RESUMO
OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.
Assuntos
5'-Nucleotidase , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Epitelial do Ovário , Proteínas Ligadas por GPI , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Humanos , Feminino , Pessoa de Meia-Idade , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/imunologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologiaRESUMO
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.
Assuntos
Antineoplásicos , Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Feminino , Humanos , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Quimioterapia de Manutenção , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/induzido quimicamente , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
BACKGROUND: Pelvic exenteration may be the only curative treatment for some patients with primary advanced or recurrent vulvar cancer but is associated with high morbidity. This study evaluated the clinical outcome of patients treated at a centralized service in Norway. METHODOLOGY: This retrospective study included patients treated with pelvic exenteration for primary locally advanced or recurrent vulvar cancer between 1996 and 2019 at Oslo University Hospital, Norway. Complications were coded according to the contracted Accordion classification. Relapse free survival (RFS), cancer specific survival (CSS) and overall survival (OS) were estimated with the Kaplan Meier method. RESULTS: The 30 patients were followed for a median of 4.94 years (95%CI: 3.37-NR). Exenteration due to primary vulvar cancer was carried out in 16 (53%) patients, 14 (47%) had recurrent vulvar cancer. Free histopathological margins were achieved in 28 (93%) patients. The 90 days morbidity for grade 3 complications was 63%, predominantly wound/surgical flap infections, 7% had no complications. 90 days mortality was 3%. Five-year RFS was 26% (95% CI 8-48%), OS was 50% (95%CI: 29-69%) and CSS was 64% (95% CI 43-79%). There was no significant difference in survival between patients with primary vs recurrent disease. The 3-year CSS for patients with negative lymph nodes and positive lymph nodes was 70% (95% CI 47-84%) and 30% (95% CI 1-72%), respectively. CONCLUSIONS: Acceptable oncologic outcomes after pelvic exenteration for primary and recurrent vulvar cancer can be achieved if surgery is centralized. Careful patient selection is imperative due to significant postoperative morbidity and considerable risk of relapse.
Assuntos
Exenteração Pélvica , Neoplasias Vulvares , Feminino , Humanos , Neoplasias Vulvares/cirurgia , Neoplasias Vulvares/patologia , Estudos Retrospectivos , Exenteração Pélvica/métodos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Morbidade , Complicações Pós-Operatórias/etiologia , Resultado do TratamentoRESUMO
OBJECTIVE: Despite its generally favorable prognosis at primary diagnosis, recurrence of endometrial cancer remains an important clinical challenge. The aim of this study was to analyze the value of molecular classification in recurrent endometrial cancer. METHODS: This study included patients with recurrent endometrial cancer who underwent primary surgical treatment between 2004 and 2015 at the Karolinska University Hospital, Sweden and the Bern University Hospital, Switzerland (KImBer cohort) with molecular classification of the primary tumor. RESULTS: Out of 594 molecularly classified endometrial cancer patients, 101 patients experienced recurrence, consisting of 2 POLEmut, 33 MMRd, 30 p53abn, and 36 NSMP tumors. Mean age at recurrence was 71 years and mean follow-up was 54 months. Overall, median time to first recurrence was 16 months (95% CI 12-20); with the shortest median time in MMRd patients, with 13 months (95% CI 5-21). The pattern of recurrence was distinct among molecular subgroups: MMRd tumors experienced more locoregional, while p53abn cases showed more abdominal recurrences (P = .042). Median survival after recurrence was best for MMRd cases (43 months, 95% CI 11-76), compared to 39 months (95% CI 21-57) and 10 months (95% CI 7-13) for the NSMP and p53abn cases respectively (log-rank, P = .001). CONCLUSION: Molecular classification is a significant indicator of survival after recurrence in endometrial cancer patients, and patterns of recurrence differ by molecular subgroups. While MMRd endometrial cancer show more locoregional recurrence and the best survival rates after recurrence, p53abn patients experience abdominal recurrence more often and had the worst prognosis of all recurrent patients.
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Neoplasias do Endométrio , Proteína Supressora de Tumor p53 , Estudos de Coortes , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genéticaRESUMO
OBJECTIVE: The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. METHODS: In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300â¯mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18â¯months after the last patient received their first dose. RESULTS: Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2â¯months (95% confidence interval [CI], 7.6-10.9) in the overall population. At 12 and 18â¯months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3â¯months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. CONCLUSION: Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.
Assuntos
Recidiva Local de Neoplasia , Neoplasias Ovarianas , Ftalazinas , Piperazinas , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Feminino , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Quimioterapia de Manutenção , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Platina/uso terapêuticoRESUMO
Introduction: Poorer end-of-life (EOL) care for elderly cancer patients has been reported. We assessed the impact of age on 13 indicators for the quality of EOL care as well as adherence to 6 national quality indicators in gynaecological cancer patients.Methods: Age-dependent differences in 13 palliative care quality indicators were studied in gynaecological cancer patients registered in the population-based Swedish Register of Palliative Care. Association between the patient's age and each quality indicator was analyzed by logistic regression, adjusted for place of death where appropriate. Adherence to six national quality indicators determined by the Swedish National Board of Health and Welfare was estimated in all patients.Results: We included 3940 patients with the following age distribution: 1.6% were 18-39 years of age, 12.3% 40-59 years, 37.2% 60-74 years, 28.9% 75-84 years and 20% were ≥85 years. Age-dependent differences in implementation rate were present for some of the 13 quality indicators. Compared to elderly cancer patients, younger patients were more likely to be cared for by a specialized palliative care service, more often informed about imminent death as well as assessed for pain. For most national quality indicators, the goal level was not met. Only for the 'on demand prescription for pain', the goal level was reached.Conclusions: EOL care did not meet national quality indicators in this population-based data from Sweden, in particular in the elderly population. Elderly gynaecological cancer patients are at high risk of poorer EOL care without the involvement of specialized palliative care services. Palliative care services need to be implemented across all institutions of EOL care to ensure good and equal care.
Assuntos
Neoplasias dos Genitais Femininos/terapia , Indicadores de Qualidade em Assistência à Saúde , Assistência Terminal/normas , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica/métodos , Feminino , Neoplasias dos Genitais Femininos/mortalidade , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Manejo da Dor/estatística & dados numéricos , Medição da Dor , Sistema de Registros , Suécia/epidemiologia , Assistência Terminal/métodos , Adulto JovemRESUMO
BACKGROUND: Data on CA-125 as a predictor of disease progression (PD) in ovarian cancer come predominantly from patients with platinum-sensitive disease receiving chemotherapy alone. We assessed concordance between CA-125-defined and RECIST-defined PD using data from the Gynecologic Cancer InterGroup (GCIG) randomized phase III AURELIA trial in platinum-resistant ovarian cancer (PROC). PATIENTS AND METHODS: Patients with PROC were randomized to receive single-agent chemotherapy with or without bevacizumab. PD by CA-125 was defined according to GCIG criteria (except that confirmatory CA-125 measurement was not required). This exploratory analysis included patients with RECIST PD and a CA-125 reading ≤28 days before and ≤21 days after RECIST-defined PD. RESULTS: Of 218 eligible patients, only 94 (43%, 95% confidence interval 36% to 50%) had concordant RECIST and CA-125 PD status (42% in the chemotherapy-alone arm; 45% in the bevacizumab combination arm, P = 0.6). There was no evidence of CA-125-defined PD in the remaining 124 patients despite PD according to imaging. There were no significant differences in baseline characteristics between patients with PD defined by both RECIST and CA-125 and those with RECIST-only PD. CA-125 was even less sensitive in detecting PD in patients with early (<8 weeks after randomization) compared with later RECIST-defined PD (69% versus 53%, respectively, not meeting CA-125 criteria; P = 0.053). There was no significant difference in survival after PD in patients with concordant PD by RECIST and CA-125 versus those with PD only by RECIST. We validated our findings in an independent study population of PROC. CONCLUSIONS: In this platinum-resistant population, PD was typically detected earlier by imaging than by CA-125, irrespective of bevacizumab treatment. Disease status by CA-125 at the time of PD was not prognostic for overall survival. Regular radiologic assessment as well as symptom benefit assessment should be considered during PROC follow-up.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Ca-125/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Bevacizumab/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Platina/uso terapêutico , Prognóstico , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
BACKGROUND: Obesity increases the risk for a number of solid malignant tumours. However, it is not clear whether body mass index (BMI) and height are associated with the risk of primary tumours of the central nervous system (CNS). METHODS: In a large population study (The Nord-Trøndelag Health Study (HUNT Study)) of 74 242 participants in Norway, weight and height were measured. During follow-up, incident CNS tumours were identified by individual linkage to the Norwegian Cancer Registry. Sex- and age-adjusted and multivariable Cox regression analyses were used to evaluate BMI and height in relation to the risk of meningioma, glioma and schwannoma. RESULTS: A total of 138 meningiomas, 148 gliomas and 39 schwannomas occurred during 23.5 years (median, range 0-25) of follow-up. In obese women (BMI ≥ 30 kg m(-2)), meningioma risk was 67% higher (hazard ratio (HR)=1.68, 95% confidence interval (CI): 0.97-2.92, P-trend=0.05) than in the reference group (BMI 20-24.9 kg m(-2)), whereas no association with obesity was observed in males. There was no association of BMI with glioma risk, but there was a negative association of overweight/obesity (BMI ≥ 25 kg m(-2)) with the risk of schwannoma (HR=0.48, 95% CI: 0.23-0.99). However, the schwannoma analysis was based on small numbers. Height was not associated with the risk for any tumour subgroup. CONCLUSION: These results suggest that BMI is positively associated with meningioma risk in women, and possibly, inversely associated with schwannoma risk.
Assuntos
Índice de Massa Corporal , Glioma/epidemiologia , Meningioma/epidemiologia , Neurilemoma/epidemiologia , Estatura , Sistema Nervoso Central/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Obesidade , Estudos Prospectivos , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel. PATIENTS AND METHODS: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients). RESULTS: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC. CONCLUSION: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Carboplatina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/fisiopatologia , Paclitaxel/administração & dosagem , Cooperação do Paciente , Estudos Prospectivos , Qualidade de Vida , Análise de SobrevidaRESUMO
BACKGROUND: Synechia formation between the middle turbinate (MT) and the lateral nasal wall is a common postoperative complication in endoscopic sinus surgery (ESS) often resulting in revision surgery. To keep the middle meatus open several procedures were described in order to medialise the MT. Long term results of these techniques are missing. The purpose of the study was to evaluate the long term results of fixing the heads of the MT to the septum by a resorbable septal-turbinate-suture (STS). MATERIAL AND METHODS: 17 patients were included in the retrospective study. All patients underwent ESS with STS because of chronic rhinosinusitis with (8) and without polyps (9). The median follow-up was 81 months (range, 36-105 months). In a total 34 nasal cavities were postoperatively examined by endoscopy. Additionally, rhinomanometry and olfaction test were performed. RESULTS: The MT was found in a central position in between septum and lateral wall in 10 nasal cavities (30 % ), in a more medial position in 24 (70 % ) and none in a lateral position. Only 2 patients presented unilateral synechia to the lateral wall and one unilateral to the septum. CONCLUSIONS: Synechia of the MT to the lateral nasal wall in ESS can be effectively avoided by a STS. The long term results showed that STS maintains the MT in a medial position with a free middle meatus without impairing the olfactory function.
Assuntos
Endoscopia/métodos , Pólipos Nasais/cirurgia , Septo Nasal/cirurgia , Doenças dos Seios Paranasais/cirurgia , Rinoplastia/métodos , Técnicas de Sutura , Conchas Nasais/cirurgia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obstrução Nasal/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Cicatrização/fisiologiaRESUMO
BACKGROUND: Obesity increases the risk of uterine cancer, but results by histological type have differed. METHODS: We followed 36,755 women for 17.8 years for uterine cancers. RESULTS AND CONCLUSION: Body mass index (BMI) was positively associated with uterine cancers as a whole, particularly for endometrioid adenocarcinomas, for which the relative risk for very obese women (BMI: > or = 40 kg m(-2)) compared with lean (BMI: 20-24 kg m(-2)) women, was 11.1 (95% confidence interval: 5.2-23.8).
Assuntos
Índice de Massa Corporal , Neoplasias Uterinas/etiologia , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
We examined the relationship of body mass index (BMI), diabetes and smoking to endometrial cancer risk in a cohort of 36 761 Norwegian women during 15.7 years of follow-up. In multivariable analyses of 222 incident cases of endometrial cancer, identified by linkage to the Norwegian Cancer Registry, there was a strong increase in risk with increasing BMI (P-trend <0.001). Compared to the reference (BMI 20-24 kg m(-2)), the adjusted relative risk (RR) was 0.53 (95% confidence interval (CI): 0.19-1.47) for BMI<20 kg m(-2), 4.28 (95% CI: 2.58-7.09) for BMI of 35-39 kg m(-2) and 6.36 (95% CI: 3.08-13.16) for BMI>or=40 kg m(-2). Women with known diabetes at baseline were at three-fold higher risk (RR 3.13, 95% CI: 1.92-5.11) than those without diabetes; women who reported current smoking at baseline were at reduced risk compared to never smokers (RR 0.55, 95% CI: 0.35-0.86). The strong linear positive association of BMI with endometrial cancer risk and a strongly increased risk among women with diabetes suggest that any increase in body mass in the female population will increase endometrial cancer incidence.
Assuntos
Índice de Massa Corporal , Complicações do Diabetes/epidemiologia , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/etiologia , Obesidade/complicações , Fumar/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias do Endométrio/fisiopatologia , Feminino , Seguimentos , Humanos , Incidência , Modelos Lineares , Registro Médico Coordenado , Pessoa de Meia-Idade , Análise Multivariada , Noruega/epidemiologia , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de Risco , Fumar/fisiopatologia , Fatores de TempoRESUMO
AIMS: Tyrosine kinase receptors Her2/neu and c-Met play an important role in breast cancer development and progression. Our aim was to determine the expression of c-Met, its ligand hepatocyte growth factor/scatter factor (HGF/SF) and Her2/neu in ductal carcinoma in situ (DCIS) lesions of the breast (n = 39) by two different immunocytochemical techniques, classical immunohistochemistry and immunofluorescence, and to correlate their expression levels with histopathological and clinical characteristics. METHODS AND RESULTS: Both methods revealed similar c-Met staining patterns in both the in situ component and the adjacent normal tissue (P < 0.001). However, an imbalance in c-Met expression between tumour and surrounding normal tissue was correlated with high-grade DCIS (Van Nuys Grade 3). No correlation existed between Her2/neu and c-Met expression. High HGF/SF immunoreactivity was observed in 43.6% of the cases, yet the adjacent cellular stroma revealed only low levels of HGF/SF. No correlation existed between c-Met, Her2/neu or HGF/SF expression and clinicopathological factors. CONCLUSION: An imbalance in c-Met expression between tumour and surrounding normal tissue is associated with an aggressive DCIS phenotype. Moreover, c-Met and HGF/SF may contribute to tumour development by different means than those controlled by Her2/neu.
Assuntos
Neoplasias da Mama/metabolismo , Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/citologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Humanos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-met/genética , Receptor ErbB-2/genéticaRESUMO
In the present study, we show that endothelial-like cells (ELCs) can develop from human CD14-positive mononuclear cells (CD14 cells) in the presence of angiogenic growth factors. The CD14 cells became loosely adherent within 24 h of culture and subsequently underwent a distinct process of morphological transformation to caudated or oval cells with eccentric nuclei. After 1 week in culture the cells showed a clear expression of endothelial cell markers, including von Willebrand factor (vWF), CD144 (VE-cadherin), CD105 (endoglin), acetylated low-density lipoprotein (AC-LDL)-receptor, CD36 (thrombospondin receptor), FLT-1, which is vascular endothelial cell growth factor (VEGF) receptor-1, and, to a weaker extent, KDR (VEGF receptor-2). Furthermore, in these cells structures resembling Weibel-Palade bodies at different storage stages were identified by electron microscopy, and upon culturing on three-dimensional fibrin gels the cells build network-like structures. In addition, cell proliferation and vWF expression was stimulated by VEGF, and the endothelial cell adhesion molecules CD54 (ICAM-1), and CD106 (VCAM-1) became transiently inducible by tumor necrosis factor-alpha (TNF-alpha). In contrast, the dendritic markers CD1a, and CD83 were not expressed to any significant extent. The expression of CD68, CD80 (B7-1), CD86 (B7-2), HLA-DR and CD36 may also suggest that ELCs might be related to macrophages, sinus lining or microvascular endothelial cells. Taken together, our observations indicate that ELCs can differentiate from cells of the monocytic lineage, suggesting a closer relationship between the monocyte/macrophage- and the endothelial cell systems than previously supposed.
Assuntos
Endotélio/citologia , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/citologia , Antígenos de Diferenciação/metabolismo , Biomarcadores/análise , Diferenciação Celular , Linhagem Celular Transformada , Células Cultivadas , Primers do DNA/química , Fatores de Crescimento Endotelial/farmacologia , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Citometria de Fluxo , Imunofluorescência , Humanos , Imuno-Histoquímica , Linfocinas/farmacologia , Microscopia Eletrônica , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neovascularização Fisiológica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Previous investigations have found elevated levels of s-IgA in the parotid saliva and normal levels in submandibular saliva of patients with Sjögren's syndrome (SS). Fox et al. also found elevated levels of cytokines (i.e., IL-2 and IL-6) in serum, salivary epithelial cells and parotid saliva of patients with SS. The oral administration of pilocarpine hydrochloride stimulates whole and parotid salivary flow. The purpose of this study was to determine the levels of s-IgA and IL-2 and IL-6 in whole saliva before and after administration of pilocarpine hydrochloride in SS subjects. Ten definitively diagnosed SS subjects were enrolled in the study, as were ten controls (C). The mean age was 57.2 years and all subjects were female. Whole unstimulated saliva (WUS) was collected by standard techniques for 5 min, after which the volume and flow rate were determined (mean WUS: SS = 0.047 vs C = 0.480 ml/min). Samples were centrifuged and the immunoglobulin analysis performed on the supernatants by immunoreactivity in a double-sandwich technique as previously described by Rudney et al. Cytokine analysis was performed similarly utilizing commercially available kits from R&D Systems. The results as analyzed by pairwise t-tests revealed comparable levels of s-IgA in the saliva of the SS patients, as compared to controls at baseline (means +/- SEM: SS-IgA = 348.1 +/- 82.0 vs C-IgA = 284.0 +/- 65.1 micrograms/ml; NS). Whole salivary flow was significantly increased (328%) in the SS subject group 60 min after the administration of 5 mg pilocarpine hydrochloride (means +/- SEM: 0.0472 +/- 0.017 vs 0.1546 +/- 0.054 ml/min; P < 0.01). There was no significant change in the concentration of s-IgA in the SS subject group following the pilocarpine dose (means +/- SEM: SS-IgA = 439.9 +/- 121.2 microliters/ml; P = NS). There were elevated levels of IL-2 in the saliva of four out of the ten and IL-6 in two out of the ten SS patients, as compared to controls (means +/- SEM: SS-IL-2 = 127.8 +/- 11.4 vs C-IL-2 = 30.8 +/- 1.6 pg/ml and SS-IL-6 = 41.4 +/- 7.1 vs C-11.6 +/- 2.8 pg/ml). There was also a significant decrease in the concentration of IL-2 in the same four out of ten SS subjects following the pilocarpine dose (means +/- SEM: SS-IL-2 = 32.4 +/- 10.3; P < 0.01). These preliminary results indicate that s-IgA levels do not change with increased salivary flow following the administration of pilocarpine hydrochloride in patients with Sjögren's syndrome. While cytokines are elevated in the whole saliva of some SS patients, a decrease in IL-2 concentration may occur with increased salivary flow.
Assuntos
Imunoglobulina A Secretora/análise , Interleucina-2/análise , Interleucina-6/análise , Interleucinas/análise , Parassimpatomiméticos/administração & dosagem , Pilocarpina/administração & dosagem , Salivação/efeitos dos fármacos , Síndrome de Sjogren/metabolismo , Administração Oral , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Saliva/química , Saliva/imunologia , Proteínas e Peptídeos Salivares/análise , Síndrome de Sjogren/imunologia , Estimulação QuímicaRESUMO
This article provides guidelines for the use of amifostine (Ethyol, Alza Pharmaceuticals, Palo Alto, CA, and U.S. Bioscience, Inc., West Conshohocken, PA), a pancytoprotective agent approved for reducing renal toxicity associated with cisplatin administration in patients with advanced ovarian or non-small cell lung cancer. Pretreatment with amifostine reduces the incidence of serious and cumulative chemotherapy-induced toxicities, thus improving quality of life, and allows administration of optimal doses and scheduling of chemotherapy and radiation therapy, translating into improved survival. Practical guidelines for administration of amifostine are provided in an effort to ameliorate emesis, amifostine's principle side effect.
Assuntos
Amifostina/uso terapêutico , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Feminino , Humanos , Enfermagem OncológicaRESUMO
A prospective study was conducted on 65 patients who had a cataract operation. One eye had intracapsular cataract extraction (ICCE) with a Choyce-IX anterior chamber lens (ACL) and the fellow eye extracapsular cataract extraction (ECCE) with a posterior chamber lens (PCL). To evaluate the cystoid macular edema (CME), a fluorescence angiogram was recorded on the day of discharge and after 6 months. The severity of the CME was classified in three stages (degrees I-III). At discharge, no eye had CME grade III. CME grade I or grade II was seen in the ICCE group in 23% and in the ECCE group in 7.6%. After 6 months one eye of each group showed CME grade III (1.5%). CME grades I and II were seen after ICCE in 13.8% and 7.8% while the eyes with ECCE presented CME in 6.1% of grade I and of grade II, respectively. Visual acuity (VA) in the eyes with grades I and II CME was the same as in eyes without CME. The VA (median) of the ICCE group was 0.8 and of the ECCE 0.7. Because of infection of the capsular bag (toxic lens syndrome), in one case the PCL together with the capsular bag had to be explanted after 7 months. As for visual acuity and clinically significant CME (grade III), there was no statistical difference between ICCE plus Choyce-IX ACL eyes versus ECCE plus PCL eyes in the same patient.
Assuntos
Extração de Catarata/métodos , Lentes Intraoculares , Edema Macular/etiologia , Complicações Pós-Operatórias/etiologia , Acuidade Visual/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Desenho de PróteseRESUMO
Determining ionized calcium after CO2 equilibration of serum with subsequent electronic conversion to pH 7.40 (Ca2+corr) gives a practicable value for the diagnosis of calcium metabolism. "Anaerobic" sampling, necessary for the measurement of the actual calcium ion concentration, is obviated. Protein or albumin concentration in serum and complex-bound calcium do not interfere. Comparison of sera from 54 patients with bone metastases or myeloma, as well as from 300 patients with other diseases, indicate that the sensitivity of Ca2+corr in the diagnosis of hypercalcaemia is about twice or three times that of total calcium and that the latter's specificity - at least when ignoring protein concentration - is unsatisfactory with 18-45% "falsely" reduced values.