RESUMO
BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. METHODS: The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. FINDINGS: Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. INTERPRETATION: The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. FUNDING: Novartis Pharmaceuticals Corporation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , DNA de Neoplasias/sangue , Fosfatidilinositol 3-Quinases/genética , Idoso , Alanina Transaminase/sangue , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aspartato Aminotransferases/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Intervalo Livre de Doença , Método Duplo-Cego , Toxidermias/etiologia , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Exantema/induzido quimicamente , Feminino , Fulvestranto , Humanos , Hiperglicemia/induzido quimicamente , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Metástase Neoplásica , Pós-Menopausa , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Transdução de Sinais/genética , Taxa de SobrevidaRESUMO
BACKGROUND: The numerous side effects of chemotherapy in patients with breast cancer are well known. However, the precise effects of chemotherapy on ovarian function in premenopausal women are poorly investigated. The patients are at risk of developing sexual hormone deficiency and impaired fertility. This prospective cohort study addresses predictive parameters of ovarian reserve after chemotherapy. METHODS: Fifty-one premenopausal women (28-46 years) with primary breast cancer were included in the trial. All of them received anthracycline-based chemotherapy (n = 18), or combinations with taxanes (n = 30), or anthracycline-free chemotherapy (n = 3). Changes in hormone levels (LH, FSH, E2 and Anti-Müllerian hormone (AMH)), antral follicle count (AFC), and amenorrhea were determined before (V1), and 6, 12 and 24 months after the initiation of chemotherapy (V2-V4). Quality of life parameters were evaluated. The additional impact of parity, BMI, and smoking on ovarian reserve was also assessed. RESULTS: AFC and AMH fell very markedly after chemotherapy and did not return to pre-treatment levels until V4. A significant positive correlation was noted in AFC before and 1 year after chemotherapy. AMH levels at V2-V4 were significantly correlated with those registered at V1. AFC and AMH were negatively correlated with age. Continued smoking had a significant detrimental effect on AFC after 24 months. LH and FSH levels increased between V1 and V2 and fell at V3 and V4, but stayed above pre-chemotherapy values. Two years after the start of chemotherapy 31/51 patients were amenorrhoic while 17 resumed their menstrual cycle; this was not influenced by the type of chemotherapy or age. Non-smokers were 13 times more likely to resume their menstruation than smokers. Quality of life (QL) was significantly lower 6 months after the initiation of chemotherapy. QL at one and 2 years after chemotherapy did not differ significantly from pre-chemotherapy scores. CONCLUSIONS: Our study contributes to a better understanding and prediction of ovarian reserve in young early breast cancer patients undergoing chemotherapy. The data suggest that personal counseling in regard of the preservation of fertility should be offered especially to patients of a higher age, with low AMH levels or low follicle counts. Patients should be advised to stop smoking in order to enhance the likelihood of preserving their fertility.
Assuntos
Neoplasias da Mama/epidemiologia , Reserva Ovariana , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Ciclo Menstrual/efeitos dos fármacos , Pessoa de Meia-Idade , Folículo Ovariano/efeitos dos fármacos , Reserva Ovariana/efeitos dos fármacos , Ovário/diagnóstico por imagem , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Pré-Menopausa , Estudos Prospectivos , Qualidade de VidaRESUMO
BACKGROUND: Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo-keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism. METHODS: Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival. RESULTS: AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker. CONCLUSION: It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.
Assuntos
20-Hidroxiesteroide Desidrogenases/análise , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Carcinoma/química , Fibroblastos/química , Hidroxiesteroide Desidrogenases/análise , Biomarcadores/análise , Carcinoma/secundário , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Carga TumoralRESUMO
PURPOSE: Often breast cancer can be treated by breast-conserving surgery (BCS), after which 10 % locoregional recurrences (LRR) occur within 10 years. After BCS mastectomy is recommended at first LRR, although another BCS could be possible. Changes in clinical parameters and in tumor biology from primary breast cancer to first and multiple LRR are described and correlated with further LRR and overall survival (OS). METHODS: 380 patients with ≥1 ≤3 LRR (1997-2007) were evaluated retrospectively and followed until 5/2009. Patients' age, tumor size, nodal involvement, distant metastases, histological subtype, hormone receptor (HR) and Her-2/neu status were assessed. LRR therapy options were evaluated. RESULTS: 247 patients had one LRR (94 two and 39 three). Mean OS was 10.1 years. Number of LRR was not correlated with OS. Positive HR status was significantly correlated with longer OS. Patients, who changed from primarily ER negative to positive at first LRR had a significantly longer OS compared to those, who remained or changed to ER negative (p < 0.01). Tumor size and grading correlated inversely with OS (both: p < 0.001). BCS at first LRR correlated with a significantly better OS than mastectomy (p < 0.001). LRR cases with chemotherapy had a shorter OS. Irradiation and/or endocrine therapy after LRR were not correlated with OS. CONCLUSIONS: Patients with positive HR status had the best survival data. HR should always be determined. In positive cases, endocrine therapy is recommended. As clinical data are good, BCS at first LRR can be suggested for more patients.
Assuntos
Neoplasias da Mama/patologia , Mastectomia Segmentar/métodos , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Hysterectomies are preformed abdominally, vaginally, laparoscopic or with robotic assistance. When choosing the route of hysterectomy, the physician should take into consideration the safest and most cost-effective route to fulfill all needs of the patient. METHODS: Data were collected retrospectively from 953 patients who underwent hysterectomy between 2002 and 2010 for benign indications at UKSH, Germany. Preoperative risk scores were assigned to patients. The data were statistically evaluated to investigate relationship between the occurrence of the complication and the preoperative score at the time of the hysterectomy. For the preoperative score, patients who had undergone a previous laparoscopy were assigned 1 point; those who had undergone a previous Pfannenstiel laparotomy were assigned 2 points; those who had undergone 1 cesarean delivery were assigned 3 points; those who had undergone 2 cesarean deliveries were assigned 4 points; those who had undergone 3 cesarean deliveries were assigned 5 points; and those with no previous operations were assigned 0 points. The preoperative score was recorded for 785 patients. RESULTS: Of the 785 women with complete data, the mean preoperative score was 1.09 ± 1.51 for AH, 0.75 ± 0.96 for VH, 1.04 ± 1.30 for LSH, 1.0 ± 1.40 for LAVH, and 1.38 ± 1.52 for TLH. The prevalent scores in the VH were 0 and 1, the LASH and TLH showed a prevalence over VH in the preoperative scores 3 and 4 and AH showed a prevalence over the other methods in the preoperative score 3-8. Intraoperative complications were recorded in 28 of 953 (2.9 %) cases: 10 (35.7 %) cases of VH; 13 (46.4 %) cases of AH; 3 (10.7 %) cases of LSH; 1 (3.6 %) case of LAVH; and 1 (3.6 %) case of TLH. The intraoperative complications appeared to be more frequently with heavier uterine weight showing a significant statically correlation (P < 0,001). Major postoperative complications occurred in 17 of 953 (1.8 %) cases. Minor postoperative complications were recorded in 56 of 953 (5.9 %) hysterectomies. Operation duration, hospital stay and hemoglobin decline correlated significantly with preoperative score (P < 0.001). CONCLUSION: The suggested preoperative score is apparently successful in screening out the high-risk patients, despite the low incidence of intra and postoperative complications. The usefulness of the preoperative scoring system is worthy of further development and evaluation. The AH was favored as the 'fallback option' with high preoperative score.
Assuntos
Histerectomia/efeitos adversos , Complicações Intraoperatórias/epidemiologia , Laparoscopia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha , Humanos , Histerectomia/métodos , Incidência , Laparoscopia/métodos , Tempo de Internação , Pessoa de Meia-Idade , Prevalência , Estudos RetrospectivosRESUMO
PURPOSE: Nilotinib is a selective tyrosine kinase inhibitor of c-Kit, Abl and platelet-derived growth factor receptor-α/ß. To evaluate nilotinib's potential use as a treatment of human ovarian cancer, we tested nilotinib's preclinical activity in ovarian cancer cell lines with different tyrosine kinase expression patterns. METHODS: The effects of nilotinib on ovarian cancer cell growth were studied alone and in combination with carboplatin and paclitaxel. Proapoptotic and antimigratory effects were examined using TUNEL and migration assays. RESULTS: Nilotinib alone and in combination with carboplatin and paclitaxel significantly inhibited cell growth in PDGFR-α-positive ovarian cancer cell lines. The combination of nilotinib with carboplatin and paclitaxel showed synergistic effects on cell proliferation. Nilotinib treatment led to the inhibition of cell migration alone and in combination with carboplatin and paclitaxel. Apoptosis induction occurred in response to nilotinib that increased in combination with carboplatin. CONCLUSIONS: Nilotinib may be a feasible targeted therapy option for the treatment of ovarian cancer.
Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Ovarianas/patologiaRESUMO
BACKGROUND: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -ß, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. METHODS: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m(2) (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -ß, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. RESULTS: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days ('ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within 'ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -ß, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). CONCLUSION: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Humanos , Mesilato de Imatinib , Pessoa de Meia-Idade , Metástase Neoplásica , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , VinorelbinaRESUMO
PURPOSE: Preimplantation genetic screening wants to improve artificial reproductive technologies, primarily by raising the rates of pregnancy, implantation and birth. We investigated if embryos derived from oocytes detected euploid for five chromosomes implant better than those which were biopsied but where the genetic detection failed. They were nevertheless transferred, thus serving as a sham control. METHOD: From 2004 to 2008 we performed 104 cycles of PGS with laser biopsy of the first polar body and FISH with five chromosomes. It was offered to all patients with eight or more oocytes, free of charge. The average female age was 36 years. If no euploid oocytes were available, not detected oocytes were transferred. RESULT: In 104 cycles 99 embryo transfers (95 %) were performed, resulting in 28 pregnancies (27 %), 20 births (71 %) and 8 miscarriages (29 %). The implantation rate in the euploid group was 19 vs. 13 % in the not detected group (n.s.). This trend was the same independent of age and embryo morphology. CONCLUSION: The pregnancy rate does not differ significantly from the national average. The trend in better implantation rates of euploid oocytes justifies a continuation of studies in this matter.
Assuntos
Biópsia , Implantação do Embrião , Transferência Embrionária , Testes Genéticos , Hibridização in Situ Fluorescente , Corpos Polares , Taxa de Gravidez , Adulto , Aneuploidia , Feminino , Humanos , Gravidez , Diagnóstico Pré-ImplantaçãoRESUMO
PURPOSE: For better selection of oocytes and embryos, preimplantation genetic screening (PGS) was introduced. As from the beginning of IVF, morphology was used as selection criteria; we investigated the combination of both. If there was a correlation between phenotype and genotype, invasive PGS might be replaced. METHOD: Therefore, 104 cycles with PGS were done by biopsy of the first polar body and FISH with five chromosomes. Morphology of the oocyte was recorded digitally and noted for 12 categories in 4-13 values; evaluation of the chromosomes was noted for five chromosomes in five values. Morphology and genetics were correlated to each other. RESULT: Correlations between morphology and genetics for day 0 were found: oocytes with an irregular or dark zona are less probable to have a normal chromosome 13 (80 vs. 53 %, p = 0.001). A medium amount of detritus in the perivitelline space makes it more probable to have a normal chromosome 18 (94 vs. 78 %, p = 0.001). A halo in the cytoplasm makes it less probable to be euploid for chromosome 22 (56 vs. 75 %, p = 0.018). For day 1, pattern "1, 2, 3 and fine" in the pronuclei makes it more probable to be euploid for chromosome 22 (78 vs. 63 %, p = 0.002). CONCLUSION: There are correlations between the oocyte genome and its morphology also on day 0. These correlations are not sufficient to replace PGS.
Assuntos
Aneuploidia , Biópsia/métodos , Hibridização in Situ Fluorescente , Corpos Polares , Diagnóstico Pré-Implantação , Adulto , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 22 , Feminino , Humanos , Oócitos , GravidezRESUMO
BACKGROUND: A substantial number of breast cancer patients are identified as being at high risk of developing metastatic disease. With increasing number of targeted therapeutics entering clinical trials, chronic administration of these agents may be a feasible approach for the prevention of metastases within this subgroup of patients. In this preclinical study we examined whether sunitinib, a multi-tyrosine kinase inhibitor which has anti-angiogenic and anti-resorptive activity, is effective in the prevention of bone metastases. METHOD: Sunitinib was administered daily with the first dose commencing prior to tumor cell inoculation. Intracardiac injection was performed with MDA-MB23 bone-seeking cells, which were stably transfected with DsRed2. In vivo plain radiography and fluorescent imaging (Berthold NightOwl) was used in the analysis of bone metastases. Histomorphometry was used for the quantification of TRAP+ cells from bone sections and immunohistochemistry was performed using an antibody reactive to CD34 for quantification of microvessel density. RESULTS: Preventive dosing administration of sunitinib does not inhibit colonization of tumor cells to bone or reduce the size of osteolytic lesions. There was a decrease in the number of TRAP+ cells with sunitinib treatment but this did not reach significance. Sunitinib inhibited tumor growth as determined by imaging of fluorescent tumor area. Immunohistochemical analyses of microvessel density revealed a concomitant decrease in the number of tumor blood vessels. CONCLUSIONS: The findings suggest that sunitinib can be used as a therapeutic agent for the treatment of bone metastases but as a single agent it is not effective in terms of prevention. Therefore a combination approach with other cytostatic drugs should be pursued.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Ósseas/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Fosfatase Ácida/metabolismo , Inibidores da Angiogênese/administração & dosagem , Animais , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Esquema de Medicação , Feminino , Humanos , Imuno-Histoquímica , Indóis/administração & dosagem , Isoenzimas/metabolismo , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/administração & dosagem , Pirróis/administração & dosagem , Sunitinibe , Fosfatase Ácida Resistente a Tartarato , Fatores de Tempo , Transfecção , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although tumor surgery aims for a complete resection respecting tumor-specific safety distance, in many cases the most peripheral part, the invasion front, remains in situ. Tumor cells at the tumor margin lose epithelial properties and acquire features of mesenchymal cells. The process of epithelial-to-mesenchymal transition (EMT) has been suggested to be of prime importance for tissue and vessel invasion. Recently, features of EMT were shown to be linked to cells with tumor-founding capability, so- called cancer stem cells (CSC). In this study we show that transcription factors associated with EMT markers Snail, Slug, Twist and Zeb1 are differentially expressed between normal breast epithelium, ductal carcinoma in situ and invasive breast cancer. Both invasive and in situ carcinoma expressed less Slug and Twist and more Zeb1 compared to normal epithelium. Using fluorescence multi-staining the number of potential CSC among invasive cancer cells varied dramatically depending on the staining combination used (18.5% for CD44(+)/CD24(-) and 2.4% for CD49f(+)/CD24(+)). Interestingly, neither transcription factors associated with EMT nor potential CSC counts varied between tumor centre and invasion front. No association of these features with clinical outcome was detected. Our results suggest that reliable in situ markers for EMT are missing for invasive breast cancer. Alternatively, the process of EMT might be activated in tumor cells at the margin as well as the centre. Furthermore, our data show that the bio-markers of CSC detect very variable cell populations within breast cancer, challenging the assumption of a hierarchical organization of CSC in these tumors.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Transição Epitelial-Mesenquimal , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição/biossíntese , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Antígeno CD24/biossíntese , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Proteínas de Homeodomínio/biossíntese , Humanos , Receptores de Hialuronatos/biossíntese , Integrina alfa6/biossíntese , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Nucleares/biossíntese , Fatores de Transcrição da Família Snail , Células Tumorais Cultivadas , Proteína 1 Relacionada a Twist/biossíntese , Homeobox 1 de Ligação a E-box em Dedo de ZincoRESUMO
STUDY OBJECTIVE: To evaluate 3 therapy strategies: hormone therapy, surgery, and combined treatment. DESIGN: Prospective, randomized, controlled study (Canadian Task Force classification I). SETTING: University-based teaching hospital. PATIENTS: Four hundred fifty patients with genital endometriosis, aged 18 to 44 years, before first laparoscopy. INTERVENTIONS: Patients were randomly assigned to 1 of 3 treatment groups: hormone therapy, surgery, or combined treatment. Patients were reevaluated at second-look laparoscopy, at 2 to 2 months after 3-month hormone therapy in groups 1 and 3 and at 5 to 6 months in group 2 (surgical treatment alone). Outcome data were focussed on the endometriosis stage, recurrence of symptoms, and pregnancy rate. MEASUREMENTS AND MAIN RESULTS: All treatment options, independent of the initial Endoscopic Endometriosis Classification stage, achieved an overall cure rate of ≥50%. A cure rate of 60% was achieved with the combined treatment, 55% with exclusively hormone therapy, and 50% with exclusively surgical treatment. Recurrence of symptoms was lowest in patients who received combined treatment. Significant benefit was achieved for dysmenorrhea and dyspareunia. An overall pregnancy rate of 55% to 65% was achieved, with no significant difference between the therapeutic options. CONCLUSION: In the quest to find the most effective treatment of genital endometriosis, this clinical randomized study shows the lowest incidence of recurrence with combined surgical and medical treatment and improved pregnancy rate in any medically treated patients with or without surgery. The highest cure rate (Endoscopic Endometriosis Classification stage 0) for endometriosis was also achieved in the combined treatment group.
Assuntos
Endometriose/terapia , Fármacos para a Fertilidade Feminina/uso terapêutico , Doenças dos Genitais Femininos/terapia , Laparoscopia , Leuprolida/uso terapêutico , Adolescente , Adulto , Terapia Combinada , Endometriose/tratamento farmacológico , Endometriose/cirurgia , Feminino , Doenças dos Genitais Femininos/tratamento farmacológico , Doenças dos Genitais Femininos/cirurgia , Humanos , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Breast cancer screening programs have been established worldwide and early detection of breast cancer has increased steadily. The most common way to confirm dignity of non-palpable and sonographically-occult suspicious findings on mammography is the stereotactically-guided vacuum-assisted breast biopsy PURPOSE: To compare two stereotactically guided vacuum-assisted breast biopsy systems measuring time effectiveness and quality of harvested material in clinical practice. MATERIAL AND METHODS: One hundred and forty-six patients presenting with suspicious microcalcifications on mammography were included in the study. Biopsies were carried out with either the Mammotome(®) system (11-gauge and 8-gauge) or the ATEC(®) system (12-gauge and 9-gauge). Lesions with a diameter <15 mm on mammography were biopsied with 11-gauge or 12-gauge devices whereas lesions >15 mm were targeted with 8-gauge and 9-gauge. Mammotome(®) system 8-gauge device was used in 34 patients, the 11-gauge system in 37 patients. The ATEC(®) system 9-gauge system was used in 37 patients and 12-gauge in 38 patients. Time was taken, focusing on preparing the system, time of collecting the samples, preparing the samples, and cleaning the site. During the biopsies 24 samples were taken. The histologic quality of the tissue samples was judged by a pathologist in a blinded fashion according to a specimen grading classification concerning tissue fragmentation, artefacts, and the adequacy of the tissue for diagnosis. RESULTS: The median overall time for the Mammotome(®) system was 879 s (11-gauge) and 934 s (8-gauge) and for the ATEC(®) system 671 s (12-gauge) and 673 s (9-gauge). The ATEC(®) system displays a significantly shorter overall time for small and large biopsy devices (U-test, P < 0.001). Concerning the mean time difference of the overall time comparing small and large systems the ATEC(®) system was 267.6 s faster using the small and 244.8 s faster using the large system. Comparing the histologic quality of tissue samples the Mammotome(®) system shows significantly higher values for the large and the small system (Chi-square test, P < 0.001). CONCLUSION: Both biopsy systems meet all requirements for daily practice and confirm the diagnosis of suspicious microcalcifications. The ATEC(®) system was observed to be faster but this difference of about 250 s might not be relevant in daily practice. The Mammotome(®) system provides a better histologic quality of tissue samples.
Assuntos
Biópsia/instrumentação , Mama/patologia , Técnicas Estereotáxicas/instrumentação , Biópsia/métodos , Calcinose/patologia , Feminino , Humanos , Pessoa de Meia-Idade , VácuoRESUMO
Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6-44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Adulto , Idade de Início , Idoso , Neoplasias da Mama/epidemiologia , Etnicidade/genética , Família , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Pessoa de Meia-Idade , Linhagem , Fenótipo , Fatores de RiscoRESUMO
Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/deficiência , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
The intracardiac injection model is a commonly used in vivo model to test therapeutic response in bone metastases. However, few studies have critically compared the performance of different imaging methods in terms of sensitivity and quantitative assessment of osteolytic lesions. We performed in vivo optical and plain radiographic imaging of bone metastases followed by high-sensitivity ex vivo micro-computed tomography (micro-CT) imaging. This approach allowed for quantitative assessment of in vivo imaging techniques using fluorescence and plain radiography. Comparison of lesions detected in vivo by fluorescent optical imaging with ex vivo micro-CT revealed that the limited spatial resolution of fluorescent optical imaging may underestimate the number of bone metastases. Radiography was compared with micro-CT for the detection of osteolytic lesions. When using dichotomous yes/no grading, there was a 64% agreement in detection of osteolytic lesions. When subjective semiquantitative grading methods were used to assess the extent of osteolytic lesions, a positive association between the micro-CT grades and the square root of the radiography-based grades was observed (p < 0.05). Micro-CT also showed a significant association with fluorescent optical values; however, no such association was observed between lesion scores based on radiographs and those based on fluorescent imaging. The findings reveal an approximate two-fold sensitivity for micro-CT compared to plain radiography in the detection of osteolytic lesions. Significant associations between micro-CT-based osteolytic lesion grade and tumor growth characterized by increased fluorescent area document the value of these two techniques for the assessment of osteolytic bone metastases.
Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Osteólise/diagnóstico por imagem , Osteólise/patologia , Microtomografia por Raio-X/métodos , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Determinação de Ponto Final , Feminino , Fluorescência , Humanos , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Coloração e RotulagemRESUMO
OBJECTIVE: To investigate the outcome of pregnancy after detection of chromosomal mosaicism and to determine the correlation between human chorionic gonadotropin (free ß-HCG) and pregnancy-associated plasma protein-A (PAPP-A) levels from first-trimester-screening with pregnancy outcome. METHODS: In a single-center, retrospective survey of the results of prenatal diagnostics performed between January 2000 and March 2011, we identified a total of 40 pregnancies with chromosomal mosaicism. Clinical characteristics and results of first-trimester screening, as well as the outcome of these cases, are described. RESULTS: Out of 40 cases, 21 were defined as confined placental mosaicism, 10 classified as true mosaicism and nine were not classifiable cases. Nuchal translucency (NT) was ≥2.5 mm in 8/30 cases with respective measurements. PAPP-A levels were ≤0.4 MoM in 9/26 cases, with respective measurements, two of them being newborns with growth restriction. Remarkably, in pregnancies of all four children born with severe growth retardation, <3rd percentile PAPP-A levels were below 0.52 MoM. CONCLUSIONS: Our observations show mosaic pregnancy outcomes to be very heterogeneous. Nevertheless, a combination of low PAPP-A and interpretation of chromosomal mosaicism might identify pregnancies at particular risk for fetal growth restriction.
Assuntos
Mosaicismo , Diagnóstico Pré-Natal/métodos , Adulto , Gonadotropina Coriônica Humana Subunidade beta/sangue , Amostra da Vilosidade Coriônica , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Recém-Nascido , Cariotipagem , Masculino , Medição da Translucência Nucal , Gravidez , Resultado da Gravidez , Primeiro Trimestre da Gravidez , Proteína Plasmática A Associada à Gravidez/metabolismo , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE: To describe early ultrasound findings in Meckel-Gruber syndrome (MKS) in first and second trimester of three families, detailed ultrasound findings have been documented in addition to pathoanatomical findings and results of DNA studies. A splice site mutation in the MKS4 gene could be detected. Clinical management accounting risk assessment for future pregnancies is discussed and early ultrasound markers in MKS are described. METHODS: All cases were examined in a tertiary center for prenatal diagnosis by ultrasound. Necroscopy confirmed the clinical diagnosis. Fetal DNA analysis was accomplished in a reference center for MKS. In addition, ultrasound findings in early pregnancy of two further cases are described. RESULTS: Three couples presented with pregnancies complicated by MKS. The earliest diagnosis was suspected in 11 + 6 weeks of gestation and was confirmed in 13 + 0 weeks by ultrasound revealing a large occipital encephalocele and polycystic kidneys. Another case with recurrent MKS in two consecutive pregnancies was diagnosed in 20 weeks and 14 weeks of gestation, respectively. Here a close molecular genetic follow-up was performed leading to the detection of two mutations in the MKS4 gene in both fetuses. The third case was diagnosed in 15 weeks of gestation. Ultrasound findings in all pregnancies were doubtless and autopsies confirmed the diagnosis. CONCLUSION: Detection of MKS is already possible in the first trimester. Knowledge of the underlying genetic defect helps counseling the couples with recurrence of MKS and chorionic villi sampling in the first trimester of pregnancy can be offered.
Assuntos
Antígenos de Neoplasias/genética , Transtornos da Motilidade Ciliar/diagnóstico por imagem , Encefalocele/diagnóstico por imagem , Proteínas de Neoplasias/genética , Doenças Renais Policísticas/diagnóstico por imagem , Adolescente , Proteínas de Ciclo Celular , Transtornos da Motilidade Ciliar/genética , Proteínas do Citoesqueleto , Encefalocele/genética , Feminino , Humanos , Mutação , Doenças Renais Policísticas/genética , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Sítios de Splice de RNA , Retinose Pigmentar , Ultrassonografia Pré-NatalRESUMO
BACKGROUND: Fibroadenomas represent the vast majority of breast pathologies in young women. 2-4% of the fibroadenomas exceed 5 cm in size or 500 g in weight and are called "giant fibroadenomas". Due to their excessive growth they are usually enucleated to clarify a malignant origin, to differentiate from phyllodes tumor and to prevent persisting deformities of the breast. CASE: We present a case of a 17-year-old female who was pregnant in the 24th week and suffered from a giant fibroadenoma in the right breast. Besides the massive swelling no other illnesses were found. The patient was clinically asymptomatic and had noticed the tumor just 8 weeks ago. On clinical examination we found a tumor of more than 10 cm in size which fulfilled the criteria of a benign process. A prior performed biopsy and an ultrasound investigation could not definitely differentiate the mass from phyllodes tumor. Because of the rapid growth and the progressive deformation of the breast a lumpectomy was indicated and performed without complications in consideration of the gestational stage. CONCLUSION: We present a rare case of giant fibroadenoma in pregnant young women. Because of the progressive structural damage of the breast immediate surgical enucleation was indicated. Safety of the fetus was provided by perioperative monitoring. The pre-operative differentiation from phyllodes tumor is still challenging.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Fibroadenoma/patologia , Fibroadenoma/cirurgia , Complicações Neoplásicas na Gravidez/patologia , Complicações Neoplásicas na Gravidez/cirurgia , Adolescente , Biópsia , Diagnóstico Diferencial , Feminino , Humanos , Mastectomia Segmentar , Tumor Filoide/diagnóstico , Gravidez , Resultado do TratamentoRESUMO
OBJECTIVE: We hypothesize that the holistic and multiplanar depiction of pelvic floor structures by dynamic MRI is of particular value in rendering information about the extent of functional changes that can lead to pelvic floor dysfunction. METHODS: 134 women were prospectively included for assessment of their pelvic floor function. RESULTS: Study groups differed significantly in the direction of their force-displacement-vectors. A shift from ventral to dorsal is present depending on parity, mode of delivery and age. Maternal age and body height correlated to the force-displacement-vector, whereas maternal weight did not. Pressing direction proved to be dependent on the inclination of the pelvis and the aperture of the levator hiatus while remaining independent from the aperture of the abdominal wall. CONCLUSION: Biomechanical data interpretation uncovered the pathogenetic relevance of progressive retroflection of the force-displacement-vector. This is responsible for the onset of a vicious cycle of trauma-related force deflection perpetuating pelvic floor traumatization.