Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial.

In this trial, acute myeloid leukemia patients (pts) aged 61-80 years received MICE (mitoxantrone, etoposide and cytarabine) induction chemotherapy in combination with different schedules of granulocyte colony-stimulating factor administration. Pts in complete remission were subsequently randomized for two cycles of consolidation therapy: mini-ICE regimen (idarubicin, etoposide and cytarabine) given according to either an intravenous (i.v.) or a 'non-infusional' schedule. Among the 346 pts randomized for the second step, 331 pts received consolidation-1 and 182 consolidation-2. A total of 290 events (255 relapses, 35 deaths in first CR) have been reported. The median follow-up was 4.4 years. No significant differences were detected in terms of disease-free survival (median 9 vs 10.4 months, P=0.15, hazard ratio (HR) =1.18, 95% confidence interval (CI) 0.94-1.49) - primary end point - and survival (median 15.7 vs 17.8 months, P=0.19, HR=1.17, 95% CI 0.92-1.50). In the 'non-infusional' arm grade 3-4 vomiting (10 vs 2%; P=0.001) and diarrhea (10 vs 4%; P=0.03) were higher than in the 'i.v.' arm, whereas time to platelet recovery >20 x 10(9)/l (median: 19 vs 23 days; P=0.02) and duration of hospitalization (mean: 15 vs 27 days; P<0.0001) was shorter. The 'non-infusional' consolidation regimen resulted in an antileukemic effect similar to the intravenous regimen, which was less myelosuppressive and associated with less hospitalization days.

Secondary acute myeloid leukaemia: results of conventional treatments. Experience of GIMEMA trials.

BACKGROUND: The aim of the study was to evaluate the outcome of acute myeloid leukaemia (AML) in patients with a previous malignancy (sAML) treated with chemo- and/or radiotherapy, enrolled in conventional trials. PATIENTS AND METHODS: In a multicentre setting, a prospective non-concurrent analysis was performed on 2513 new AML patients, aged 12-78 years, consecutively enrolled in EORTC-GIMEMA trials between 1987 and 2001. Thirty-eight patients with sAML were identified and compared with a group of 114 de novo AML patients matched according to age, French-American-British criteria, white blood cell count at diagnosis, trial and time of diagnosis of AML. Induction treatment response, disease-free survival (DFS), duration and overall survival (OS) were evaluated in the two groups. RESULTS: Comparing the complete remission (CR) rate between 38 sAML patients and 114 de novo AML patients, selected according to the previously reported criteria, we observed no difference in the CR rates [25/38 (66%) versus 66/114 (58%); Pearson chi(2) 0.7393, P=0.390] as well as no differences while comparing the DFS and the OS between the two groups. CONCLUSION: The results of this study suggest that sAML patients are characterised by a good performance status permitting their recruitment in conventional trials without a previous myelodysplastic phase. Similar to de novo AML patients, sAML patients show good response to treatment and the possibility of cure.

Association between vitiligo and spondyloarthritis.

OBJECTIVE: To establish if spondyloarthritis (SpA) and vitiligo occur together more frequently than by chance. METHODS: All consecutive patients with SpA seen in a 6 month period were evaluated for vitiligo by an experienced dermatologist. The control group included the 2 consecutive patients without SpA seen after each patient with SpA. RESULTS: Two hundred thirty-four patients with SpA (131 men, 103 women; mean age 59 +/- 18.3 yrs) were seen in the study period. Of these, 43 had ankylosing spondylitis (AS), 112 psoriatic arthritis (PsA), 14 SpA associated with inflammatory bowel disease, 64 undifferentiated SpA, and one reactive arthritis. The 468 control patients (360 women, 108 men; mean age 68.5 +/- 2 yrs) had various degenerative and inflammatory rheumatic diseases. Eight (3.4%) patients out of 234 with SpA had type A vitiligo. In the control group, 5 (1.06%) out of 468 had type A vitiligo. The difference was statistically significant (p < 0.05). Of the 8 patients with coexisting vitiligo and SpA, 4 had PsA, 2 primary AS, one AS associated with Crohn's disease, and one undifferentiated SpA. Of the 5 patients with vitiligo in the control group, one had rheumatoid arthritis, one S ogren's syndrome, one palindromic rheumatism, one crystal arthropathy, and one osteoarthritis. CONCLUSION: Our results suggest that vitiligo and SpA do not coexist by chance and that vitiligo should be included in the list of diseases associated with SpA.

Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma.

PURPOSE: A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas. PATIENTS AND METHODS: From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 3 and idarubicin 12 mg/m(2) on day 1). RESULTS: In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P =.021). CONCLUSION: Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.

Fever in young lambs: hypoxemia alters the febrile response to a small dose of bacterial pyrogen.

Experiments were done on eight young lambs to investigate the effects of hypoxemia on the body temperature, metabolic and cardiovascular responses to intravenous administration of a small dose of bacterial pyrogen (0.3 micrograms lipopolysaccharide extracted from Salmonella Abortus Equi; SAE). Each lamb was anaesthetized with halothane and prepared for sleep staging and measurements of cardiac output, arterial and mixed-venous haemoglobin oxygen saturations, body-core and ear-skin temperatures. Three experiments were done on each lamb, the first being done no sooner than three days after surgery. The first experiment consisted of establishing the thermal neutral environment during normoxemia (ie, environmental temperature at which total body oxygen consumption was minimal while body temperature was maintained) for each lamb. The second and third experiments were done at the lamb's thermoneutral environment as determined on day 1. One experiment was done during normoxemia (ie, control condition, SaO2 approximately 90%) and one experiment was done during hypoxemia (ie, experimental condition, SaO2 approximately 50%). Measurements were made during a control period and during one-minute experimental periods at 10 minute intervals for 120 minutes following administration of 0.3 micrograms of bacterial pyrogen in sterile saline. Administration of SAE produced a short-lived fever of about 0.8 degrees C in the normoxemic lambs, whereas no change in body-core temperature was observed in the hypoxemic lambs. During normoxemia, the increase in body-core temperature was preceded by peripheral vasoconstriction, the onset of shivering, and a surge in total body oxygen consumption. The increase in total body oxygen consumption was met primarily by an increase in total body oxygen extraction during the development of fever. Cardiac index, heart rate, and systemic oxygen transport increased during the peak body-core temperature response. Systemic arterial blood pressure did not change significantly during the febrile response; however, pulmonic arterial blood pressure increased. During hypoxemia, peripheral vasoconstriction and shivering occurred following administration of SAE, but there was no change in total body oxygen consumption or body-core temperature. Thus, our data provide evidence that hypoxemia alters the febrile response of young lambs to bacterial pyrogen. The precise mechanism remains to be determined.

Fever in young lambs: temperature, metabolic and cardiorespiratory responses to a small dose of bacterial pyrogen.

Experiments were done on ten lambs ranging in age from 15 to 25 days to define the temperature, metabolic and cardiorespiratory responses to intravenous administration of a small dose of bacterial pyrogen (SAE). Administration of SAE but not normal saline produced a short-lived fever of about 0.7 degrees C. The increase in body-core temperature was preceded by a surge in total body oxygen consumption and the onset of shivering which was influenced by behavioral state (ie, shivering was inhibited during active sleep). The increase in total body oxygen consumption was initially met by an increase in total body oxygen extraction and then by an increase in systemic oxygen delivery. Systemic arterial blood pressure did not change significantly during the febrile response; however, pulmonic arterial blood pressure increased significantly. Thus, our experiments provide new data on oxygen supply and demand during the development of fever and that shivering thermogenesis is inhibited in active sleep following the administration of bacterial pyrogen in young lambs. The influence of active sleep on the overall febrile response, and whether or not there is a shift from shivering thermogenesis to non-shivering thermogenesis remains to be determined.

Comparison of the adverse effects of adrenal and ovarian steroids on early pregnancy in mice.

In one experiment, female C57- and HS-stain mice were inseminated according to standard procedures and randomly assigned to conditions involving administration of various adrenal and ovarian steroids in the first trimester of pregnancy. The pattern of effects was similar in the two strains, although generally C57 females produced fewer and smaller litters than did HS females. Oestradiol benzoate injections completely blocked pregnancy at doses far less than those effective for other steroids. Corticosterone injections did not produce any significant pregnancy block. Androstenedione injections produced a pregnancy block at 500 micrograms per day. Dehydroepiandrosterone produced a mild pregnancy block at both 500 micrograms and 100 micrograms per day. In a second experiment, the dose-response curve for oestradiol was examined. Daily doses of 0.333 microgram and greater completely blocked pregnancy, a dose of 0.111 microgram did so in the majority of females, and smaller doses had little effect. These results, taken together with other data, suggest that oestrogenic action may mediate the stress-induced block of pregnancy.

Evaluation of LAK-mediated tumor cell killing in a plasma clot clonogenic assay.

An assay based on the inhibition of the cloning capacity in a plasma clot semisolid medium assay has been used to test the sensitivity of the Raji cell line to lymphokine-activated killer (LAK) cells. This method overcomes some limitations intrinsic to the widely employed 51Cr release assay and always shows a higher degree of sensitivity. No inhibition of colony growth was found when the effector cells were plated without prior pre-incubation with interleukin 2 or with the addition of the medium derived from the LAK cells. Though more time-consuming than the classic 51Cr release assay, this technique does not require radioactive material. This test may be suitable for a more precise evaluation of LAK activity and for the study of the mechanisms involved in cell killing.

X-chromosome inactivation in human liver: confirmation of X-linkage of ornithine transcarbamylase.

Histochemical assay for ornithine transcarbamylase (OTC) activity in fixed frozen hepatic sections from a woman heterozygous for OTC deficiency revealed two populations of hepatocytes: those with normal activity and those with no activity. This observation, in conjunction with data from previous family studies, confirms the hypothesis that the gene for OTC is X-linked. It also provides the first cytologic demonstration of cellular mosaicism for a liver-specific cell product.

Assignment of three gene loci (PGK, HGPRT, G6PD) to the long arm of the human X chromosome by somatic cell genetics.

The intrachromosomal localization of three X-linked gene loci (PGK, HGPRT and G6PD) has been determined using a somatic cell genetic approach. A human cell line possessing an X/14 translocation was used as one parent in the formation of human/mouse hybrids. The translocation separates the human X into two parts: Xp and t(Xq14q). The data indicate that all three X-linked loci segregate with the t(Xq14q) rearrangement product thus permitting their assignment to the X chromosome's long arm. Secondary rearrangements and data from other laboratories suggest that the order of the the three markers from the centromere to the distal end of the X long arm is PGK, HGPRT, G6PD. It was also observed that NP, an autosomal locus, segregated with the t(Xq14q) chromosome. This provides strong support for the assignment of NP to 14.