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Background: The main purpose of our study was to evaluate the ability of renal functional reserve (RFR) to stratify the risk of acute kidney injury (AKI) occurrence within 100 days of hematopoietic stem cell transplantation (HSCT) and to predict any functional recovery or the onset of chronic kidney disease. A secondary aim was to identify the clinical/laboratory risk factors for the occurrence of AKI., Methods: The study design is prospective observational. We enrolled 48 patients with normal basal glomerular filtration rate (bGFR) who underwent allogenic HSCT. A multiparameter assessment and the Renal Functional Reserve Test (RFR-T) using an oral protein load stress test were performed 15 days before the HSCT., Results: Different RFRs corresponded to the same bGFR values. Of 48 patients, 29 (60%) developed AKI. Comparing the AKI group with the group that did not develop AKI, no statistically significant difference emerged in any characteristic related to demographic, clinical or multiparameter assessment variables except for the estimated GFR (eGFR). eGFR ≤100 mL/min/1.73 m 2 was significantly related to the risk of developing AKI (Fisher's exact test, P  = .001). Moreover, RFR-T was lower in AKI+ patients vs AKI- patients, but did not allow statistical significance (28% vs 40%). In AKI patients, RFR >20% was associated with complete functional recovery (one-sided Fisher's exact test, P  = .041). The risk of failure to recover increases significantly when RFR ≤20% (odds ratio = 5.50, 95% confidence interval = 1.06-28.4)., Conclusion: RFR identifies subclinical functional deterioration conditions essential for post-AKI recovery. In our cohort of patients with no kidney disease (NKD), the degree of pre-HSCT eGFR is associated with AKI risk, and a reduction in pre-HSCT RFR above a threshold of 20% is related to complete renal functional recovery post-AKI. Identifying eGFR first and RFR second could help select patients who might benefit from changes in transplant management or early nephrological assessment., Competing Interests: The authors have no conflicts of interest to declare. The results presented in this paper have not been published previously in whole or part, except in abstract format., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure-response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma., Methods: In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888., Findings: Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1-13). After a median follow-up of 21·3 months (IQR 18·7-25·9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10·9 months (95% CI 8·2-13·6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever., Interpretation: Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study., Funding: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although there is evidence for strong connectivity between the amygdala and the visual cortex and some evidence for reduced occipital lobe gray matter volume in patients with post-traumatic stress disorder (PTSD), few studies have directly examined the effects of PTSD on occipital function. The current study used functional and structural MRI to examine occipital cortex function and structure in male combat veterans with and without PTSD. Left occipital gray matter volume was reduced in PTSD patients relative to the controls and correlated negatively with the severity of PTSD symptoms. Functional activity in the lateral occipital complex to aversive and nonaversive pictures presented in novel and repeated presentations was not altered by PTSD. These findings suggest that PTSD adversely affects occipital lobe volume but not the reactivity of the lateral occipital complex to generally aversive, trauma nonspecific stimuli.

Background: Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. An accelerated rate of biological aging could contribute to this increased risk. To investigate, we assessed leukocyte telomere length (LTL), an emerging marker of biological age, in men and women with and without PTSD. We also examined childhood trauma, a risk factor for both PTSD and short LTL, as a potential contributor to short LTL in PTSD., Methods: Participants included 43 adults with chronic PTSD (n = 18 with multiple categories of childhood trauma) and 47 control subjects (none with multiple categories of childhood trauma) (mean age = 30.55, SD = 7.44). Exclusion criteria included physical illness, medication use, obesity, alcohol or substance abuse, and pregnancy. Structured clinical interviews were conducted to assess PTSD and other psychiatric disorders and childhood trauma exposure. LTL was measured with a quantitative polymerase chain reaction method., Results: As predicted, participants with PTSD had shorter age-adjusted LTL than control subjects. Exposure to childhood trauma was also associated with short LTL. In fact, childhood trauma seemed to account for the PTSD group difference in LTL; only participants with PTSD and exposure to multiple categories of childhood trauma had significantly shorter LTL than control subjects., Conclusions: Childhood trauma is associated with short LTL in individuals with PTSD. Chronic exposure to the psychobiological sequelae of childhood trauma could increase risk for PTSD and short LTL. Thus, the lasting psychological impact of exposure to trauma in childhood might be accompanied by equally enduring changes at the molecular level., (Copyright © 2011 Society of Biological Psychiatry. All rights reserved.)

The goal of this study was to determine whether posttraumatic stress disorder (PTSD) was associated with an increase in time-related decline in macrostructural brain volume and whether these changes were associated with accelerated cognitive decline. To quantify brain structure, three-dimensional T1-weighted MRI scans were performed at baseline and again after a minimum of 24months in 25 patients with PTSD (PTSD+) and 22 controls (PTSD-). Longitudinal changes in brain volume were measured using deformation morphometry. For the group as a whole, PTSD+ patients did not show significant ongoing brain atrophy compared to PTSD-. PTSD+ patients were then subgrouped into those with decreasing or increasing symptoms. We found little evidence for brain markers of accelerated atrophy in PTSD+ veterans whose symptoms improved over time, with only a small left parietal region showing greater ongoing tissue loss than PTSD-. PTSD patients whose symptoms increased over time showed accelerated atrophy throughout the brain, particularly brainstem and frontal and temporal lobes. Lastly, for the sample as a whole, greater rates of brain atrophy were associated with greater rates of decline in verbal memory and delayed facial recognition., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

There have been several attempts to use gene microarrays from peripheral blood mononuclear cells to identify new biological pathways or targets for therapy in Posttraumatic Stress Disorder (PTSD). The few studies conducted to date have yielded an unclear pattern of findings, perhaps reflecting the use of heterogeneous samples of circulating immune cells for analysis. We used gene microarrays on a homogeneous sample of circulating monocytes to test the hypothesis that chronic PTSD would be associated with elevated inflammatory activity and to identify new pathways dysregulated in the disorder. Forty-nine men (24 PTSD+ and 25 age-matched trauma-exposed PTSD- controls) and 18 women (10 PTSD+ and 8 age-matched PTSD- controls) were recruited. Gene expression microarray analysis was performed on CD14+ monocytes, immune cells that initiate and respond to inflammatory signaling. Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes). A rigorous correction for multiple comparisons and verification with qPCR showed that of only 3 genes that were differentially expressed, all were under-expressed. There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects. In contrast, preliminary data from our pilot female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation. The results indicate differential patterns of monocyte gene expression in PTSD, and the preliminary data from our female pilot subjects are suggestive of gender dimorphism in biologic pathways activated in PTSD. Changes in immune cell gene expression may contribute to medical morbidity in PTSD., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Posttraumatic stress disorder (PTSD) accounts for a substantial proportion of casualties among surviving soldiers of the Iraq and Afghanistan wars. Currently, the assessment of PTSD is based exclusively on symptoms, making it difficult to obtain an accurate diagnosis. This study aimed to find potential imaging markers for PTSD using structural, perfusion, and diffusion magnetic resonance imaging (MRI) together. Seventeen male veterans with PTSD (45 ± 14 years old) and 15 age-matched male veterans without PTSD had measurements of regional cerebral blood flow (rCBF) using arterial spin labeling (ASL) perfusion MRI. A slightly larger group had also measurements of white matter integrity using diffusion tensor imaging (DTI) with computations of regional fractional anisotropy (FA). The same subjects also had structural MRI of the hippocampal subfields as reported recently (W. Zhen et al. Arch Gen Psych 2010;67(3):296-303). On ASL-MRI, subjects with PTSD had increased rCBF in primarily right parietal and superior temporal cortices. On DTI, subjects with PTSD had FA reduction in white matter regions of the prefrontal lobe, including areas near the anterior cingulate cortex and prefrontal cortex as well as in the posterior angular gyrus. In conclusion, PTSD is associated with a systematic pattern of physiological and structural abnormalities in predominantly frontal lobe and limbic brain regions. Structural, perfusion, and diffusion MRI together may provide a signature for a PTSD marker., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Post-traumatic stress disorder (PTSD) confers an increased risk for disorders with an inflammatory etiology. PTSD-related dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary adrenal (HPA) axis and associated alterations in inflammatory activity may contribute to this increased risk. However, little is known about convergent SNS, HPA and inflammatory signaling at the level of the immune cell transcriptome in PTSD. To explore such signaling, we examined the prevalence of specific transcription factor binding motifs in the promoter regions of differentially expressed genes in monocytes from individuals with PTSD and matched controls. Participants included 49 men (24 PTSD+ and 25 trauma-exposed controls) and 18 women (10 PTSD+ and 8 controls). Men with PTSD showed up-regulation of target genes for the NF-κB/Rel family of transcription factors, which convey inflammatory signals, up-regulation of target genes for CREB/ATF transcription factors, which convey adrenergic signals from the SNS, and down-regulation of target genes for the glucocorticoid receptor, which conveys glucocorticoid signals from the HPA axis. Women with PTSD also showed significant up-regulation of target genes for NF-κB and non-significant down-regulation of target genes for GR, but significant down-regulation of target genes for CREB/ATF. Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in PTSD.

The "first night effect" (FNE) is the alteration of sleep architecture observed on the first night of polysomnographic (PSG) studies. It is unclear whether the FNE reflects adaptation to the equipment, sleeping environment, or both. Moreover, it is possible that certain patient populations, such as those with posttraumatic stress disorder (PTSD), demonstrate greater adaptation effects that are highly context dependent. We assessed FNE in participants with PTSD and healthy controls in a cross-sectional study consisting of PSG testing at home and in the hospital. Contrary to our expectations, the PTSD group showed no adaptation effects in either setting. Only the control group assigned to the "hospital first" condition showed significant decreases in total sleep time on night 1 versus night 2 of the study. The results suggest that the FNE is related to adaptation to the combination of the hospital environment and the recording equipment., (Copyright © 2010 Society for Psychophysiological Research.)

Introduction: Some studies have found that antidepressants increase serum brain-derived neurotrophic factor (BDNF) levels in patients with major depression and the expression of BDNF mRNA in limbic structures of rats., Objectives: This study addressed whether the SSRI escitalopram increases serum BDNF levels in subjects with PTSD and whether BDNF levels are associated with treatment response., Methods: Medically healthy male subjects (N=16) with chronic PTSD completed a 12 week open-label trial of flexible dose (5-20 mg/day) escitalopram monotherapy. BDNF levels were obtained at baseline, and at weeks 4, 8 and 12., Results: PTSD symptoms significantly declined over the course of the 12 week escitalopram treatment. Despite a substantial improvement in PTSD symptoms, there was virtually no change in BDNF levels over time. Nevertheless, mean BDNF levels across the trial were strongly correlated with the slope of PTSD symptoms over the 12 weeks (r=0.58, p=0.018). Lower mean BDNF was associated with a greater decrease in PTSD symptoms over the course of the trial., Conclusions: PTSD subjects with low BDNF levels demonstrated the largest treatment response from an agent with putative neurotrophic effects., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Prolonged disruption of sleep in animal studies is associated with decreased neurogenesis in the dentate gyrus. Our objective was to determine whether insomnia severity in a sample of posttraumatic stress disorder (PTSD) patients and control subjects was associated with decreased volume in the CA3/dentate hippocampal subfield., Methods: Volumes of hippocampal subfields in 17 veteran men positive for PTSD (41 +/- 12 years) and 19 age-matched male veterans negative for PTSD were measured with 4-T magnetic resonance imaging. Subjective sleep quality was measured by the Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index., Results: Higher scores on the ISI, indicating worse insomnia, were associated with smaller volumes of the CA3/dentate subfields (r = -.48, p < .01) in the combined sample. Adding the ISI score as a predictor for CA3/dentate volume to a hierarchical linear regression model after first controlling for age and PTSD symptoms accounted for a 13% increase in incremental variance (t = -2.47, p = .02)., Conclusions: The findings indicate for the first time in humans that insomnia severity is associated with volume loss of the CA3/dentate subfields. This is consistent with animal studies showing that chronic sleep disruption is associated with decreased neurogenesis and dendritic branching in these structures., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aviation, military, police, and health care personnel have been particularly interested in the operational impact of sleep restriction and work schedules given the potential severe consequences of making fatigue-related errors. Most studies examining the impact of sleep loss or circadian manipulations have been conducted in controlled laboratory settings using small sample sizes. This study examined whether the relationship between prior night sleep duration and performance on the psychomotor vigilance task could be reliably detected in a field study of healthy police academy recruits. Subjects (N = 189) were medically and psychiatrically healthy. Sleep-wake activity was assessed with wrist actigraphy for 7 days. Subjects performed the psychomotor vigilance task (PVT) for 5 min on a personal digital assistant (PDA) device before and after their police academy workday and on comparable times during their days off. Mixed-effects logistic regression was used to estimate the probability of having > or =1 lapse on the PVT as a function of the previous night sleep duration during the 7 days of field testing. Valid estimates of sleep duration were obtained for 1082 nights of sleep. The probability of a lapse decreased by 3.5%/h sleep the night prior to testing. The overall probability of having a lapse decreased by 0.9%/h since awakening, holding hours of sleep constant. Perceived stress was not associated with sleep duration or probability of performance lapse. These findings demonstrate the feasibility of detecting sleep and circadian effects on cognitive performance in large field studies. These findings have implications regarding the daytime functioning of police officers.

Context: Most neuroimaging studies of posttraumatic stress disorder (PTSD) have focused on potential abnormalities in the whole hippocampus, but the subfields of this structure, which have distinctive histological characteristics and specialized functions, have not been investigated. Studies of individual subfields may clarify the role of the hippocampus in PTSD., Objective: To determine if PTSD is associated with structural alterations in specific subfields of the hippocampus., Design: Case-control study., Participants: A total of 17 male veterans with combat trauma and PTSD (mean [SD] age, 41 [12] years) and 19 age-matched male veterans without PTSD who were recruited from the outpatient mental health clinic of the San Francisco Veterans Affairs Medical Center and by advertising in the community., Interventions: High-resolution magnetic resonance imaging at 4 T., Main Outcome Measure: Volumes of hippocampal subfields., Results: Posttraumatic stress disorder was associated with 11.4% (1.5%) (P = .02) smaller mean (SD) cornu ammonis 3 (CA3)/dentate gyrus subfield volumes, irrespective of age-related alterations, whereas other subfields were spared. Age was associated with reduced volume of the CA1 subfield (P = .03). Total hippocampal volume was also reduced in PTSD by a mean (SD) of 6.5% (0.6%) but, related to both PTSD (P = .05) and age (P = .01), was consistent with the measurements in the subfields., Conclusions: The findings indicate for the first time in humans that PTSD is associated with selective volume loss of the CA3/dentate gyrus subfields, consistent with animal studies, implying that chronic stress suppresses neurogenesis and dendritic branching in these structures.

Numerous studies have demonstrated explicit and working memory deficits related to posttraumatic stress disorder (PTSD), but few have addressed longitudinal changes in memory functioning. There is some evidence to suggest an interactive effect of PTSD and aging on verbal memory decline in Holocaust survivors (Yehuda et al., 2006). However, the longitudinal trajectory of neuropsychological functioning has not been investigated in Vietnam veterans, a younger but substantial population of aging trauma survivors. We administered tests of visual and verbal memory, and working memory to derive different dependent measures in veterans between the ages of 41 and 63, the majority of whom served in the Vietnam War. Twenty-five veterans with PTSD and 22 veterans without PTSD were assessed over two time points (mean age at follow-up = 54.0; mean inter-test interval = 34 months). The PTSD+ group, consisting of veterans with chronic, primarily combat-related PTSD, did not show a significant change in PTSD symptoms over time. Compared to veterans without PTSD, veterans with PTSD showed a greater decline in delayed facial recognition only, and this decline was extremely subtle.

Fludarabine plus cyclophosphamide (FC) at conventional doses is an effective treatment for chronic lymphocytic leukaemia (CLL). However, FC at standard doses may give hematological and non-hematological toxicity, predominantly in the elderly. Intravenous or oral low-dose FC regimens remain highly effective in elderly patients with Low-Grade Lymphomas other than CLL and are well tolerated. We tested efficacy and toxicity of oral FC at reduced doses in 26 elderly patients (median 71 years) with previously untreated (UT-CLL, n = 14) or relapsed/refractory CLL (R-CLL, n = 12), unfit for conventional treatments. Twentyfour-of-26 (92%) patients (14/14, 100% UT-CLL; 10/12, 83.5% R-CLL) obtained a response, with 12/26 (46%) complete responses (9/14, 64.2% in UT-CLL; 3/12, 25% in R-CLL). Non-hematological toxicity was mild and myelosuppression was documented in 8/26 (31%) patients (4/14, 28% UT-CLL; 4/12, 33% R-CLL). With a median follow-up of 24 months, median event-free survival was 48 months with no differences between UT-CLL and R-CLL and all responders were alive. Low-dose oral FC treatment showed good efficacy in both untreated and refractory/relapsed CLL. The treatment is useful in elderly patients who cannot benefit of more aggressive schedules and is easy to administer on an outpatient basis., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Magnetic resonance spectroscopic imaging (MRSI) studies suggest hippocampal abnormalities in posttraumatic stress disorder (PTSD), whereas findings of volume deficits in the hippocampus, as revealed with magnetic resonance imaging (MRI), have been inconsistent. Co-morbidities of PTSD, notably alcohol abuse, may have contributed to the inconsistency. The objective was to determine whether volumetric and metabolic abnormalities in the hippocampus and other brain regions are present in PTSD, independent of alcohol abuse. Four groups of subjects, PTSD patients with (n=28) and without (n=27) alcohol abuse and subjects negative for PTSD with (n=23) and without (n=26) alcohol abuse, were enrolled in this observational MRI and MRSI study of structural and metabolic brain abnormalities in PTSD. PTSD was associated with reduced N-acetylaspartate (NAA) in both the left and right hippocampus, though only when normalized to creatine levels in the absence of significant hippocampal volume reduction. Furthermore, PTSD was associated with reduced NAA in the right anterior cingulate cortex regardless of creatine. NAA appears to be a more sensitive marker for neuronal abnormality in PTSD than brain volume. The alteration in the anterior cingulate cortex in PTSD has implications for fear conditioning and extinction.

Twenty-five elderly patients with untreated indolent non-Hodgkin lymphoma were treated with oral fludarabine 25 mg/m(2)/d (40 mg total dose) and cyclophosphamide 150 mg/m(2)/d, both for four consecutive days, repeated every 28 d for four cycles. In all, 21 (84%) patients were responsive: 10 patients achieved complete remission while partial response was obtained in 11. During an observation period of 37 months, there was an overall survival rate of 70% and a median event-free survival of 20 months. Haematological and extra-haematological toxicity were mild. This reduced-dose Flu-based oral regimen showed good efficacy and was simple to administer on an outpatient basis.

Background: Metyrapone blocks cortisol synthesis which results in removal of negative feedback, a stimulation of hypothalamic corticotropin releasing factor (CRF) and a reduction in delta sleep. We previously reported a diminished delta sleep and hypothalamic-pituitary-adrenal (HPA) response to metyrapone in men with post-traumatic stress disorder (PTSD). In this study, we aimed to extend these findings to women., Methods: Three nights of polysomnography were obtained in 17 women with PTSD and 16 controls. On day 3, metyrapone was administered throughout the day up until bedtime. Plasma adrenocorticotropic hormone (ACTH), cortisol, and 11-deoxycortisol were obtained the morning following sleep recordings the day before and after metyrapone administration., Results: There were no significant between-group differences in hormone concentration and delta sleep at baseline. Relative to controls, women with PTSD had decreased ACTH and delta sleep responses to metyrapone. Decline in delta sleep was associated with the magnitude of increase in ACTH across groups., Conclusions: Similar to our previous findings in men, the ACTH and sleep electroencephalogram response to metyrapone is attenuated in women with PTSD. These results are consistent with a model of downregulation of CRF receptors in an environment of chronically increased CRF activity or with enhanced negative feedback regulation in PTSD.

Cytogenetic abnormalities are among the most important factors affecting the outcome of patients with acute myeloid leukaemia (AML), but approximately 40-50% of AML cases display a normal karyotype at diagnosis. Multidrug resistance (MDR) proteins overexpression is associated with worse prognosis in acute leukaemias, but its role in normal karyotype AML is less defined. We analysed the expression of P-glycoprotein (PGP), MDR-related protein (MRP) and lung resistance protein (LRP) in 135 adult patients with normal karyotype AML and its correlation with other biological features of the disease, to evaluate the impact of MDR proteins on response to therapy and on survival. Increased PGP expression was associated with lower rate of complete remission (CR; p = 0.006), similarly to advanced age. Cases overexpressing PGP displayed also a shorter event-free survival (EFS; 4 vs. 10 months, p = 0.035) and the increased expression of at least one MDR protein was associated with a reduced overall survival (OS; p = 0.038). Also age was predictive of worse prognosis. Our data confirm the prognostic role of MDR proteins, in particular of PGP, also in AML patients with normal karyotype at diagnosis. This finding could be used to stratify patients with different prognosis and to design risk-adapted therapeutic strategies.

Objective: The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD)., Method: Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34)., Results: Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects., Conclusions: These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.

Studies have shown differences in neuropsychological functioning between groups with posttraumatic stress disorder (PTSD) and control participants. Because individuals with PTSD often have a history of comorbid alcohol abuse, the extent to which an alcohol confound is responsible for these differences remains a concern. The current study compares neuropsychological testing scores in 4 groups of veterans with and without PTSD (PTSD+ and PTSD-, respectively) and with and without a history of alcohol abuse (ETOH+ and ETOH-, respectively): n for PTSD+/ETOH- = 30, n for PTSD+/ETOH- = 37, n for PTSD-/ETOH+ = 30, and n for PTSD-/ETOH- = 31. Results showed that PTSD, when alcohol, educational level, vocabulary, and depression are controlled for, was associated with decreased verbal memory, attention, and processing speed performance. Alcohol abuse history was associated with decreased visual memory performance. By controlling for alcohol and depression, the authors can more conclusively demonstrate that verbal memory and attention differences are associated with PTSD.

Thirty untreated patients, median age 69 years (range 60 - 75 years), with diffuse large B-cell lymphoma (B-DLCL) were treated with a pegylated liposomal doxorubicin (PL-doxorubicin) modified CHOP-rituximab regimen. PL-doxorubicin 30 mg/m2, was given in combination with standard dosage of prednisone, vincristine, cyclophosphamide, rituximab (according to CHOP-R regimen) every 21 days for six courses. Cardiac toxicity was evaluated by mean of echocardiography for left ventricular ejection fraction (LVEF) evaluations and serum troponin-I levels. Overall response and complete response rates were 76% and 59%. Projected two year event free survival and overall survival are 65.5% and 68.5%. No treatment-related mortality was documented. WHO grade III-IV neutropenia and thrombocytopenia were 86% and 3%. Extra-hematological III-IV toxicity was represented, respectively, by a single case of infection, mucositis, and bleeding. LVEF evaluations and the troponin levels did not show significant changes over the course of the treatment. One patient with a previous history of atrial fibrillation experienced a single episode of arrhythmia. None of the patients developed palmar-plantar erythrodysesthesia. This regimen appears an active regimen for the treatment of elderly patients with B-DLCL. The replacement of conventional doxorubicin with PL-doxorubicin seems to be associated with a negligible incidence of extra-hematological toxicity, in particular cardiac and infectious complications.

Background and Objective: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder which is treated effectively by interferon-alpha (IFN-alpha), deoxycoformycin (DCF) and 2-clorodeoxyadenosine (2-CdA). As a third of patients treated with DCF do not achieve a complete remission (CR) and many of them tend to relapse, we evaluated the potential role of IFN-alpha, randomly administered after DCF, in increasing the number of patients attaining CR and/or duration of CR., Methods: From March 1997 to December 2000, 167 previously untreated HCL patients, from 37 Italian institutions, were enrolled in the study. A total of 138 males and 29 females, with a median age of 55 yr were included in the study. All patients received six courses of DCF 4 mg/m(2) i.v. every other week and then two additional courses once a month. Complete and partial responders were randomly assigned to receive or not receive IFN-alpha at a dose of 3 MU s.c. three times a week for 6 months., Results: Of the 167 patients enrolled in the study, 145 (86.8%) obtained a CR or a partial remission (PR) and were therefore suitable for randomization. One hundred and thirty-five patients were successively randomized to receive IFN-alpha (63 cases; arm A) or not (72 cases; arm B). Progression of disease was observed in eight (arm A) and 12 (arm B) patients with a median time of 27.8 and 26.9 months, respectively. As far as the improvement in response was concerned, no significant difference in the two subgroups was observed. In fact, five patients in arm A and six patients in arm B showing a good PR at the end of DCF therapy, subsequently attained a late CR., Conclusions: From our data there does not appear to be any significant role for IFN-alpha in improving the proportion and the duration of CR in HCL patients previously treated with DCF.

Alexithymia has been associated with both posttraumatic stress disorder and neuroendocrine responses to stress. This study examined the relationship of alexithymia to salivary cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in a sample of police academy recruits exposed to a video stress challenge. Alexithymia scores were negatively associated with catecholamine response to the video challenge but no association was found between alexithymia scores and cortisol reactivity.

We describe the case of a 61-year-old patient with refractory splenic marginal zone lymphoma and secondary autoimmune hemolytic anemia, both successfully treated with rituximab. This case demonstrates that rituximab monotherapy might also be a valid therapeutic approach in marginal zone lymphoma and autoimmune hemolytic anemia after failure of first-line treatment. Maintenance therapy, although expensive, could be useful to improve event-free survival in patients with unfavorable clinical behavior.

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis and sleep disturbances have been described separately in post-traumatic stress disorder (PTSD). It is not known if HPA alterations and sleep disturbances are associated in PTSD. This study examined sleep and HPA activity in 20 male medication-free subjects with PTSD and 16 matched healthy controls. Two nights of polysomnography were obtained and 24-h urinary cortisol was collected during day 2. Subjects self-administered a low-dose (0.5 mg) salivary dexamethasone test at home. Compared with controls, PTSD subjects had higher 24-h urinary microg cortisol/g creatinine (mean+/-SD 40+/-17 vs 28+/-12, p=0.03) but not significantly higher 24-h urinary cortisol (mean+/-SD 52+/-15 microg/day vs 43+/-23, p=0.19). PTSD subjects showed a trend towards less cortisol suppression after dexamethasone (73%+/-18 vs 83%+/-10, p=0.06). In the combined sample, delta sleep was significantly and negatively correlated with 24-h urinary cortisol (r=-0.36, p=0.04), and with 24-h urinary cortisol/g creatinine on a trend level (r=-0.34, p=0.06). Our results suggest that increased cortisol is negatively associated with delta sleep. This may contribute to sleep abnormalities in conditions associated with elevated cortisol, possibly including PTSD. Future studies should explore the temporal relationship between HPA activity, sleep disturbances, and psychopathology after a traumatic event.

Recurrent cytogenetic abnormalities are typically found in about one third of B-cell chronic lymphocytic leukemia patients (B-CLL) by standard cytogenetic analysis and their prognostic relevance is well known. We report a case of a B-CLL patient showing both trisomy 12 and a t(14;22)(q32;q11). Trisomy 12 is often associated with aggressive disease and resistance to chemotherapy, however, our patient is in good health and currently untreated after 7 years, suggesting in this case a relatively good prognosis and a questionable role for translocations involving the 14q32 locus.

This study compared attention and declarative memory in a sample of combat veterans with posttraumatic stress disorder (PTSD, n = 24) previously reported to have reduced concentrations of the hippocampal neuronal marker N-acetyl aspartate (NAA), but similar hippocampal volume compared to veteran normal comparison participants (n = 23). Healthy, well-educated males with combat-related PTSD without current depression or recent alcohol/drug abuse did not perform differently on tests of attention, learning, and memory compared to normal comparison participants. Further, hippocampal volume, NAA, or NAA/Creatine ratios did not significantly correlate with any of the cognitive measures when adjustments for multiple comparisons were made. In this study, reduced hippocampal NAA did not appear to be associated with impaired declarative memory.

A synergistic effect of fludarabine (FLU) and cyclophosphamide (CY) has been extensively demonstrated in the treatment of chronic lymphoproliferative disorders (CLD), although a high incidence of severe neutropenia and infectious complications, particularly in elderly patients, have been reported. Based on a previous clinical experience in elderly CLD patients treated with a combination of low-dose intravenous (i.v.) FLU and CY in whom we obtained good response rates and negligible toxicity, we tested efficacy and safety of the new oral formulation of FLU combined with CY at low doses. A total of 28 elderly patients with relapsed/refractory or untreated CLD were treated with oral FLU and CY (25 and 150 mg/m2 respectively, both for 4 days every 4 weeks). The treatment design consisted in four consecutive courses and the median value of courses per patient was 3. Overall, 25 out of 28 evaluable patients were responsive to the treatment (six CR and 19 PR; ORR 89%), while the remaining three patients did not show any appreciable response (two progressive and one stable disease). Hematological toxicity was low in the majority of patients (grade 2-3 neutropenia/anemia in 8/28 cases); however, two fatal infections occurred and one additional patient died because of disease progression. Extra-hematological toxicity was generally mild. This preliminary report suggests that oral combination of FLU and CY at low dose is effective as the i.v. formulation and standard doses, since it may induce rapid responses in about 90% of elderly patients with CLD, with an acceptable toxicity.

Mucormycosis is a rare complication in cancer patients. This report presents the case of a acute myeloblastic leukemia patient who developed an ascending paralysis due to disseminated mucormycosis. The presentation was unusual because the early symptoms were fever and pain, and the disease was misdiagnosed because of a concomitant infection by Enterococcus faecium.

Background: This study examined the relationship of hypothalamic-pituitary-adrenal measures and hippocampal N-acetylaspartate (NAA) in posttraumatic stress disorder (PTSD) patients and control subjects., Methods: Eleven patients with combat-related PTSD and 11 control subjects were evaluated with magnetic resonance spectroscopy as well as by morning salivary cortisol samples before and after administration of low-dose dexamethasone (.5 mg)., Results: Left hippocampal NAA was strongly associated with both pre-dexamethasone cortisol levels (n = 22, r =.53, p =.013) and post-dexamethasone cortisol levels (n = 22, r =.63, p =.002). After accounting for clinical symptom severity and hippocampal volume, cortisol levels accounted for 21.9% of the variance (F = 5.6, p =.004) in left hippocampal NAA and 12.6% of the variance (F = 3.2, p =.035) in right hippocampal NAA., Conclusions: This study shows a positive relationship between cortisol levels and hippocampal NAA in subjects without hypercortisolemia. Within the range of values seen in our subjects, cortisol may have a trophic effect on the hippocampus.

Metyrapone blocks cortisol synthesis, which results in the stimulation of hypothalamic cortiocotropin-releasing factor (CRF) and a reduction in delta sleep. We examined the effect of metyrapone administration on endocrine and sleep measures in male subjects with and without chronic PTSD. We hypothesized that metyrapone would result in a decrease in delta sleep and that the magnitude of this decrease would be correlated with the endocrine response. Finally, we utilized the delta sleep response to metyrapone as an indirect measure of hypothalamic CRF activity and hypothesized that PTSD subjects would have decreased delta sleep at baseline and a greater decrease in delta sleep induced by metyrapone. Three nights of polysomnography were obtained in 24 male subjects with combat-related PTSD and 18 male combat-exposed normal controls. On day 3, metyrapone was administered during normal waking hours until habitual sleep onset preceding night 3. Endocrine responses to metyrapone were measured in plasma obtained the morning following sleep recordings, the day before and after administration. Repeated measures ANOVAs were conducted to compare the endocrine and sleep response to metyrapone in PTSD and controls. PTSD subjects had significantly less delta sleep as indexed by stages 3 and 4, and total delta integrated amplitude prior to metyrapone administration. There were no differences in premetyrapone cortisol or ACTH levels in PTSD vs controls. PTSD subjects had a significantly decreased ACTH response to metyrapone compared to controls. Metyrapone caused an increase in awakenings and a marked decrease in quantitative measures of delta sleep that was significantly greater in controls compared to PTSD. The decline in delta sleep was significantly associated with the magnitude of increase in both 11-deoxycortisol and ACTH. The results suggest that the delta sleep response to metyrapone is a measure of the brain response to increases in hypothalamic CRF. These data also suggest that the ACTH and sleep EEG response to hypothalamic CRF is decreased in PTSD.

Background: This study assesses the efficacy of nefazodone treatment (target dose of 400-600 mg/day) on objective and subjective sleep quality in Vietnam combat veterans with chronic DSM-IV posttraumatic stress disorder (PTSD)., Method: Medically healthy male Vietnam theater combat veterans with DSM-IV PTSD (N = 10) completed a 12-week open-label trial. Two nights of ambulatory polysomnography were obtained at baseline and at the end of the trial. PTSD and depressive symptoms and subjective sleep quality were assessed at baseline and after 12 weeks. Data were collected in 1999 and 2000., Results: Nefazodone treatment led to a significant decrease in PTSD and depressive symptoms (p <.05), an improvement in global subjective sleep quality, and a reduction in nightmares. Nefazodone also resulted in a substantial improvement in objective measures of sleep quality, particularly increased total sleep time, sleep maintenance, and delta sleep as measured by period amplitude analysis., Conclusion: Nefazodone therapy results in an improvement of both subjective and objective sleep quality in subjects with combat-related PTSD.

Background: We examined P300 measures in patients with posttraumatic stress disorder (PTSD) and control subjects at two different time points to determine event-related potential (ERP) stability over time and the relationship of changes in ERPs to changes in symptom levels., Methods: Auditory and visual P300 was recorded in a three-condition novelty oddball task in 25 male subjects with combat-related PTSD and 15 male combat-exposed normal control subjects at two time points separated by 6-12 months. Regression analyses were conducted to compare the temporal stability of ERP measures in PTSD and control subjects. Variability in ERP measures over time within PTSD subjects was examined for association with changes in symptom levels., Results: There were no significant differences in P300 amplitude or latency in PTSD versus control subjects at either time point, regardless of stimulus type (target, novel) or modality (auditory, visual). Nine of 24 P300 measures were significantly less predictable over time in the PTSD group compared to control subjects. Variability of P300 measures over time was not associated with fluctuations in symptoms of depression or PTSD., Conclusions: P300 ERPs are more variable cross-sectionally and over time in PTSD subjects compared to trauma exposed control subjects. Measures of variability about the group mean appear to be more informative about the cognitive electrophysiology of PTSD than measures of central tendency.

Recently, several reports have been published claiming the efficacy of anti-CD20 monoclonal antibody (rituximab) in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and some related autoimmune complications. We used anti-CD20 monoclonal antibody in a patient with advanced stage and heavily pre-treated B-CLL with a concomitant bone marrow aplasia requiring a remarkable transfusional support of both red blood cells and platelets. The treatment was conducted according to standard dosage and schedule and the patient did not experience any severe side effect. A progressive reduction of transfusions and a certain recovery of bone marrow cellularity was observed after six months from the end of therapy. This case suggests that rituximab can play a role in this subset of B-CLL patients with very few effective therapeutic options and in which the clinical features may be due both to neoplastic proliferation and concomitant autoimmune disorder.

Background: Previous magnetic resonance imaging studies of posttraumatic stress disorder reported hippocampal volume loss. The goals of this study were 1) to determine the relationship between hippocampal atrophy and posttraumatic stress disorder in the absence of alcohol abuse, and 2) to test if loss of N-acetylaspartate (a neuron marker) in the hippocampus of posttraumatic stress disorder occurs separate from atrophy. In addition, volume changes in the entorhinal cortex were also explored., Methods: Eighteen male patients with combat-related posttraumatic stress disorder (mean age 51.2 +/- 2.5 years) and 19 male control subjects (mean age 51.8 +/- 3.2 years) were studied using magnetic resonance imaging and Proton magnetic resonance spectroscopic imaging. Both groups had no alcohol and drug abuse during the past 5 years., Results: Posttraumatic stress disorder and control subjects had similar volumes of hippocampus and entorhinal cortex. In contrast to volume, N-acetylaspartate was significantly reduced by about 23% bilaterally in the hippocampus of posttraumatic stress disorder when compared with control subjects, and creatine-containing compounds were reduced by 26% in the right hippocampus of posttraumatic stress disorder., Conclusions: N-acetyl asparate and creatine reductions imply that there are hippocampal abnormalities in posttraumatic stress disorder. Furthermore, these metabolite changes seem to be better indicators of posttraumatic stress disorder pathology than volume losses.

Background and Objectives: Recently, a chimeric monoclonal antibody (MoAb) directed against the CD20 antigen (rituximab) has been successfully introduced in the treatment of several CD20-positive B-cell neoplasias and particularly of follicular lymphomas. Based on these premises we evaluated the efficacy and the toxicity of chimeric anti-CD20 monoclonal antibody (MoAb) in relapsed/progressed hairy cell leukemia (HCL)., Design and Methods: Ten patients with relapsed/progressed HCL entered the study. Eight patients were males and two females with a median age of 55 years (range 41-78) and all of them had been previously treated with 2-chlorodeoxyadenosine and/or deoxycoformycin and a-interferon. Two out of 10 patients were anemic (Hb < 10 g/dL), 4 thrombocytopenic (Plt < 100 x 10(9)/L), 3 had fewer than 1.0 x 10(9)/L neutrophils and 3 had circulating hairy cells (HC). All patients received 375 mg/m2 i.v. of anti-CD20 MoAb once a week for 4 doses., Results: All patients were evaluable for response, one patient showing a complete remission and 4 a partial response. Adverse reactions, such as fever, chills, bone pain, hypotension and thrombocytopenia, were transient and mild (grade 1-2) and occurred only during the first course of treatment. One month after the last infusion, patients who had had anemia, neutropenia or thrombocytopenia, recovered normal peripheral blood values. Circulating HC also disappeared within one month. Immunostained bone marrow biopsies were checked 1, 3 and 6 months after the end of therapy and in 5 out of 10 patients a >50% reduction of bone marrow HC infiltration was recorded., Interpretation and Conclusions: On the basis of these preliminary results observed in 10 patients with progressed HCL, it appears that treatment with anti-CD20 MoAb is safe and effective in at least 50% of patients, particularly in those with a less evident bone marrow infiltration (50%) and in those previously splenectomized.

CD56 antigen, a 200-220 kDa cell surface glycoprotein, identified as an isoform of the neural adhesion molecules (NCAM), has been found frequently expressed in several lympho-hematopoietic neoplasms including acute myeloid leukemias (AML). In fact, in these latter diseases it has been reported that the presence of CD56 antigen on the blasts of AML patients with t(8;21) (q22;q22), and in those with M3 subtype, identifies a subgroup of patients with a more unfavorable prognosis. On the basis of these findings, we evaluated in 152 newly diagnosed AML patients CD56 surface expression, and results were correlated with morphology, immunophenotype, cytogenetic pattern and clinical outcome. CD56 antigen was recorded in 37 out of 152 cases (24%) and particularly in those with M2 and M5 cytotypes. Moreover, CD56 expression was significantly associated with P-glycoprotein (PGP) hyperexpression (P = 0.007), unfavorable cytogenetic abnormalities (P = 0.008) and with a reduced probability of achieving complete remission (CR) (36% vs 68%) (P = 0.035) as well as with a shorter survival (6 vs 12 months) (P = 0.032). In conclusion, CD56 antigenic expression on AML cells represents an important adverse prognostic factor and therefore its presence should be regularly investigated for a better prognostic assessment of AML patients at diagnosis.

This study assesses the efficacy of fluvoxamine treatment on different domains of subjective sleep quality in Vietnam combat veterans with chronic posttraumatic stress disorder (PTSD). Medically healthy male Vietnam theater combat veterans (N = 21) completed a 10-week open label trial. Fluvoxamine treatment led to improvements in PTSD symptoms and all domains of subjective sleep quality. The largest effect was for dreams linked to the traumatic experience in combat. In contrast, generic unpleasant dreams showed only a modest response to treatment. Sleep maintenance insomnia and the item "troubled sleep" showed a large treatment response, whereas sleep onset insomnia improved less substantially. These therapeutic benefits contrast with published reports that have found activating effects of Selective Serotonin Reuptake Inhibitors on the sleep electroencephalogram.

Background and Objectives: In recent years fludarabine alone or in combination with other drugs has been reported to be effective in the treatment of B-cell chronic lymphocytic leukemia (B-CLL), both as first line and salvage therapy. Among the different combination regimens, the association of fludarabine and cyclophosphamide has shown a considerable therapeutic efficacy, although a relevant number of infectious complications have been described, particularly in elderly patients. The aim of this work was to evaluate the efficacy, the toxicity, and the incidence of infectious episodes of a regimen combining lower doses of fludarabine and cyclophosphamide in elderly patients with B-CLL refractory to conventional therapy., Design and Methods: Twenty patients with progressive B-CLL with a median age of 75 years (4 in stage B and 16 in stage C) and refractory to conventional therapy were enrolled in this study. The combination regimen was as follows: fludarabine 15 mg/m2/day i.v. [max 25 mg] and cyclophosphamide 200 mg/m2/day i.v. for four days., Results: All patients enrolled were evaluable for response. Three out of 20 (15%) patients achieved a complete remission (CR), 14/20 (70%) a partial response (PR) with an overall response rate (CR+PR) of 85%, according to National Cancer Institute-Working Group response criteria. Three patients were considered resistant. In four out of 20 patients (20%), a severe neutropenia (neutrophils < 0.5x10(9)/L) occurred and one of them developed an infectious complication which required treatment with systemic antibiotics and granulocyte colony- stimulating factor (G-CSF). Non-hematologic toxicity was negligible in all patients but one, who despite a adequate therapy with allopurinol and hydration, experienced a tumor lysis syndrome with transient but severe renal impairment., Interpretation and Conclusions: The association of low-dose fludarabine and cyclophosphamide appeared to be effective in this subset of B-CLL patients, reproducing a similar overall response rate obtained with other fludarabine-based combination therapies. In addition, in this group of elderly patients, toxic side effects were negligible and infectious complications remarkably low.

Background: Posttraumatic stress disorder (PTSD) may be associated with a general impairment of cognitive function that extends beyond the processing of trauma-specific stimuli. Suppression of the auditory P50 response to repeated stimuli occurs in normal subjects and reflects the central nervous system's ability to screen out repetitive stimuli, a phenomenon referred to as sensory gating. This study examines P50 sensory gating to nonstartle auditory stimuli in PTSD subjects and normal controls., Methods: P50 generation and gating were studied using a conditioning/testing paradigm in 15 male subjects with PTSD and 12 male controls. P50 test/conditioning (T/C) ratios were estimated using the Singular Value Decomposition method., Results: The amplitude of the P50 response to the conditioning stimulus did not differ in subjects with PTSD compared to normal controls. The P50 T/C ratio is increased in PTSD subjects (mean = .408, SD = .275) as compared to the controls (mean = .213, SD = .126, two tailed t, p = .024)., Conclusions: This study provides evidence that PTSD is associated with impaired gating to nonstartle trauma-neutral auditory stimuli.

The CD45RA and CD45RO isoforms of the leukocyte common antigen identify functionally distinct CD4+ T cell subsets: CD4+/CD45RA+ cells which represent a more 'naive' stage of T cell compartment and CD4+/CD45RO+ 'memory' cells. Phenotypic and functional abnormalities in T cell compartment have been frequently reported in patients with hairy cell leukemia (HCL) and, in more recent studies, a significant reduction in the absolute number of CD4+ lymphocytes bearing the CD45RO antigen has also been recorded. In our study we evaluated the CD45RA and CD45RO expression on CD4+ T cells by three-color staining in flow cytometry in 38 HCL patients, 19 untreated and 19 previously treated with 2-chlorodeoxyadenosine (2-CdA), administered at a daily dose of 0.1 mg/kg c.i. for 7 days. In HCL untreated patients, the proportion and the absolute number of CD4+/CD45RA+ and of CD4+/CD45RO+ T cell subsets were similar to normal controls. In contrast, HCL patients at 3-5 years by the end of treatment with 2-CdA, together with a reduction in the absolute number of CD4+ T cells, showed a persistent and significant decrease in the proportion and absolute number of CD4+/CD45RA+ cells as compared with both untreated HCL patients and normal controls (41 +/- 16% vs 57 +/- 14% and vs 65 +/- 7%) (P = 0.01 and 0.0001) and (0.201 +/- 0.137 x 10(9)/l vs 0.549 +/- 0.238 x 10(9)/l and vs 0.696 +/- 0.078 x 10(9)/l) (P = 0.00009 and P = 0.00001). In addition, together with the reduction of CD4+/CD45RA+ cells, we recorded a concomitant increase in the proportion of the CD4+/CD45RO+ cells as compared to untreated HCL patients and normal controls (62 +/- 16% vs 47 +/- 15% and vs 42 +/- 12%) (P = 0.08 and 0.02). These findings may suggest that CD4+/CD45RA+ cells are more sensitive than CD4+/CD45RO+ to the toxic effect of 2-CdA.