Caspofungin for the treatment of invasive fungal disease in hematological patients (ProCAS Study).

Caspofungin is an echinocandin with proven efficacy in invasive candidiasis (IC) and invasive aspergillosis (IA). This multicenter, prospective, non-comparative, observational ProCAS study was aimed to assess the effectiveness and safety of caspofungin in adult hematological patients with IC or IA under everyday clinical conditions. Favorable outcomes included complete and partial responses on the last day of caspofungin therapy. Safety was assessed up to 14 days post-caspofungin. A total of 115 patients (69 male) with a median age of 52 years (range, 23-78 years) were analyzed. Underlying disease was acute myeloid leukemia in 45 patients (39%), and 21 (18%) were allogeneic stem cell transplant recipients. Thirty-four (29.5%) patients had a diagnosis of IA and 26 (22.6%) had IC (candidemia). The median duration of caspofungin therapy was 14 days (range, 1-100). The overall favorable response rate was 77% (20/26) for patients with IC (69% first-line) and 79% (27/34) for those with IA. Antifungal therapy with caspofungin was generally well tolerated, only two (1.7%) patients having a non-serious drug-related adverse reaction. These results suggest that caspofungin, either alone or in combination, should be considered an effective and safe option for the treatment of invasive mycoses in patients with severe hematological disorders.

Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis.

Fluorescence in situ hybridization (FISH) has become a powerful technique for prognostic assessment in multiple myeloma (MM). However, the existence of associations between cytogenetic abnormalities compels us to re-assess the value of each abnormality. A total of 260 patients with MM at the time of diagnosis, enrolled in the GEM-2000 Spanish transplant protocol, have been analyzed by FISH in order to ascertain the independent influence on myeloma prognosis of IGH translocations, as well as RB and P53 deletions. Survival analyses showed that patients with t(4;14), RB or P53 deletions had a significantly shorter survival than patients without these abnormalities. However, patients with RB deletions without other abnormalities in FISH analysis, displayed a similar outcome to those patients without genetic changes by FISH (46 vs 54 months, P=0.3). In the multivariate analysis the presence of t(4;14), RB deletion associated with other abnormalities, age >60 years, high proportion of S-phase cells and advanced stage of the disease according to the International Staging System retained their independent prognostic influence. In summary, RB deletion as a sole abnormality does not lead to a shortening in the survival of MM patients, whereas t(4;14) confers the worst prognosis in MM patients treated with high-dose chemotherapy.

Prolonged survival after liver transplantation for Hodgkin's disease-induced fulminant liver failure.

A 30-year-old male with a past history of nodular lymphocyte predominance Hodgkin's disease in apparent complete remission for two years received a liver transplantation because of fulminant liver failure. Histopathological examination of the explanted liver showed massive infiltration by Hodgkin's disease. In spite of a nodal recurrence of Hodgkin's disease, the patient is alive and in excellent general condition six years after liver transplantation.

Are myeloma patients with renal failure candidates for autologous stem cell transplantation?

INTRODUCTION: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insufficiency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. MATERIALS AND METHODS: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were defined: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. RESULTS AND CONCLUSION: Patients from groups BA and BB presented with a significantly higher number of adverse prognostic factors, reflecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insufficiency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine < 2 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically significant difference favoring group AA (P<0.01). PFS did not differ significantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).

Correlation and prognostic value of serum soluble ICAM-1, beta-2 microglobulin, and IL-2alphaR levels in non-Hodgkin's lymphoma.

Serum levels of sICAM-1, sIL-2alphaR, and beta-2 microglobulin were measured in 63 patients with non-Hodgkin's lymphoma (NHL). The correlation between these serum markers as well as their relationship with NHL features and disease outcome were analyzed. Although in high-grade NHL sICAM-1 levels correlated with tumor mass, no correlation was found between sICAM-1 levels and tumor burden in low-grade NHL. When compared with sICAM-1 and beta-2 microglobulin, sIL-2alphaR showed the strongest correlation with the tumor burden. However, in multivariate analysis, including serum markers employed as continuous variables, the only parameteres which entered the regression model were beta-2 microglobulin (p=0.012) and sICAM-1 (p=0.019). In a dichotomized model, beta-2 microglobulin, aggressive histology, sICAM-1, age and number of nodal involved sites were found to be prognostically significant. Finally, by combining sICAM-1 and beta-2 microglobulin serum levels, a simple prognostic model useful for NHL was obtained.

Hydroxyurea-induced acute interstitial pneumonitis in a patient with essential thrombocythemia.

Hydroxyurea is a drug widely used to control myeloproliferative disorders, due in part to its relative lack of severe side effects. We present a case of acute interstitial pneumonitis in a patient who was treated with hydroxyurea for essential thrombocythemia. The clinical course suggests that the interstitial pneumonitis was induced by hydroxyurea. This is the first case of hydroxyurea-induced acute interstitial pneumonitis reported in the literature.

Tumor burden and serum level of soluble CD25, CD8, CD23, CD54 and CD44 in non-Hodgkin's lymphoma.

We studied the value of soluble CD25, CD8, CD23, CD54 and CD44 serum levels as tumor burden markers in lymphoma. Soluble CD25 compared with the others sCD and the usual serum factors (albumin, lactate dehydrogenase, beta 2-microglobulin, uric acid and C-reactive protein), showed the strongest correlation with the Ann Arbor stage and the number of affected localizations. sCD25 level is the most sensitive serum marker for tumor burden in lymphoma.

[Detection of soluble interleukin-2 receptor in the serum of patients with non-Hodgkin's lymphoma]. / Determinación del receptor soluble de la interleucina 2 en el suero de pacientes con linfoma no hodgkiniano.

BACKGROUND: Patients with non-Hodgkin's lymphoma (NHL) have increased serum levels of soluble interleukin-2 receptor (sCD25). In this study the authors investigate: a) the value of sCD25, compared to other serum markers, as tumor marker, and b) the relationship of the sCD25 with the response to therapy and prognosis. PATIENTS AND METHODS: Serum interleukin-2 receptor (sCD25) levels were measured at diagnosis in 63 patients with NHL (low-grade lymphoma 30 and high-grade lymphoma 33). RESULTS: High levels of sCD25 were found in these patients compared to a control group (median 1,757 U/ml vs 385 U/ml; p < 0.0001). Significant differences were also found between the high-grade group and the low-grade group, as a whole and within the same Ann Arbor stage. sCD25 showed a correlation coefficient higher than other serum parameters (albumin, LDH, beta 2-microglobulin, uric acid, C-reactive protein) with Ann Arbor stage and with the number of involved lymph nodes or extralymphatic organs. In the high-grade NHL, the median of sCD25 (3,000 U/ml) separates patients with differences in the overall survival (p = 0.0138) and in percentage of complete remisions (p = 0.0079). All the patients with sCD25 < or = 3,000 U/ml reached the remision. The association sCD25 > 3,000 U/ml and albumin < 3.5 g/dl selected to 5 out of 6 patients who failed induction chemotherapy, and only 2 out of 22 who reached the remision. CONCLUSIONS: The sCD25 is the best serum factor for estimating tumor burden in NHL. sCD25 level isolates or associated with albumin provides prognostic information.

Splenectomy for poor graft function after allogeneic bone marrow transplantation in patients with chronic myeloid leukemia.

We report four patients with chronic myeloid leukemia (CML) that showed poor graft function after a non-T-depleted bone marrow transplantation (BMT) from an HLA-compatible sibling donor and who were successfully treated with splenectomy. Conditioning was done with cyclophosphamide (CY) and total body irradiation (TBI) without additional splenic irradiation. Three patients had enlarged spleens before BMT. The nucleated cell dose infused ranged from 2.3-3.2 x 10(8)/kg. Bone marrow (BM) examination prior to splenectomy showed BM aplasia (three cases) or hypocellularity (one case). At splenectomy no patient had evidence of cytomegalovirus (CMV) infection or severe acute GVHD; and three patients had moderately enlarged spleens. All patients were transfusion dependent. Complete hematological recovery was obtained in all patients. BM cellularity was normal 1 month after splenectomy. Complete chimerism of donor origin was documented. The four patients are alive (+16 to +58 months after BMT). Thus, in patients with CML, a poor graft function may be successfully corrected by splenectomy.

Familial myeloproliferative syndrome.

Familial chronic myeloproliferative syndrome (CMS) was observed in five members from two different generations of the same kindred. Diagnosis included agnogenic myeloid metaplasia (case 1), polycythemia vera (case 2), and essential thrombocythemia (cases 3-5). Cases 1-3 were siblings, case 5 was the daughter of case 1, and case 4 was the cousin of cases 1, 3. Age at diagnosis ranged from 28 to 75 years, cases 1 and 3 were male, and the others were female. The diagnosis was made after an episode of cerebral thrombosis in one patient, during a study for headache and dizziness in another, and fortuitously in the three remainders. All patients had splenomegaly and varying degrees of thrombocytosis. The cytogenetic exam was normal in all four cases. A woman patient was treated with interferon during a pregnancy. Fetal growth was retarded, and the newborn showed bone and genital malformations. No environmental leukemogen factor was found. This familial case strengthens Dameshek's theory of a common pathogenesis of CMS and suggests a genetic and hereditary etiology.

[Plasma cell leukemia: our experience in 4 cases]. / Leucemia de células plasmáticas: nuestra experiencia de cuatro casos.

Clinical findings and response to treatment in four cases with plasma cell leukemia (PCL) out of 152 patients of multiple myeloma diagnosed at the Hospital La Paz from 1969 to 1988 are studied. Three of the four plasma cell leukemia cases presented a primary form, and one a secondary form. Our cases had a lower incidence of lymphadenopathy and splenomegaly than reported in previous series. The incidence of serum M band in PCL was similar to that found in multiple myeloma. The four patients received combination chemotherapy; one of them attained PR lasting for 2 months, and the remaining three failed to respond to similar therapy. The mean duration of survival was less than 8 months. Current treatments are reviewed.

Evaluación histíca y morfométrica en piel sana de ratas tratadas con EGF tópico / Histic and morphometric evaluation on healthy skin of rats treated topically with EGF

Se realizó la evaluación morfológica de los efectos ocasionados por la aplicación tópica del EGF recombinante en ratas de ambos sexos de la linea Long-Evans. Se formaron dos grupos uno recibió tratamiento durante 30 dias con pomada de EGF y un grupo control que sólo recibió aplicaciones de unguento hidrófilo. Se efectuaron 5 muestreos a partir de los 15 dias de comenzado el tratamiento, al final del mismo (30 dias) y a los 45. 60 y 90 dias de comenzado el tratamiento. Se tomaron fragmentos de piel tratada y no tratada, así como sus respectivas necropsias. Las muestras se fijaron en formalina neutra al 10% y se procesaron por la técnica de inclusión de parafina. La evaluación de los casos se efectuó siguiendo las consideraciones histícas formuladas por la OMS, así como estudios morfométricos. Se destacan entre los hallazgos un ligero aumento de la capa de queratina en los grupos que recibieron EGF y áreas focales de acantosis acompañada de incremento del número de mitosis

Hematological abnormalities in hemophilic patients with human immunodeficiency virus infection.

Hematological abnormalities are common in patients with AIDS or AIDS-related complex. We studied cytological characteristics in peripheral blood and bone marrow samples of 33 hemophilic patients with HIV Infection and in six HIV negatives. The HIV-positive patients presented leukopenia (60.6%), thrombocytopenia (69.9%), and anemia (57.5%). Bone marrow showed abnormalities of maturation in one or more cell lines similar to those described in other HIV-infected groups of patients. These findings were more prominent in megakaryocytes and granulocytic series. Lymphocytosis, plasmocytosis, and increased hemophagocytosis were also common. These alterations do not appear in HIV-negative patients and seem related to a direct effect of HIV on bone marrow cells or to alterations in T-cell regulatory functions.

[Pathogenesis of peripheral cytopenias in hemophiliac patients]. / Observaciones sobre la patogenia de las citopenias periféricas en pacientes hemofílicos.

The frequent occurrence of peripheral cytopenias is a common clinical fact in patients with HIV-1 infection, and its pathogenetic mechanism is not clear, although several hypotheses have been proposed. Such cytopenias are frequently observed in haemophilic patients, in whom the immunologic alteration induced by continuous antigenic stimulants derived from plasma concentrate therapy has been postulated as an additional causative factor. One-hundred and forty five haemophiliacs treated with commercial antihaemophilic concentrates were studied. The patients were divided into three therapeutic groups according to the mean number of units of therapeutic factor VIII administered per Kg every year in the four years prior to the study (group I: less than 500 U; group II: between 501 and 1500 U; group III: more than 1500 U). The occurrence of cytopenias in the patients was co-ordinated with the presence or absence of HIV infection and the therapeutic group. The statistical studies showed clear correlation between peripheral cytopenias and presence of anti-HIV markers, regardless of the amount of concentrates perceived (except for the total neutrophil count).

El factor de crecimiento epidérmico inhibe el crecimiento de carcinomas epidermoides humanos en ratones atímicos / Epidermal growth factor inhibits the growth of human epidermoid carcinomas in athymic mice

El factor de crecimiento epidérmico (EGF), polipéptido mitogénico para células de origen epitelial y mesenquimatoso tiene, sin embargo, un efecto inhibidor de la proliferación in vitro de las células de muy alto contenido de receptores. Los resultados previos de nuestro laboratorio habían demostrado que el EGF podía inhibir in vivo la incorporación de timidina en células del tumor ascítico de Ehrlich. En este artículo presentamos una evaluación directa del efecto del EGF (humano, recombinante) en el crecimiento de tumores trasplantables de ratón y de xenotrasplantes de tumores humanos en ratones atímicos. Los tumores de Ehrlich (carcinoma mamario), RL-67 (carcinoma de pulmón) y CETA (carcinoma epidermoide de labio), fueron los tumores con mayor contenido de receptores de EGF dentro de nuestro banco de tumores trasplantables. En estos modelos, no obstante, el EGF (20 mg/kg/día, subcutáneo, 10 días) no mostró efecto inhibidor del crecimiento tumoral. Sin embargo, en los tumores humanos obtenidos por xenotrasplantes en ratones atímicos de células de carcinoma de vulva (A431) y fragmentos de carcinoma epidermoide de pulmón (CPH3), la administración de EGF produjo una inhibición del crecimiento tumoral. Este efecto fue reversible cuando se interrumpió el tratamiento. Estos resultados indican la posibilidad de regular in vivo el crecimiento de tumores con receptores de EGF, mediante la administración de este factor en dosis muy superiores a las concentraciones fisiológicas, lo cual constituye potencialmente una nueva modalidad de hormonoterapia

Isolation and characterization of an antitumor active agar-type polysaccharide of Gracilaria dominguensis.

Cold water extraction of the red alga Gracilaria dominguensis, followed by cetyltrimethylammonium bromide fractionation, gave a highly sulfated, agar-type polysaccharide which inhibited the transplantation of Ehrlich ascites carcinoma in mice. The structure of the polysaccharide has been investigated by methylation analysis, and 1H- and 13C-n.m.r. spectroscopy, and was shown to be mainly composed of alternating (1----3)-linked beta-D-galactopyranosyl 6-sulfate and (1----4)-linked 3,6-anhydro-alpha-L-galactopyranosyl residues.