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Introduction In Italy a Covid-19 pandemic pattern was observed, characterized by several waves, with an excess total mortality of 178000 deaths. Alessandria, Italy is the Piedmont province with the highest proportion of mortality from Covid-19 in the first 4 months of 2020, compared to the rest of the region. Objectives To analyze mortality in patients hospitalized for Covid-19 in the Alessandria Hospital (AO AL), considering the first 3 waves. Materials and methods Subjects aged ≥18 with a diagnosis of Covid-19 admitted to the AO AL in the first 50 days of the first 3 waves were included. The first wave started on 24 February 2020 (first day of available data by the Ministry of Health), the second wave on 14 September 2020 (first day of the 2020/21 school year), the third wave on 15 February 2021 (peak of cases detected by the Italian College of Health). The causes of death were obtained from the National Institute of Statistics death cards and codified according to the International Classification of Diseases, 9th revision, classification. Results We included 825 subjects (median age: 73 years; male prevalence: 60.7%). The subjects hospitalized in the first wave were 464, in the second wave 255, in the third wave 106. A total of 309 subjects died (37.5%), of which 218 in the first wave (70.6%), 69 in the second wave (22.3%), 22 in the third wave (7.1%). The most frequent causes of death were “Covid-19 pneumonia” (61.5%) and “respiratory distress syndrome” (19.4%). Death occurred after hospital discharge in 40% of cases. 6 months after admission, the survival rate was 53% among patients of the first wave, 73% and 78% for those of the second and third wave. Patients hospitalized in the first and second waves showed a greater risk of death compared to patients of the third wave (HR = 2.8; 95% CI 1.8-4.4 and HR = 1.4; 95% CI 0.8-2.2). Conclusions Data showed a difference in mortality between the 3 waves with a statistically significant variation between the first and third waves. Key messages • Data showed a difference in mortality between the 3 waves. • Data showed a statistically significant variation in mortality between the first and third waves.

Objective To evaluate the effect of alfaxalone and methadone administered intramuscularly (IM), with or without ketamine, on sedation and echocardiographic measurements in healthy cats. Study design A randomized, blinded, clinical study. Animals A group of 24 client-owned cats. Methods Baseline echocardiographic evaluation (bEchoCG) was performed. Cats were given IM alfaxalone (2 mg kg–1) and methadone (0.3 mg kg–1) with (AMK group) or without (AM group) ketamine (1 mg kg–1). A sedation score (0–5, indicating none to good sedation) was assigned at 5 (T5), 10 (T10) and 15 (T15) minutes after IM injection. At T15, a second echocardiographic evaluation (sEchoCG) was performed. Data are shown as median (range). Significance was p Results Finally, 21 cats were included. Sedation score was significantly higher in the AMK (11 cats) than in the AM group (10 cats): 4 (1–5) versus 0.5 (0–4) at T5 (p = 0.003); 4 (1–5) versus 1.5 (0–5) at T10 (p = 0.043); and 4 (1–5) versus 2 (0–5) at T15 (p = 0.024). All echocardiographic measurements obtained were within reference ranges. Between the groups, aortic root area (p = 0.009) and end-diastolic aortic dimension (p = 0.011) were significantly higher in the AM group at bEchoCG and sEchoCG, respectively. Within each group, values at bEchoCG and sEchoCG showed no significant differences, except for pulmonary peak velocity (0.85 m second–1; p = 0.028) in the AMK group and ejection time (154 m second; p = 0.03) in the AM group; both variables decreased after sedation. Conclusions and clinical relevance In this population of healthy cats, neither protocol produced clinically meaningful effects on the echocardiographic variables evaluated. Alfaxalone with methadone produced mild sedation, whereas the addition of 1 mg kg–1 ketamine induced adequate sedation for diagnostic procedures.

This study investigated the perioperative effects of preemptive intra-articular lidocaine (L group), dexmedetomidine (D group) and lidocaine-dexmedetomidine (LD group) in dogs. Physiological variables were intraoperatively recorded at 5 min intervals starting from baseline (5 min before intra-articular injection). If nociception occurred, IV fentanyl was administered. Postoperative pain was assessed using the Short Form-Glasgow Composite Measure Pain Scale. Twenty-four dogs (eight in each group) were included in this prospective, randomized, masked clinical study. In the LD group, systolic arterial pressure significantly increased at T10 (P = 0.027), T15 (P = 0.021) and T20 (P = 0.022), compared with baseline. In the D and LD groups, mean arterial pressure significantly increased at T10 (P = 0.022; 0.024), T15 (P = 0.024; 0.09) and T20 (P = 0.019; 0.021), compared with baseline and diastolic arterial pressure significantly increased at T10 (P = 0.026; 0.047), T15 (P = 0.021; 0.023), T20 (P = 0.011; 0.012) and T25 (P = 0.019; 0.027), compared with baseline. In the LD group, heart rate significantly decreased at T5 (P = 0.031), T10 (P = 0.026) and T15 (P = 0.034), compared with baseline. Atrioventricular blocks appeared more frequently in the LD group than in L and D groups (P = 0.002). Group L received more fentanyl than the D and LD groups (P = 0.03). No differences in postoperative pain score were detected (P = 0.121). These findings suggested systemic absorption of intra-articular dexmedetomidine. Intra-articular lidocaine-dexmedetomidine was associated with a greater incidence of atrioventricular blocks. Intra-articular dexmedetomidine, alone and combined with lidocaine, provided better intraoperative analgesia than lidocaine in dogs undergoing arthroscopy, although the 12 h postoperative analgesic effect of the three treatments was similar.

The aim of the present study was to compare sedation quality and cardiorespiratory parameters in healthy dogs after intramuscular injection of dexmedetomidine and ketamine with or without methadone. Forty client-owned dogs were randomly divided into two groups and received IM dexmedetomidine (5 µg kg−1) and ketamine (1 mg kg−1), associated (DKM group) or not (DK group) with methadone (0.2 mg kg−1). Sedation, heart rate (HR), respiratory rate (ƒR), mucous membrane and rectal temperature were recorded at baseline (T0) and after 5 (T5), 10 (T10) and 20 (T20) minutes. From T10, cardiac rhythm was monitored with a continuous lead II electrocardiogram. Ease of venous catheter placement, total propofol dose and any apnea episodes were recorded. Sedation was significantly greater in the DKM group, and a significant increase from T5 to T20 within DKM (P = .0002) and DK (P = .008) was also observed. Within each group, HR was significantly lower at all time points compared to baseline. No significant differences between groups were found in the number of arrhythmogenic events (atrioventricular blocks). In both group ƒR decreased over time. The propofol dose required for anesthesia induction was significantly lower (P = .027) in the DKM group. In conclusion, a good level of sedation was achieved in both groups, although this was greater in DKM. Smooth animal-operator interaction and ease of venous catheter placement showed that DK was a useful sedative protocol in healthy patients.

Objective To evaluate whether subcutaneous (SC) metoclopramide (0.2 mg kg−1) administered 30 minutes prior to (T30) or simultaneously with (T0) intramuscular (IM) morphine (0.2 mg kg−1) and dexmedetomidine (0.003 mg kg−1) reduces the incidence of nausea and emesis in healthy dogs. Study design Prospective, randomized and blinded study. Animals A total of 45 dogs scheduled for elective procedures. Methods Dogs were assigned randomly to three groups to be administered SC metoclopramide (0.2 mg kg−1) 30 minutes before (group M30) or simultaneously (group M0) to IM morphine (0.2 mg kg−1) and dexmedetomidine (0.003 mg kg−1). Dogs in the control group (group C) were administered SC saline at T30 and T0. Dogs were observed for 30 minutes after premedication to evaluate signs of nausea (continuous lip-licking and sialorrhoea) and emesis. Signs of pain or discomfort caused by SC injections were also recorded. Results There were no statistical differences amongst groups for age, body weight and sex. More dogs developed continuous lip-licking in group C (12/15, 80.0%) compared to dogs in group M30 (1/15, 6.7%) and dogs in group M0 (5/15, 33.3%; p = 0.0001 and p = 0.01, respectively). More dogs developed sialorrhoea in group M0 (8/15, 53.3%) and in group C (10/15, 66.7%) compared to dogs in group M30 (2/15, 13.3%; p = 0.03 and p = 0.004, respectively). More dogs vomited in group M0 (4/15, 26.7%) and in group C (9/15, 60.0%) compared to dogs in group M30 (0/15, 0.0%; p = 0.05 and p = 0.0003, respectively). None of the dogs demonstrated signs of pain or discomfort during SC metoclopramide injection. Conclusions and clinical relevance: Subcutaneous metoclopramide at 0.2 mg kg−1 may reduce IM morphine and dexmedetomidine-induced nausea and emesis if administered 30 minutes in advance. It is effective in reducing lip-licking even when administered concurrently with IM morphine–dexmedetomidine.

Somma F, Cretella G, Carotenuto M, Pecci R, Bedini R, De Biasi M, Angerame D. Quality of thermoplasticized and single point root fillings assessed by micro-computed tomography. International Endodontic Journal Abstract Aim To evaluate ex vivo the quality of root fillings completed by two thermoplasticized gutta-percha techniques (Thermafil and System B) and a cold gutta-percha technique (single point) by μCT analysis. Methodology A total of 30 freshly extracted human single-rooted permanent teeth were selected. Root canals were prepared with ProTaper Universal instruments and then randomly divided into three groups (n = 10) depending on the filling technique. In group 1, canals were filled with a single-point technique; group 2 was filled with Thermafil; in group 3 System B was used. In group 1 and group 3, the root filling was performed using ProTaper Universal gutta-percha points, in group 2 Thermafil obturators were used; AH-Plus sealer was used in all groups. Assessment of the root filling was carried out by μCT, using a desktop X-ray micro focus CT scanner. Percentage of root canal filling materials and voids was calculated for each specimen. Data were statistically analysed using Kruskal–Wallis test (P

The role of sleep in cognitive processes has been confirmed by a growing number of reports for all ages of life. Analysing sleep electroencephalogram (EEG) spectra may be useful to study cortical organisation in individuals with Borderline Intellectual Functioning (BIF), as seen in other disturbances even if it is not considered a disease. The aim of this study was to determine if the sleep EEG power spectra in children with BIF could be different from typically developing children.Eighteen BIF (12 males) (mean age 11.04; SD ± 1.07) and 24 typical developing children (14 men) (mean age 10.98; SD ± 1.76; P = 0.899) underwent an overnight polysomnography (PSG) recording in the Sleep Laboratory of the Clinic of Child and Adolescent Neuropsychiatry, after one adaptation night. Sleep was subdivided into 30-s epochs and sleep stages were scored according to the standard criteria and the power spectra were calculated for the Cz-A2 channel using the sleep analysis software Hypnolab 1.2 (SWS Soft, Italy) by means of the Fast Fourier Transform and the power spectrum was calculated for frequencies between 0.5 and 60 Hz with a frequency step of 1 Hz and then averaged across the following bands delta (0.5-4 Hz), theta (5-7 Hz), alpha (8-11 Hz), sigma (11-15 Hz), and beta (16-30 Hz), gamma (30-60 Hz) for S2, SWS and REM (Rapid Eye Movement) sleep stages.BIF have a reduced sleep duration (total sleep time; P0.001), and an increased rate of stage shifts (P0.001) and awakenings (P0.001) and WASO (wakefulness after sleep onset) % (P0.001); the stage 2% (P0.001), and REM% (P0.001) were lower and slow-wave sleep percentage was slightly higher (P0.001). All children with BIF had an AHI (apnoea-hypopnea index) less than 1 (mean AHI = 0.691 ± 0.236) with a mean oxygen saturation of 97.6% and a periodic leg movement index (PLMI) less than 5 (mean PLMI = 2.94 ± 1.56). All sleep stages had a significant reduction in gamma frequency (30-60 Hz) (P0.001) and an increased delta frequency (0.5-4.0 Hz) (P0.001) power in BIF subjects compared with typically developing children.Our findings shed light on the importance of sleep for cognition processes particularly in cognitive borderline dysfunction and the role of EEG spectral power analysis to recognize sleep characteristics in BIF children.

In a screening of potential targets within Notch signaling, miR-34a was seen to be a regulator of the Notch pathway through its targeting of Notch ligand Delta-like 1 (Dll1). Down-regulation of Dll1 expression by miR-34a negatively regulates cell proliferation, and induces apoptosis and neural differentiation in MB cells. MiR-34a expression negatively affects CD133+/CD15+ tumor-propagating cells. Adenoviruses carrying the precursor miR-34a induce neurogenesis of tumor spheres derived from a genetic animal model of MB (Patch1+/- p53-/-), thus providing further evidence that the miR-34a/Dll1 axis controls both autonomous and non autonomous signaling of Notch. In vivo, miR-34a overexpression carried by adenoviruses reduces tumor burden in cerebellum xenografts of athymic mice, thus demonstrating an anti-tumorigenic role of miR-34a in vivo.

134 patients with acquired aplastic anaemia (AA) were given HALG 15 mg/kg/d for 5 d and methylprednisolone for 1 month, and randomized to receive (n = 69) or not (n = 65) oxymetholone 2 mg/kg/d p.o. daily for 4 months. Early mortality (120 d) was comparable in the two arms 12/69 (17%) and 11/65 (17%), and correlated with the severity of the disease (39%, 10% and 6% respectively in patients with neutrophil counts (PMN)0.2, 0.2-0.5,0.5 x 10(9)/l). The response rate at 120 d was significantly greater in patients receiving androgens (56% v 40%; P = 0.04); it was 68% v 48% (P = 0.02) in patients surviving 120 d, and 78% v 27% (P = 0.03) in females with PMN less than 0.5 x 10(9)/l. In a multivariate Cox analysis on patients with less than 0.5 x 10(9)/l PMN, the probability of responding without androgens was reduced compared to the androgen treatment arm (P = 0.05). Survival was comparable in the two groups (71% v 65%). It was superior (74% v 50%), but not significantly (P = 0.1) in females with PMNor = 0.5 x 10(9)/l receiving androgens. Side-effects, including biochemical abnormalities and virilization, could be controlled and were reversible. In conclusion, the addition of androgens to HALG and methylprednisolone as first line treatment of aplastic anaemia significantly improves the response rate at 4 months, particularly in females with low neutrophil counts, although there is no significant effect on short-term survival. The reversible side-effects warrant the use of androgens as an adjunct to the first course of ALG in females with severe AA.

A simple prognostic classification of Ph+ chronic myeloid leukemia (CML) was proposed in 1984 by an international study Group [23] and is now widely used for clinical purposes. That study was retrospective, and was based on disease features at diagnosis. To test prospectively and to check the value of the classification, and to investigate if additional information on the early course of leukemia can help in refining the prognosis, 505 Ph+, nonblastic and nontransplanted patients first registered between 1984 and 1986 were followed up to June 1990. It was found that the prognostic formulation predicted survival in that series exactly the same way as in the original series (median survival: > 60 months for low-risk patients, 46 months for intermediate-risk patients, and 32 months for high-risk ones). It was also found that several objective or subjective assessments of disease course during the first 8 months after diagnosis were significantly related to survival length within any risk group. This study provides full confirmation of Sokal's international prognostic classification, and shows that the definition of prognosis can be improved some months after diagnosis by taking into account the course of the disease and the response to therapy. These conclusions apply to patients receiving conventional treatment. The course of Ph+ chronic myeloid leukemia (CML) is rigidly programmed to progress to an acute phase, which is called blastic metamorphosis (BM) and which can develop either suddenly (blastic crisis) or by a slow progression (accelerated phase) [7,24,29]. In all recent series, 2-year survival ranged between 65% and 80%, median survival was slightly shorter than 4 years, and the proportion of patients who were still alive after 10 years was less than 10% [24,29]. However, a number of prognostic variables were identified [2,8,9,12,15,16,19,23, 28] and a prognostic formulation that was claborated by an international study [23] was shown to provide a reliable estimate of survival length and is currently used for that purpose. The value of that formulation, and the formulation itself, require periodical controls and revisions. For that purpose, the Italian Cooperative Study Group on CML registered and followed up all CML patients who were first seen between 1984 and 1986. A very preliminary analysis of that cohort of patients has already been performed, but it was limited to the first 2 years after diagnosis [10]. This report extends prior findings, confirming the validity of the formula up to the 5th year after diagnosis, and shows that the definition of prognosis can be significantly improved by taking into account dynamic clements which reflect the course of the disease and the response to conventional treatment during the first 8 months after diagnosis.

Objective To describe the natural history of sporadic and familial hemiplegic migraines (SHM and FHM) with onset in the pediatric age. Methods Retrospective observational study of 28 cases, visiting 9 Italian Centers for Juvenile Headache, diagnosed as SHM or FHM (ICHD-III b version, 2013) with onset under 16 years and with a longitudinal follow-up. Results 28 cases (17 females, 11 males): 23 SHM (14 females, 9 male), 5 FHM (3 females, 2 male). Family history was positive for migraine without aura (5/28) or with aura non hemiplegic (8/28). Triggering factors were found in 13/28 cases. Age at HM onset: mean 10.1 y, range 4–16 y (5/28 cases under 6 y). Mean duration of aura was 11h 13' (range 5′–48 h). Between HM attacks, neurologic examination was normal in 26/28 cases. At follow-up: mean age 16.9 y (range 6.5–47 y), mean duration of follow-up 8.1 y (range 2.5–38 y). The frequency of attacks ranged from 2 per month to less than 1 per year (mean 5–6 every year). During follow-up, FHM and SHM cases showed some differences: in cases with SHM attacks were less frequent but more severe while FHM patients had less intense but more frequent attacks and also a longer duration of disease. Preventive therapy for HM was prescribed to 12/28 cases. Conclusion In the Literature data on the natural history of HM are quite limited, particularly in children. In the majority of our cases, the frequency and the type of attacks were quite variable, and in less than half of the cases trigger factors were identified. The majority of our patients had a good prognosis, even in cases with early onset of HM and/or prolonged and/or severe HM attacks. The natural history of SHM seems to differ from the FHM.

Calcitriol (C) improves anemia in chronic renal failure. This improvement may be related to the suppression of iPTH release, but also to a direct effect on erythropoiesis.In order to verify this hypothesis, 33 patients with chronic renal failure were enrolled: 24 were undergoing hemodialysis, 9 managed conservatively. All patients were free from other chronic or hematological disease, had a negative DFO test and aluminum levels below 20 mcg/l. iPTH range was 250-480 pg/l. None had yet been treated with C. In vitro study- Samples were drawn for a basal erythroid precursors (Burst Forming Unit-Erythroid BFU-E) study. After mononuclear cells were isolated by centrifugation with Ficoll-Hypaque, they were incubated for 15 days with rHuEPO 3U/ml (A), rHuEPO 3U/l + C 30 pg (B), rHuEPO 3U/ml + C 300 pg (C), rHuEPO 30 U/ml + C 300 pg (D) was performed. Ex vivo study- After the basal evaluation, 10 pts on dialysis were treated with C (Calcijex-Abbott) 1 g three times a week. BFU-E studies were performed after 1,2 and 4 months.In vitro, culture B showed an increased BFU-E proliferation vs A (41+/- 23 vs 27+/-15, p less than 0.02); in C and D cultures proliferation was 61+/-31 and 78+/- 42 respectively, p less than 0.01 vs A. There was no difference among pts with renal failure and pts treated conservatively. During the in vivo study all cultures showed a progressive proliferation increase, without a plateau level (basal, after 1, 2, 4 months respectively): in A: 17+/-8, 22+/-13, 30.9+/-14.9, 41.4+/-20; in B: 27.3+/-15, 35.6+/-20, 45.5+/-21, 57+/-26; in C: 48.2+/-20.6, 63.7+/-32, 75.7+/-37, 83+/-40; in D: 72+/-24, 91+/-42, 106+/-42, 110+/-42.3 (always p less than 0.001). The hematocrit and hemoglobin increase was constant but not significant. The iPTH decrease was not related to BFU-E proliferation.In chronic uremia C has a direct effect on erythroid precursor proliferation, both in vitro and ex vivo, with a sinergystic effect with rHuEPO. This effect is not related to iPTH suppression. C may be a useful adjuvant therapy for rHuEPO treatment.

It has been suggested that calcitriol (C) could improve anemia in chronic renal failure. However it remains debatable whether vitamin D has a specific effect on erythropoiesis, or it acts via suppression of hyperparathyroidism.We enrolled 29 patients with chronic renal failure, free from malignancies, iron deficiency or other chronic or hematological diseases. Aluminium accumulation was also excluded by DFO test. 22 were on hemodialysis and 7 on conservative management, creatinine clearance ranging 22-48 ml/min. Their mean age was 62+/-28 years and duration of renal disease was 98+/-51 months. No patient under-went rHu-Epo or Vitamin D treatment. 4 subjects were enrolled as controls. Samples of peripheral blood were drawn for the Burst Forming Unit-Erythroid (BFU-E) assay. After isolation of mononuclear cells by density gradient centrifugation with Fycoll-Hypaque, a 15-day incubation was set up with four different conditions: a) adding standard dose, 3 U/ml, of r-HuEpo (Dompè Biotec), standard colture; b) combined doses of r-HuEpo, 3 U/ml, and C (Abbott), 30 pg; c) standard dose, 3 U/ml, of r-HuEpo and high dose, 300 pg, of C; and lastly d) combined high doses of r-HuEpo, 30 U/ml, and C, 300 pg.In the b colture (combined low doses) a higher BFU-E proliferation was found vs standard (a) colture (33.2+/-15.5 vs 17.1+/-9.2, p0.02); interestingly, either in the c and d studies BFU-E showed an even higher proliferation (52.3+/-24 and 86.3+/-37.8 respectively, p0.01 vs a). No difference was found when evaluating separately preterminal and hemodialysis patients. In control subjects only colture d showed an increased BFU-E proliferation.C has a direct effect on erythroid precursors proliferation in vitro, acting in a sinergystic manner with rHuEpo. C may be useful as adjuvant therapy for renal anemia.

Recombinant erythropoietin (r-EPO) induces erythroid responses in patients affected by myelodysplastic syndromes (MDS). However, the response rate declines to 10-15% in MDS with substantial transfusion needs. Both in vitro and in vivo studies have suggested that the addition of growth factors (G-CSF, GM-CSF) or interleukin-3 (IL-3) may potentiate the effect of r-EPO on dysplastic erythropoiesis. The aim of this study was to evaluate the effects of the combination of r-EPO with G-CSF, GM-CSF or IL-3 on the anemia of heavily transfusion-dependent MDS patients, previously unresponsive to r-EPO alone.Sixty patients with transfusion-dependent MDS, already treated without significant erythroid response with r-EPO alone, were scheduled to receive, for at least 8 weeks, r-EPO subcutaneously at the dose of 300 U/kg t.i.w. in combination with G-CSF (300 microcg s.c. t.i.w., 27 patients), or GM-CSF (300 microcg s.c. t.i.w., 23 patients), or IL-3 (5 microcg/kg s.c. t.i.w., 10 patients), after a two-week pre-phase during which G-CSF, GM-CSF and IL-3 were administered daily at the same dose, as single drugs.Ten patients were not evaluable for erythroid response because of relevant side effects related to GM-CSF or IL-3 administration. Overall, among 50 patients who completed the study, there were 3 erythroid responses (as determined by complete abolition of red-cell transfusions): 1 (4%) in the G-CSF + r-EPO and 2 (10.5%) in the GM-CSF + r-EPO treated groups. No patient responded to the combination of r-EPO + IL-3. All responders had inappropriate serum levels of endogenous EPO and a relatively short disease duration. Both responders to GM-CSF + r-EPO developed acute myeloid leukemia 2-9 months after the start of the combined therapy. A third elderly patient, treated with the same association, developed marrow hypoplasia. A significant increase in leukocyte count occurred in 96% of patients who received r-EPO + G-CSF, 78.9% of those treated with r-EPO + GM-CSF and 66% of subjects receiving r-EPO + IL-3. A significant increase in platelet count was observed in a single patient receiving r-EPO and GM-CSF, while a slight decrease in platelet count with respect to baseline levels occurred in about 20% of patients.Our results suggest that the combination of r-EPO with G-CSF, GM-CSF or IL-3, at least at the doses and schedules employed in the present study, has limited efficacy on the anemia of heavily transfusion-dependent MDS patients previously unresponsive to r-EPO alone. However, in this setting of patients, the combination of G-CSF or GM-CSF + r-EPO may occasionally be effective in subjects with low circulating levels of serum EPO and short disease duration.

One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P =.001) and 88% versus 87% for patients aged less than versus more than 16 years (P =.8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF. (Blood. 2000;95:1931-1934)

Twenty-five patients (22 adults and 3 infants) with ALL1/AF4-positive acute lymphoblastic leukemia (ALL) were prospectively monitored by reverse transcriptase-polymerase chain reaction (RT-PCR) between January 1992 and July 1999. After high-dose induction and consolidation chemotherapy without bone marrow transplantation, all patients had a complete hematologic remission. Using nested RT-PCR (sensitivity 10(-4)), we observed conversion to PCR negativity in 11 (44%) of the patients. Thirteen of the 14 patients who did not have a molecular remission had a relapse at a median time of 4 months (range, 1 - 20 months). Of the 11 patients who had a conversion to PCR negativity, 5 reconverted to PCR positivity within 1 to 14 months. These 5 patients all progressed to hematologic relapse after 2, 3, 4, 4, and 7 months, respectively. Of the remaining 6 patients, 4 are in persistent hematologic and molecular remission at 12, 14, 88, and 96 months, whereas 2 are early in their follow-up. Actuarial probabilities of relapse and overall survival were 100% and 0% at 14 and 24 months and 67% and 43% at 96 and 100 months, respectively, in patients who had persistent RT-PCR positivity and in those who had a molecular remission. For both relapse and survival, the differences observed between the two groups were significant (P =.003 and P.005, respectively). This study, which represents the first prospective analysis of residual-disease monitoring carried out in a substantial series of patients with t(4;11)-positive ALL, emphasizes the clinical relevance of RT-PCR-based methods to monitor minimal residual disease in this leukemia subset. (Blood. 2000;95:96-101)

CD34+ hematopoietic progenitor cells (HPCs) constitute a heterogeneous population both in size and in immunological features. Lack of CD38, HLA-DR and lineage committed antigens as well as the co-expression of Thy-1 (CDw90) and c-kit receptor (CD117), are able to identify the so-called stem cells. A flow cytometric study was carried out to investigate the co-expression of Thy-1 and c-kit receptors, both members of Ig superfamily adhesion molecules, involved in cell to cell and cell to stroma interactions, on bone marrow (BM), mobilized peripheral blood (PB) and human umbilical cord blood (HUCB) CD34+ HPCs.Lysed whole blood from 15 BM, 25 mobilized PB and 25 HUCB samples were used to perform a five-dimensional flow cytometric evaluation of both CDw90 and CD117 on CD34+ cells.Few CD34+ cells co-expressed Thy-1 antigen in all three compartments (BM: 11.2 +/- 7.2%; PB: 6.2 +/- 3.6%; HUCB: 6 +/- 2.9%; BM vs PB0.04; BM vs HUCB0.008; PB vs HUCB ns). c-kit receptor was detected on the majority of CD34+ HPCs, particularly in HUCB (HUCB: 80.7 +/- 8.2%; BM: 72.3 +/- 13.1%; PB: 64.2 +/- 17%; HUCB vs BM0.03; HUCB vs PB0.0001; BM vs PB ns). CD34+Thy-1+ and CD34+c-kit+ HPCs generally displayed HLA-DR antigen, as expression of early cell commitment. However, the most immature CD34+Thy-1+HLA-DR- (HUCB: 1 +/- 0.6%; BM: 0.4 +/- 03%; PB: 0.7 +/- 0.5%; HUCB vs BM0.0001; BM vs PB0.04; HUCB vs PB ns) and CD34+c-kit+HLA-DR- HPCs (HUCB: 6.5 +/- 4.4%; BM: 6.3 +/- 4.8%; PB: 2.2 +/- 1.8%; HUCB vs BM ns; BM vs PB0.0001; HUCB vs PB0.0001) were mainly detected in HUCB. Finally, the greatest percentage of CD34+Thy-1+c-kit+ cells was found in BM (6.9 +/- 4.1%) followed by leukapheretic samples (4.4% +/- 2.7) and then by HUCB (3.7 +/- 1.2%; BM vs PB ns; BM vs HUCB0.001; HUCB vs PB ns).Since the blood release or HPCs is probably due to a perturbation of the adhesive interactions between these cells and the marrow stroma, the different pattern of Thy-1 and c-kit receptor expression on CD34+ HPCs found in the three hemopoietic compartments evaluated can lead to new knowledge about the mobilization kinetics in which the Ig superfamily adhesion molecules are involved.

The CD117 molecule is an antigen more frequently found on early normal and leukemic hematopoietic cells, but its correlation with the FAB subtypes and with other lineage and stage associated antigens is still not well established. In this study we investigated the surface expression of CD117 antigen in 135 patients with acute leukemia in relationship to de novo or secondary origin of AML, subtypes of FAB classification, expression of other antigens such as CD34, HLA-DR, CD15, CD14, CD45RA, CD45RO, CD11b, CD11c, CD4, CD7, mixed antigen co-expression (LyAg + AML and MyAg + ALL) and features of leukemic mass.The CD117 antigen expression (clone 95C3) was determined by flow cytometry in a series of 135 patients with acute leukemia at diagnosis consecutively observed during the years 1995-1997: 82 AML (including 51 cases of de novo AML, 22 cases of AML following myelodysplastic syndromes (MDS), 9 cases of myeloid blastic crisis of chronic myeloid leukemia (BC-CML) and 53 ALL. All cases were stratified in CD117+ and CD117- groups and the differences were analyzed by using appropriate statistical analyses.CD117 antigen was found over 10% in 74% of AML without significant differences of positivity between AML after MDS or BC-CML and de novo AML. We did not note a significant correlation between FAB classification and CD117 which was expressed in 100% of M1 and M7 cases, in 80% of M0 cases, in 75% of M2 cases, in 70% of M3 cases and in 82% of M4 cases. Instead, in M5 subtype CD117 was strictly restricted to earlier stages: ten of the eleven M5b (91%) cases completely lacked CD117 antigen expression, whereas 100% of M5a cases were positive. The results of Pearson's coefficient showed: 1) a significant inverse relationship between CD117 and CD15, CD4 and CD14 (only in M5 subtypes) and CD11b, CD11c and CD45RO (in all cases); 2) a significant direct correlation between CD117 and CD34 and CD45RA (in all cases); and 3) an independent expression between CD117 and CD15 associated with a low correlation between CD117 and HLA-DR antigen (only in non-monocytic cases). In ALL, whether of B or T lineages, surface expression of CD117 was never observed.We conclude that the CD117 antigen shows a high specificity for AML, independently upon FAB classification, and represents a reliable marker in characterizing the differentiative degree of the monocytic blasts.

One of the most important potential advantages in the use of human umbilical cord blood (HUCB) for hematopoietic reconstitution after myeloablative therapy seems to be the lower occurrence of acute graft-versus-host-disease (GvHD) in recipients after allogeneic transplantation. Since mature T cells play an important role in GvHD pathogenesis, we tried to verify whether a different immunophenotypic pattern exists between HUCB and peripheral blood (PB) T cells.An immunophenotypic study on 40 HUCB and 40 PB samples from healthy adult volunteers was performed, by means of flow cytometry using a large panel of monoclonal antibodies in double labeling.The absolute lymphocyte count was greater in HUCB (5233 +/- 1808 microL) than in adult PB (1941 +/- 378 microL). Significant differences in percentage were found between cord and adult T-cells, respectively (CD3+: 59.9 +/- 12 vs 74.9 +/- 4.6%), CD3- CD16+ and/or CD56+ natural killer (NK) cells (23.8 +/- 10.1 vs 10.8 +/- 5.3%) and CD3+CD16+ and/or CD56+ cytotoxic T lymphocyte subset (0.3 +/- 0.3 vs 10.7 +/- 4.1%). There was no difference in CD4/CD8 ratio (1.7 +/- 0.5 vs 1.6 +/- 0.2%) between the two groups. In absolute terms, HUCB contained an higher number of all lymphocyte subsets, with the exception of CD3+CD16+ and/or CD56+ T lymphocyte subpopulation, CD3+CD25+ and CD3+HLADR+ activated T-cells. CD38, a marker of activation and immaturity, was present on virtually all cord T cells and on approximately half of the adult T cells. The large majority of HUCB T cells co-expressed CD45RA naive antigen (CD4+CD45RA+: 87.6 +/- 5.2%, CD8+ CD45RA+: 93.5 +/- 7.8%; CD4+CD45RO+: 12.3 +/- 5.2%; CD8+CD45RO+: 6.4 +/- 7.8%) whereas in adult PB T cells an higher number of CD45RO+ memory cells was detected (CD4+CD45RA+: 44.8 +/- 9.6%; CD8+CD45RA: 71.5% +/- 8.1%; CD4+CD45RO+: 55.2 +/- 9.6%; CD8+ CD45RO+: 28.5 +/- 8.1%). Finally, less than 14% of lymphocytes were shown to belong to B lineage in both sources, while, in absolute terms, they were more represented in HUCB with respect to adult PB.In the present study we found significant difference between HUCB and adult PB lymphocytes in their immunophenotypic profile. In particular HUCB showed T lymphocytes that appeared to be phenotypically immature. Indeed, as a likely consequence of poor antigenic experience during pregnancy, the majority of HUCB cells were naive, expressing the RA isoform of the CD45 molecule. These findings could justify the previously reported reduced cord blood lymphocyte alloreactivity when allogeneic transplantation is performed and require further functional studies in order to confirm the impairment of HUCB immune system response to alloantigens.

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow-up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin's disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin's disease, is needed.

The in vitro inhibitory effect of all-trans retinoic acid (ATRA) on myeloma cell growth may be synergistically potentiated by the activity of dexamethasone (DEX) and alpha-interferon (IFN). We treated 10 patients with advanced, refractory multiple myeloma (MM) using a combination of ATRA (100 mg p.o., once a day for two weeks every month), DEX (40 mg i.v., for 4 days every 4 weeks) and IFN (3 MU s.c., three times a week). Eight patients completed at least three months of treatment and were evaluable for response. Two of them showed a partial response which persists after 15 to 17 months. Three patients experienced a stable plateau phase of 4 to +11 months, with a significant improvement in the performance status and bone pain. Progressive disease was seen in the remaining three patients. We conclude that the association of ATRA, DEX and IFN warrants further consideration in MM patients.

Although less specific than sCD23, sCD54 levels have clinico-prognostic relevance in B-cell chronic lymphocytic leukemia (CLL). Since serological markers are now emerging as potentially important in CLL, we tried to verify whether sCD54 might complement clinical stages.Serum levels of sCD54 were determined at the time of diagnosis in 115 previously untreated CLL patients. Results were correlated with clinicobiological parameters as well as with survival.Life-expectancy was significantly shorter in patients with higher serum levels of sCD54 (p0.001); however, in a Cox's multivariate survival analysis, the only variables which entered the regression model at a significant level were bone marrow (BM) histology (p = 0.03) and lymphocyte doubling time (LDT) (p = 0.04). Interestingly, when LDT was excluded from analysis the only significant variables were clinical stages (p0.05) and sCD54 (p0.05). These results suggest that sCD54 and LDT give similar prognostic information.In CLL, sCD54 is a reliable prognostic parameter whose value is independent of clinical stages. When investigated in relation to clinical outcome, serum levels of sCD54 were able to predict progression to a more advanced clinical stage. On the basis of these data, an integrated clinico-biological classification which separates intermediate risk into two prognostic subgroups is proposed.

The prognostic significance of CD34 antigen expression in acute lymphoblastic leukemias (ALL), especially in adult patients, is still not well established. In the present report we analyzed a series of biological and clinical findings from 128 ALL patients in order to evaluate the possible clinical significance of this marker.The clinical and biological significance of CD34 expression, an early marker of hemopoietic cells, was analyzed by flow cytometry in a series of 128 patients affected by ALL, including 78 adults and 50 children under 15 years old.Overall, 68.7% of patients showed significant (10%) CD34 expression. There was no difference between CD34+ and CD34- ALL with respect to age, sex, FAB morphology, hepatosplenomegaly, Plt count, Hb level, DNA index, P-170 expression. CD34+ ALL displayed a significantly lower frequency of extramedullary involvement, a lower LDH level and lower WBC count, lower proliferative activity (as evaluated by the Ki67 monoclonal antibody) than CD34- ALL. CD34 expression was also associated with early phenotypes in both B- and T-ALL, co-expression of myeloid antigens, and the presence of the Ph1 chromosome. Due to a different distribution of prognostic factors investigated, DFS and OS were both significantly better in CD34+ than in CD34- childhood ALL, whereas no statistical difference was found in adults. Multivariate analyses confirmed these data in children.Expression of the CD34 antigen is a positive prognostic factor in childhood ALL. In adult ALL the presence of this marker on leukemic cell does not seem to influence the clinical outcome of these patients.

Nonionic-iodinated contrast (NIC) and gadolinium-based contrast (GBC) media enhance the sensitivity of CT and MRI procedures, respectively (Schultz and others 2009, Zhao and others 2010). The intravenous administration of contrast media, especially iodinated compounds, is reported to be associated with contrast-induced nephropathy, characterised by an increase in serum creatinine of 44 ∝mol/l, or by more than 25 per cent from the baseline values, within 48–72 hours (Barrett and Parfrey 2006). The aim of this prospective study, with standardised sampling collection, was to assess biochemical changes associated with the intravenous administration of NIC and GBC during routine CT and MRI in dogs, as suggested in a retrospective study by Pollard and others (2008). The study, approved by the Ethics Committee of the Universita degli Studi di Milano (authorisation number 24/11), was performed on 42 dogs (ASA 1 or 2) consecutively admitted, under informed consent, for routine CT or MRI. Dogs were allocated into three groups of 14 patients each. The NIC and the GBC groups included dogs undergoing contrast-enhanced CT, using intravenous iohexol (Omnipaque 300; GE Healthcare) or iodixanol (Visipaque 270; GE Healthcare), or MRI, using intravenous gadodiamide (Omniscan 287; GE Healthcare). The control group (CTR) included dogs undergoing CT or MRI without …

CD23 is a functionally relevant molecule in B-cell chronic lymphocytic leukemia (CLL) which mediates growth and differentiation signals in B-cells. An intriguing feature of CD23 is its ability to be cleaved from the cell surface and released into the serum.Serum levels of soluble CD23 (sCD23) were determined with a sandwich enzyme immunoassay at the time of diagnosis in 90 previously untreated CLL patients, in order to evaluate whether they reflected disease activity and tumor load. Results were correlated with those dealing with CD23 expression on leukemic cells to verify whether the cellular counterpart determines serum levels.CD23 was detected on peripheral blood mononuclear cells (PBMC) from 78 out of 90 (86.6%) B-CLL patients, without correlation with clinical stage. Circulating levels of sCD23 in the serum of patients with CLL were highly elevated in comparison to 15 normal controls (p0.0005); this increase reflected tumor mass as defined by either clinical stage (p0.0005) or bone marrow (BM) histology (p0.0005). Neither percentage nor absolute number of CD23+ cells correlated with circulating levels. Interestingly, life expectancy was significantly shorter in patients with higher serum levels of sCD23 (p0.0005). When integrated into the Binet clinical staging system, sCD23 led to isolation of two subgroups with different prognosis among intermediate-risk patients. Furthermore, longitudinal studies support the idea that sCD23 can be utilized as an indicator of disease progression.sCD23 is a highly sensitive and suitable marker with prognostic potential in B-CLL.

Human umbilical cord blood (HUCB) is a possible alternative to bone marrow (BM) and mobilized peripheral blood (PB) for transplantation of hematopoietic progenitors. The aim of this study was to evaluate the phenotypic profile of CD34+ progenitors present in HUCB.A flow cytometric analysis was performed on 20 HUCB samples, using a large panel of monoclonal antibodies recognizing different lineage or activation antigens, in double labeling with CD34.A toal of 13,897 +/- 2,529 cells/microL, 0.84 +/- 0.83% of which were CD34+, was found. The large majority of CD34+ cells were committed toward initial myeloid differentiation (CD33+, CD13+) and expressed the transferrin receptor (CD71). A substantial proportion of these cells (about 40%) co-expressed CD45RA and CD117, while a very small number displayed markers of advanced myeloid commitment, such as CD14, CD15 and CD41 (less than 2%), or those of lymphoid differentiation: CD2, CD5, CD7, CD10 and CD19 (less than 6%). About 11% of HUCB CD34+ cells were primitive progenitors, as suggested by the absence of HLA-DR and CD38 on their surface.As previously observed in BM and mobilized PB, the phenotype of HUCB CD34+ cells is quite heterogeneous. In particular, HUCB contains subpopulations of both early and committed hematopoietic progenitors which may represent a valid source for transplantation.

We report a case of de novo plasma cell leukemia, resistant to standard VMD (vincristine, mitoxantrone, dexamethasone) and CVP (cyclophosphamide, vincristine and prednisone) protocols, treated with a chemotherapy intensification regimen (high-dose cyclophosphamide, modified EDAP, Dexa-BEAM) and peripheral blood stem cell transplantation, performed using fractionated total body irradiation and high dose melphalan. The patient is currently alive and well, in very good partial remission 12 months after transplant and 22 months after diagnosis, disclosing a significant proportion of bone marrow and peripheral blood CD3+, CD8+, CD57+, HLA-Dr+ large granular lymphocytes with cytotoxic activity against neoplastic plasma cells.

Hematopoietic progenitor cells (HPC), identified by expression of the CD34 surface antigen, show morphological and phenotypic heterogeneity in bone marrow (BM) and peripheral blood (PB).CD34+ HPC subpopulations present in 18 PB leukaphereses after high-dose chemotherapy in cancer patients and in 11 BM samples from patients with stage IA lymphoma were characterized. In order to identify CD34+ HPC subsets within these two compartments, the expression of lineage- or activation-associated antigens and the c-kit gene product (CD117) was studied by flow cytometry, using a large panel of monoclonal antibodies (MoAb) in double labelling.We observed a higher proportion of CD34+/CD13+ and CD34+/CD33+ cells (myeloid commitment) in harvested leukapheresis products than in BM. On the contrary, a higher percentage of CD34+/CD10+ and CD34+/CD19+ cells (B-lymphoid commitment) was found in BM. The percentage of the most immature subset of CD34+ HPC (CD38- and HLA-DR-) was also higher in BM than in mobilized PB. No differences in proportions were found with respect to the expression of CD14, CD15, CD45RA (myeloid commitment), CD2, CD5, CD7 (T-lymphoid commitment), CD117, CD71 and CD45RO antigens. In terms of absolute values, however, significantly higher amounts of CD34+ HPC co-expressing CD13, CD33, CD5, CD7, CD71, CD117, CD45RA, CD45RO were detected in leukaphereses than in BM. The absolute number of immature HPC (CD34+/CD38- and CD34+/HLA-Dr-) was also significantly increased in mobilized PB.Our data confirm the heterogeneous phenotypic profile of HPC, thus supporting the hypothesis that different CD34+ subpopulations may have clinical relevance on the rapidity and long-term durability of engraftment in patients who undergo high-dose chemotherapy followed by rescue with HPC. We also demonstrated that mobilized PB is a particularly rich source of both primitive and committed HPC, more than BM.

Essential thrombocythemia (ET) is a clonal disorder of the myeloid stem cell that causes pathologic expansion of the megakaryocytic elements in the bone marrow, with a persistent increase in the platelet count. In order to avoid the mutagenic effects of radioactive phosphorous and alkylating agents, various European clinicians use pipobroman rather than hydroxyurea as single chemotherapeutic treatment, since it is simple and well tolerated and does not lead to hematological complications or the risk of visceral cancer. Here we describe a 63-year-old ET patient who showed myelodysplastic transformation (RAEB-t) of the primary disease after about eight years of therapy with pipobroman at variable dosages.

Patients with severe aplastic anemia (SAA) and a neutrophil (PMN) count of less than 0.5 x 10(9)/L are exposed to a high risk of early mortality when treated with antilymphocyte globulin (ALG) and steroids, with the major problem being infectious complications. The addition of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to ALG may reduce early mortality by improving neutrophil counts in the short term. To test the feasibility of this approach, the SAA Working Party of the European Group for Blood and Marrow Transplantation (EBMT) designed a pilot study that included rhG-CSF (5 micrograms/kg/d, days 1 through 90), horse ALG (HALG; 15 mg/kg/d, days 1 through 5), methylprednisolone (2 mg/kg/d, days 1 through 5, then tapering the dose), and cyclosporin A (CyA; 5 mg/kg/d orally, days 1 through 180). Patients with newly diagnosed acquired SAA (untreated) and with neutrophil counts ofor = 0.5 x 10(9)/L were eligible. Forty consecutive patients entered this study and are evaluable with a minimum follow up of 120 days: the median age was 16 years (range, 2 to 72 years), the interval from diagnosis to treatment was 24 days, and the median PMN count was 0.19 x 10(9)/L. Twenty-one patients had hemorrhages, and 19 were infected at the time of treatment. Overall, treatment was well tolerated: the median maximum PMN count during rhG-CSF administration was 12 x 10(9)/L (range, 0.4 x 10(9)/L to 44 x 10(9)/L). There were three early deaths (8%) due to infection. Four patients (10%) showed no recovery, whereas 33 patients (82%) had trilineage hematologic reconstitution and became transfusion-independent at a median interval of 115 days from treatment. Median follow up for surviving patients is 428 days (range, 122 to 1,005). Actuarial survival is 92%: 86% and 100% for patients with PMN counts less than 0.2 x 10(9)/L or between 0.2 x 10(9)/L and 0.5 x 10(9)/L, respectively. This study suggests that the addition of rhG-CSF to ALG and CyA is well tolerated, is associated with a low risk of mortality, and offers a good chance of hematologic response. This protocol would appear to be an interesting alternative treatment for SAA patients with a low PMN count who lack an HLA-identical sibling.

The efficacy and toxicity of teicoplanin and vancomycin in the initial empirical antibiotic regimen in febrile, neutropenic patients with hematologic malignancies were compared in a prospective, randomized, unblinded, multicenter trial in the setting of 29 hematologic units in tertiary-care or university hospitals. A total of 635 consecutive febrile patients with hematologic malignancies and chemotherapy-induced neutropenia were randomly assigned to receive intravenously amikacin plus ceftazidime plus either teicoplanin at 6 mg/kg of body weight once daily or vancomycin at 1 g twice daily. An efficacy analysis was done for 527 evaluable patients: 275 treated with teicoplanin and 252 treated with vancomycin. Overall, successful outcomes were recorded for 78% of patients who received teicoplanin and 75% of those who were randomized to vancomycin (difference, 3%; 95% confidence interval [CI], -10 to 4%; P = 0.33). A total of 102 patients presented with primary, single-agent, gram-positive bacteremia. Coagulase-negative staphylococci accounted for 42%, Staphylococcus aureus accounted for 27%, and streptococci accounted for 21% of all gram-positive blood isolates. The overall responses to therapy of gram-positive bacteremias were 92 and 87% for teicoplanin and vancomycin, respectively (difference, 5%; CI, -17 to 6%; P = 0.22). Side effects, mainly represented by skin rash, occurred in 3.2 and 8% of teicoplanin- and vancomycin-treated patients, respectively (difference, -4.8%; CI, 0.7 to 8%; P = 0.03); the rate of nephrotoxicity was 1.4 and 0.8% for the teicoplanin and vancomycin groups, respectively (difference, 0.6%; CI, -2 to 1%; P = 0.68). Further infections were caused by gram-positive organisms in two patients (0.7%) treated with teicoplanin and one patient (0.4%) who received vancomycin (difference, 0.3%; CI, -0.9 to 1.0%; P = 0.53). Overall mortalities were 8.5 and 11% for teicoplanin- and vancomycin-treated patients, respectively (difference, -2.5%; CI, - 2 to 7%; P = 0.43); death was caused by primary gram-positive infections in three patients (1%) in each treatment group. When used for initial empirical antibiotic therapy in febrile, neutropenic patients, teicoplanin was at least as efficacious as vancomycin, but it was associated with fewer side effects.

A series of immunological abnormalities has been described in patients with beta-thalassemia. The aim of this study was to investigate whether the measurement of serum levels of selected cytokines and soluble molecules (deriving from cell membrane antigens) involved in the immune response could be useful for a better definition of such alterations.Serum levels of interleukin-2 (IL-2), IL-6, tumor necrosis factor (TNF), soluble (s) CD4, sCD8, sCD23 and sCD25 were measured using immunoenzymatic assays in 45 transfusion-dependent patients affected by beta-thalassemia major and correlated to conventional immunological indexes, such as peripheral lymphocyte subpopulations and circulating immunoglobulins.Patients with beta-thalassemia major showed increased TNF, sCD8, sCD23 and sCD25 and lower sCD4 values compared to normal controls. IL-2 and IL-6 were found to be undetectable or within the normal range in all patients. Splenectomized patients presented lower levels of sCD8 and sCD23 than those observed in unsplenectomized ones. A series of correlations involving TNF, sCD8, sCD23, sCD25, serum immunoglobulins and some lymphocyte subpopulations was observed. In addition, serum markers of immune activation (TNF, sCD23, sCD25) correlated directly with the annual blood transfusion requirement. Despite this series of immunological anomalies, no patient had a history of repeated infectious episodes.Polytransfused beta-thalassemic patients are characterized by a partial functional immunodeficiency determined by increased activity of CD8+ suppressor/cytotoxic lymphocytes and possibly reduced activity of the CD4+ helper/inducer subset. B-lymphocytes also appear highly activated. The allo-antigenic stimulation of transfusions seems to play a major role in the determination of these defects; however, this functional immunological imbalance does not seem to have any clinical relevance.

BACKGROUND. Tumor necrosis factor (TNF) and interleukin-1 beta (IL-1) are two cytokines with erythropoietic inhibitory activity which may be involved in the pathogenesis of some types of anemia that may respond to recombinant erythropoietin (r-EPO). The aim of the present study was to evaluate whether TNF and IL-1 serum levels are related to clinical response in patients with myelodysplastic syndromes (MDS) receiving r-EPO. TNF and IL-1 serum levels were measured by means of immunoenzymatic assays in 26 patients affected by MDS and treated with r-EPO administered subcutaneously at dosages up to 1050 U/kg a week, for at least two months. Four patients (15%) showed a significant response, with an increase of hemoglobin2 g/dL and complete suspension of transfusions. Higher mean serum levels of both TNF (54.2 +/- 93 vs 4.2 +/- 7.9 pg/mL, p0.001) and IL-1 (114 +/- 58.5 vs 36.1 +/- 21.7 pg/mL, p0.001) were measured in MDS patients than in a group of 42 normal controls. However, responders showed significantly lower mean levels of TNF (8.2 +/- 9.6 vs 58.5 +/- 65.2 pg/mL, p0.05) and IL-1 (30 +/- 24.8 vs 127.8 +/- 51.4 pg/mL, p0.001) than those of non responders. In terms of absolute values, all responders evidenced undetectable or normal levels of both cytokines. No relationship was found between TNF or IL-1 and values of hemoglobin, serum erythropoietin, ferritin, soluble transferrin receptor or transfusional requirements. MDS patients who respond to r-EPO have lower serum levels of TNF and IL-1 than those who do not respond.

Invasive pulmonary aspergillosis (IPA) in the presence of hematologic malignancies is an increasingly common condition characterized by high morbidity and mortality. Plain chest films are a valuable tool for diagnosis but the radiologist must be familiar with the morphological features of the disease to interpret radiographic abnormalities and to differentiate IPA from opportunistic pneumonia. The chest films of 16 leukemia and IPA patients performed from January 1987 to September 1993 were reviewed. The natural course of infection from its early stage (nodular lesions) to the subsequent phases when eventual medullary recovery plays a critical role was thus traced. Our major finding was related to the histogenesis of primary pulmonary lesions: the most common features we observed--i.e., the spherical rather than triangular shape of necrosis areas, with no relationship to the pleura or scissural delimitation suggest that supposed ischemia from vascular infiltration cannot be the only pathogenetic factor of pulmonary injury, in spite of the well-known angioinvasivity of the fungus Aspergillus.