Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial.

BACKGROUND: Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. PATIENTS AND METHODS: Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). RESULTS: Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189). CONCLUSIONS: Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.

Methods for inactivation of seafood Anisakis larvae and prevention of human anisakiasis: a mini-review.

Anisakiasis is an arising zoonosis induced by parasitic nematodes belonging to the family Anisakidae. Anisakiasis is often caused by the ingestion of larval nematodes in uncooked or minimally processed seafood dishes, which are regularly consumed by humans. Significant potential sources of infection are raw fish (e.g., sushi and sashimi) that can be found in traditional Japanese cuisine and can be part of the culinary tradition of consumption of raw or marinated fish that is particularly diffused in European countries. During the last five decades, the global prevalence of human anisakiasis has been rising, becoming an emergent major public health problem. Thus, there is an unmet need for well-defined and cost-effective methods aimed at killing Anisakis larvae, thus reducing the incidence of anisakiasis. In this mini-review, we discuss the clinical features of anisakiasis as well as the effectiveness and mechanisms of action of the main methods employed for increasing seafood safety and killing Anisakis larvae, including freezing, heating, use of high hydrostatic pressure, salting process, pepsin digestion method and use of garlic oil.

Novel therapeutic approaches based on the pathological role of gut dysbiosis on the link between nonalcoholic fatty liver disease and insulin resistance.

The growing global epidemic of obesity and type 2 diabetes mellitus has determined an increased prevalence of NAFLD (non-alcoholic fatty liver disease), making it the most common chronic liver disease in the Western world and a leading cause of liver transplantation. In the last few years, a rising number of studies conducted both on animal and human models have shown the existence of a close association between insulin resistance (IR), dysbiosis, and steatosis. However, all the mechanisms that lead to impaired permeability, inflammation, and fibrosis have not been fully clarified. Recently, new possible treatment modalities have received much attention. To reach the review purpose, a broad-ranging literature search on multidisciplinary research databases was performed using the following terms alone or in combination: "NAFLD", "gut dysbiosis", "insulin resistance", "inflammation", "probiotics", "Chinese herbs". The use of probiotics, prebiotics, symbiotics, postbiotics, fecal microbiota transplant (FMT), Chinese herbal medicine, antibiotics, diet (polyphenols and fasting diets), and minor therapies such as carbon nanoparticles, the MCJ protein, water rich in molecular hydrogen, seems to be able to improve the phenotypic pattern in NAFLD patients. In this review, we provide an overview of how IR and dysbiosis contribute to the development and progression of NAFLD, as well as the therapeutic strategies currently in use.

Daratumumab plus bortezomib or daratumumab plus lenalidomide as salvage therapy for patients with myeloma: initial follow-up of an Italian multicentre retrospective clinical experience by 'Rete Ematologica Pugliese'.

We report herein a multicentre retrospective analysis of 192 consecutive patients with symptomatic refractory/relapsed multiple myeloma (RRMM) treated with daratumumab in combination with bortezomib or lenalidomide as salvage therapy at 9 haematological centres in Puglia. Choice of both regimens was based on previous treatment and/or physicians' preference. Considering the under-representation of older patients (very old patient ≥ 80 years) in clinical trials and the prognostic and predictive importance and value of frailty status, here, we further characterised the patient cohort by age. The overall response rate (ORR) was generally lower than what was previously reported in the CASTOR (ORR 72.6% vs 85%) and POLLUX (ORR 86.5% vs 93%) trials. The lower ORR in our analysis compared to the CASTOR and POLLUX trials could be related to a less selected population. Similarly, amongst very old patients, the ORR was encouraging: ORR to treatment with DVd (daratumumab + bortezomib + dexamethasone) was 66.7%, and ORR to treatment with DRd (daratumumab + lenalidomide + dexamethasone) was 92.3%. Median TTP (time to progression) was 10.8 months (1-year TTP: 44.7%; 2-year TTP: 25.3%) in the DVd group; median TTP was not reached in the DRd group (1-year TTP: 82.7%; 2-year TTP: 71.4%). Median OS (overall survival) was not reached either in the DRd group (1-year OS: 85.9%; 2-year OS: 73.7%) or the DVd group (1-year OS: 70.2%; 2-year OS: 58.9%).

Risk factors for diabetic foot ulcers: an Albanian retrospective study of inpatients with type 2 diabetes.

OBJECTIVE: The aim of this study was to assess the impact of glucose control, diabetes-related complications and cardiometabolic risk factors on the risk of diabetic foot ulcers (DFUs) and DFU complications in Albanian adult inpatients with T2D. PATIENTS AND METHODS: We conducted a retrospective case-control study on 482 Albanian adult inpatients with T2D. DFU was defined as a full-thickness skin lesion requiring ≥14 days for healing and was classified at the time of hospital admission. Demographic and biochemical parameters of the study participants, the presence of comorbidities and diabetes-related complications at the time of hospital admission were evaluated through a retrospective chart review. RESULTS: Mean age of study participants was 54.8±10.7 years. Participants (284 males and 198 females) were divided into two groups: DFU (cases; n=104) and non-DFU (controls; n=378). Multivariate analysis (performed by a logistic regression model) revealed that the most relevant independent variables associated with DFU were BMI [OR=0.62; p=0.007], HDL-cholesterol [OR=0.00; p<0.0001], triglycerides [OR=7.48; p=0.0004], cigarette smoking [OR=26.46; p=0.005], duration of diabetes [OR=1.53; p<0.0001], fasting plasma glucose (FPG) [OR=1.06; p<0.0001], systolic blood pressure (SBP) [OR=1.13; p=0.0004] and insulin therapy alone [OR=0.11; p=0.02]. ROC curve analysis showed that FPG (AUC=0.83), glycated hemoglobin (HbA1c) (AUC=0.75), triglycerides (AUC=0.78) and HDL-cholesterol (AUC=0.82) were the most reliable biomarkers able to detect DFU. In the DFU group, the most relevant independent variables associated with previous minor lower-extremity amputations (LEAs) were represented by HbA1c [OR=1.47; p=0.03], age <55 years [OR=0.12; p=0.05] and female sex [OR=4.18; p=0.03]; whereas the most relevant independent variables associated with diabetic peripheral neuropathy (DPN) were HbA1c [OR=1.70; p=0.006], SBP [OR=1.08; p=0.05], BMI [OR=1.20; p=0.03] and lack of cigarette smoking [OR=0.07; p=0.01]. Correlation analysis (performed through the nonparametric Spearman's rank correlation test or through the parametric Pearson test, as appropriate) revealed a significant positive relationship between HbA1c and FPG (r=0.58; p<0.0001), ulcer surface area (r=0.50; p<0.0001), ulcer grade (r=0.23; p=0.02), minor LEAs (r=0.20; p=0.04), DPN (r=0.41; p<0.0001), and metformin therapy alone (r=0.72; p<0.0001). There was a significant inverse correlation between HbA1c and insulin therapy alone (r=-0.31; p=0.01) and combined metformin and insulin therapy (r=-0.60; p<0.0001). Both DFU and non-DFU groups exhibited suboptimal mean LDL-cholesterol levels (>100 mg/dl) and mean HbA1c values >7.5%. Moreover, in DFU group HbA1c values were markedly elevated (≥10%) particularly in patients with a grade 3 ulcer and an ulcer surface area ≥4 cm2, as well as in patients with history of minor LEAs and in patients affected by DPN. CONCLUSIONS: The present study suggested that longer duration of diabetes, cigarette smoking, lower HDL-cholesterol levels, poor glucose control, and elevated triglyceride and SBP values may all represent major risk factors for the development of DFU in Albanian patients with T2D. Thus, community interventions and health policies aimed to improve the management of diabetes and related cardiometabolic risk factors should be urgently implemented in Albania, in order to prevent DFUs and other diabetes complications in patients with T2D.

Systemic lupus erythematosus and pregnancy: the challenge of improving antenatal care and outcomes.

OBJECTIVES: The objective of this article is to describe maternal and perinatal outcomes in women with systemic lupus erythematosus (SLE) followed in a high-risk prenatal outpatient clinic at a referral center. METHODS: This observational study included pregnant women with SLE who underwent prenatal follow-up and childbirth at the Women's Hospital, University of Campinas, from January 2012 to January 2018. All women were followed according to the institution's protocol for pregnant women with SLE. They were subdivided into two groups according to the presence of disease activity during the preconception and gestation periods, and evaluated according to the Systemic Lupus Erythematosus Disease Activity Index and Systemic Lupus Erythematosus Pregnancy Disease Activity Index scales. Data were retrieved from patients' medical records. Chi-square, Fisher exact and Mann-Whitney tests and multivariable analyses were performed. Statistical significance level was 5% (p < .05). RESULTS: A total of 125 cases were initially included; those who were lost to follow-up or gave birth at another hospital were further excluded, with 102 pregnancies (of 95 women) remaining. The mean age of the women was 27.7 years (SD 5.44), and 48% were in their first gestation. The average duration of disease was 6.79 years (SD 5.38), with 92.1% receiving SLE-specific therapy. SLE flare occurred in 8.9% during the preconception period and 23.5% during gestation. Preterm premature rupture of membranes (16.6%), preeclampsia or eclampsia (15.6%) and preterm labor (12.7%) were the most frequent complications. The mean gestational age at birth was 34.4 weeks (SD 5.9); the preterm birth rate was 46.8%, the low birth weight rate was 35.1%, and intensive neonatal care admission was 40.4%. Four fetal deaths and one maternal death occurred, all of them in the group with SLE flares. Multivariable logistic regression analysis showed that preconception lupus activity had a six-fold increased rate of gestational loss (odds ratio (OR): 6.14 (95% confidence interval (CI) 1.26-29.99)), and lupus activity during pregnancy had a five-fold increased rate of prematurity at less than 34 weeks (OR: 5.02 (95% CI: 1.90-13.30)). CONCLUSIONS: Despite the low percentages of women with pregestational and pregnancy-active disease, we found high incidences of maternal and perinatal complications. Preconception SLE activity increased gestational loss, and SLE activity during pregnancy increased prematurity. Effective immunosuppressive therapy was able to decrease clinical and laboratory activity of SLE; however, unfavorable perinatal outcomes still occurred, even when lupus activity was under control. Pregnancy in women with SLE is always a challenge.

'Real-life' report on the management of chronic GvHD in the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α.

Ceramide regulates several different cellular responses including mechanisms leading to apoptosis. Serum- and glucocorticoid-inducible protein kinase (SGK)-1 is a serine threonine kinase, which activates survival pathways in response to stress stimuli. Recently, we demonstrated an anti-apoptotic role of SGK-1 in human umbilical endothelial cells treated with high glucose. In the present study, since ceramide induces apoptosis by multiple mechanisms in diabetes and its complication such as nephropathy, we aimed to investigate whether SGK-1 may protect even against apoptosis induced by ceramide in kidney cells. Human embryonic kidney (HEK)-293 cells stable transfected with SGK-1 wild type (SGK-1wt) and its dominant negative gene (SGK-1dn) have been used in this study. Apoptotic stimuli were induced by C2-ceramide and TNF-α to increase endogenous synthesis of ceramide. Upon activation with these stimuli, SGK-1wt transfected cells have a statistically significant reduction of apoptosis compared with SGK-1dn cells (P<0.001). This protection was dependent on activation of caspase-3 and Poly-ADP-ribose-polymerase-1 (PARP-1) cleavage. SGK-1 and AKT-1 two highly homologous kinases differently reacted to ceramide treatment, since SGK-1 increases in response to apoptotic stimulus while AKT-1 decreases. This enhancement of SGK-1 was dependent on p38-mitogen-activated-protein kinases (p38MAPK), cyclic-adenosine-monophosphate/protein kinase A (cAMP/PKA) and phosphoinositide-3-kinase (PI3K) pathways. Especially, by using selective LY294002 inhibitor, we demonstrated that the most involved pathway in the SGK-1 mediated process of protection was PI3K. Treatment with inhibitor of SGK-1 (GSK650394) significantly enhanced TNF-α-dependent apoptosis in HEK-293 cells overexpressing SGK-1wt. Caspase-3, -8 and -9 selective inhibitors confirmed that SGK-1 reduced the activation of caspase-dependent apoptosis, probably by both intrinsic and extrinsic pathways. In conclusion, we demonstrated that in kidney cells, overexpression of SGK-1 is protective against ceramide-induced apoptosis and the role of SGK-1 can be potentially explored as a therapeutic target in conditions like diabetes, where ceramide levels are increased.

Role of Serum and Glucocorticoid-Inducible Kinase (SGK)-1 in Senescence: A Novel Molecular Target Against Age-Related Diseases.

Senescence is a phenomenon characterized by a progressive decline of body homeostasis. Premature senescence acts when the cellular system is not able to adequately respond to noxious stimuli by synthesis of stressor molecules. Among those, serum-and-glucocorticoidinducible kinase-1 (SGK-1) dramatically increases under typical physiopathological conditions, such as glucocorticoid or mineralcorticoids exposure, inflammation, hyperglycemia, and ischemia. SGK-1 has been implicated in mechanism regulating oxidative stress, apoptosis, and DNA damage, which are all leading to a state of accelerating aging. Moreover, SGK-1-sensitive ion channels participate in the regulation of renal Na(+)/K(+) regulation, blood pressure, gastric acid secretion, cardiac action potential, and neuroexcitability. Recently, we demonstrated in endothelial cells as an increase in SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated nitric oxide production after hyperglycemia. Moreover, we showed as SGK-1 delays the onset of senescence by increasing telomerase activity, significantly decreasing reactive oxygen species (ROS) production, and by directly interacting with hTERT. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against chronic diseases such as diabetes typical of aging. SGK-1 has been also associated with cancer, neurodegenerative diseases, and cardiovascular disease, among other age-related diseases. However, to date, the data available on SGK-1 and aging, are sparse, controversial, and only from C. elegans experimental models. In this review we sought to discuss the possible implication of SGK-1 in mechanisms regulating senescence and age-related diseases. Moreover, we aimed to discuss and identify the possible role of SGK-1 as possible molecular target to counteract and prevent aging.

Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey.

A prospective cohort study was conducted in nine hematology wards at tertiary care centres or at university hospitals located throughout Italy from January 2009 to December 2012. All of the cases of bacterial bloodstream infection (BBSI) occurring in adult patients with hematologic malignancies were included. A total of 668 bacterial isolates were recovered in 575 BBSI episodes. Overall, the susceptibility rates of Gram-negative bacteria were 59.1% to ceftazidime, 20.1% to ciprofloxacin, 79.1% to meropenem, 85.2% to amikacin, 69.2% to gentamicin and 69.8% to piperacillin/tazobactam. Resistance to third-generation cephalosporins was found in 98/265 (36.9%) of Enterobacteriaceae isolates. Among Klebsiella pneumoniae strains, 15/43 (34.9%) were resistant to carbapenems. Of 66 Pseudomonas aeruginosa isolates, 46 (69.7%) were multidrug resistant. Overall, the susceptibility rates of Gram-positive bacteria were 97.4% to vancomycin and 94.2% to teicoplanin. Among the monomicrobial cases of BBSI, the 21-day mortality rate was significantly higher for those caused by Gram-negative bacteria compared to those caused by Gram-positive bacteria (47/278, 16.9% vs. 12/212, 5.6%; p < 0.001). Among Gram-negative bacteria, the mortality rate was significantly higher for BBSI caused by K. pneumoniae, P. aeruginosa, and Acinetobacter baumannii. Our results confirm the recently reported shift of prevalence from Gram-positive to Gram-negative bacteria as causative agents of BBSIs among patients with hematologic malignancies and highlight a worrisome increasing frequency in antimicrobial resistance among Gram-negative bacteria.

Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy.

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem after SCT. A retrospective survey (January 2010 to July 2013) involving 52 Italian centers was performed to assess the epidemiology and the prognostic factors of CRKp infections in auto- and allo-SCT. Cases of CRKp infection were reported in 53.4% of centers. CRKp infections were documented in 25 auto-SCTs and 87 allo-SCTs, with an incidence of 0.4% (from 0.1% in 2010 to 0.7% in 2013) and 2% (from 0.4% in 2010 to 2.9% in 2013), respectively. A CRKp colonization documented before or after transplant was followed by an infection in 25.8% of auto-SCT and 39.2% of allo-SCT patients. The infection-related mortality rates were 16% and 64.4%, respectively. A pre-transplant CRKp infection (hazard ratio (HR) 0.33, 95% confidence intervals (CIs) 0.15-0.74; P=0.007) and a not CRKp-targeted first-line treatment (HR 2.67, 95% CI 1.43-4.99; P=0.002) were independent factors associated with an increased mortality in allo-SCT patients who developed a CRKp infection. Our study shows challenging findings of CRKp infections in SCT patients in Italy particularly after allo-SCT. The detection of carriers and the definition of early therapeutic strategies represent critical aspects of the management of CRKp infections after SCT.

Hema e-Chart registry of invasive fungal infections in haematological patients: improved outcome in recent years in mould infections.

The electronic surveillance system Hema e-Chart allowed us to prospectively collect data and to perform an analysis of invasive fungal infections (IFI) diagnosed in febrile patients as well as the procedures allowing their diagnosis and outcome according to the treatment given. Every patient admitted to 26 Italian Haematology Units with a new diagnosis of haematological malignancy and who was a candidate for chemotherapy was consecutively registered between March 2007 and March 2009. In all, 147 haematological patients with mycoses were identified. Yeasts were found in 23 infections; moulds were diagnosed in 17 proven, 35 probable and 72 possible mycoses. Galactomannan (GM) antigen was the most important test to diagnose probable mould infection; it was positive (cut-off >0.5) in 27 (77%) probable and in nine (53%) proven mould infections. Among patients with probable/proven mould infection who received no prophylaxis or non-mould-active prophylaxis with fluconazole, more patients (n = 26, 78.8%) had GM antigen positivity compared with patients (n = 10, 52.6%) given prophylaxis with mould-active drugs (p <0.05). First-line antifungal therapy was effective in 11/23 (48%) yeast infections and in 37/52 (71.2%) proven/probable mould infections. Twenty patients (14%) died within 12 weeks. The fungal attributable mortality was 30.4% and 17.3% in yeast and proven/probable mould infections, respectively. Among risk factors only age was independently associated (p 0.013) with mortality; sex, underlying haematological malignancy, previous prophylaxis and presence of neutropenia at diagnosis were not significant. A diagnosis of mould infection seemed to have a trend for a better outcome than the diagnosis of yeast infection (p 0.064).

Postural balance in patients with social anxiety disorder

Body stability is controlled by the postural system and can be affected by fear and anxiety. Few studies have addressed freezing posture in psychiatric disorders. The purpose of the present study was to assess posturographic behavior in 30 patients with social anxiety disorder (SAD) and 35 without SAD during presentation of blocks of pictures with different valences. Neutral images consisted of objects taken from a catalog of pictures, negative images were mutilation pictures and anxiogenic images were related to situations regarding SAD fears. While participants were standing on a force platform, similar to a balance, displacement of the center of pressure in the mediolateral and anteroposterior directions was measured. We found that the SAD group exhibited a lower sway area and a lower velocity of sway throughout the experiment independent of the visual stimuli, in which the phobic pictures, a stimulus associated with a defense response, were unable to evoke a significantly more rigid posture than the others. We hypothesize that patients with SAD when entering in a situation of exposure, from the moment the pictures are presented, tend to move less than controls, remaining this way until the experiment ends. This discrete body manifestation can provide additional data to the characterization of SAD and its differentiation from other anxiety disorders, especially in situations regarding facing fear.

Postural balance in patients with social anxiety disorder.

Body stability is controlled by the postural system and can be affected by fear and anxiety. Few studies have addressed freezing posture in psychiatric disorders. The purpose of the present study was to assess posturographic behavior in 30 patients with social anxiety disorder (SAD) and 35 without SAD during presentation of blocks of pictures with different valences. Neutral images consisted of objects taken from a catalog of pictures, negative images were mutilation pictures and anxiogenic images were related to situations regarding SAD fears. While participants were standing on a force platform, similar to a balance, displacement of the center of pressure in the mediolateral and anteroposterior directions was measured. We found that the SAD group exhibited a lower sway area and a lower velocity of sway throughout the experiment independent of the visual stimuli, in which the phobic pictures, a stimulus associated with a defense response, were unable to evoke a significantly more rigid posture than the others. We hypothesize that patients with SAD when entering in a situation of exposure, from the moment the pictures are presented, tend to move less than controls, remaining this way until the experiment ends. This discrete body manifestation can provide additional data to the characterization of SAD and its differentiation from other anxiety disorders, especially in situations regarding facing fear.

Subsets of CD34+ and early engraftment kinetics in allogeneic peripheral SCT for AML.

This study aimed to identify which graft product subset of CD34+ cells might be the most predictive of early hematopoietic recovery following allogeneic peripheral SCT (allo-PBSCT). The relationship between the number of 'mature' subsets of CD34+ cells (CD34+/CD33+, CD34+/CD38+, CD34+/DR+ and CD34+/CD133-) and 'immature' subsets of CD34+ cells (CD34+/CD33-, CD34+/CD38-, CD34+/DR- and CD34+/CD133+) and early neutrophil and platelet engraftment were studied in a homogeneous series (for disease, pre transplant chemotherapy, conditioning regimen and GVHD prophylaxis) of 30 AML patients after allo-PBSCT from HLA-identical siblings. In our experience, the total CD34+/CD133+ cell number was inversely correlated with the days required for the recovery of 0.5 x 10(9)/l neutrophils (r=or-0.82, P=0.02) and platelets of 20 x 10(9)/l (r=or-0.60, P=0.06); this correlation was better than the total CD34+ cell dose and neutrophil (r=or-0.70, P=0.04) and platelet engraftment (r=or-0.56, P=0.07). We suggest that a high number of CD34+/CD133+ PBSC may be associated with faster neutrophil and platelet recovery; these findings may help to predict the repopulating capacity of PBSC in patients after allo-PBSCT, especially when a relatively low number of CD34+ cells is infused.

Gemtuzumab ozogamicin with cytarabine and mitoxantrone as a third-line treatment in a poor prognosis group of adult acute myeloid leukemia patients: a single-center experience.

We analyzed the safety and efficacy of gemtuzumab ozogamicin (GO) combined with cytarabine and mitoxantrone in the treatment of 21 patients with acute myeloid leukemia (11 refractory and 10 in second relapse). Patients' median age was 52 years (range 36-68); all patients had previously been treated with anthracycline-containing regimens (daunorubicin and idarubicin). GO at a dosage of 3 mg/m2 was administered as a 2-h intravenous infusion on days 1 and 14, cytarabine at 100 mg/m2 on days 1-7, and mitoxantrone at 12 mg/m2 on days 1-3. Infusion-related events were observed in 15 of 21 (71.4%) patients. The incidence of grade 1 or 2 elevations of bilirubin and hepatic transaminases was 4 of 21 (19%) and 3 of 21 (14.2%). In response to chemotherapy, 2 of 21 (9.5%) achieved complete remission and 2 of 21 (9.5%) achieved complete remission with incomplete platelet recovery, with an overall remission rate of 4 of 21(19%); median survival of these 4 patients was 7 months. Four of 21 patients (19%) died during aplasia after chemotherapy; no veno-occlusive disease occurred. No treatment-related cardiotoxicity or cerebellar toxicity was observed. In our experience, the addition of GO to mitoxantrone and cytarabine is feasible in refractory or second relapse acute myeloid leukemia patients but yields a low response rate when used as a third-line treatment.

FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia.

Relapsed or refractory adult acute lymphoblastic leukemias (ALL) have poor prognosis. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of the salvage regimen is acceptable. Twenty three patients with relapsed/refractory adult ALL were treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA). Five patients had primary refractory disease, and 18 were in first relapse. Nine (39.1%) patients achieved complete remission (CR) following salvage therapy, whereas 13 (56.5%) patients were refractory, and one patient died in aplasia due to infection. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5x10(9)/l and 1x10(9)/l was 20 (range 16-25) and 24 (range 20-28) days from the start of chemotherapy, respectively. Platelet levels of more than 20x10(9)/l and 100x10(9)/l were achieved in a median time of 23 (range 19-25) and 33 (range 28-39) days, respectively. Fever more than 38.5 degrees C was observed in 18 of 23 patients (78.2%), 13 had fever of unknown origin, and 5 had documented infections. Nonhematological side effects, consisting mainly of mucositis (18/23 or 78.2%) and transient liver toxicity increase (10/23 or 43.4%), were generally tolerated. All nine patients who achieved CR received a second course with FLAG-IDA, and seven patients underwent allogeneic stem cell transplantation (four from a matched donor, one from a mismatched donor, and two from an unrelated donor), while two did not reach that stage due to early relapse from CR. The median overall survival (OS) for all 23 patients was 4.5 (range 1-38) months; for the nine responders, the disease-free survival (DFS) and the OS were 6 (range 3-38) and 9 (7-38) months, respectively; the seven patients who received allogeneic stem cell transplantation had a DFS of 10 (range 7-38) months. In our experience, FLAG-IDA is a well-tolerated regimen in relapsed/refractory ALL patients; the toxicity is acceptable, enabling patients who have achieved CR to receive allogeneic transplantation.

Variations of telomerase activity in cultured mouse fibroblasts upon proliferation of polyomavirus.

Telomerase plays a central role in various biological phenomena such as cell differentiation and proliferation, apoptosis, malignant transformation and virus infection, for instance HIV and papillomavirus. In addition, it has recently been shown that, in human fibroblasts transformed by monkey polyomavirus SV40, telomeres became stabilized as a consequence of telomerase activation. However, no information exists on the effects of acute infection by murine polyomavirus on the telomeres maintenance and telomerase activity in the host cell. In this paper we report on a differential activity of telomerase in productively infected cells. The results showed a decreased activity of the enzyme as assessed by the TRAP assay. The decrease had already occurred at a non-lytic time of infection and was observed both after infection and naked DNA transfection. Therefore nuclear decapsidation is not involved in the determination of the phenomenon that is attributed to the proliferation of the virus.

Good and poor CD34+ cells mobilization in acute leukemia: analysis of factors affecting the yield of progenitor cells.

SUMMARY: The factors possibly affecting the collection of peripheral blood stem cells (PBSC) were evaluated in 104 de novo acute leukemia patients (66 myeloid and 38 lymphoblastic leukemias) in first cytological complete remission (CR); all patients achieved CR after first-line induction chemotherapy. The acute myeloid leukemia patients (AML) were given consolidation-mobilization chemotherapy with cytarabine, and daunoblastin or mitoxantrone or idarubicin; the acute lymphoblastic leukemia patients (ALL) were given consolidation-mobilization chemotherapy with cytarabine and etoposide. In all patients, the collection of PBSC was performed during recovery after giving consolidation chemotherapy and granulocyte colony-stimulating factor (G-CSF). Two main groups were considered according to the CD34+ cells x 10(6)/kg b.w. collected, that is, poor mobilizers (PM), with a collection of <2 x 10(6)/kg and good mobilizers, with a collection of >2 x 10(6)/kg. Of 104 patients, 27 (25.9%) were PM; 20/27 had AML and 7/27 had ALL. At multivariate analysis, a lower CD34+ cells count premobilization chemotherapy (CD34 steady state), the presence of FUO (fever of unknown origin) or infection, and a lower number of CD34+ cells on the first day of collection correlated with poor mobilization. These results may enable early recognition of patients who may have poor mobilization, and aid selection of patients for different mobilization regimens.

Fungemia in acute leukemia patients: a single institution's experience.

A retrospective study was conducted in 22 episodes of candidemia in 445 patients with acute leukemia (AL) (incidence 4.9%) observed at our Institution between February 1996 and November 2003 to evaluate the variables related to the onset and outcome of infection. Of 22 patients, 20 (90.9%) had refractory/relapsed AL. C. albicans was responsible for 7/22 of the fungemia cases (32%) and C. non albicans for 15/22 (68%). The median absolute neutrophil count was 0.1 x10(9)/L (range 0.04-0.3) at the time of the candidemia diagnosis. The fungemia responded to antifungal therapy in 15/22 (68.1%) patients; among patients with a positive outcome of the fungemia, in 14/15 (93.3%) the neutrophil count recovered within 7 days after the diagnosis of candidemia (p < 0.05). The mortality rate due to candidemia was 31.9% (1/7: 14.2% and 6/15: 40% in the C. albicans and C. non albicans groups, respectively). In our experience the determinants of a positive outcome of fungemia were infection by the C. albicans species and recovery of the neutrophil count.