RESUMEN
BACKGROUND: The AIO KRK-0104 randomised phase II trial investigated the efficacy and safety of two capecitabine-based regimens: combination of capecitabine and irinotecan (CAPIRI) plus cetuximab (CAPIRI-C) and combination of capecitabine with oxaliplatin (CAPOX) plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment-related skin toxicity (ST) was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed ST (Cape-ST) and parameters of treatment efficacy. METHODS: Patients with mCRC were randomised to cetuximab (400 mg m(-2), day 1, followed by 250 mg m(-2) weekly) plus CAPIRI (irinotecan 200 mg m(-2), day 1; capecitabine 800 mg m(-2), twice daily, days 1-14, every 3 weeks), or cetuximab plus CAPOX (oxaliplatin 130 mg m(-2), day 1; capecitabine 1000 mg m(-2), twice daily, days 1-14, every 3 weeks). RESULTS: Of 185 recruited patients, 149 (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumour assessment and were evaluable for efficacy. Capecitabine-attributed ST, predominantly hand-foot syndrome, was observed in 32.2% of patients. Capecitabine-attributed ST grade 1-3 was associated with a significantly higher disease control rate (DCR) (97.9 vs 86.1%, P=0.038) compared with grade 0 toxicity. Moreover, Cape-ST grade 1-3 related to a markedly longer progression-free survival (PFS) (9.9 vs 5.6 months, P<0.001) and overall survival (OS) (32.8 vs 22.4 months, P=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for both arms, whereas the effect on OS remained apparent as a strong trend. CONCLUSION: This analysis supports the hypothesis that for the evaluated regimens, a correlation exists between Cape-ST and treatment efficacy regarding DCR, PFS, and OS.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Enfermedades de la Piel/inducido químicamente , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Capecitabina , Carcinoma/diagnóstico , Carcinoma/patología , Cetuximab , Ensayos Clínicos como Asunto/métodos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Alemania , Humanos , Incidencia , Irinotecán , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Enfermedades de la Piel/epidemiología , Resultado del TratamientoRESUMEN
The use of erythropoiesis-stimulating agents (ESA) in cancer patients is still under debate. However, little is known about rationales, strategies, objectives, and effectiveness of anaemia treatments in common practice. The Cancer Anaemia Registry prospectively surveyed about 2000 cancer patients with anaemia throughout Germany. The main objectives of anaemia treatment regardless of modality were to improve quality of life (QOL) and to correct haemoglobin (Hb) levels. The Hb threshold for any anaemia treatment (means ± SD: 9.4 ± 1.2 g/dL) but not for blood transfusions (8.7 ± 1.0 g/dL) depended on cancer type and treatment strategy. Physicians preferred ESA as first-line treatment to prevent transfusions in patients with solid tumours, if they thought that chemotherapy caused the anaemia. If they suspected other causes or patients had lymphoproliferative malignancies, physicians preferred transfusions or attempted to correct underlying disorders; both mainly to improve QOL or prognosis. Effectiveness of all strategies was comparable. However, ESA most effectively prevented transfusions; primary transfusions appeared less suitable for correcting Hb or improving QOL. Using supportive treatments for QOL improvement was common whereas diagnostic measures and intravenous iron therapy were underused. Prospective clinical trials using QOL as end point and evaluating diagnostics in cancer-associated anaemia are warranted.
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Anemia/terapia , Hematínicos/uso terapéutico , Neoplasias/complicaciones , Anciano , Anemia/etiología , Transfusión Sanguínea , Femenino , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/terapia , Estudios Prospectivos , Sistema de RegistrosRESUMEN
OBJECTIVE: Given the safety concerns regarding off-label use of erythropoiesis-stimulating agents (ESAs) in the treatment of cancer-associated anemia, data from the German Cancer Anemia Registry (CAR) were analyzed to examine whether current practice in Germany adheres to treatment guidelines. RESEARCH DESIGN AND METHODS: CAR was a web-based registry gathering patient data for 12 weeks following anemia diagnosis or until the primary treatment objective was achieved. RESULTS: Of over 2000 patients surveyed, 783 were treated with ESAs. Treatment was primarily aimed at improvement of quality of life (37.3%), hemoglobin correction (32.7%), and prevention of transfusions (24.4%). The average hemoglobin level triggering ESA treatment was 9.7 g/dL (6.0 mmol/L), however, starting levels varied with cancer type. For 67.8% of patients, transfusions could be avoided. ESA treatment was stopped at 11.2 g/dL (7.0 mmol/L) and maximum hemoglobin levels during the study averaged 11.8 g/dL (7.3 mmol/L). In 4.8% of the women and 6.0% of the men, maximum hemoglobin levels were >14 g/dL (8.7 mmol/L); in 15.6% and 9.1%, respectively, levels were between 13 and 14 g/dL. The median hemoglobin level triggering transfusion was 8.3 g/dL (5.2 mmol/L), irrespective of the malignant disease. CONCLUSION: Current use of ESAs for the treatment of cancer-associated anemia in Germany appears to be in good compliance with treatment guidelines. Similar results obtained from other studies in Europe and the US indicate this to be true beyond Germany.
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Anemia/diagnóstico , Anemia/tratamiento farmacológico , Adhesión a Directriz , Hematínicos/uso terapéutico , Internet , Sistema de Registros , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/sangre , Anemia/etiología , Femenino , Alemania , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/terapia , Práctica Profesional , Estudios ProspectivosRESUMEN
BACKGROUND AND OBJECTIVE: 5-hydroxytryptamine 3 (5-HT3) receptor antagonists have proved to be highly efficacious in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). However, several questions remain concerning the relative efficacy of various approved anti-emetics, especially with respect to dosage, duration and timing of administration, as well as differences in toxicity profiles. Thus it seemed appropriate to assess the current therapeutic results in routine daily practice, when applying antiemetic therapy according to established guidelines. PATIENTS AND METHODS: Within LINO e.V., a group of medical oncologists in private ambulant practice (LINO: Association of private-practice medical oncologists in Bavaria), a total of 738 cycles of moderately or highly emesis-inducing chemotherapy were randomly assigned to three treatment options: (1)granisetron 1 mg (GRA1). (2) 3 mg (GRA3), and (3) ondansetron 8 mg (OND8), each combined with 8 mg dexamethasone. Incidence and severity of acute (day 1) and delayed CINV (day 2-5) and the subjective assessment of efficacy were documented on questionnaires filled in by the patients. RESULTS: All of the three regimens adequately prevented vomiting in the majority of the patients. However, all measured effects showed an uniform trend towards slightly decreased efficacy with 8 mg of ondansetron. These differences were predominantly detected with respect to delayed CINV on days 2 to 5, especially after chemotherapy with anthracyclin/cyclophosphamide combination therapy. CONCLUSION: Granisetron, at two different dosage regimens, and ondasetron showed adequate reduction in chemotherapy-induced nausea and vomiting, but ondansetron worked slightly less so.
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Antineoplásicos/efectos adversos , Náusea/inducido químicamente , Neoplasias/tratamiento farmacológico , Antagonistas del Receptor de Serotonina 5-HT3 , Vómitos/inducido químicamente , Humanos , Náusea/prevención & control , Vómitos/prevención & controlRESUMEN
HISTORY AND CLINICAL PRESENTATION: A severely ill 84-year old patient, known to suffer from a chronic congestive heart failure, was admitted to the emergency room because of increasing dyspnea. His blood pressure was stable (125/80), his heart rate normal (66/min), the respiratory rate, however, was elevated at 35/min and he exhibited substantial peripheral edema. There were no signs indicating an infectious process. EXAMINATIONS: Blood gas analysis yielded a marked, respiratorically compensated metabolic acidosis with a base excess of -8.6. The chest roentgenography showed a markedly dilated heart without pulmonary-vascular congestion or infiltrates. The serum lactate was substantially increased at 11.4 mmol/l (0.6-2.44). TREATMENT AND COURSE: A cardiovascular beriberi syndrome was suspected and 100 mg of thiamine administered i.v. Within hours the clinical picture improved significantly. Two hours after administration of thiamine serum lactate concentration was 5.7 mmol/l, about 12 hours later the patient suffered no longer from dyspnea and the lactate was at a normal level. CONCLUSION: Thiamine deficiency as a cause for an elevated serum lactate or lactate acidosis with or without cardiovascular failure may not be overlooked. Without adequate treatment it may end lethally, although it can be treated easily, effectively and without side effects. The potential frequency of thiamine deficiency among the normal population even in our society may be under-estimated due to the particular properties of this vitamin.
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Acidosis Láctica/etiología , Diuréticos/administración & dosificación , Furosemida/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Deficiencia de Tiamina/complicaciones , Acidosis Láctica/diagnóstico , Anciano , Anciano de 80 o más Años , Disnea/etiología , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Humanos , Lactatos/sangre , Masculino , Tiamina/administración & dosificación , Tiamina/uso terapéutico , Deficiencia de Tiamina/tratamiento farmacológico , Deficiencia de Tiamina/etiologíaRESUMEN
We examined the bone marrow of 109 patients with myelodysplastic syndrome (MDS) at the time of diagnosis and during the course of the disease by means of Southern blot analysis and/or cytogenetic studies to detect and evaluate clonal markers, their implications for the prognosis of the disease, and the response to treatment. The patients either were enrolled in an EORTC study and received low-dose Ara-C with (n=31) or without (n=21) growth factors, according to the study protocol, or were treated supportively (only one patient received regular chemotherapy for concomitant lymphoma). Full or at least partial remission was achieved by 34% of the treated patients (n=54). In 57% (53 of 93) of all patients a clonal marker of either kind was detected by Southern blot analysis and/or cytogenetic examination. Clonal chromosomal aberrations were found in 45% (35 of 77) of the cases examined at diagnosis, with solitary del(5q) aberrations occurring in 10% of the cases and complex aberrations in 18%, trisomy 8 or monosomy 7 being a frequent finding. Of all patients, 49% (28 of 57) were characterized by one or more gene rearrangements (e.g., Ig-JH, TcR-beta, M-bcr, GM-CSF, G-CSF, or IL-3) at diagnosis. In five of 21 cases (24%) studied in hematological remission of the disease chromosomal aberrations were still detectable, and in seven of 23 (30%) a gene rearrangement persisted. We also found six cases with multiple clones exhibiting different susceptibilities to treatment and thereby indicating the oligoclonal character of this disease. Clinical evaluation revealed that the prognosis of the respective patients was directly related to the particular clonal markers detected at diagnosis: Risk groups were subdivided according to the karyotypes, with a solitary del(5q) aberration meaning a favorable, a normal karyotype an intermediate, solitary aberrations without del(5q) a poor, and complex karyotypes a very poor prognosis. We showed that densitometry helps to increase the sensitivity of Southern blot analysis by quantifying the amount of altered DNA, which often increases shortly before or at progression of MDS. Overall, there was a high level of concordance of both clonality examinations with the clinical course of the disease and the response rate. Therefore, we recommend cytogenetic studies and Southern blot analysis to detect clonal markers at diagnosis of MDS, to detect oligoclonality and clonal evolution, or to quantify the amount of clonal DNA, which appears to be a sensitive tool for evaluating the prognosis and response to therapy in MDS.
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Síndromes Mielodisplásicos/genética , Anciano , Southern Blotting , Aberraciones Cromosómicas , Células Clonales , Citogenética , Femenino , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Pronóstico , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
We have assessed the value of p210 protein detection in peripheral blood cells for follow-up of chronic myelogenous leukaemia (CML) patients. Quantification was achieved by comparing the relative intensities of the p210 bands with those of the normal abl protein (p145). Serial dilution of Ph-positive K562 cells with Ph-negative HL60 or KG1 cells revealed a linear correlation between the p210/p145 ratio and the number of Ph-positive cells (r = 0.998; p < 0.001) with a sensitivity of detecting less than 1% Ph-positive cells in 5 x 10(6) cells. Ninety-six consecutive patients were enrolled in the study and a total of 155 Western blot analyses have been performed and compared to chromosomal analyses of bone marrow. Parallel RT-PCR analyses have been performed on 99 occasions. All patients with positive cytogenetic findings also probed positive for p210. In 23 instances p210 was detectable despite negative chromosomal analysis. In 16 samples these results were confirmed by RT-PCR. In patients with partial cytogenetic remission (n = 26) the results of the p210 assay correlated significantly with the percentage of Ph-positive metaphases (r = 0.69; p < 0.001). In conclusion, monitoring of CML patients by quantification of the bcr-abl protein is a feasible and sensitive alternative to chromosomal analysis of bone marrow.
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Proteínas de Fusión bcr-abl/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucocitos Mononucleares/química , Western Blotting , Estudios de Seguimiento , Células HL-60/química , Humanos , Células K562/química , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Neoplasia Residual , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
A constitutional de-novo deletion of the long arm of the Y chromosome was detected by standard cytogenetic analysis in a 38-year old male who, except for small testes and cryptozoospermia, was phenotypically normal. The deletion was further characterized by fluorescent in-situ hybridization (FISH) and digital image analysis using contigs of overlapping yeast artificial chromosome (YAC) clones, spanning almost the entire Y chromosome. These results showed that the deletion involved a large interstitial segment on the proximal long arm of the Y chromosome (Yq11.1-->Yq11.22) as well as a more distal portion of the Y chromosome, including the entire heterochromatic region (Yq11.23-->qter). The breakpoints as determined by the YAC probes were defined within the published Vergnaud intervals so that region 6B and 6C was mostly retained. However, the AZFc region harbouring the DAZ locus on distal subinterval 6F was lost in the deletion, making the absence of this region the most probable location for the patient's infertility. The data underline the usefulness of FISH as an alternative technique to conventional banding for the refined detection of chromosome Y deletions/rearrangements.
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Deleción Cromosómica , Infertilidad Masculina/genética , Cromosoma Y/genética , Adulto , Humanos , Hibridación Fluorescente in Situ , Infertilidad Masculina/patología , Cariotipificación , Masculino , Espermatozoides/patologíaRESUMEN
We report the case of a 49-year-old woman who presented with a monoclonally IgG kappa expressing myeloma since October 1989. Four years later, after 24 cycles of Melphalan-containing chemotherapy, bone marrow (BM) cells of the patient cytologically revealed myelodysplastic changes for the first time. Cytogenetic examination of the BM obtained in January 1994 showed two clonally aberrant main lines. Each of them represented one of the hematological neoplastic diseases. The quantitatively major clone (MDS-clone) showed a deletion of the long arm of chromosome 7, typical for secondary myeloid disorders. The other clone (myeloma (MM) clone) was characterized by a reciprocal translocation between the short arm of chromosome 8, band q24, a region known to contain the c-myc gene, and the long arm of chromosome 2, band p12, where the Ig kappa gene is located. An unusual finding, however, was that an abnormality of the long arm of chromosome 16 could be detected in both obviously unrelated clones. In the further course of the disease, the MDS and MM clones could be detected, both of them showing cytogenetically a clonal evolution characterized by additional clonal abnormalities. Our data stress the significance of cytogenetics in detecting typical clonal abnormalities in different malignant hematological disorders and in detecting "clonal evolution" as an indicator of the progress of the disease. Moreover, our data suggest that MM and MDS may arise from a common stem cell, which may be characterized by a clonal cytogenetic abnormality.
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Aberraciones Cromosómicas , Mieloma Múltiple/genética , Síndromes Mielodisplásicos/genética , Femenino , Humanos , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Síndromes Mielodisplásicos/etiologíaRESUMEN
We examined the bone marrow of 45 patients with MDS at the time of diagnosis and in the course of the disease by means of Southern blot analysis and cytogenetic studies to detect and evaluate clonal markers and their implication on the prognosis of the disease and the response to treatment. All patients were enrolled in an EORTC study and received low-dose Ara-C with or without growth factors according to the study protocol. Thirty patients (67%) were characterized by different clonal markers, such as various gene rearrangements (eg Ig-JH, tcR-beta, bcr, GM-CSF, G-CSF or IL-3) and/or chromosomal markers at the time of diagnosis or early in the course of the disease. In 23 of 30 cases that could be studied in the course of the disease, a statement about the clonal situation was possible: in three cases (8%) the clonal situation did not change, in nine cases (39%) at least a transient reduction of clonal cells could be demonstrated, suggesting partial or complete response to therapy. In eight cases (35%) a change for the worse could be seen. In four cases (17%) involvement of multiple clones could be demonstrated with the clones exhibiting different susceptibilities to treatment. Clinical evaluation showed that patients without clonal markers at diagnosis had a better prognosis as compared to patients who presented with clonal markers. We suggest that clonality analysis at diagnosis and in the course of the disease will be a useful tool to study the biology and response to treatment in MDS.
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Aberraciones Cromosómicas , Reordenamiento Génico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Southern Blotting , Citarabina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Marcadores Genéticos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Probabilidad , Pronóstico , Proteínas Recombinantes/uso terapéutico , Tasa de Supervivencia , Factores de TiempoRESUMEN
Patients with chronic myeloid leukemia (CML) show the Philadelphia (Ph) translocation in more than 95% of the cases. The remaining cases, without the cytogenetic or molecular equivalent of the BCR-ABL rearrangement, are "Philadelphia negative" and may have alternate chromosomal aberrations. Ph negative CML patients are known to have a poor prognosis. We report on a young patient with a hypereosinophilic syndrome in the presence of a clonal translocation t(4;7) with a peripheral leukocytosis, a severe thrombocytopenia, and anemia at first presentation, who developed bone marrow changes typical of CML. Bone marrow function and hypereosinophilia improved only partially and temporarily under therapy. The patient died 10 months after diagnosis of diffuse leukemic embolism and organ infiltration resulting in paraplegia. The case demonstrates that beside "idiopathic" hypereosinophilic syndromes (HES), a proportion of such patients suffer from eosinophilic leukemias. In these cases, karyotype analysis may help to distinguish these states by the identification of clonal chromosomal abnormalities. A karyotype anomaly hitherto not reported can be added to the list of aberrations in hypereosinophilic states associated with myeloproliferative processes.
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Aberraciones Cromosómicas/patología , Síndrome Hipereosinofílico/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adulto , Bandeo Cromosómico , Trastornos de los Cromosomas , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 7 , Humanos , Síndrome Hipereosinofílico/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Masculino , Translocación GenéticaRESUMEN
Langerhans cells (LC) of the skin represent bone marrow-derived dendritic antigen-presenting cells and are therefore important in pathophysiological processes such as rejection, graft-versus-host disease, and graft-versus-leukemia-reaction after bone marrow transplantation (BMT). For understanding of these diseases, the evaluation of the chimeric status of LC following BMT is of great interest. To analyze the sex chromosome constitution of LC in the skin, we established a modified and refined technique of combined immunophenotyping and fluorescence in situ hybridization (FISH) and investigated frozen sections of skin biopsies from nine patients after allogeneic sex-mismatched BMT and of two healthy donors for control. LC were specifically labeled using a fluorescent CD1 a antibody and hybridized simultaneously with X and Y chromosome-specific DNA probes. The results of this practical application on nine leukemia patients show the appearance of donor-type LC and the persistence of host-type LC at various times (36 up to 1395 days) after sex-mismatched BMT. Complete chimerism of LC could not be detected in any case. The frequency of recipient-specific LC ranged from 7% to 92% and showed no correlation with time postgrafting. We conclude from our results of 1461 analyzed LC that combined immunophenotyping and interphase cytogenetic analysis by FISH is the method of choice for the assessment of chimerism in a particular cell type after sex-mismatched BMT. Its practical application on other tissues affected by BMT-related pathophysiological processes reveals further knowledge of the time-dependent course of chimeric patterns after BMT.
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Trasplante de Médula Ósea , Quimera , Sondas de ADN/metabolismo , Células de Langerhans/química , Cromosomas Sexuales , Enfermedad Aguda , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide/terapia , Masculino , Síndromes Mielodisplásicos/terapia , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMEN
Chronic graft-versus-host disease after bone marrow transplantation presents, in a few cases, as mild to severe scleroderma-like changes. Patients with chronic graft-versus-host disease with and without sclerodermatous skin changes were analysed for antinuclear autoantibodies (ANA) and antinucleolar autoantibodies (ANoA) and the results correlated with disease symptoms and histocompatibility locus antigen (HLA) pattern. Nineteen patients with chronic graft-versus-host disease and scleroderma-like skin changes, 18 with chronic graft-versus-host disease without scleroderma, and 17 controls on immunosuppressive treatment were screened for ANA and ANoA using enzyme-linked immunosorbent assay, immunodiffusion and immunoblot techniques. Four patients with severe scleroderma had antibodies to topoisomerase I, two had antibodies against PM-Scl, both characteristic serological findings in idiopathic systemic scleroderma. One patient had La/SSB antibodies and, in three cases, antibodies to the nucleolar antigen C23 (nucleolin) could be identified. A possible correlation between antinucleolin antibodies and disease activity was observed. HLA-A1, -B1, and -B2 were found significantly more often in patients with scleroderma-like symptoms in comparison to patients without scleroderma-like symptoms. Chronic graft-versus-host disease with scleroderma-like manifestations can be associated with the occurrence of ANA specific for idiopathic scleroderma. The development of scleroderma after bone marrow transplantation might have a HLA-linked genetic background.
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Anticuerpos Antinucleares/sangre , Enfermedad Injerto contra Huésped/inmunología , Antígenos de Histocompatibilidad Clase I/sangre , Proteínas de Unión al ARN , Esclerodermia Localizada/inmunología , Anticuerpos Antinucleares/inmunología , Especificidad de Anticuerpos , Western Blotting , Trasplante de Médula Ósea , Enfermedad Crónica , Electroforesis en Gel de Poliacrilamida , Humanos , Proteínas Nucleares/inmunología , Fosfoproteínas/inmunología , Factores de Tiempo , NucleolinaRESUMEN
Chronic myelogenous leukemia is a clonal proliferative disorder of pluripotent hematopoietic stem cells. Cure may be achieved by myeloablative conditioning treatment and marrow transplantation. In addition, allogeneic marrow can exert a graft-versus-leukemia effect. The graft-versus-leukemia effect may be directed against leukemia-specific antigens or against antigens on all hematopoietic cells, or it can be part of a graft-versus-host reaction. We report an informative post-transplant course of a patient with yet another leukemia-specific effect. This patient was transplanted with marrow from his HLA-identical sister in an advanced phase of CML and developed acute and chronic GVHD. After a severe pneumonia a high proportion of his metaphases in the bone marrow were male and Philadelphia chromosome negative. Later all metaphases were again female and leukemic cells could not be detected by reverse transcriptase polymerase chain reaction analysis (RT-PCR) for BCR/ABL. This course indicates that normal hematopoietic stem cells may survive intensive chemotherapy, bone marrow transplantation and GVHD. They may be recruited from a dormant state into proliferation during severe infections. In contrast, CML may be eliminated by the graft-versus-host reaction that recognizes recruited cells and spares dormant cells.
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Enfermedad Injerto contra Huésped/fisiopatología , Células Madre Hematopoyéticas/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/fisiopatología , Adulto , Femenino , Humanos , Cariotipificación , Masculino , Inducción de Remisión , Donantes de TejidosRESUMEN
Contribution of host-related cytokine release in the course of pretransplant conditioning to early tissue damage and induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) has been shown in experimental models. We performed a clinical phase I/II trial applying a monoclonal antibody neutralizing human tumor necrosis alpha (TNF alpha) during pretransplant conditioning as additional prophylaxis in high-risk patients admitted to allogeneic BMT; TNF alpha serum levels and clinical courses in 21 patients receiving anti-TNF alpha prophylaxis were compared with data from 22 historical controls. Absence of significant release of TNF alpha in the period of busulphan (BUS) treatment, but significant induction of TNF alpha by total body irradiation (TBI) and cyclophosphamide (CY) conditioning were correlated with significantly earlier onset of acute GVHD in patients receiving TBI/CY regimens as compared with BUS/CY-treated patients. Prophylactic application of monoclonal anti-TNF alpha seemed to postpone onset of acute GVHD from day 15 to day 25 (P < .05) after TBI/CY and from day 33 to day 53 after BUS/CY (P < .10) conditioning. Application of monoclonal anti-TNF alpha in low and intermediate doses was safe and not associated with an increased incidence of infectious or hematologic complications. Thus, our data provide indirect and direct evidence for involvement of conditioning-related cytokine release in induction of early acute GVHD in the clinical setting and support further investigation of this novel approach in randomized trials.
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Anticuerpos Monoclonales/uso terapéutico , Trasplante de Médula Ósea/métodos , Enfermedad Injerto contra Huésped/prevención & control , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedad Aguda , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Complejo Antígeno-Anticuerpo/metabolismo , Relación Dosis-Respuesta Inmunológica , Femenino , Supervivencia de Injerto , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Persona de Mediana EdadRESUMEN
Carrier detection in X-linked immunodeficiencies (X-SCID, WAS, XLA) relies on the demonstration of non-random X inactivation patterns in blood cell lineages. Only a limited number of cells are available after cell separation methods. PCR-based techniques are therefore necessary to analyze active and inactive X chromosomes. Amplifying a polymorphic CAG repeat in the first exon of the androgen receptor gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme allows to distinguish between the paternal and maternal alleles and to identify their methylation status. DNA from B-, T-lymphocytes and total peripheral leukocytes of normal males, females and obligate carriers of X-linked immunodeficiencies were analyzed. The results of this PCR-based X inactivation assay are concordant with the standard methylation studies at the DXS255 locus using Southern blotting. This PCR assay provides a rapid and informative (heterozygosity > 90%) method in carrier detection of X-linked immunodeficiencies and other X-linked disorders, which show non-random X inactivation in cell lineages from the affected tissues.
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Compensación de Dosificación (Genética) , Tamización de Portadores Genéticos/métodos , Ligamiento Genético/genética , Síndromes de Inmunodeficiencia/genética , Reacción en Cadena de la Polimerasa/métodos , Receptores Androgénicos/genética , Cromosoma X/genética , ADN/análisis , Femenino , Humanos , Masculino , MetilaciónAsunto(s)
Deleción Cromosómica , Infertilidad Masculina/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Aberraciones Cromosómicas Sexuales/genética , Adulto , Mapeo Cromosómico , Errores Diagnósticos , Humanos , Infertilidad Masculina/diagnóstico , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Masculino , Linaje , Cromosoma YAsunto(s)
Quimera , Enfermedad Injerto contra Huésped/terapia , Inmunoterapia Adoptiva , Interferón-alfa/uso terapéutico , Enfermedad Aguda , Animales , Perros , Femenino , Enfermedad Injerto contra Huésped/complicaciones , Humanos , Leucemia/complicaciones , Leucemia/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Transfusión de Linfocitos , Linfoma/complicaciones , Linfoma/terapia , Masculino , Mieloma Múltiple/complicaciones , Mieloma Múltiple/terapia , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/terapia , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/terapiaRESUMEN
BACKGROUND: Although testicular cancer and Hodgkin disease are the neoplasms with the highest incidence in young men, only 13 cases of metachronous and 2 cases of synchronous occurrence in the same person were reported before 1991. METHODS: A 30-year-old man is described, in whom, 2 years after radiation therapy for Stage IIIA Hodgkin disease, a testicular nonseminomatous germ cell tumor developed with metastatic spread to the retroperitoneal lymph nodes, lung, and left supraclavicular fossa. The second case report describes a 31-year-old man in whom a metastasizing nonseminomatous testicular cancer, with elevation of levels of the serum tumor markers alpha-fetoprotein and human chorionic gonadotropin, developed simultaneously with axillary lymphadenopathy that was histologically confirmed Hodgkin disease. RESULTS: After five cycles of cisplatin-based chemotherapy and secondary retroperitoneal lymphadenectomy, the patient with metachronous disease has remained in complete remission for 8 years. The patient with synchronous occurrence has been disease-free for 14 months after five cycles of chemotherapy consisting of cisplatin, etoposide, and doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH). CONCLUSIONS: The metachronous and synchronous occurrence of testicular cancer and Hodgkin disease is a rare association of two curable neoplasms. The presence of both malignant neoplasms should be taken into consideration in young male patients, especially if disease distribution diverges from a regular pattern.