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The increasing volume of the data and experience with direct oral anticoagulants (DOACS) in the primary and secondary prevention of venous thromboembolism in oncologic patients (CAVTE) has recently lead to changes in several international guidelines. We reflect these changes within the conditions in Slovak republic. In the primary prevention of CAVTE we recognise oncosurgical patients and nonsurgical patients: hospitalised and out patients. Low molecular weight heparins are still dominant in the primary prevention of CAVTE. Regarding the treatment and the secondary prevention of CAVTE, we recommend always to consider the possibility to use DOACs as they proved to be non inferior to LMWH. However, LMWH should be prefered over DOACs as well as over warfarin (VKA) in all patients who are in a clinically unstable condition with the high risk of bleeding and/or interaction with the systemic treatment. Primarily in the patients with intraluminal tumours of the upper part of the gastrointestinal tract and genitourinary tumours with the high risk of bleeding. As for the lack of data, LMWH are still preferd also in patients with primary tumours and metastatic disease of the central nervous system and in hemato oncology.
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Neoplasias , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Consenso , Hemorragia/induzido quimicamente , Hemorragia/complicações , Hemorragia/prevenção & controle , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Neoplasias/complicações , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle , VarfarinaRESUMO
BACKGROUND: Infective endocarditis (IE) is still a significant cause of mortality in European hospitals, despite of the fact, that large nationwide studies were performed in last twenty years and pathogens are well known. The aim of the study was to assess risk factors, mortality, etiology and proportion of elderly patients within a longitudinal nation wide survey of infectious endocarditis in Slovakia. PATIENTS AND METHODS: Etiology, risk factors and outcome of 1003 cases of infective endocarditis (IE) in Slovakia over the last 33 years have been assessed. RESULTS: The majority of IE were caused by Staphylococci (28.3%), 15.6% were due to Viridans streptococci, 10% due to Enterococci, 8.2% by gram-negative bacteria, Acinetobacter baumannii and Pseudomonas aeruginosa, 3.7% by other organisms and 31.0% of all cases were culture negative. The following risk factors were recorded: age > 65 (36.8%), rheumatic fever (15.3%), dental surgery (8.7%), previous non-cardiological surgery (8.2 %), neoplasia (8.1%), diabetes (7.8%), any endoscopy (8.5%) and dialysis (4.6%). All patients were treated with antimicrobials, 507 (51%) also with surgery. Survival rate at day 60 after diagnosis was 88.1% (n=883). Only age >65 (34.3% vs. 49.5%, p=0.045) and persistent bacteremia (with three or more positive blood cultures 15.7% vs. 34.5%, p=0,001) were significantly associated with higher attributable mortality. Concerning risk factors, etiology and therapeutic strategies, rheumatic fever and neoplasia showed decrease in tendency. Dental surgery and tonsillitis were less frequent as well (26.7% vs. 2%, p<0,001 and 16% vs. 1%, p<0.001). There was a significant shift in etiology after 1997: culture-negative endocarditis was surprisingly more frequently observed in the 2007-2017 period than before and represented 10.7% of all cases in 1984-1990 in comparison to 25.1-25.6% in 2007-2010 and 2011-2017. Staphylococci decreased from 48% to 29.6% (2007-2017), but are still major pathogens. Persistent bacteremia (3 or more positive blood cultures 5.3% vs. 24.7%, p<0,001) was less commonly observed within the 1st period (1984-1990) in comparison to 2007-2010. More patients in the 1st period (1984-1990) had embolization complications of IE than in the fifth and sixth period (2007-2017) (76 vs. 16.3% p<0.001). CNS embolization decreased from 14% to less than 5% (p<0.003). Attributable mortality was lower too (26.7% vs. 9.5%, p<0.001) because of increased proportion of cardiac surgery in the treatment of IE in 2007-2017 in comparison to 1984-1990. CONCLUSIONS: Study has showed significant shifts in etiology, risk factors and complications over the observed time periods in Slovakia.
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BACKGROUND: WNT/ßcatenin (WNTß) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of ßcatenin in germ cell tumors (GCTs) and explore associations with the inflamed environment. METHODS: Surgical specimens from 247 patients were analyzed. Βcatenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of ßcatenin and PD-L1 encoding genes. RESULTS: ßcatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P < 0.0001). A high expression (weighted histoscore > 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (ßcatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes. CONCLUSION: Herein, we showed that ßcatenin is associated with male adult GCT characteristics as well as supressed immune environment.
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Biomarcadores Tumorais , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , beta Catenina/metabolismo , Adolescente , Adulto , Idoso , Antígeno B7-H1/metabolismo , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/imunologia , Neoplasias Embrionárias de Células Germinativas/mortalidade , Prognóstico , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/mortalidade , Microambiente Tumoral/imunologia , Via de Sinalização Wnt , Adulto JovemRESUMO
BACKGROUND: We evaluated systemic immune-inflammation index (SII) and its association with patient outcome in germ-cell tumours (GCTs). METHODS: Two independent cohorts of patients were analysed; the discovery set (n=171) from a single institution and the validation set (n=181) previously included in a study evaluating PD-L1 in GCTs. The SII was calculated using platelet (P), neutrophil (N) and lymphocyte (L) counts before chemotherapy and correlated with survival using regression analyses and Kaplan-Meier method. RESULTS: In the discovery cohort, the SII was associated with poor risk clinical features. Patients with low SII had significantly longer progression-free survival (HR=0.22, 95% CI 0.12-0.41, P<0.001) and overall survival (OS) (HR=0.16, 95% CI 0.08-0.32, P<0.001) compared to high SII. This index was independent of International Germ Cell Cancer Collaborative Group criteria in multivariable Cox regression analysis for OS and was validated in an independent cohort. When combining PD-L1 expression on tumour infiltrating lymphocytes (TILs) and SII, we identified three distinctive prognostic groups. CONCLUSIONS: High SII was associated with poor outcome in GCTs. Combination of PD-L1 positive TILs and SII could further refine prognosis in GCTs.
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Inflamação/imunologia , Neoplasias Embrionárias de Células Germinativas/imunologia , Neoplasias Testiculares/imunologia , Adolescente , Adulto , Idoso , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Humanos , Inflamação/sangue , Inflamação/patologia , Estimativa de Kaplan-Meier , Linfócitos/imunologia , Linfócitos/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/sangue , Neoplasias Embrionárias de Células Germinativas/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Intervalo Livre de Progressão , Análise de Regressão , Estudos Retrospectivos , Neoplasias Testiculares/sangue , Neoplasias Testiculares/patologia , Adulto JovemRESUMO
PURPOSE: Testicular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs. RESULTS: PD-L1 positive TILs were found significantly more often in seminomas (95.9% of patients) and embryonal carcinomas (91.0%) compared to yolk sac tumors (60.0%), choriocarcinomas (54.5%) or teratomas (35.7%) (All p < 0.05). TGCTs patients with high infiltration of PD-L1 positive TILs (HS ≥ 160) had significantly better progression-free survival (HR = 0.17, 95% CI 0.09 - 0.31, p = 0.0006) and overall survival (HR = 0.08, 95% CI 0.04 - 0.16, p = 0.001) opposite to patients with lower expression of PD-L1 (HS < 150). PD-1 expressing TILs were not prognostic in TGCTs. MATERIALS AND METHODS: Surgical specimens from 240 patients with primary TGCTs were included into this translational study. The PD-1 and PD-L1 expression on tumor and TILs were detected by immunohistochemistry using anti-PD-1 and anti-PD-L1 monoclonal antibody. Scoring was performed semiquantitatively by weighted histoscore (HS) method. CONCLUSIONS: The prognostic value of PD-L1 expressing TILs in TGCTs was demonstrated for the first time.
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Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Embrionárias de Células Germinativas/imunologia , Neoplasias Testiculares/imunologia , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/mortalidade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Modelos de Riscos Proporcionais , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/mortalidade , Análise Serial de Tecidos , Adulto JovemRESUMO
Testicular germ cell tumors (TGCTs) represent a highly curable malignancy, however a small proportion of patients fails to be cured with cisplatin-based chemotherapy. Carbonic anhydrase IX (CA IX) is upregulated by hypoxia in several cancer types and correlates with a poor prognosis. The present translational study evaluated expression and prognostic value of CA IX in TGCTs. Surgical specimens from 228 patients with TGCTs were processed by the tissue microarray method and subjected to immunohistochemistry with the M75 monoclonal antibody. CA IX expression was evaluated in tumors vs. adjacent normal testicular tissues and correlated with clinicopathological characteristics and clinical outcome. CA IX expression was detected in 62 (30.2%) of TGCTs compared to 0 (0%) of normal tissue adjacent to testicular tumor (P<0.001). The highest frequency of the CA IX expression was detected in teratoma (39.0%), followed by seminoma (22.7%), yolk sac tumor (22.2%), embryonal carcinoma (11.9%) and choriocarcinoma (7.7%). None of germ cell neoplasias in situ (GCNIS) exhibited CA IX expression. Patients without the CA IX tumor expression showed significantly better progression-free survival, but not overall survival, compared to patients with the CA IX expression [hazard ratio (HR), 0.57; 95% CI, 0.32-1.02; P=0.037 and HR, 0.58; 95% CI, 0.29-1.16; P=0.088, respectively]. There was no significant correlation between the CA IX expression and clinicopathological variables. The intratumoral CA IX expression can serve as a prognostic marker in the TGCT patients. These results suggest that activation of the hypoxia-induced pathways may be important in the treatment failure in TGCTs patients.
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BACKGROUND: Cytokines are the communicators of immune system and are involved in all immune responses. The aim of this study was to assess the correlation among plasma cytokines, patient and tumor characteristics, and clinical outcome in chemonaive testicular germ-cell tumor (TGCT) patients. PATIENTS AND METHODS: This study included 92 metastatic chemotherapy-naive TGCT patients treated with platinum-based chemotherapy from July 2010 to March 2014. Plasma was isolated before first administration of chemotherapy, and the concentration of 51 plasma cytokines were analyzed using multiplex bead arrays. RESULTS: At a median follow-up of 33.2 months (range, 0.1-54.8 months), 10.9% of patients experienced disease progression, and 7.6% died. Several cytokines were associated with different baseline clinicopathologic features. Elevated plasma levels of interferon (IFN)-α2, interleukin (IL)-2Rα, IL-16, hepatocyte growth factor (HGF), and monocyte chemotactic protein (MCP)-3 were significantly associated with worse progression-free survival and overall survival (OS). Moreover, elevated levels of stem-cell growth factor (SCGF)-ß were also associated with worse OS. Patients with elevated levels of all 6 cytokines experienced significantly worse outcomes compared to patients who had fewer than 6 cytokines elevated (hazard ratio = 12.06; 95% confidence interval, 7.39-19.49; P = .002 for progression-free survival, and hazard ratio = 39.65; 95% confidence interval, 25.03-62.18; P < .00001 for OS, respectively). Results were independent of International Germ Cell Cancer Collaborative Group criteria. CONCLUSION: We found a correlation among progression free-survival, OS, and circulating cytokines in TGCT. This suggests the existence an association between plasma cytokines and baseline clinicopathologic features in TGCT. Plasma cytokines could be used for identification of high-risk patients who are candidates for new therapeutic approaches.
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Citocinas/sangue , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Neoplasias Testiculares/tratamento farmacológico , Progressão da Doença , Intervalo Livre de Doença , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/uso terapêutico , Masculino , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Metástase Neoplásica , Neoplasias Embrionárias de Células Germinativas/sangue , Neoplasias Embrionárias de Células Germinativas/imunologia , Neoplasias Embrionárias de Células Germinativas/mortalidade , Compostos Organoplatínicos/uso terapêutico , Prognóstico , Estudos Prospectivos , Neoplasias Testiculares/sangue , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/mortalidade , Pesquisa Translacional BiomédicaRESUMO
Despite the fact that testicular germ cell tumors (TGCTs) are one of the most chemosensitive solid tumors, a small proportion of patients fail to be cured following cisplatin-based first line chemotherapy. Upregulation of carbonic anhydrase IX (CA IX) in various solid tumors is associated with poor outcome. The current prospective study investigated the prognostic value of serum CA IX level in TGCTs. In total, 83 patients (16 non-metastatic following orchiectomy with no evidence of disease, 57 metastatic chemotherapy-naïve and 10 metastatic relapsed chemotherapy-pretreated) starting adjuvant and/or new line of chemotherapy and 35 healthy controls were enrolled in the study. Serum CA IX values were determined using an enzyme-linked immunosorbent assay, and intratumoral CA IX was analyzed by immunohistochemistry. Metastatic chemotherapy-naïve patients had significantly higher mean CA IX serum levels than healthy controls (490.6 vs. 249.6 pg/ml, P=0.005), while there was no difference in serum CA IX levels in non-metastatic or relapsed TGCT patients compared with healthy controls. There was no significant difference in the mean serum CA IX levels between different groups of patients and between the first and second cycle of chemotherapy, nor association with patients/tumor characteristics. Serum CA IX was not prognostic for progression-free survival [hazard ratio (HR)=0.81, P=0.730] or overall survival (HR=0.64, P=0.480). However, there was a significant association between intratumoral CA IX expression and serum CA IX concentration (rho=0.51, P=0.040). These results suggest that serum CA IX level correlates with tumor CA IX expression in TGCT patients, but fails to exhibit either a prognostic value or an association with patients/tumor characteristics.
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Germ cell tumors (GCTs) are extraordinarily sensitive to cisplatin (CDDP)-based chemotherapy. DNA damage represents one of the most important factors contributing to toxic effects of CDDP-based chemotherapy. This study was aimed to evaluate the prognostic value of DNA damage level in peripheral blood lymphocytes (PBLs) from chemo-naïve GCT patients. PBLs isolated from 59 chemotherapy-naïve GCT patients were included into this prospective study. DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage tail DNA by the Metafer-MetaCyte analyzing software. The mean ± SEM (standard error of the mean) of endogenous DNA damage level was 5.25 ± 0.64. Patients with DNA damage levels lower than mean had significantly better progression free survival (hazard ratio [HR] = 0.19, 95% CI (0.04 - 0.96), P = 0.01) and overall survival (HR = 0.00, 95% CI (0.00 - 0.0), P < 0.001) compared to patients with DNA damage levels higher than mean. Moreover, there was significant correlation between the DNA damage level and presence of mediastinal lymph nodes metastases, IGCCCG (International Germ Cell Cancer Collaborative Group) risk group, and serum tumor markers level. These data suggest that DNA damage levels in PBLs of GCT patients may serve as an important prognostic marker early identifying patients with poor outcome.
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Dano ao DNA , Linfócitos/metabolismo , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/mortalidade , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaio Cometa , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. Loss of the tumor-suppressor gene phosphatase and tensin homolog marks the transition from intratubular germ cell neoplasia to invasive GCT and is correlated with disease progression. Inactivation of phosphatase and tensin homolog is associated with deregulation of the PI3K/Akt pathway and increased mammalian target of rapamycin signaling. This study aimed to determine the efficacy and toxicity of a mammalian target of rapamycin inhibitor, everolimus, in patients with refractory TGCTs. METHODS: From December 2011 to February 2015, 15 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies; 4 tumors (26.7%) were absolutely refractory to cisplatin and 9 patients (60.0%) had visceral nonpulmonary metastases. Everolimus was administered at a dose of 10mg daily until progression or unacceptable toxicity. The primary end point was the objective response rate, according to Response Evaluation Criteria in Solid Tumors. RESULTS: No objective response was observed, but 6 patients (40.0%) achieved 12-week progression-free survival. During a median follow-up period of 3.6 months (range: 1-35.1mo), all patients experienced disease progression and 11 patients (80.0%) died. Median progression-free survival was 1.7 months (95% CI: 1.1-4.0mo) and median overall survival was 3.6 months (95% CI: 2.0-11.0mo). CONCLUSIONS: This study failed to achieve its primary end point and our data suggest limited efficacy of everolimus against unselected heavily pretreated refractory TGCTs. CONDENSED ABSTRACT: Everolimus showed limited efficacy in unselected heavily pretreated refractory TGCTs. Prolonged disease stabilization could be achieved in selected patients.
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Everolimo/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Terapia de Salvação , Neoplasias Testiculares/tratamento farmacológico , Adulto , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Taxa de Sobrevida , Neoplasias Testiculares/patologia , Adulto JovemRESUMO
PURPOSE: Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development, which is excreted in glucuronidated form into the intestine. This study aimed to determine the effectiveness of the probiotics in the prevention of irinotecan induced diarrhea due to reduction of intestinal beta-d-glucuronidase activity. METHODS: Between January 2011 and December 2013, 46 patients with colorectal cancer starting a new line of irinotecan based therapy were included. Patients were randomized 1:1 to probiotics (PRO) or placebo (PLA). Probiotic formula Colon Dophilus™, was administered at a dose of 10×10(9)CFU of bacteria tid, orally for 12 weeks of chemotherapy. The study was prematurely terminated due to slow accrual, when 46 of 220 planned patients were accrued. RESULTS: Twenty-three patients were randomized to PRO and 23 patients to PLA. Administration of probiotics compared to placebo led to a reduction in the incidence of severe diarrhea of grade 3 or 4 (0% for PRO vs. 17.4% for PLA, p=0.11), as well as reduction of the overall incidence of diarrhea (39.1% for PRO vs. 60.9% for PLA, p=0.24) and incidence of enterocolitis (0% for PRO vs. 8.7% for PLA). Patients on PRO used less antidiarrheal drugs compared to PLA. There was no infection caused by probiotic strains recorded. CONCLUSIONS: Administration of probiotics in patients with colorectal cancer treated with irinotecan-based chemotherapy is safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity.
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Camptotecina/análogos & derivados , Diarreia/induzido quimicamente , Diarreia/prevenção & controle , Probióticos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Camptotecina/efeitos adversos , Diarreia/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
Approximately 20%-25% of patients with breast cancer demonstrate amplification of the human epidermal receptor type 2 (HER2) gene, resulting in an overexpression of the HER2 receptor. This overexpression is associated with aggressive disease, relatively poor prognosis, and worse clinical outcomes. Neoadjuvant therapy is the standard treatment in patients with locally advanced, inflammatory, or inoperable primary breast cancer. It is generally used to downstage the tumors and therefore to improve surgical options including breast-conserving surgery rather than mastectomy. It has been confirmed that patients with pathological complete response (pCR) to neoadjuvant treatment have better disease-free survival (DFS) and overall survival (OS). Neoadjuvant treatment can also serve as in vivo test of sensitivity to the used therapeutic regimen. The preferred neoadjuvant approach to patients with HER2-positive breast cancer is a sequential anthracycline-taxane-based chemotherapy in combination with trastuzumab. Addition of other anti-HER2 agents has increased pCR rate up to 75% and will probably become a new therapeutic direction. In the first part of this paper, we summarize the information about HER2-positive breast cancer, the various treatment possibilities, and the results of the major neoadjuvant trials. The second part focuses on the data concerning the importance of pCR and the potential risk of cardiotoxicity associated with this treatment.
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Docetaxel (D) plus gemcitabine (G) is an active combination in anthracycline pre-treated breast cancer. Impact of sequential administration of these drugs is unclear. This trial aimed to compare concomitant DG with sequential D --> G. Patients were randomised to eight cycles of gemcitabine 1,000 mg/m2 on days 1 + 8 plus docetaxel 75 mg/m2 on day 8, or 4 cycles of docetaxel 100 mg/m2 on day 1, followed by four cycles of gemcitabine 1,250 mg/m2 on days 1 + 8, in a 21-day schedule. Time to progression (TTP) was defined as primary endpoint; secondary endpoints were overall response rate (ORR), response duration (RD), overall survival (OS) and toxicity. Due to poor recruitment, the trial was terminated after 100 of a pre-planned 430 patients. Patient characteristics were well balanced. No significant difference was observed in terms of TTP, ORR, RD and OS. Grade 3/4 adverse events encompassed leucopoenia (29 vs.68%, P < 0.001), neutropoenia (49 vs. 83%, P < 0.001) and febrile neutropoenia (4 vs. 9%, n.s.), all favouring D --> G. No difference in efficacy was observed between concomitant and sequential treatment. D --> G produced significantly more episodes of haematological toxicity due to the administration of docetaxel at 100 mg/m2 without GCSF support.
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Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Desoxicitidina/análogos & derivados , Taxoides/administração & dosagem , Adulto , Idoso , Desoxicitidina/administração & dosagem , Progressão da Doença , Docetaxel , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva , Fatores de Tempo , GencitabinaRESUMO
PURPOSE To evaluate the safety, maximum tolerated dose (MTD), and pharmacokinetics of patupilone administered once every 3 weeks with proactive standardized diarrhea management in patients with resistant or refractory ovarian, fallopian, or peritoneal cancer. PATIENTS AND METHODS Patients received patupilone (6.5 to 11.0 mg/m(2)) every 3 weeks via 20-minute infusion. Adverse events, dose-limiting toxicities (DLT), MTD, and tumor response were determined. The tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 125 levels. Results Forty-five patients were enrolled. Adverse events were mild to moderate in intensity, and grade 3 diarrhea (13%) was the most commonly reported serious adverse event. Grade 3 peripheral neuropathy was noted in two patients (4%). Diarrhea, peripheral neuropathy, and fatigue were the most common DLTs; however, these were uncommon in the first cycle and the MTD was therefore not reached in this study. Overall response (OR; complete and partial responses; median cycles, 8) per RECIST in patients with measurable disease (n = 36) was 19.5%. Median duration of disease stabilization (complete and partial responses and stable disease) was 15.8 months. These results appear improved from a previous study in a similar patient population using a weekly schedule (2.5 mg/m(2)/week; N = 53; OR, 5.7%). CONCLUSION Patupilone once every 3 weeks was well-tolerated at doses up to 11.0 mg/m(2). Patupilone demonstrated promising antitumor activity in patients with drug-resistant/refractory disease. An ongoing phase III study in this patient population is testing the 10.0 mg/m(2) dose.
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Antineoplásicos/administração & dosagem , Epotilonas/administração & dosagem , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Epotilonas/efeitos adversos , Epotilonas/farmacocinética , Feminino , Humanos , Dose Máxima Tolerável , Pessoa de Meia-IdadeRESUMO
Addition of epirubicin to adjuvant chemotherapy can provide important benefits for patients with early breast cancer, but the optimal dose remains unclear. Further improvements can be achieved with dose-dense regimens, but densification of fluorouracil/epirubicin/cyclophosphamide (FEC) has proved difficult, with FEC(60) providing little benefit over standard chemotherapy and FEC(100) associated with toxicity. We investigated the feasibility of two intermediate dose-dense FEC regimens. Patients were randomised to six cycles of FEC(75) or FEC(90), with all three drugs given on day 1 of each 14-day cycle. Patients also received pegfilgrastim 6 mg as a single subcutaneous injection on day 2 of each cycle. The primary efficacy endpoint was the proportion of subjects receiving > or =85% relative dose intensity and was achieved by 96% and 88% of patients in the FEC(75) and FEC(90) arms, respectively. Of 147 FEC(75) infusions, 4.1% were delayed, while 9.8% of 143 FEC(90) infusions were delayed. The most common reasons for delay were adverse events and personal/logistical reasons. One dose reduction occurred during the study (FEC(90)), related to diarrhoea. Grade 3-4 haematological toxicities were reported in two patients in the FEC(90) arm. There were no incidences of febrile neutropenia during the study. The most common adverse events were increases in liver enzymes and gastrointestinal events; no event resulted in discontinuation. Only one patient (FEC(90)) experienced serious adverse events (vomiting and throat oedema). In conclusion, dose-dense FEC(75 )and FEC(90) are feasible with pegfilgrastim support. These regimens are associated with a very low risk of Grade 3-4 toxicity.
Assuntos
Neoplasias da Mama/terapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Epirubicina/uso terapêutico , Feminino , Filgrastim , Fluoruracila/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Oncologia/métodos , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes , Resultado do TratamentoRESUMO
BACKGROUND: The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles. RESULTS: Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. CONCLUSION: No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Desoxicitidina/uso terapêutico , Epirubicina/uso terapêutico , Fluoruracila/uso terapêutico , Taxoides/uso terapêutico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias da Mama/mortalidade , Ciclofosfamida/toxicidade , Desoxicitidina/análogos & derivados , Desoxicitidina/toxicidade , Epirubicina/toxicidade , Feminino , Fluoruracila/toxicidade , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Taxoides/toxicidadeRESUMO
OBJECTIVES: The aims of this study were to evaluate risk factors, clinical presentation, outcome and antimicrobial susceptibility in patients with Escherichia coli bacteremia occurring over seven years in a single cancer hospital. METHODS: Sixty five episodes of bacteremia from E. coli appearing over seven years from 12,301 admissions in a single cancer institution were retrospectively analyzed. RESULTS: The proportion of bacteremia caused by E. coli among Gram-negative bacteremia was 20.8% (the second most common organism after Pseudomonas aeruginosa), and infection-associated mortality was 17%. The incidence in 1989-1995 varied from 14.3 to 24.7%. The most common risk factors were: solid tumors as the underlying disease (70.7%); central venous catheter insertion (32.3%); prior surgery (46.2%), and prior chemotherapy within 48 h (44.4%). Neutropenia and urinary catheters did not place patients at high risk in any of the subgroups. When we compared the two subgroups of 61 cases of bacteremia - monomicrobial and polymicrobial (when E. coli was isolated from blood culture with another microorganism) - we found that acute leukemia and breakthrough (recurrence while receiving antibiotics) bacteremia were more frequently associated with polymicrobial E. coli bacteremia. There was also a difference in infection-associated mortality: monomicrobial bacteremia due to E. coli only had a significantly lower mortality in comparison with polymicrobial E. coli bacteremia (8.9 vs 35.0%, respectively; P<0.03). CONCLUSION: The susceptibility of 115 E. coli strains isolated from 65 episodes of bacteremia was stable. Only two episodes caused by quinolone-resistant strains occurred, both in 1995, after six years of using ofloxacin for prophylaxis in neutropenic patients in our hospital. We found that 85.2-91.3% of all strains were susceptible to aminoglycosides, 97.8% to quinolones, and 90-100% to third generation cephalosporins and imipenems. The patients most commonly infected had solid tumors and the mortality was only 17%.
Assuntos
Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Infecções por Escherichia coli/epidemiologia , Escherichia coli/efeitos dos fármacos , Neoplasias/complicações , Antibacterianos/farmacologia , Bacteriemia/complicações , Farmacorresistência Bacteriana , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/microbiologia , Feminino , Bactérias Gram-Negativas/isolamento & purificação , Humanos , Incidência , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
Because of controversial data on virulence and mortality, six cases of fungemia caused by Candida glabrata were reviewed in a single cancer institution within 8 years. Risk factors and outcome of C. glabrata, Candida albicans, and other non-albicans Candida spp. appearing within the same period under the same antibiotic policy at the same institution were compared. Among other non-albicans Candida spp. in 1990-1997 C. glabrata fungemias showed a decreasing tendency, from 9% to 4.5% in 1997. Analyzing the proportion of C. glabrata among blood cultures, among 170 positive blood cultures 12 were caused by C. glabrata (6.2% among all pathogens and 24% among non-albicans Candida spp.). C. glabrata among all fungemias was diagnosed as the fourth most common pathogen after C. albicans, C. krusei, and C. parapsilosis. Three of six C. glabrata fungemias were breakthrough. Two appeared during prophylaxis with itraconazole and one during fluconazole prophylaxis. Five of six received broadspectrum antibiotic therapy with third-generation cephalosporines, five of six had vascular catheter insertion, four of six were neutropenic, and two of six received amphotericin B therapy. One patient died before his blood cultures were reported to be positive. Overall mortality of C. glabrata fungemia was 16.7%. One patient died of underlying disease with fungemia. There were no significant differences in risk factors between C. glabrata and C. albicans. However, overall and crude mortality was lower in C. glabrata than in C. albicans (25.5% vs. 16.7%; P = 0.03). Attributable mortality was lower in comparison to C. albicans (0 vs. 15.7% in C. albicans; P = 0.001).
RESUMO
The aim of this study was to assess whether multiresistant gram-negative bacteremias (MRGNB) were associated with specific risk factors for higher mortality than sensitive gram-negative bacteremias. Two groups of subjects: (51 cases and 102 controls) were matched for sex, age, underlying disease, and neutropenia. There were no significant differences in the incidence of cytotoxic chemotherapy administered, vascular catheter insertion, catheter as source of bacteremia, and etiology of bacteremia. The proportion of Klebsiella-Enterobacter, Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia was similar in the two groups. Prior surgery (21.6% vs 7.9%, P < 0.05) was significantly associated with sensitive gram-negative bacteremia. Previous prophylaxis with ofloxacin (45.1% vs 24.5%; P < 0.05) and prior therapy with broad-spectrum antibiotics (41.2% vs 27.5%; P < 0.05), such as first and second generation cephalosporins (19.6% vs 7.8%; P < 0.05), third generation cephalosporins (41.2% vs 13.7%; P < 0.01), aminoglycosides (39.2% vs 9.8%; P < 0.01), ofloxacin (11.8% vs 2.0%; P < 0.005), and imipenem (19.6% vs 2.0%; P < 0.001) were significantly more frequently observed among cases than controls. Cases (patients with bacteremia due to multiresistant gram-negative bacteremias) were also significantly more frequently infected with bacteria resistant to ceftazidime (68.6% vs 17.6%; P < 0.001), amikacin (52.9% vs 7.8%; P < 0.001), imipenem (50.1% vs 23.5%; P < 0.05), ciprofloxacin (32.1% vs 5.9%; P < 0.001), and piperacillin (41.2% vs 7.8%; P < 0.01). With regard to outcome, attributable mortality was similar (15.7% vs 13.8%; not significant) in the two groups; however, cure rates were lower among cases (patients infected with MRGNB) because crude mortality was higher in cases (35.3% vs 13.8%; P < 0.01) than in controls.
RESUMO
The aim of this study was to retrospectively compare the incidence, risk factors, and outcome in patients seen over a 7-year period at the National Cancer Institute in the Slovak Republic, with vancomycin-sensitive or vancomycin-resistant enterococcal bacteremia. The total incidence of enterococcal bacteremia at the National Cancer Institute increased from 5.1% in 1991 to 11.1% in 1993 and then decreased to 4.3% in 1995. Analysis of the 77 episodes of enterococcal bacteremia from 66 patients showed that 69 episodes from 60 patients were due to vancomycin-sensitive Enterococcus faecalis (group 1) and 8 episodes from 8 patients were due to vancomycin-resistant Enterococcus faecium (group 2). The features most frequently associated with enterococcal bacteremia were the insertion of a central venous catheter, neutropenia lasting more than 10 days, previous therapy with cephalosporins or vancomycin, previous prophylaxis with quinolones, and the incidence of superinfections. There was no difference in the clinical course or outcome between the 2 study groups. Previous therapy with aminoglycosides, cephalosporins, vancomycin or imipenem, neutropenia less than 10 days in length, malignancies other than leukemia or solid tumors, and the incidence of breakthrough bacteremia significantly correlated with patients with vancomycin-resistant E. faecium rather than patients with vancomycin-sensitive E. faecalis. The overall mortality was similar in both groups and averaged 32.5% for all enterococcal bacteremic patients. In this study, the major risk factors associated with cancer patients for developing vancomycin-resistant enterococcal bacteremia were previous therapy with aminoglycosides, cephalosporins or vancomycin, superinfections with other organisms and the incidence of breakthrough bacteremia.