Publications by authors named "Emanuela Morelli"

27 Publications

  • Page 1 of 1

Health Related Quality of Life in Patients with Onco-hematological Diseases.

Clin Pract Epidemiol Ment Health 2020 30;16:174-179. Epub 2020 Jul 30.

Dipartimento di Scienze Mediche e Sanita Pubblica, Universita di Cagliari, Cagliari, Italy.

Background: HRQoL is generally conceptualized as a broad multidimensional construct that refers to patients' perceptions of the impact of disease and its treatment on their physical, psychological, and social functioning and well-being. Little is known in patients with onco-hematological cancer in comparison with the general population and other chronic diseases.

Objective: We assessed HRQoL in patients diagnosed with haematological cancers in comparison with the general population and other chronic diseases.

Methods: The questionnaire Short Form (SF)-12 was administered to 62 patients with onco-hematological disease and results were compared with 702 controls (184 healthy people, 37 Major Depression, 201 Multiple Sclerosis; 23 Wilson disease; 46 Carotidal Atherosclerosis; 60 Celiac disease; 151 solid tumours).

Results: HRQoL in patients diagnosed with a haematological cancer was significantly worse in comparison with the general population (F= 43.853, p <0.00001) but similar when compared with solid tumour and other chronic diseases such as Major Depression and Carotid Atherosclerosis. In addition, HRQoL in patients diagnosed with a haematological cancer was significantly higher than that due to Celiac disease (p <0.00001) and Wilson's disease (p= 0.02), and lower than that due to Multiple Sclerosis (p= 0.032).

Conclusion: This study confirmed that haematological cancers negatively affects overall HRQoL. The results showed an impact of haematological cancers on HRQoL that is similar to what found in patients with solid tumors, Major Depression and Carotid Atherosclerosis. Current successful therapeutic strategy achieved in the treatment of haematological cancers not only positively impact on survival rate but also could improve the overall HRQoL.
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http://dx.doi.org/10.2174/1745017902016010174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431682PMC
July 2020

First Report of De Novo Nivolumab-Induced Oligoarthritis in a Young Man With Relapsing Classic Hodgkin Lymphoma.

J Clin Rheumatol 2020 Jun 6. Epub 2020 Jun 6.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research WAO Center of Excellence University of Naples Federico II Naples, Italy and Institute of Experimental Endocrinology and Oncology "G. Salvatore" National Research Council Naples, Italy Hematology-Oncology and Stem Cell Transplantation Unit Istituto Nazionale Tumori Fondazione "G. Pascale" IRCCS Naples, Italy Rheumatology, Allergology and Clinical Immunology Department of "Medicina dei Sistemi" University of Rome Tor Vergata Rome, Italy Postgraduate Program in Clinical Immunology and Allergy University of Naples Federico II Naples, Italy Hematology-Oncology and Stem Cell Transplantation Unit Istituto Nazionale Tumori Fondazione "G. Pascale" IRCCS Naples, Italy Department of Translational MedicalSciences and Center for Basic and Clinical Immunology Research WAO Center of ExcellenceUniversity of Naples Federico II Naples, Italy.

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http://dx.doi.org/10.1097/RHU.0000000000001459DOI Listing
June 2020

The Microbiota-Gut-Brain Axis.

Physiol Rev 2019 10;99(4):1877-2013

APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
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http://dx.doi.org/10.1152/physrev.00018.2018DOI Listing
October 2019

[Acute kidney failure in differentiation syndrome: a possible complication during therapy with differentiating agents for acute promyelocytic leukemia. A case report].

G Ital Nefrol 2019 Jul 24;36(4). Epub 2019 Jul 24.

UOC Nefrologia e Dialisi, Ospedale San Giovanni Bosco, Torino, Italia.

Differentiation syndrome (DS), previously known as retinoic acid syndrome or ATRA (all-trans retinoic acid) or ATO (arsenic trioxide) syndrome, is a life-threatening complication of the therapy with differentiating agents in patients with acute promyelocytic leukemia (APL). The latter is a rare subtype of acute myeloid leukemia and represents a hematological emergency. The clinical manifestations of DS, after induction therapy with differentiating agents, include unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, congestive heart failure and acute renal failure. The therapy is based on early intravenous administration of high-dose dexamethasone, in order to counteract the cytokine storm responsible for the DS. Among the supportive measures for the management of DS, furosemide (in 87% of patients) and dialysis (12% of patients) are used to manage acute renal failure, peripheral and pulmonary edema. We describe a case of acute renal failure, treated with haemodialysis, in a young patient with APL and an early and severe DS after induction therapy. This is a rare condition, not well known among nephrologists, where early recognition and treatment are crucial for the prognosis.
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July 2019

Circulating dendritic cells deficiencies as a new biomarker in classical Hodgkin lymphoma.

Br J Haematol 2019 02 13;184(4):594-604. Epub 2018 Nov 13.

Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia.

No robust biomarkers have been yet validated to identify the recurrence of disease in classical Hodgkin Lymphoma (cHL) patients upon induction treatment. The relevance of the inflammatory microenvironment in cHL prompted us to investigate the key immunomodulator myeloid dendritic cells type-1 (mDC1), type-2 (mDC2) and plasmacytoid dendritic cells (pDC). Blood DC levels were assessed in 52 newly diagnosed patients through multiparametric flow-cytometry. All but two patients received ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). The median counts of all DC subsets were lower in cHL patients than in healthy controls (P < 0·001). Median mDC counts were inferior for the advanced vs early stage patients for both mDC1s and mDC2s (P = 0·008; P = 0·0007 respectively). Also, median mDC2 counts were reduced in case of bulky (P = 0·0004) and extra-nodal (P = 0·046) disease. Patients with B symptoms had lower levels for mDC1s (P = 0·046), mDC2s (P = 0·009) and pDCs (P = 0·040). All the DC subtypes increased at the end of treatment in 26 patients (P < 0·001): 4·6-fold for mDC1, 2·4-fold for mDC2, 4·5-fold for pDC and aligned DCs subsets with the reference frequencies and the interquartile ranges of the controls. In conclusion, DCs may contribute to the disturbed immunological interplay typical of cHL, prompting a further evaluation of their value as a potential new biomarker.
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http://dx.doi.org/10.1111/bjh.15676DOI Listing
February 2019

5-HT2C receptor blockade reverses SSRI-associated basal ganglia dysfunction and potentiates therapeutic efficacy.

Mol Psychiatry 2020 12 17;25(12):3304-3321. Epub 2018 Aug 17.

Department of Psychiatry, Columbia University, New York, NY, 10032, USA.

Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find that 5-HT2C receptor antagonism potentiates the antidepressant and anxiolytic effects of SSRIs. Together our findings demonstrate opposing roles for 5-HT2C receptors in the effects of SSRIs on motor function and affective behavior, highlighting the potential benefits of 5-HT2C receptor antagonists for both reduction of motor side effects of SSRIs and augmentation of therapeutic antidepressant and anxiolytic effects.
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http://dx.doi.org/10.1038/s41380-018-0227-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378140PMC
December 2020

Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.

Cell 2016 Dec;167(6):1481-1494.e18

Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria. Electronic address:

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.
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http://dx.doi.org/10.1016/j.cell.2016.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554935PMC
December 2016

Persistent complex bereavement disorder in caregivers of terminally ill patients undergoing supportive-expressive treatment: a pilot study.

J Ment Health 2017 Apr 5;26(2):111-118. Epub 2016 Apr 5.

c Fondazione Roma Sanità , Rome , Italy , and.

Background: The proposal of persistent complex bereavement disorder (PCBD) in the DSM-V increased the interest on the impact of grief on the psychological health.

Aims: Investigating the time course of psychological symptoms, emotional and social abilities in caregivers (undergoing or not to supportive-expressive treatment) of terminally ill cancer patients from 1 months before loss to 14 months after it.

Method: Thirty-three of 60 caregivers were assessed by PG-12, HAM-A, HAM-D, TAS-20 and ASQ, at the admission in Hospice, and after 3, 10 and 14 months from the loss. Twelve caregivers adhered to follow a supportive-expressive treatment and 21 caregivers did not.

Results: PG-12, anxiety, and depression scores decreased in both groups over time. The score of difficulty in identifying emotions and confidence with closeness decreased significantly only in the treated-group. PG-12 score at T0 was able to predict the DSM V diagnosis of PCBD at T3.

Conclusions: Findings showed a decrease of the anxiety, depression, security in the attachment style and an increase of the ability to identify emotions during the first year after loss in caregivers of terminally ill cancer patients. Pre-loss assessment of prolonged grief risk seems useful to predict the diagnosis of PCBD 1 year after loss.
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http://dx.doi.org/10.3109/09638237.2016.1167855DOI Listing
April 2017

Spirituality and Awareness of Diagnoses in Terminally Ill Patients With Cancer.

Am J Hosp Palliat Care 2017 Jul 7;34(6):505-509. Epub 2016 Feb 7.

3 Palliative Care Unit, Fondazione Roma Sanità, Italy.

Objective: Aims of the present study were to investigate the association between awareness of own illness condition and psychological outcome in end-of-life phase and to test the association between the spirituality and the awareness of own illness condition.

Methods: Three hundred and ninety-nine terminally ill patients with cancer were enrolled in a hospice in central Italy. One hundred patients satisfied the inclusion criteria. The Systems of Belief Inventory, the Hospital Anxiety and Depression Scale, and a psychological interview to determine the level of awareness of the illness diagnosis (aware; partially aware; and not aware) were administered to terminally ill patients.

Results: The main finding was that the awareness of one's own illness condition was positively associated with the extrinsic spirituality and negatively associated with intrinsic spirituality (regression model R = .26; R = .07; adjusted R = .05; F = 3.45; P = .036). The aware group showed lower anxiety and depression ( F = 1.9; P = . 075; F = 2.6; P = .04) scores than partially aware and not aware groups. The psychological outcome was not associated with the spirituality level.

Conclusion: In terminally ill patients with cancer, the levels of depression and anxiety were lower in patients aware of their own illness state. Moreover, higher levels of extrinsic and lower levels of intrinsic spirituality predicted the awareness of one's own illness state.
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http://dx.doi.org/10.1177/1049909116630985DOI Listing
July 2017

Multidisciplinary approach and anesthetic management of a surgical cancer patient with methylene tetrahydrofolate reductase deficiency: a case report and review of the literature.

J Med Case Rep 2015 Aug 20;9:175. Epub 2015 Aug 20.

Division of Anesthesia, Department of Anesthesia, Endoscopy and Cardiology, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCSS, Naples, Italy.

Introduction: Hyperhomocysteinemia is a known risk factor for myocardial infarction, stroke, peripheral vascular disease, and thrombosis. Elevated plasma homocysteine levels have been demonstrated in patients with recurrent episodes or a single episode of thrombosis. Here we describe the development of cardiovascular disease as a complication of a surgical intervention in a patient with colorectal cancer and hyperhomocysteinemia.

Case Presentation: A 65-year-old Caucasian man complained of pain and constipation, attributed to previously diagnosed adenocarcinoma (stage IIB) of the hepatic flexure. An anamnestic investigation showed that he had undergone two surgical interventions. During both, he suffered thrombotic postoperative complications, a deep vein thrombosis of the upper extremity after the first operation and retinal vein occlusion after the second. He was diagnosed with hyperhomocysteinemia associated with a homozygous C677T mutation of the gene encoding the enzyme methylenetetrahydrofolate reductase. Our patient was initially treated with folic acid and high-dose B vitamins. On day 7 he underwent a right hemicolectomy. Anesthesia was performed with sevoflurane in 40% O2 and without the use of nitrous oxide. Postoperatively, our patient remained on folic acid and B vitamins and was without immediate or subsequent complications.

Conclusions: Neoplastic disease and related surgery followed by the administration of chemotherapeutic drugs alter the hemostatic balance in cancer patients. Those suspected of also having a thrombophilic disease require a thorough laboratory diagnostic workup, including a molecular analysis aimed at identifying the genetic mutation responsible for the hyperhomocysteinemia, as indicated. The case described in this report highlights the importance of a multidisciplinary approach that includes expertise in peri-operative anesthesia, surgery, oncology, and hematology.
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http://dx.doi.org/10.1186/s13256-015-0662-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546078PMC
August 2015

Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function.

J Neurosci 2014 Sep;34(37):12379-93

Columbia University, New York, New York 10027, New York State Psychiatric Institute, New York, New York 10032, and.

Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2-P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2-P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors.
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http://dx.doi.org/10.1523/JNEUROSCI.1020-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160773PMC
September 2014

Attachment style dimensions can affect prolonged grief risk in caregivers of terminally ill patients with cancer.

Am J Hosp Palliat Care 2015 Dec 25;32(8):855-60. Epub 2014 Aug 25.

Fondazione Roma, Hospice-SLA-Alzheimer, Rome, Italy.

Objective: The aim of the present study was to evaluate the predictive role of attachment dimensions on the risk of prolonged grief. Sixty caregivers of 51 terminally ill patients with cancer who had been admitted in a hospice were selected.

Methods: Caregivers were interviewed using Attachment Scale Questionnaire, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Prolonged Grief Disorder 12 (PG-12).

Results: The consort caregivers showed higher PG-12 level compared to the sibling caregivers. Anxiety, depression, need for approval, and preoccupation with relationships levels were significantly correlated with PG-12 scores.

Conclusion: Female gender, high levels of depression, and preoccupation with relationships significantly predicted higher levels of prolonged grief risk.
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http://dx.doi.org/10.1177/1049909114547945DOI Listing
December 2015

l-DOPA reverses the impairment of Dentate Gyrus LTD in experimental parkinsonism via β-adrenergic receptors.

Exp Neurol 2014 Nov 21;261:377-85. Epub 2014 Jul 21.

Fondazione Santa Lucia, IRCCS, Rome, Italy. Electronic address:

Parkinson's disease (PD) patients exhibit motor and non-motor symptoms that severely affect quality of life. Cognitive alterations in PD subjects have been related to both structural and functional hippocampal changes. Here we investigated the effects of the 6-hydroxydopamine (6-OHDA) lesion in the Medial Forebrain Bundle (MFB) on the hippocampus focusing on the Dentate Gyrus (DG). In vivo microdialysis measurements revealed that the 6-OHDA injection disrupts both dopaminergic and noradrenergic transmission in rat DG. In vitro electrophysiological recordings showed that these neurochemical alterations were accompanied by impairment of long-term depression (LTD) at medial perforant path/DG synapses. Furthermore, this alteration was reversed by l-DOPA treatment. Notably, the therapeutic effect of l-DOPA on LTD was blocked by the antagonism of β-noradrenergic receptors, but not by dopamine D1 or D2 receptor antagonists. Thus, while the dopaminergic transmission does not seem to be implicated in this therapeutic effect of l-DOPA, the noradrenergic system plays a central role in the synaptic dysfunction of the DG in experimental PD. Our work provides new evidence on the role of catecholamines in DG synaptic plasticity and sheds light on the possible synaptic mechanisms underlying cognitive deficits in PD. Furthermore, our results indicate that l-DOPA exerts a therapeutic effect on the parkinsonian brain through different, coexistent, mechanisms.
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http://dx.doi.org/10.1016/j.expneurol.2014.07.006DOI Listing
November 2014

[Bereavement and complicated grief: towards a definition of Prolonged Grief Disorder for DSM-5].

Riv Psichiatr 2014 May-Jun;49(3):106-14

Mourning is a natural response to a loss and a condition which most people experience several times during their lives. Most individuals adjust adequately to the loss of a relative, neverthless, a small but noteworthy proportion of bereaved individuals experience a syndrome of prolonged psychological distress in relation to bereavement. Prolonged distress and disability in connection with bereavement has been termed Complicated Grief (CG) or Prolonged Grief Disorder (PGD). The purpose of this paper is to analyze the literature on loss and mourning making a review of the main studies published between 1993 and 2013, identified through a search conducted on Medline/PubMed, in order to describe the epidemiological and clinical aspects of "normal" grief and "complicated" grief, pointing out the path of the clinical definition of PGD and proposed diagnostic criteria for inclusion in the next edition of the Diagnostic and Statistic Manual of Mental Disorders, Fifth edition (DSM-5). The two main diagnostic systems proposed by Horowitz and Prigerson are also compared.
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http://dx.doi.org/10.1708/1551.16903DOI Listing
February 2016

Environmental enrichment restores CA1 hippocampal LTP and reduces severity of seizures in epileptic mice.

Exp Neurol 2014 Nov 20;261:320-7. Epub 2014 May 20.

Fondazione Santa Lucia, IRCCS, Laboratory of Neurophysiology, Rome, Italy; Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy. Electronic address:

We have analyzed the effects of environmental enrichment (EE) in a seizure-prone mouse model in which the genetic disruption of the presynaptic protein Bassoon leads to structural and functional alterations in the hippocampus and causes early spontaneous seizures mimicking human neurodevelopmental disorders. One-month EE starting at P21 reduced seizure severity, preserved long-term potentiation (LTP) and paired-pulse synaptic responses in the hippocampal CA1 neuronal population and prevented the reduction of spine density and dendrite branching of pyramidal neurons. These data demonstrate that EE exerts its therapeutic effect by normalizing multiple aspects of hippocampal function and provide experimental support for its use in the optimization of existent treatments.
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http://dx.doi.org/10.1016/j.expneurol.2014.05.010DOI Listing
November 2014

Predictive role of different dimensions of burden for risk of complicated grief in caregivers of terminally ill patients.

Am J Hosp Palliat Care 2014 Mar 20;31(2):189-93. Epub 2013 May 20.

1Dynamic and Clinical Psychology Department, Sapienza University of Rome, Rome, Italy.

The aim of the study was to test whether high levels of caregiver burden, as other confirmed predictors, are associated with the risk of prolonged grief disorder in caregivers of terminally ill patients. A predictive study was carried out in order to test the hypothesis. A demographic schedule, the Prolonged Grief 12 (PG-12), the Toronto Alexithymia Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Caregiver Burden Inventory were administered to 60 caregivers of 51 patients who were admitted in Hospice. In the regression analysis, difficulty in recognizing emotions, total burden, depression, and developmental burden dimension were significant predictors of PG-12 levels. Findings showed that feeling of deprivation of existential expectations represents the greater risk factor for the prolonged grief disorder, among the burden dimensions.
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http://dx.doi.org/10.1177/1049909113490227DOI Listing
March 2014

RD-CODOX-M/IVAC with rituximab and intrathecal liposomal cytarabine in adult Burkitt lymphoma and 'unclassifiable' highly aggressive B-cell lymphoma.

Br J Haematol 2012 Jan 21;156(2):234-44. Epub 2011 Nov 21.

Haematology-Oncology and Stem Cell Transplantation Unit, Fondazione 'G. Pascale,' IRCCS, Naples, Italy.

Specific trials on adult Burkitt lymphoma (BL) and 'unclassifiable' lymphomas with features intermediate between BL and diffuse large B-cell lymphoma (BL/DLBCL) are advocated which include substantial numbers of older patients, to improve treatment feasibility, while countering risks of systemic and central nervous system (CNS) recurrences. We prospectively evaluated a modified CODOX-M/IVAC (CODOX-M: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate; IVAC: ifosfamide, etoposide and high-dose cytarabine) regimen by the addition of rituximab (R) and liposome-encapsulated cytarabine (D) to increase antitumour activity and halve the number of intrathecal treatments. Thirty adults (40% >60years) with BL (n=15) and BL/DLBCL (n=15) were accrued. Primary endpoints were progression-free survival (PFS), CNS recurrence, and liposomal cytarabine-associated toxicity. Eighty percent of patients received the whole treatment programme, the remaining cases received at least three full courses. Application of the RD-CODOX-M/IVAC regimen resulted in remarkable 4-year PFS (78%) and complete remission (CR) rates (93%). However, PFS was significantly lower in patients older than 60years as compared to younger ones (49%vs 93%, P=0·03; median, 36months), despite high actual dose-intensity, CR rate and tolerability. Reduced-intensity intratechal prophylaxis through liposomal cytarabine was effective because the CNS failure rate was low (3·4%) and without severe neurological toxicities. The RD-CODOX-M/IVAC strategy is feasible and highly effective, but improving outcomes in elderly patients remains a priority.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08947.xDOI Listing
January 2012

Chronic 5-HT transporter blockade reduces DA signaling to elicit basal ganglia dysfunction.

J Neurosci 2011 Nov;31(44):15742-50

Division of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, New York 10032, USA.

Serotonin (5-HT)-selective reuptake inhibitors (SSRIs) are widely administered for the treatment of depression, anxiety, and other neuropsychiatric disorders, but response rates are low, and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs inhibit dopaminergic activity, but mechanistic insight remains scarce. Here we show that in mice, chronic 5-HT transporter (5-HTT) blockade during adulthood but not during development impairs basal ganglia-dependent behaviors in a dose-dependent and reversible fashion. Furthermore, chronic 5-HTT blockade reduces striatal dopamine (DA) content and metabolism. A causal relationship between reduced DA signaling and impaired basal ganglia-dependent behavior is indicated by the reversal of behavioral deficits through L-DOPA administration. Our data suggest that augmentation of DA signaling would reduce side effects and increase efficacies of SSRI-based therapy.
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http://dx.doi.org/10.1523/JNEUROSCI.2989-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758550PMC
November 2011

The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia.

Blood 2011 Dec 13;118(24):6353-61. Epub 2011 Oct 13.

Onco-Hematology Unit, Azienda Ospedaliera Annunziata, Cosenza, Italy.

Identification of patients at risk of early disease progression is the mainstay of tailored management in chronic lymphocytic leukemia (CLL). Although application of established biomarkers is limited by intrinsic detection/readout complexities, abnormality of κ and λ serum-free light chain ratio [sFLC (κ/λ)] was proposed as a straightforward prognosticator in CLL. By analyzing 449 therapy-naive patients, we show that an abnormal sFLC(κ/λ), along with CD38, ZAP-70, IGHV mutations, cytogenetics and stage, independently predicts treatment-free survival (TFS) but becomes prognostically irrelevant if the cumulative amount of clonal and nonclonal FLCs [sFLC(κ + λ)], a variable associated with cytogenetic risk, exceeds the threshold of 60.6 mg/mL. Patients with sFLC(κ + λ) above cut-off displayed a poorer TFS outcome, irrespective of sFLC(κ/λ). Only ZAP-70, cytogenetics, stage, and TFS remained associated with sFLC(κ + λ) in a multivariate model. By assigning 1 point each for these variables, the 3-year probability of TFS was 94.8%, 84.5%, 61.6%, and 21.1% for patients scoring 0, 1, 2, and 3 + 4, respectively (P < .0001). These data, and the demonstration that monoclonal and polyclonal B cells concur to FLC synthesis in tumor tissues, suggest that sFLC(κ/λ) and sFLC(κ + λ) mirror distinct biologic processes in CLL. sFLC(κ + λ) assessment represents a sensitive and cost-effective tool for identifying CLL patients requiring early treatment.
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http://dx.doi.org/10.1182/blood-2011-04-345587DOI Listing
December 2011

Efficacy and safety of the third-generation chloroethylnitrosourea fotemustine for the treatment of chemorefractory T-cell lymphomas.

Eur J Haematol 2011 Dec 31;87(6):547-53. Epub 2011 Jul 31.

Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione 'G.Pascale', IRCCS, Naples.

Patients with recurring T-cell non-Hodgkin lymphoma (T-NHL) are incurable and candidate for investigational agents. Here, we report on five patients with T-NHL refractory to multiple chemotherapy lines, including in all cases alkylators and gemcitabine, who received the third-generation chloroethylnitrosourea fotemustine at a dose of 120 mg/m(2) every 21 d, up to eight courses. Median actual dose intensity was 79%; toxicity was manageable and mainly hematological. One complete remission, one partial remission, two protracted disease stabilization, and one transient, minor response were achieved. Time to progression ranged from 48 to 240+ d. This is the first evidence ever reporting the activity of fotemustine in end-stage T-NHL. Formal studies with this agent are warranted in T-cell malignancies.
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http://dx.doi.org/10.1111/j.1600-0609.2011.01683.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263425PMC
December 2011

Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high 'life threat' impact cardiopathy.

Br J Haematol 2011 Sep 28;154(5):579-89. Epub 2011 Jun 28.

Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione G. Pascale, IRCCS, Naples, Italy.

This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high 'life threat' impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73years, range: 62-82; 37% >75years) at a median interval of 15·6 (range, 13-29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n=3), therapy discontinuations (no-response n=2; toxicity n=6), relapse (n=6) and death in CR (n=3). Incidence of cardiac grade 3-5 adverse events was 7/41 (17%; 95% confidence interval: 8-31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P=0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P=0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08786.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258483PMC
September 2011

Hepatitis B and C in hematopoietic stem cell transplant.

Mediterr J Hematol Infect Dis 2009 Dec 3;1(3):e2009016. Epub 2009 Dec 3.

Pediatric Hematology Hematology Departments, San Camillo Hospital, Circonvallazione Gianicolense 87, 00152 Rome, Italy.

Although the risk of acquisition of hepatitis B or hepatitis C virus through blood products has considerably reduced since the last decade, some infected patients are candidates to stem cell transplantation. Others may have no alternative than an infected donor. In all these cases, recipients of transplant are prone to short and long term liver complications. The evolution of liver tests under chemotherapy before transplant may give useful information to anticipate on the risk of hepatitis reactivation after transplant, both for HBv and HCv. More than sixty percent of the patients who are HBsAg-positive before transplant reactivate after transplant, and 3% develop acute severe liver failure. Because both viral replication and immune reconstitution are the key factors for reactivation, it is crucial to closely follow liver function tests and viral load during the first months of transplant, and to pay a special attention in slowly tapering the immunosuppression in these patients. Lamivudine reduces HBv viremia, but favors the emergence of HBv polymerase gene mutants and should be individually discussed. Both in case of HBv or HCv hepatitis reactivation with ALT ≥ 10N concomitantly to an increase in viral load at time of immune reconstitution, steroids should be given. In case there is no alternative than a HBv or HCv positive geno-identical donor, the risk of viral hepatitis, including acute liver failure and late complications, should be balanced with the benefit of transplant in a given situation.
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http://dx.doi.org/10.4084/MJHID.2009.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033124PMC
December 2009

Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.

J Neurosci 2008 Jan;28(1):199-207

Sackler Institute for Developmental Psychobiology, Division of Developmental Neuroscience, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.

Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.
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http://dx.doi.org/10.1523/JNEUROSCI.3973-07.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671162PMC
January 2008

Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice.

Science 2006 Jul;313(5786):536-40

Department of Biology, Columbia University and the New York State Psychiatric Institute, New York, NY 10032, USA.

Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. We demonstrate that global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalized conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, "top-down" influences on risk assessment.
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http://dx.doi.org/10.1126/science.1123432DOI Listing
July 2006