RESUMO
BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.
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Quimiorradioterapia , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Idoso , Humanos , Pessoa de Meia-Idade , Cetuximab/uso terapêutico , Quimiorradioterapia/efeitos adversos , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapiaRESUMO
INTRODUCTION: Fever of unknown origin is by far the most common diagnosis in low-risk febrile neutropenic patients undergoing chemotherapy. The current empirical regimen combines amoxicillin-clavulanic acid and fluoroquinolones in low-risk neutropenic patients. The aim of this study was to assess the appropriateness of antibiotherapy and the outcome of bloodstream infections (BSI) in patients with expected neutropenia of short duration. METHODS: This 2-year monocentric retrospective study included all consecutive neutropenic febrile adult patients with expected duration of neutropenia ≤ 7 days. They were classified into low- and high-risk groups for complications using the MASCC index. Appropriateness of initial empirical antibiotic regimen was assessed for each BSI. Multivariate analysis was performed to identify factors associated with mortality. RESULTS: Over the study period, 189 febrile episodes with positive blood cultures in neutropenic patients were reported, of which 44 occurred during expected duration of neutropenia ≤ 7 days. Patients were classified as high-risk (n = 27) and low-risk (n = 17). Gram-negative bacteria BSI represented 57% of cases, including only two multidrug-resistant bacteria in high-risk patients. Initial empirical antibiotherapy was appropriate in 86% of cases, and inappropriate in the event of coagulase-negative Staphylococcus BSI (14%), although the outcome was always favorable. In low-risk patients, no deaths and only 12% of severe complications were reported, contrasting with mortality and complication rates of 48% (p < 0.001) and 63% in high-risk patients (p < 0.001), respectively. CONCLUSIONS: Outcome of BSI is favorable in low-risk febrile neutropenic patients, even with inappropriate empirical initial antibiotic regimen for coagulase-negative Staphylococcus BSI. Initial in-hospital assessment and close monitoring of these patients are however mandatory.
Assuntos
Antibacterianos/administração & dosagem , Bacteriemia/tratamento farmacológico , Neutropenia Febril/microbiologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Bacteriemia/sangue , Bacteriemia/microbiologia , Neutropenia Febril/sangue , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/tratamento farmacológico , Feminino , Febre/sangue , Febre/microbiologia , Infecções por Bactérias Gram-Negativas/sangue , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/microbiologia , Estudos RetrospectivosRESUMO
BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.
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Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Pirróis/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Metástase Neoplásica , Estudos Retrospectivos , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. PATIENTS AND METHODS: Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). RESULTS: A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). CONCLUSIONS: These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Idoso , Anticorpos Monoclonais/imunologia , Sequência de Bases , Biomarcadores Tumorais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Receptores ErbB/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Análise de Sequência de DNARESUMO
BACKGROUND: Chemotherapy increases the risk of infections, often severe, and some of them are vaccine-preventable infections. We aimed to assess vaccination coverage and associated factors in oncology and hematology patients. METHODS: Consecutive adult patients followed in a French university hospital for hematological malignancy or solid cancer voluntarily completed an anonymous questionnaire in September and October 2016. It included questions on underlying disease, chemotherapy, flu, and pneumococcal vaccination uptakes, and attitudes toward vaccination. Factors associated with vaccination uptake were assessed by multivariate logistic regression. RESULTS: The response rate was 41.9% (N=671) among 1,600 questionnaires distributed; 232 patients had underlying hematological malignancy and 439 had solid cancer. Half of the patients were aged over 65 years. Chemotherapy was ongoing or discontinued for less than one year in 74.7% of patients. In patients aged <65 years undergoing chemotherapy, flu vaccination rate was 19.9% whereas patients aged >65 years had coverage of 47%. Pneumococcal vaccine uptake was 7.3%. However, 64.7% of patients were favorable to vaccination. Vaccine uptake was associated with age >65 years (OR 4.5 [2.9-7.0]), information about vaccination delivered by the family physician (OR 12.9 [5.5-30.1]), follow-up in hematology unit (OR 2.0 [1.3-3.1]), and positive opinion about vaccination (OR 2.0 [1.3-3.1]). CONCLUSION: Despite specific recommendations regarding immunocompromised patients, anti-pneumococcal and flu vaccinations were rarely conducted, even in elderly patients. Targeted information campaigns to family physicians, oncologists, and patients should be implemented to improve vaccine coverage in patients with underlying malignancies.
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Hospedeiro Imunocomprometido , Neoplasias/imunologia , Cobertura Vacinal , Vacinação/estatística & dados numéricos , Adulto , Idoso , Formação de Anticorpos , Atitude Frente a Saúde , Suscetibilidade a Doenças , Feminino , Seguimentos , França , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Hospitais Universitários , Humanos , Programas de Imunização/estatística & dados numéricos , Imunogenicidade da Vacina , Vacinas contra Influenza , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Médicos de Família/psicologia , Vacinas Pneumocócicas , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Vacinação/psicologiaRESUMO
Two studies were carried out to evaluate heat-killed Mycobacterium vaccae SRL172 as an immunotherapeutic agent for patients with metastatic, post-nephrectomy, renal cell carcinoma. In the first study, 60 patients in France and the UK received injections of SRL172, and their survival was compared with that of historical controls who had been treated either with biological response modifiers (IL-2, IFN-alpha) or chemotherapy. In the second study, 36 patients were randomised to receive treatment with IL-2 alone or IL-2 plus SRL172. Survival and adverse events related to the treatments were assessed and compared between treatment groups. The first study showed that those treated with SRL172 alone survived equally as long as those receiving IL-2 or IFN-alpha and both treatment groups survived longer than those on chemotherapy (p<0.001), a result supported by Cox's proportional hazards regression analysis. The second study, stopped early due to drug supply issues, showed that the addition of SRL172 to IL-2 made no difference to survival compared to IL-2 alone, in the limited numbers treated. Adverse events occurring in those receiving SRL172 in the first study were mild and in the second study those receiving IL-2 alone had significantly more adverse events than those receiving SRL172 plus IL-2 (p<0.001). It is concluded that SRL172 may have activity in metastatic renal cancer and has very low toxicity, making it worthy of further study.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Bacterianas/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Renais/terapia , Imunoterapia/métodos , Neoplasias Renais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vacinas Bacterianas/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-2/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
AIM: This study was aimed to determine p73 status in thyroid tumours. METHODS: Differential expression of the TAp73, DeltaTAp73 transcripts was measured in a panel of 60 thyroid malignancies by quantitative RT-PCR. RESULTS: By comparison to normal thyroid tissue surrounding the tumours, we observed significant downregulation of TP73 transcripts in adenomas and in differentiated carcinomas. Correlations were found in normal tissue specimens between the expression of TAp73 and DeltaNp73 transcripts and that of p53, p14ARF p16INK4a, but these correlations were lost in carcinomas (PTC or FTC). CONCLUSIONS: We have found significant variations of TAp73, DeltaNp73, p53, p14ARF p16INK4a, expressions and correlations between the expressions of those different genes in thyroid cancer.
Assuntos
Adenocarcinoma Folicular/química , Adenoma Oxífilo/química , Carcinoma Papilar/química , Proteínas de Ligação a DNA/análise , Proteínas Nucleares/análise , Neoplasias da Glândula Tireoide/química , Proteínas Supressoras de Tumor/análise , Estudos de Casos e Controles , Inibidor p16 de Quinase Dependente de Ciclina/análise , Proteínas de Ligação a DNA/genética , França , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Nucleares/genética , Isoformas de Proteínas , RNA Mensageiro/genética , Transcrição Gênica , Proteína Supressora de Tumor p14ARF/análise , Proteína Supressora de Tumor p53/análise , Proteínas Supressoras de Tumor/genéticaRESUMO
Interleukin (IL) 6 was measured in the serum of 138 patients with metastatic renal carcinoma before the initiation of IL-2 treatment. IL-6 was detectable in 66 patients with renal cancer (48%) and in only 8 of 70 normal adults (11%). Serum C reactive protein (CRP) and IL-6 levels are correlated, suggesting that IL-6 is involved in CRP increase in these patients. The interval between diagnosis of the primary tumor and metastasis was shorter in patients with a detectable serum IL-6 and/or serum CRP level greater than 50 mg/liter. Serum IL-6 and CRP levels were higher in subgroups of patients previously defined as having a poor life expectancy according to the Eastern Cooperative Oncology Group criteria. Pretreatment concentrations of IL-6 and CRP were higher in patients who experienced progressive disease after IL-2 treatment. Patients with detectable IL-6 had a shorter survival from the beginning of IL-2 treatment than patients without circulating IL-6 (median, 8 versus 16 months). Similarly, the median survival from the beginning of IL-2 therapy of patients with CRP levels greater than 50 mg/liter was 6 months, compared to 16 months in those with CRP levels below this threshold. None of the 21 patients with serum IL-6 concentrations greater than 300 pg/ml achieved response to any of the three IL-2 regimens. This subgroup has a median survival of 5 months after IL-2 treatment and consisted of 15% of the patients in our series. These results indicate that serum IL-6 and CRP levels are adverse prognosis factors in patients with metastatic renal cell carcinoma. Serum IL-6 level could help in the selection or stratification of the patients in future IL-2 trials.
Assuntos
Proteína C-Reativa/análise , Carcinoma de Células Renais/sangue , Interleucina-6/sangue , Neoplasias Renais/sangue , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Feminino , Humanos , Interleucina-2/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de SobrevidaRESUMO
PURPOSE: To evaluate the activity and the toxicity of the combination of cisplatin (CDDP)/recombinant interleukin-2 (rIL-2) and interferon alfa-2a (IFN alpha) in disseminated malignant melanoma (DMM). PATIENTS AND METHODS: Between December 1990 and March 1992, 39 patients with biopsy-proven metastatic malignant melanoma (MM), bidimensionally measurable lesions and an Eastern Cooperative Oncology Group (ECOG) performance status < or = 2 entered this protocol. Seventy-nine percent had received previous chemotherapy including platinum complex (15%) and alpha interferon (44%). They received CDDP (100 mg/m2 on day 0) followed by IL-2 18.10(6) IU/m2/d continuous intravenous (IV) infusion from day 3 to day 6 and from day 17 to day 21. The cycle was repeated on day 28. Subcutaneous IFN alpha 9.10(6) IU three times weekly was administered throughout the treatment period. From day 66 or 94, patients were administered a maintenance cycle with CDDP 100 mg/m2, subcutaneous IL-2 5.10(6) IU/m2/d from day 15 to day 19 and from day 22 to day 26 and IFN alpha 9.10(6) IU three times weekly repeated every 5 weeks (maximum four cycles). RESULTS: Among 39 assessable patients, five patients achieved complete responses (CRs). Sixteen patients had partial responses (PRs). The overall objective response rate was 53.8%. The number of metastatic sites was the only response-predictive factor. Toxicity was manageable in a routine patient setting and there was no life-threatening toxicity. CONCLUSION: These results seem to indicate a possible synergy between CDDP/rIL-2 and IFN alpha in MM.
Assuntos
Cisplatino/uso terapêutico , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Melanoma/terapia , Adulto , Idoso , Terapia Combinada/efeitos adversos , Feminino , Humanos , Imunoterapia/métodos , Interferon alfa-2 , Masculino , Melanoma/tratamento farmacológico , Melanoma/secundário , Pessoa de Meia-Idade , Proteínas Recombinantes , Indução de Remissão , Resultado do TratamentoRESUMO
PURPOSE: For patients with Hodgkin's disease (HD) who do not achieve complete response (CR), who experience a relapse within the first year of CR, and for those who have two or more relapses, the outcome is poor. Salvage chemotherapy regimens at conventional doses produce a CR rate that ranges from 10% to 50% and a 5-year disease-free survival (DFS) between 10% and 25%. On the other hand, high-dose chemotherapy regimens given in combination with bone marrow transplantation (BMT) produce a CR rate that ranges from 40% to 80% and a 3-year DFS of approximately 40%. We report the 5-year results of a prospective study in patients with refractory HD who were treated with three courses of intensive chemotherapy without BMT. PATIENTS AND METHODS: Thirty-nine adult patients with refractory HD were treated with three courses of intensive chemotherapy. Each cycle of chemotherapy comprised vindesine 1 mg/m2/d in continuous intravenous (IV) infusion from day 1 to day 5; Adriamycin (doxorubicin; Roger Bellon Laboratories, Neuilly, France) 40 mg/m2/d in continuous IV infusion from day 1 to day 3; carmustine 140 mg/m2/d at day 3; etoposide 200 mg/m2/d from day 3 to day 5; and methylprednisolone 120 mg/m2/d from day 1 to day 5. After the third cycle of chemotherapy, irradiation (20 Gy) was performed whenever possible and depended on previous irradiation. RESULTS: At the end of the treatment, 31 patients (79%) were in CR. Among these patients, 10 relapsed after a median time of 3 months. The overall 5-year survival rate was 46%. The freedom from progression (FFP) and the freedom from treatment failure (FFTF) rates were 48% and 43%, respectively. The main toxicities were hematologic (neutropenia and thrombocytopenia) and digestive. Four patients died due to treatment-related complications (two from septic shocks, one from respiratory insufficiency, and one from posttransfusional AIDS). CONCLUSION: The results of this study seem to be comparable to those results obtained with high-dose chemotherapies with autologous BMT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Feminino , Doença de Hodgkin/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Terapia de Salvação , Análise de SobrevidaRESUMO
PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Assistência Ambulatorial , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , França , Humanos , Interferon-alfa/administração & dosagem , Interleucina-2/administração & dosagem , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Análise de Sobrevida , Falha de TratamentoRESUMO
OBJECTIVE: To delineate the interaction between in vivo HIV replication and host antiviral immunity during disease progression in order to elucidate the pathogenesis of AIDS. DESIGN: In a cohort of HIV-seropositive patients, the serum concentration of viral particles, the blood concentration of mononuclear cells harbouring infectious virus and the serum titre of isolate-specific neutralizing antibodies were correlated with the rates of CD4+ T-cell depletion and disease progression. METHODS: Using a quantitative reverse-transcriptase linked polymerase chain reaction assay, the concentration of viral particles was measured in blood samples from 103 initially symptom-free subjects who were followed up for > or = 24 months. The concentration of infectious virus and the neutralizing antibodies to autologous HIV isolates were assessed in 37 out of the 103 subjects. The rate of decrease in CD4 cells over the 24 months was calculated for each subject. RESULTS: Rapidly progressing patients (rate of decrease in CD4 cells > or = 60%) had a high concentration of viral particles and a high concentration of infectious virus associated with an undetectable serum titre of isolate-specific neutralizing antibodies. Stable patients (rate of decrease in CD4 cells < 30%) had a low concentration of infectious virus and either a low concentration of viral particles with the absence of isolate-specific neutralizing antibodies or a high concentration of viral particles with the presence of isolate-specific neutralizing antibodies. Slowly progressing patients (rate of decrease in CD4 cells > or = 30 and < 60%) showed an intermediate profile. CONCLUSIONS: Progression to AIDS is associated with a shift in the balance between viral replication and host immunity that increases the concentration of infected cells and destroys the CD4+ T-lymphocyte population.
Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Síndrome da Imunodeficiência Adquirida/etiologia , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/microbiologia , Linfócitos T CD4-Positivos/imunologia , Anticorpos Anti-HIV/sangue , Infecções por HIV/etiologia , Infecções por HIV/microbiologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Cinética , Contagem de Leucócitos , Testes de Neutralização , Reação em Cadeia da Polimerase , Viremia/sangue , Viremia/imunologia , Viremia/microbiologia , Replicação ViralRESUMO
Recombinant interleukin-2 (rIL-2) has been reported to be active in metastatic renal cell carcinoma and malignant melanoma. The purpose of this trial was to determine the efficacy and toxicity of rIL-2 administered in continuous infusion in patients with Hodgkin's disease (HD) and non-Hodgkin lymphoma (NHL). 21 patients with HD (4 patients), diffuse large-cell NHL (7) or low-grade NHL (10) in failure or relapse after multiple-conventional treatments were included in this trial. rIL-2 therapy consisted of an induction period of two cycles separated by 3 weeks of rest, and, in the absence of progressive disease or undue toxicity, a maintenance period of 4 monthly cycles. Each induction cycle comprised the continuous infusion of rIL-2: 18 x 10(6) IU/m2 per day on days 1-5 and days 12-16. Each maintenance cycle comprised the continuous infusion of rIL-2: 18 x 10(6) IU/m2 per day on days 1-5. Among the 21 treated patients, 5 (all of those with low-grade NHL) responded to the induction phase (1 complete response, 4 partial responses) and 2 patients had a mixed response. Conversely, no response was observed in patients with HD or large-cell NHL. The median duration of response was 4 months. rIL-2 administered as a continuous infusion was well tolerated and most patients received the full dosage, and management did not require intensive care. During the induction period, 2 patients experienced grade III cardiovascular or renal toxicity. During the maintenance period, rIL-2 had to be interrupted in 1 patient because of a myocardial infarction. This trial confirms the inefficacy of rIL-2 for the treatment of large-cell NHL and HD. Conversely, in low-grade NHL, rIL-2 activity needs to be explored by further studies. rIL-2 may have a place in the early phase of the disease, when the immune system is not compromised, as an adjuvant treatment in residual disease in order to improve the duration of response.
Assuntos
Doença de Hodgkin/tratamento farmacológico , Interleucina-2/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Recombinantes/uso terapêutico , Fatores de TempoRESUMO
Optimistic results were obtained in the treatment of 39 patients with surgically incurable metastatic malignant melanoma using a regimen including 2 to 3 monthly induction cycles of cis-diamminedichloroplatinum (CDDP), recombinant interleukin-2 (rIL-2) and interferon alpha-2a (IFN alpha-2a). 33 of 39 patients were pretreated with chemotherapy (dacarbazine and/or fotemustine:31, CDDP:6) and 17 of 39 with IFN alpha-2a. Overall response rate was 54% with 13% achieving a complete response for up to 59+ weeks. Moderate to severe side-effects were reversible on rIL-2 cessation and toxicity was manageable in a routine inpatient setting. These results are especially encouraging as they were seen in previously treated patients, classically low responders, including 3 who were resistant to cisplatin or other platinum complexes. The question remains if this regimen bypasses traditional mechanisms of drug resistance.
Assuntos
Cisplatino/uso terapêutico , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Melanoma/secundário , Melanoma/terapia , Adulto , Idoso , Feminino , Humanos , Interferon alfa-2 , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêuticoRESUMO
This prospective phase II study was undertaken to evaluate the efficacy and toxicity of early intensive therapy followed by purged autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma with high tumor burden. All patients received the VCAP regimen (vindesine, cyclophosphamide, doxorubicin and prednisone) as conventional chemotherapy and DHAP as second-line therapy. Twenty-nine consecutive patients were included in the study. Twenty-seven patients were grafted, seven in first complete remission (CR) and 20 in first partial remission (PR). Preparative therapy consisted of cyclophosphamide and total body irradiation (TBI) in all the patients. With a median follow-up of 6 years, the actuarial overall survival is 64% and the actuarial event-free survival is 55%. Two treatment-related early deaths were observed. Eleven patients were informative for serial PCR analysis of minimal residual disease after ABMT: two relapsed, four remained disease-free with PCR positivity and five were disease-free with PCR negativity. These encouraging results lay the basis of future prospective randomized trials comparing autologous stem cell transplantation as front-line treatment with conventional chemotherapy for patients with bad prognostic factors.
Assuntos
Purging da Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Linfoma Folicular/terapia , Linfoma não Hodgkin/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Genes de Imunoglobulinas , Genes bcl-2 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Doenças Pulmonares Intersticiais/etiologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/genética , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Neutropenia/etiologia , Reação em Cadeia da Polimerase , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Recidiva , Indução de Remissão , Sepse/etiologia , Análise de Sobrevida , Trombocitopenia/etiologia , Translocação Genética , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Clinical and pathological characteristics as well as outcome of 45 Hodgkin's disease (HD) cases collected by the French registry of HIV-associated tumors between January 1987 and December 1989 (all clinically staged according to the Ann Arbor system) were analyzed and compared with those of a cohort of 407 patients with clinical stages (CS) IA to IVB enrolled between September 1981 and August 1988 in a multicentric clinical trial. The route of HIV infection, initial CD4 cell count at the time of HD diagnosis and CDC class of HIV infection were studied as well as the progression to AIDS onset were recorded. HIV-HD is characterized by a predominance of advanced CS (75%), B symptoms (80%) and mixed cellularity histology (49%), as well as by early bone marrow involvement (24%); a specific feature is the rare occurrence of mediastinal involvement (13% in HIV-HD versus 71% in primary HD). With standard therapies, 79% of the patients achieved a complete remission, but hematological and infectious complications were very frequent. The proportion of intravenous drug abusers (IVDA) in HIV-HD (38%) is higher than in French HIV-infected population as a whole (20.8%). Median CD4 cell count was 306/microliters at the time of HD diagnosis, while only 5 cases (11%) were preceded by an AIDS manifestation; progression to AIDS rate was 94% at 2 years. Overall 2-year survival was 41%, with 71% for patients with an initial CD4 cell count over 300/microliters and 0% for those with CD4 cell count lower than 300/microliters (p < 0.01); opportunistic infections were the most frequent cause of death. HIV-HD seems to occur preferentially in.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Doença de Hodgkin , Linfoma Relacionado a AIDS , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Contagem de Linfócito CD4 , Estudos de Coortes , Terapia Combinada , Comorbidade , Dacarbazina/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Feminino , França/epidemiologia , Infecções por HIV/epidemiologia , Infecções por Herpesviridae/epidemiologia , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Doença de Hodgkin/virologia , Homossexualidade Masculina , Humanos , Tábuas de Vida , Linfoma Relacionado a AIDS/mortalidade , Linfoma Relacionado a AIDS/patologia , Linfoma Relacionado a AIDS/terapia , Linfoma Relacionado a AIDS/virologia , Masculino , Mecloretamina/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Teleterapia por Radioisótopo , Sistema de Registros , Indução de Remissão , Fatores de Risco , Abuso de Substâncias por Via Intravenosa/epidemiologia , Análise de Sobrevida , Infecções Tumorais por Vírus/epidemiologia , Vimblastina , Vincristina/administração & dosagemRESUMO
Isolated acquired factor VII (FVII) deficiency (0.15 U/ml) was identified in a 30-year-old man with pleural liposarcoma. The patient underwent surgery with continuous FVII concentrate infusion. No anti-FVII antibody or FVII/anti-FVII complex was detected. However, the short half-life and low recovery of FVII after concentrate infusion suggested the presence of an antibody. Whatever the mechanism, this FVII deficiency was related to the presence of the liposarcoma. FVII level normalized during tumour regression and fell again when the liposarcoma relapsed.
Assuntos
Deficiência do Fator VII/etiologia , Lipossarcoma/complicações , Neoplasias Pleurais/complicações , Adulto , Autoanticorpos/sangue , Fator VII/imunologia , Fator VII/metabolismo , Fator VII/uso terapêutico , Humanos , Imunoglobulina G/sangue , MasculinoRESUMO
We report the results of a chemotherapy regimen combining oxaliplatin, 5-fluorouracil, and folinic acid in patients with metastatic renal cell carcinoma. The objective of this pilot study was to define the potential efficacy of this second-line combination in patients previously treated with interleukin-2 alone or in combination with interferon alpha. Fourteen patients with metastatic renal cell carcinoma in failure after immunotherapy were included in this trial. During treatment, patients received six chemotherapy courses (Folfox regimen) administered every 2 weeks. Each cycle combined oxaliplatin day (D) D1 and folinic acid plus 5-fluorouracil D1 and D2. At completion of treatment, no objective response was observed and two patients presented stable disease. This chemotherapy schedule in patients with metastatic renal cell carcinoma previously treated with immunotherapy does not seem to be effective.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Idoso , Carcinoma/secundário , Feminino , Fluoruracila/administração & dosagem , Humanos , Imunoterapia , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias Renais/secundário , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos , Projetos Piloto , PrognósticoRESUMO
The data of the 27 asymptomatic HIV-1 seropositive patients with CD4+ cell count between 300 and 600/microliters treated by Cyclosporin A (CSA) (7.5 mg/kg/day) in our institution between October 1985 and 1987 were reviewed in October 1993. Hemoglobin concentration, platelet count, total lymphocytes, CD4+ and CD8+ cell counts and serum core protein p24 antigenemia, as well as creatininemia measured before CSA onset, at CSA cessation and twice a year were recorded as well as clinical signs and CSA toxicities. In October 1993 median duration of CSA treatment was 11 months, median follow-up after CSA cessation was 45 months and median total follow-up was 67 months. Toxicities of CSA were those commonly encountered in other pathologies. Under CSA no patient progressed toward clinical AIDS (1987 definition). The mean CD4+ cell count of the 27 patients remained unchanged (gain of 1 cell/year) under CSA treatment, while it decreased at a rate of 50 cells/year after CSA cessation (p < 0,005). On the other hand CSA treatment had no significant impact on the evolution of total lymphocyte count, CD8+ cell counts, and P24 antigenémia.
Assuntos
Ciclosporina/uso terapêutico , Soropositividade para HIV/tratamento farmacológico , Imunossupressores/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , Ciclosporina/efeitos adversos , Feminino , Seguimentos , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-IdadeRESUMO
Eighty-one patients with disseminated non-small cell lung cancer (stage IV) were treated with 2 monthly cycles of initial chemotherapy combining cisplatin with vindesine. The initial chemotherapy-responding patients (CR, PR, MR) were randomized to 2 cycles or 4 cycles of maintenance chemotherapy. After initial chemotherapy, the response rate was 33% (CR, PR, MR) with 18.5% objective responses. The overall 1-year survival rate was 15% with 37% for responders as opposed to 2% for non-responders. Maintenance chemotherapy did not improve the response rate obtained after initial cycles. The small number of patients does not allow us to reach a definite conclusion on the optimum duration of maintenance chemotherapy. In the absence of large placebo versus chemotherapy randomized trials, no definite conclusion can be made on the benefit of chemotherapy in disseminated non-small cell lung cancer. This study suggests, however, that chemotherapy is associated with a significantly longer survival in responding patients.