns were right in 73.8% (females-69.2%, males-82.5%) and 72.7% (females-66.6%, males-83.9%) of cases, respectively. In patients with a histological or radiological diagnosis of appendicitis, the mean Acute Inflammatory Response Score and Acute Appendicitis Score were 7.0 (high risk ≥ 9) and 12.5 (high risk ≥ 16), respectively. Clinicians had superior diagnostic accuracy when compared with both the clinical scores used. CONCLUSION: Seniority was associated with improved diagnostic accuracy in clinically predicting acute appendicitis. This study showed that the clinical judgement of experienced surgeons is more reliable than clinical scores in the diagnosis of appendicitis.
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Apendicite , Feminino , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Estudos Prospectivos , Apendicite/diagnóstico , Apendicite/cirurgia , Serviço Hospitalar de Emergência , Antibacterianos , Inflamação , Doença Aguda , ApendicectomiaRESUMO
BACKGROUND: In early 2020, the COVID-19 pandemic significantly altered management of surgical patients globally. International guidelines recommended that non-operative management be implemented wherever possible (e.g. in proven uncomplicated appendicitis) to reduce pressure on healthcare services and reduce risk of peri-operative viral transmission. We sought to compare our management and outcomes of appendicitis during lockdown vs a non-pandemic period. METHODS: All presentations to our department with a clinical diagnosis of acute appendicitis between 12/03/2020 and 30/06/2020 were compared to the same 110-day period in 2019. Quantity and severity of presentations, use of radiological investigations, rate of operative intervention and histopathological findings were variables collected for comparison. RESULTS: There was a reduction in appendicitis presentations (from 74 to 56 cases), and an increase in radiological imaging (from 70.27% to 89.29%) (P = 0.007) from 2019 to 2020. In 2019, 93.24% of patients had appendicectomy, compared to 71.42% in 2020(P < 0.001). This decrease was most pronounced in uncomplicated cases, whose operative rates dropped from 90.32% to 62.5% (P = 0.009). Post-operative histology confirmed appendicitis in 73.9% in 2019, compared to 97.5% in 2020 (P = 0.001). Normal appendiceal pathology was reported for 17 cases (24.64%) in 2019, compared to none in 2020 (P < 0.001) - a 0% negative appendicectomy rate (NAR). DISCUSSION: The 0% NAR in 2020 is due to a combination of increased CT imaging, a higher threshold to operate, and is impacted by increased disease severity due to delayed patient presentation. This study adds to growing literature promoting routine use of radiological imaging to confirm appendicitis diagnosis. As we enter a second lockdown, patients should be encouraged to avoid late presentations, and surgical departments should continue using radiological imaging more liberally in guiding appendicitis management.
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Apendicectomia/estatística & dados numéricos , Apendicite/epidemiologia , Apendicite/cirurgia , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apendicite/diagnóstico , COVID-19/prevenção & controle , COVID-19/transmissão , Protocolos Clínicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Padrões de Prática Médica , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood-brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. METHODS: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. RESULTS: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. CONCLUSION: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.
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Proteínas ADAM/metabolismo , Materiais Biomiméticos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/farmacologia , Proteínas ADAM/biossíntese , Proteínas ADAM/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genéticaRESUMO
BACKGROUND: Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. METHODS: Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. RESULTS: Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. CONCLUSIONS: Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies.
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Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Moléculas de Adesão Celular/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Embrião de Galinha , Membrana Corioalantoide , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Invasividade Neoplásica/patologia , RNA Interferente Pequeno/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Superfície Celular/sangue , Receptores de Superfície Celular/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: Fine needle aspiration biopsy (FNAB) is the tool of choice for evaluating thyroid nodules with the majority classified as benign following initial assessment. However, concern remains about false negative results and some guidelines have recommended routine repeat aspirates. We aimed to assess the utility of routine repeat FNAB for nodules classified as benign on initial biopsy and to examine the impact of establishing a multidisciplinary team for the care of these patients. METHODS: We performed a retrospective review of 400 consecutive patients (413 nodules) who underwent FNAB of a thyroid nodule at our hospital between July 2008 and July 2011. Data recorded included demographic, clinical, histological and radiological variables. RESULTS: Three hundred and fifty seven patients (89 %) were female. Median follow-up was 5.5 years. Two hundred and fifty eight (63 %) nodules were diagnosed as benign. The rate of routine repeat biopsy increased significantly over the time course of the study (p for trend = 0.012). Nine Thy 2 nodules were classified differently on the basis of routine repeat biopsy; one patient was classified as malignant on repeat biopsy and was diagnosed with papillary thyroid carcinoma. Eight were classified as a follicular lesions on repeat biopsy-six diagnosed as benign following lobectomy; two declined lobectomy and were followed radiologically with no nodule size increase. CONCLUSIONS: The false negative rate of an initial benign cytology result, from a thyroid nodule aspirate, is low. In the setting of an experienced multidisciplinary thyroid team, routine repeat aspiration is not justified.
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Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia , Biópsia por Agulha Fina , Reações Falso-Negativas , Humanos , Irlanda , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de TempoRESUMO
INTRODUCTION: Most breast cancer-related deaths result from metastasis, a process involving dynamic regulation of tumour cell adhesion and migration. The adhesion protein CD44, a key regulator of cell migration, is enriched in cholesterol-enriched membrane microdomains termed lipid rafts. We recently reported that raft affiliation of CD44 negatively regulates interactions with its migratory binding partner ezrin. Since raft affiliation is regulated by post-translational modifications including palmitoylation, we sought to establish the contribution of CD44 palmitoylation and lipid raft affiliation to cell migration. METHODS: Recovery of CD44 and its binding partners from raft versus non-raft membrane microdomains was profiled in non-migrating and migrating breast cancer cell lines. Site-directed mutagenesis was used to introduce single or double point mutations into both CD44 palmitoylation sites (Cys286 and Cys295), whereupon the implications for lipid raft recovery, phenotype, ezrin co-precipitation and migratory behaviour was assessed. Finally CD44 palmitoylation status and lipid raft affiliation was assessed in primary cultures from a small panel of breast cancer patients. RESULTS: CD44 raft affiliation was increased during migration of non-invasive breast cell lines, but decreased during migration of highly-invasive breast cells. The latter was paralleled by increased CD44 recovery in non-raft fractions, and exclusive non-raft recovery of its binding partners. Point mutation of CD44 palmitoylation sites reduced CD44 raft affiliation in invasive MDA-MB-231 cells, increased CD44-ezrin co-precipitation and accordingly enhanced cell migration. Expression of palmitoylation-impaired (raft-excluded) CD44 mutants in non-invasive MCF-10a cells was sufficient to reversibly induce the phenotypic appearance of epithelial-to-mesenchymal transition and to increase cell motility. Interestingly, cell migration was associated with temporal reductions in CD44 palmitoylation in wild-type breast cells. Finally, the relevance of these findings is underscored by the fact that levels of palmitoylated CD44 were lower in primary cultures from invasive ductal carcinomas relative to non-tumour tissue, while CD44 co-localisation with a lipid raft marker was less in invasive ductal carcinoma relative to ductal carcinoma in situ cultures. CONCLUSION: Our results support a novel mechanism whereby CD44 palmitoylation and consequent lipid raft affiliation inversely regulate breast cancer cell migration, and may act as a new therapeutic target in breast cancer metastasis.
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Neoplasias da Mama/patologia , Receptores de Hialuronatos/metabolismo , Lipoilação , Microdomínios da Membrana/metabolismo , Invasividade Neoplásica/patologia , Mama/citologia , Mama/fisiologia , Carcinoma Ductal de Mama/patologia , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proteínas do Citoesqueleto/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Humanos , Receptores de Hialuronatos/genética , Mutagênese Sítio-Dirigida , Ligação Proteica , Processamento de Proteína Pós-TraducionalAssuntos
Neoplasias da Mama/patologia , Mamoplastia/efeitos adversos , Infecção da Ferida Cirúrgica/complicações , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
INTRODUCTION: Appendicectomy remains the standard treatment for appendicitis. There is a lack of clarity on the timeframe in which surgery should be performed to avoid unfavourable outcomes. AIM: To perform a systematic review and network meta-analysis to evaluate the impact the (1)time-of-day surgery is performed (2), time elapsed from symptom onset to hospital presentation (patient time) (3), time elapsed from hospital presentation to surgery (hospital time), and (4)time elapsed from symptom onset to surgery (total time) have on appendicectomy outcomes. METHODS: A systematic review was performed as per PRISMA-NMA guidelines. The time-of-day which surgery was done was divided into day, evening and night. The other groups were divided into < 24 h, 24-48 h and > 48 h. The rate of complicated appendicitis, operative time, perforation, post-operative complications, surgical site infection (SSI), length of stay (LOS), readmission and mortality rates were analysed. RESULTS: Sixteen studies were included with a total of 232,678 patients. The time of day at which surgery was performed had no impact on outcomes. The incidence of complicated appendicitis, post-operative complications and LOS were significantly better when the hospital time and total time were < 24 h. Readmission and mortality rates were significantly better when the hospital time was < 48 h. SSI, operative time, and the rate of perforation were comparable in all groups. CONCLUSION: Appendicectomy within 24 h of hospital admission is associated with improved outcomes compared to patients having surgery 24-48 and > 48 h after admission. The time-of-day which surgery is performed does not impact outcomes.
Assuntos
Apendicectomia , Apendicite , Tempo de Internação , Humanos , Apendicectomia/métodos , Apendicite/cirurgia , Tempo de Internação/estatística & dados numéricos , Metanálise em Rede , Fatores de Tempo , Complicações Pós-Operatórias , Tempo para o Tratamento , Resultado do Tratamento , Duração da CirurgiaRESUMO
Inflammatory fibroid polyps (IFP) are rare benign neoplasms most commonly occurring within the respiratory tract but are rarely also observed in the gastro-intestinal tract. Herein we present the case of a 73-year-old female presenting with ileo-ileal intussusception secondary to IFP. The patient was treated with emergency laparotomy with segmental bowel resection and primary anastomosis. Histopathological analysis of the excised bowel segment initially revealed a low-grade, mural based spindle cell neoplasm with surrounding benign, reactive lymphadenopathy. Immunohistochemical analysis demonstrated that the lesional cells stained positive for Vimentin, Smooth Muscle Actin (SMA), and CD34. On secondary analysis of the specimen, the morphology and immunohistochemical profile of the mass was in keeping with IFP. No invasive malignancy was identified. Such cases have been previously reported under the pseudonym 'the great mimicker', due to their striking similarity to malignant processes. This case report aims to add to the small body of research reporting such atypical presentations.
RESUMO
PURPOSE: There are a wide variety of intraoperative techniques available in breast surgery to achieve low rates for positive margins of excision. The objective of this systematic review was to determine the pooled diagnostic accuracy of intraoperative breast margin assessment techniques that have been evaluated in clinical practice. METHODS: This study was performed in accordance with PRISMA guidelines. A systematic search of the literature was conducted to identify studies assessing the diagnostic accuracy of intraoperative margin assessment techniques. Only clinical studies with raw diagnostic accuracy data as compared with final permanent section histopathology were included in the meta-analysis. A bivariate model for diagnostic meta-analysis was used to determine overall pooled sensitivity and specificity. RESULTS: Sixty-one studies were eligible for inclusion in this systematic review and meta-analysis. Cytology demonstrated the best diagnostic accuracy, with pooled sensitivity of 0.92 (95 % CI 0.77-0.98) and a pooled specificity of 0.95 (95 % CI 0.90-0.97). The findings also indicate good diagnostic accuracy for optical spectroscopy, with a pooled sensitivity of 0.86 (95 % CI 0.76-0.93) and a pooled specificity of 0.92 (95 % CI 0.82-0.97). CONCLUSION: Pooled data indicate that optical spectroscopy, cytology and frozen section have the greatest diagnostic accuracy of currently available intraoperative margin assessment techniques. However, long turnaround time for results and their resource intensive nature has prevented widespread adoption of these methods. The aim of emerging technologies is to compete with the diagnostic accuracy of these established techniques, while improving speed and usability.