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1.
Medicine (Baltimore) ; 99(1): e18298, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895768

RESUMO

INTRODUCTION: Leptomeningeal dissemination due to HER2-overexpressing breast cancer is a rare and hard to treat complication with short-term dismal prognosis. PATIENT CONCERNS: A 34-year-old female previously treated because of HER2+ breast cancer is admitted to the Neurology Department in December 2016 due to sensory-motor neurological semiology. DIAGNOSIS: A wide set of diagnostic tests is performed and finally cytologic findings after repeated CSF confirm leptomeningeal infiltration by breast carcinoma (panCK+, GATA3+). INTERVENTIONS: Weekly intrathecal triple therapy with methotrexate, cytarabine and hydrocortisone plus trastuzumab is carried out during 4 months. OUTCOMES: Clinical and pathological response that lasts more than 24 months. CONCLUSION: Leptomeningeal carcinomatosis is an oncological situation where conventional therapies have limited activity. In HER2+ advanced breast cancer patients, intrathecal therapy with anti-HER2 therapy (trastuzumab) is feasible and may reach long-term disease control, especially in cases of low-tumor burden.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Ductal/patologia , Carcinomatose Meníngea/tratamento farmacológico , Carcinomatose Meníngea/secundário , Trastuzumab/uso terapêutico , Adulto , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Feminino , Humanos , Carcinomatose Meníngea/patologia , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Complicações Neoplásicas na Gravidez/patologia , Receptor ErbB-2
2.
Medicine (Baltimore) ; 97(48): e13410, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508942

RESUMO

RATIONALE: Triple-negative breast cancer (TNBC) is associated with unfavorable prognosis due to lack of targeted agents. Bevacizumab, an anti-angiogenic monoclonal antibody against vascular endothelial growth factor A, has shown clinical effects in patients with TNBC. PATIENT CONCERNS: We reported a 49-year-old woman presenting with a giant breast tumor. DIAGNOSES: Stage IV TNBC with chest wall metastasis. INTERVENTIONS: The patient underwent long-term use of bevacizumab combined with chemotherapy. OUTCOMES: The patient was on follow-up for 46 months, a remarkable improvement of the chest wall cutaneous lesion was observed. LESSONS: Bevacizumab may provide benefits for TNBC patients with chest wall metastasis.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/secundário , Neoplasias Torácicas/tratamento farmacológico , Neoplasias Torácicas/secundário , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal/patologia , Cisplatino/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Torácicas/patologia , Parede Torácica/efeitos dos fármacos , Parede Torácica/patologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
3.
Int Immunopharmacol ; 65: 279-283, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30342344

RESUMO

OBJECTIVE: Breast cancer and its surgical treatment and chemotherapy have great impact on the immune system. This study aimed to monitor the various T cells in breast cancer patients and evaluate the immune functions. METHODS: Blood samples were collected from 249 breast cancer patients at the following time points: 1-3 days preoperative, postoperative (before the chemotherapy), after 3 chemotherapy cycles, and after 6 chemotherapy cycles. The percentages of the CD3+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells were measured using flow cytometry. Another 200 healthy women were used as control. RESULTS: Patients with stage II/III breast cancer had significantly lower percentages of CD3+, CD4+, CD8+, CD45RA+, and CD28+ T cells in comparison with normal control and those with stage I breast cancer (P < 0.05). The percentages of CD45RO+ T cells and CD4+CD25+ (Treg) cells were significantly higher in stage II/III malignancies versus stage I, and was significantly higher in stage I malignancies versus the normal control (P < 0.05). Breast cancer patients had significantly lower percentages of CD3+ and CD4+ T cells in comparison with the normal control (P < 0.05). The preoperative percentages of CD3+ and CD4+ T cells were significantly reduced after 3 cycles and after 6 cycles of chemotherapy (P < 0.05). In patients with stage II/III malignancies, there was a higher percentage of CD45RO+ T cells than CD45RA+ T cells, which was reversed after surgery. After 6 chemotherapy cycles, the percentage of Treg cells was significantly reduced in comparison with that before the chemotherapy in the patients with stage II/III malignancies. CONCLUSIONS: Patients with breast cancer had significantly suppressed immune functions. Surgical removal of the tumor may improve the immune functions. Chemotherapy significantly reduced the percentages of CD3+ and CD4+ T cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/imunologia , Linfócitos T CD4-Positivos/imunologia , Carcinoma Ductal/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Antígenos CD/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/cirurgia , Contagem de Células , Feminino , Humanos , Imunomodulação , Imunofenotipagem , Imunossupressão , Mastectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias
4.
MAbs ; 10(7): 1003-1017, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30130447

RESUMO

Ado-trastuzumab emtansine (Kadcyla®; T-DM1) is an antibody-drug conjugate developed to treat trastuzumab-resistant disease. Despite initial favorable outcomes, most patients eventually cease to respond due to developing acquired resistance to T-DM1. Currently, there is no targeted therapy to treat T-DM1-resistant disease. To explore novel therapeutic targets to improve therapeutic efficacy of T-DM1, we generated T-DM1-resistant cells using trastuzumab-resistant JIMT1 cells. We found that the loss of human epidermal growth factor receptor 2 confers T-DM1 resistance, which in turn activates a compensatory mechanism that increases epidermal growth factor receptor (EGFR) expression. Upregulation of EGFR increases the protein levels of α5ß1 and αVß3 integrins, resulting in enhanced motility and invasion of T-DM1-resistant cells. This study delineates previously unappreciated relationships between α5ß1 and αVß3 and suggests that specific integrins should be carefully selected as therapeutic targets to treat T-DM1-resistant disease. Specifically, silencing ß1 integrin expression by siRNA in T-DM1-resistant cells destabilizes α5, but increases expression of αV, a critical integrin mediating the invasion and metastases in many different cancers. As a consequence, T-DM1-resistant cells gain metastatic potential and become more invasive. This finding is underscored by the fact that ß1 integrin blockage induced by an inhibitory antibody, MAB 13, significantly increases invasion of T-DM1-resistant cells. However, the increased cell invasion induced by ß1 integrin blockage can be significantly reduced by either EGFR inhibitor or specific siRNA against αV integrin. The discovery of functional cooperation between EGFR and αV integrin in regulating cell growth and invasion provides an opportunity to develop novel therapeutic strategy by dual-targeting EGFR and specific integrin to overcome T-DM1 resistance.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Maitansina/análogos & derivados , Trastuzumab/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Integrina alfa5beta1/genética , Integrina alfa5beta1/metabolismo , Integrina alfaVbeta3/metabolismo , Maitansina/uso terapêutico , Invasividade Neoplásica , RNA Interferente Pequeno/genética , Receptor Cross-Talk , Receptor ErbB-2/genética , Transdução de Sinais
5.
Technol Cancer Res Treat ; 17: 1533033818794939, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30157721

RESUMO

Breast cancer represents a rising problem concerning public health worldwide. Current efforts are aimed to the development of new minimally invasive and conservative treatment procedures for this disease. A treatment approach for invasive breast ductal carcinoma could be based on electroporation. Hence, in order to determine the effectiveness of electrochemotherapy in the treatment of this disease, 12 electrode models were investigated on realistic patient-specific computational breast models of 3 patients diagnosed by Digital Breast Tomosynthesis imaging. The electrode models exhibit 4, 5, and 6 needles arranged in 4 geometric configurations (delta, diamond, and star) and 3 different needle spacing resulting in a total of 12 needle-electrode arrays. Electric field distribution in the tumors and a surrounding safety margin of 1 cm around the tumor edge is computed using the finite element method. Efficiency of the electrode arrays was determined hierarchically based on (1) percentage of tumor volume reversibly electroporated, (2) percentage of tumor volume irreversibly electroporated, (3) percentage of treated safety margin volume, (4) minimal invasiveness, that is, minimal number of electrodes used, (5) minimal activated electrode pairs, and (6) minimal electric current. Results show that 3 electrode arrays (4 needle-delta, 5 needle-diamond, and 6 needle-star) with fixed-geometry configuration could be used in the treatment with electrochemotherapy of invasive breast ductal carcinomas ranging from 1 to 5 cm3 along with a surrounding safety margin of 1 cm.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Eletroquimioterapia , Idoso , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Carcinoma Ductal/diagnóstico por imagem , Carcinoma Ductal/patologia , Eletrodos , Feminino , Análise de Elementos Finitos , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Agulhas , Imagens de Fantasmas
6.
Nat Commun ; 9(1): 1723, 2018 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-29712904

RESUMO

The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , MAP Quinase Quinase Quinases/genética , Fatores de Transcrição/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular , Senescência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Everolimo/farmacologia , Feminino , Humanos , Lactonas/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Masculino , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Camundongos , Camundongos SCID , Mitoxantrona/farmacologia , Fenótipo , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Resorcinóis/farmacologia , Transdução de Sinais , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Clin Oncol ; 23(3): 584-590, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29397469

RESUMO

BACKGROUND: This study aimed to investigate the efficacy of docetaxel in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P). PATIENTS AND METHODS: We retrospectively identified 79 CRPC patients with distant metastasis at initial diagnosis from June 2002 to January 2014. All patients received initial androgen deprivation therapy and 46 received docetaxel chemotherapy after progressing to CRPC. The primary outcome of interest was cancer-specific survival (CSS) from the time of CRPC diagnosis. The Cox regression model was used to confirm whether IDC-P and docetaxel would act as independent factors for prognosis. RESULTS: IDC-P was found in 62 of 79 patients. The median CSS in the IDC-P-present group was 18.2 versus 45.6 months in the IDC-P-absent group (HR 2.67; 95% CI 1.18 to 6.06; P = 0.019). Docetaxel was administered to 36 patients with IDC-P and 10 patients without IDC-P, with a median CSS of 20.5 versus 53.2 months, respectively (HR 2.98; 95% CI 1.02 to 8.64; P = 0.044). Multivariate analysis demonstrated that the presence of IDC-P and docetaxel were independent prognostic factors for CSS (P = 0.026 and 0.005, respectively) and overall survival (OS) (P = 0.029 and 0.001, respectively). CONCLUSION: The presence of IDC-P is an independent prognostic factor in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis. Docetaxel may prolong CSS and OS in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Ductal/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal/mortalidade , Carcinoma Ductal/patologia , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
9.
Immunobiology ; 223(6-7): 449-459, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29459011

RESUMO

Angiogenesis and lymphangiogenesis play a crucial role in tumor growth, invasion and metastasis. Tumor-associated macrophages (TAM) induce both angiogenesis and lymphangiogenesis in mouse breast cancer models and positively correlate with these processes in human breast cancer patients. Neoadjuvant chemotherapy (NAC) is a widely used therapeutic option for cancer treatment. However, the effect of NAC on the distribution of TAM within intratumoral compartments and their correlation with angiogenesis and lymphangiogenesis remained unknown. In the present study we analyzed the effect of NAC on the distribution of CD68+ and stabilin-1+ TAM in five functionally distinct areas of human breast cancer and their correlations with microvessel density (MVD) and lymphatic microvessel density (LMVD), identified by CD31 and LYVE1, respectively. We found that NAC enhances blood vessel density in soft fibrous stroma and in coarse fibrous stroma. Without NAC the amount of CD68+ TAM in gaps of ductal tumor structures positively correlate with CD31+ microvessel density in soft fibrous stroma. NAC had enhancing effect on the amount of CD68+ TAM but not stabilin-1+ TAM in soft fibrous stroma. However, no correlation between TAM and CD31+ microvessel density was identified after NAC. NAC did not enhance the lymphatic microvessel density. But after NAC stabilin-1 expressing subpopulation of TAM positively correlated with expression of LYVE-1. We hypothesized that CD68+ TAM can support tumor angiogenesis primarily before NAC, while stabilin-1+ TAM can contribute to the maintenance of lymphatic microvessel density after NAC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Macrófagos/imunologia , Microvasos/patologia , Terapia Neoadjuvante , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Ductal/imunologia , Carcinoma Ductal/patologia , Moléculas de Adesão Celular Neuronais/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Neovascularização Patológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Retorno de Linfócitos/metabolismo , Proteínas de Transporte Vesicular/metabolismo
10.
Orbit ; 37(6): 463-467, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29424598

RESUMO

Primary ductal adenocarcinoma of the lacrimal gland is a rare but highly aggressive epithelial malignancy with a poor prognosis. Early diagnosis, along with genetic testing of these tumors, is imperative for proper management. We present a case of a 54-year-old man with decreasing vision over the past three years and increasing proptosis in his right eye over the past three months, secondary to a lacrimal gland mass diagnosed as primary ductal adenocarcinoma. The diagnosis was made using histological and immunohistochemical profiles (positivity for cytokeratin AE1/3, CAM5.2, androgen receptor, human epidermal growth factor receptor 2, and gross cystic disease fluid protein 15) seen in previous cases, alongside a tumor genetic profile that showed actionable mutations. Uniquely in this case, after failing traditional chemotherapy, repeat biopsy revealed a change in genetics with the malignancy no longer showing actionable mutations. These findings show that these immunohistochemical findings can act as diagnostic biomarkers, while genetic testing can reveal actionable mutations for targeted therapy.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal/genética , Neoplasias Oculares/genética , Mutação da Fase de Leitura , Testes Genéticos , Doenças do Aparelho Lacrimal/genética , Proteínas de Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA2/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal/diagnóstico por imagem , Carcinoma Ductal/tratamento farmacológico , Neoplasias Oculares/diagnóstico por imagem , Neoplasias Oculares/tratamento farmacológico , Histona Acetiltransferases/genética , Humanos , Imuno-Histoquímica , Doenças do Aparelho Lacrimal/diagnóstico por imagem , Doenças do Aparelho Lacrimal/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , PTEN Fosfo-Hidrolase/genética , Cuidados Paliativos , Receptor ErbB-2/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Acuidade Visual
11.
Gan To Kagaku Ryoho ; 45(1): 190-192, 2018 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-29362351

RESUMO

We report a case of advanced breast cancer with liver metastasis(T2N1M1, Stage IV )achieving a significant improvement of QOL by multi-disciplinary therapy. The patient was 37-year-old woman who had breast lump and axillary lymph nodes swelling with liver metastasis. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma, negative for estrogen receptor and progesterone receptor, and positive for HER2/neu protein expression. The Ki-67 positive cell index was 40%. She received 16 courses of DOC plus HER plus PER(docetaxel 75mg/m / 2, trastuzumab 6 mg/kg, pertu- zumab 450mg/body, and received 4 courses of EC(epirubicin 90mg/m / 2, cyclophosphamide 600 mg/m2). The breast lesion and liver metastatic lesion disappeared after chemotherapy. We checked up whole body. There was no metastatic lesion. Therefore, we diagnosed a clinical complete response. We performed muscle preserving mastectomy and axillary lymph nodes dissection. The pathological diagnosis from resected specimens were pathological complete response. The surgical margin was negative. She was started the endocrine therapy by tamoxifen(20mg/day). Three years after surgery, she was well without metastases. Multi-disciplinary therapy can improve patient QOL and the clinical outcomes in Stage IV advanced breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Neoplasias da Mama/cirurgia , Carcinoma Ductal/cirurgia , Terapia Combinada , Feminino , Humanos , Estadiamento de Neoplasias , Resultado do Tratamento
12.
BJU Int ; 121(6): 971-978, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28977728

RESUMO

OBJECTIVE: To determine the relevance of intraductal carcinoma of the prostate (IDC-P) in advanced prostate cancer by first examining whether IDC-P was originally present in patients who later developed advanced prostate cancer and then using patient-derived xenografts (PDXs) to investigate the response of IDC-P to androgen deprivation therapy (ADT). MATERIALS AND METHODS: We conducted a retrospective pathology review of IDC-P in primary prostate biopsy or surgery specimens from 38 men who subsequently developed advanced prostate cancer. Overall survival was calculated using the Kaplan-Meier method. To demonstrate the response of IDC-P to ADT, we established PDXs from seven patients with familial and/or high-risk sporadic prostate cancer. After castration and testosterone restoration of host mice, we measured the volume and proliferation of IDC-P within PDX grafts. RESULTS: We found that IDC-P was a prominent feature in the primary prostate specimens, present in 63% of specimens and often co-existing with poorly differentiated adenocarcinoma. Overall survival was similar in patients with or without IDC-P. In the PDXs from all seven patients, IDC-P was identified and present at a similar volume to adenocarcinoma. Residual IDC-P lesions persisted after host castration and, similar to castrate-tolerant adenocarcinoma, testosterone restoration led to tumour regeneration. CONCLUSION: The study showed that IDC-P is prevalent in aggressive prostate cancer and contains cells that can withstand androgen deprivation. Thus, IDC-P appears functionally relevant in advanced prostate cancer. The presence of IDC-P may be a trigger to develop innovative clinical management plans.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Carcinoma Ductal/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Ductal/patologia , Xenoenxertos/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Transplante Heterólogo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Indian J Cancer ; 55(3): 210-213, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30693880

RESUMO

INTRODUCTION: This study was undertaken to evaluate the clinicopathological characteristics of patients with breast cancer at our institute, a tertiary-care cancer center in northern India. MATERIALS AND METHODS: This retrospective study included all patients with breast cancer registered at our institute from January 1st, 2014 to December 31st, 2016. We retrieved data (demographic, baseline clinical characteristics, pathology, and treatment details) from prospectively maintained clinical case records. Patients with incomplete case records or missing baseline information were excluded. RESULTS: We included 550 patients with breast cancer. The median age was 48 years (23-85). The median clinical tumor size was 5.0 cm. The TNM (AJCC-7th edition) stage distribution was stage I, 22 (4%); stage II, 182 (33%); stage III, 247 (44.9%); and stage IV, 99 (18%). Locally advanced breast cancer constituted 40% of the cases. Bone (48 [48.5%]) was the most common site for metastasis followed by lung. Infiltrating ductal carcinoma (528 [96%]) was the most common histologic subtype. Majority of patients, 325 (59%), were positive for estrogen receptor/progesterone receptor whereas 160 (29%) patients were HER2/neu positive. Triple negative breast cancer (TNBC) constituted 28% (154) of patients. In the nonmetastatic subgroup, 343 (76%) patients underwent modified radical mastectomy. Neoadjuvant chemotherapy (NACT) was given in 120 (26.6%) patients, of these 23 (19%) achieved pathological complete remission. Sequential anthracyline and taxane were used as NACT/adjuvant chemotherapy in most cases. Of the eligible patients, 48 (30%) received anti-HER2/neu therapy. CONCLUSION: This is one of the largest comprehensive data from a single center in India. Majority of our patients are younger in age and have advanced disease. TNBC and HER2/neu positive breast cancer are more common in our population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Carcinoma Ductal/diagnóstico , Terapia Neoadjuvante , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carcinoma Ductal/tratamento farmacológico , Feminino , Humanos , Índia , Masculino , Mastectomia Radical Modificada , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Indução de Remissão , Estudos Retrospectivos , Taxoides/uso terapêutico , Adulto Jovem
15.
Eur J Med Chem ; 142: 376-382, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28818506

RESUMO

The selective destruction of tumour cells while sparing healthy tissues is one of the main challenges in cancer therapy. Antibody-drug conjugates (ADCs) are arguably the most rapidly expanding class of targeted cancer therapies. Efficient drug conjugation and release technologies are essential for the development of these new therapeutic agents. In response to the ever-increasing demand for efficient drug release systems, we have developed a new class of ß-galactosidase-cleavable linkers for ADCs. Within this framework, novel payloads comprising a galactoside linker, the monomethyl auristatin E (MMAE) and cysteine-reactive groups were synthesized, conjugated with trastuzumab and evaluated both in vitro and in vivo. The ADCs with galactoside linkers demonstrated superior therapeutic efficacy in mice compared to the marketed trastuzumab emtansine used for the treatment of breast cancer.


Assuntos
Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Imunoconjugados/química , Imunoconjugados/farmacologia , Maitansina/análogos & derivados , Trastuzumab/química , Trastuzumab/farmacologia , beta-Galactosidase/metabolismo , Animais , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imunoconjugados/metabolismo , Imunoconjugados/uso terapêutico , Maitansina/química , Maitansina/metabolismo , Maitansina/farmacologia , Maitansina/uso terapêutico , Camundongos Nus , Trastuzumab/metabolismo , Trastuzumab/uso terapêutico
16.
J Card Fail ; 23(6): 476-479, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28315399

RESUMO

Chemotherapy-induced cardiomyopathy (CCMP) is a complication of chemotherapy treatment occurring in 9% of patients treated with the use of anthracyclines. Currently, risk stratification is based on clinical risk factors that do not adequately account for variable individual susceptibility. This suggests the presence of other determinants. In this case series, we describe 2 women with breast cancer who developed severe heart failure within months after chemotherapy. Genetic screening revealed truncating frameshift mutations in TTN, encoding the myofilament titin, in both women. To our knowledge, this is the 1st report of an association between truncating TTN variants and CCMP. Because truncations in TTN are the most common cause of familial and sporadic dilated cardiomyopathy, further research is needed to establish their prevalence in patients presenting with CCMP.


Assuntos
Antineoplásicos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Conectina/genética , Variação Genética/genética , Adulto , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Ductal/diagnóstico por imagem , Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/genética , Cardiomiopatias/diagnóstico por imagem , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade
17.
Sci Rep ; 7: 39732, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28054562

RESUMO

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the 'fuzzy' interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.


Assuntos
Antineoplásicos/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Ductal/metabolismo , Proteínas Intrinsicamente Desordenadas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Trifluoperazina/análogos & derivados , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Ductal/tratamento farmacológico , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Senescência Celular , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos , Humanos , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/tratamento farmacológico , Ligação Proteica , Trifluoperazina/química , Trifluoperazina/farmacologia , Trifluoperazina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Gan To Kagaku Ryoho ; 44(12): 1933-1935, 2017 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-29394825

RESUMO

A 64-year-old woman visited hospital with a chief complaint of a nodule at the left neck skin. Skin biopsy revealed adenocarcinoma, and the diagnosis was skin metastasis of unknown primary origin. Positron emission tomography and computed tomography showed multiple bone and lymph node metastasis, left breast tumor, bladder tumor, and hydronephrosis. A needle biopsy of breast revealed invasive ductal carcinoma, and transurethral biopsy of bladder revealed adenocarcinoma. The findings were similar to those for the breast and the expression pattern of estrogen-receptor was the same. We diagnosed her with breast cancer and bladder metastasis. We administered systemic chemotherapy, however she died 10 days later. Bladder metastasis of breast cancer is rarely encountered in clinical practice and is often accompanied by life threatening symptoms. Careful histopathological examinations and rapid systemic chemotherapy are significant.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal/secundário , Neoplasias da Bexiga Urinária/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Bexiga Urinária/tratamento farmacológico
19.
Breast Dis ; 36(2-3): 65-71, 2016 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-27662272

RESUMO

BACKGROUND: Oncotype DX® test is beneficial in predicting recurrence free survival in estrogen receptor positive (ER+) breast cancer. Ability of the assay to predict response to neoadjuvant chemotherapy (NCT) is less well-studied. OBJECTIVE: We hypothesize a positive association between the Oncotype DX® recurrence score (RS) and the percentage tumor response (%TR) after NCT. METHODS: Pre-therapy RS was measured on core biopsies from 60 patients with ER+, HER2- invasive breast cancer (IBC) who then received NCT. Pre-therapy tumor size was measured using imaging. %TR, partial response (PR; >50%), pathologic complete response (pCR) and breast conserving surgery (BCS) rates were measured. RESULTS: Median RS was 20 (2-69). Median %TR was 42 (0-97)%. PR was observed in 43% of patients. There was no association between %TR and pre-NCT tumor size, age, Nottingham score or nodal status (p > 0.05). No statistically significant association with %TR was seen with RS as a categorical or continuous variable (p = 0.21 and 0.7, respectively). Response to NCT improved as ER (p = 0.02) by RT-PCR decreased. Lower ER expression by IHC correlated with response (p = 0.03). CONCLUSIONS: In patients with ER+ IBC receiving NCT, RS did not predict response to NCT using %TR. The benefit of the assay prior to NCT requires further study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Perfilação da Expressão Gênica , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Taxoides/administração & dosagem , Carga Tumoral
20.
Expert Rev Proteomics ; 13(4): 383-94, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26985644

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers; despite a low incidence rate it is the fourth leading cause of cancer-related death in the world. Improvement of the diagnosis, prognosis and treatment remains the main focus of pancreatic cancer research. Rapid developments in proteomic technologies has improved our understanding of the pancreatic cancer proteome. Here, the authors summarise the recent proteomic strategies undertaken in the search for: novel biomarkers for early diagnosis, pancreatic cancer-specific proteins which may be used for novel targeted therapies and proteins which may be useful for monitoring disease progression post-therapy. Recent advances and findings discussed here provide great promise of having a significant clinical impact and improving the outcome of patients with this malignancy.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Proteômica/métodos , Animais , Carcinoma Ductal/tratamento farmacológico , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias Pancreáticas/tratamento farmacológico
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