Additional booster doses in patients with chronic lymphocytic leukemia induce humoral and cellular immune responses to SARS-CoV-2 similar to natural infection regardless ongoing treatments: A study by ERIC, the European Research Initiative on CLL.

Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.

Clinicopathologic spectrum of cutaneous diseases in patients with hematologic malignancies with or without allogeneic bone marrow transplantation: an observational cohort study in 101 patients.

AIM: Objective of the study was to determine the most common cutaneous lesions in patients with haematologic malignancies observed at dermatologic consultation and to identify the impact parameters related to the haematologic condition, like disease type/duration, remission, chemotherapy and transplantation, have on skin manifestations. METHODS: A total of 101 consecutive patients with onco-haematological malignancies referred for dermatological consultation over a two-year period were included in this prospective single-centre observational cohort study. RESULTS: The most common finding was infection (19.8%), followed by drug adverse reactions (16.8%) and malignant neoplasia (11.9%). Elderly patients and those with a longer disease duration had a higher frequency of cutaneous neoplasia. Squamous cell carcinoma was the most frequent cutaneous neoplasia; three cases of melanoma were diagnosed and had a high Breslow thickness. Cutaneous involvement due to the haematological malignancies was observed in 5 patients. Common chronic dermatoses (psoriasis and eczema) were found in 10% of patients. Transplant had no effect on the percentage of infections or tumours. CONCLUSION: Patients with haematological malignancies have a higher incidence of adverse drug reactions with peculiar morphologic features and a lower incidence of common chronic dermatoses than patients referred for dermatological consultation by their general practitioner or other hospital services. Infectious dermatoses were less frequent than in solid organ transplanted patients. The complex variety of cutaneous lesions, the differential diagnostic pitfalls and the prognostic relevance of early skin tumour diagnosis, evidence the importance of a correct dermatological approach.

Anticancer innovative therapy: Highlights from the ninth annual meeting.

The Ninth Annual Conference of "Anticancer Innovative Therapy", organized by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Fondazione IRCCS INT) and hosted by Hotel Michelangelo, was held in Milan on 25 January 2019. Cutting-edge science was presented in two main scientific sessions: i) pre-clinical evidences and new targets, and ii) clinical translation. The Keynote lecture entitled "Cancer stem cells (CSCs): metabolic strategies for their identification and eradication" presented by M. Lisanti, was one of the highlights of the conference. One key concept of the meeting was how the continuous advances in our knowledge about molecular mechanisms in various fields of research (cancer metabolism reprogramming, epigenetic regulation, transformation/invasiveness, and immunology, among others) are driving cancer research towards more effective personalized antineoplastic strategies. Specifically, recent preclinical data on the following topics were discussed: 1. Polycomb group proteins in cancer; 2. A d16HER2 splice variant is a flag of HER2 addiction across HER2-positive cancers; 3. Studying chromatin as a nexus between translational and basic research; 4. Metabolomic analysis in cancer patients; 5. CDK4-6 cyclin inhibitors: clinical activity and future perspectives as immunotherapy adjuvant; and 6. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. In terms of clinical translation, several novel approaches were presented: 1. Developing CAR-T cell therapies: an update of preclinical and clinical development at University of North Carolina; 2. Vγ9Vδ2 T-cell activation and immune suppression in multiple myeloma; 3. Predictive biomarkers for real-world immunotherapy: the cancer immunogram model in the clinical arena; and 4. Mechanisms of resistance to immune checkpoint blockade in solid tumors. Overall, the pre-clinical and clinical findings presented could pave the way to identify novel actionable therapeutic targets to significantly enhance the care of persons with cancer.

Microvesicles released from multiple myeloma cells are equipped with ectoenzymes belonging to canonical and non-canonical adenosinergic pathways and produce adenosine from ATP and NAD.

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles.

Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma.

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vgamma9/Vdelta2 (gammadelta) T cells of normal donors and multiple myeloma (MM) patients. gammadelta T cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of gammadelta T cells was observed in 100% of normal donors and 50% of MM patients. gammadelta T cells produced IFN-gamma, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM gammadelta T cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of gammadelta T cells and by enhancing the immunosensitivity of myeloma cells to gammadelta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.

Altered expression of growth-regulated protooncogenes in human malignant plasma cells.

The expression of three growth-regulated protooncogenes, c-myc, c-myb, and p53, and the S-phase-specific histone H3 gene, was compared in bone marrow cells from multiple myeloma patients and normal controls by measuring the amount of specific RNA by Northern blot analysis. Four samples contained at least 72% of myeloma cells, one sample 43%, and one 11%. Expression of the protooncogenes was similar in normal and myeloma bone marrow cells, whereas that of histone H3 gene was significantly reduced (between 10 and 15 times) in samples containing at least 43% of malignant plasma cells and not detectable in those containing more than 72% of neoplastic cells. Protooncogene levels of expression were compared to those of the H3 gene to distinguish the increased expression of a growth-regulated gene due to a true deregulation from overexpression reflecting solely an increase in the fraction of cycling cells. The ratios of expression of protooncogenes to histone H3 were markedly increased in multiple myeloma cells; the highest ratios were found in the patients with the highest number of malignant plasma cells. These results suggest that the expression of three growth-regulated oncogenes (c-myc, c-myb, p53) is altered in myelomatous plasma cells.

Early responder myeloma: kinetic studies identify a patient subgroup characterized by very poor prognosis.

In order to assess the prognostic value of rapid tumor mass reduction in responding multiple myeloma (MM) patients, 100 consecutive patients were analyzed, and bone marrow plasma cell kinetic characteristics were evaluated at diagnosis. Forty-two patients obtained a tumor mass reduction greater than or equal to 50% with three cycles of chemotherapy and within 3 months (early responder myeloma [ERM]), and 23 in greater than 3 months (slow responder myeloma [SRM]). Survival rates in these two groups were not statistically different (P = .07). The labeling index (LI) of bone marrow plasma cells was significantly higher in ERM patients than in SRM patients (1.8 +/- 2.0 v 0.8 +/- 0.7, P = .006). The LI was used to separate the ERM patients into two well-defined subgroups. ERM patients with a LI greater than or equal to 2% showed a median survival of 16.4 months, whereas ERM patients with a LI less than 2% did not reach the median survival at 46.9 months (P less than .0044). Remission duration was also significantly different: 12.2 months in the high LI subgroup and 26.3 months in the low LI subgroup (P less than .0025). Early response itself does not correspond to shorter remission duration and shorter survival, but it is a poor prognostic factor if associated with a high plasma cell proliferative activity.

Constitutive production of tumor necrosis factor-alpha in hairy cell leukemia: possible role in the pathogenesis of the cytopenia(s) and effect of treatment with interferon-alpha.

PURPOSE: In view of the pleomorphic role cytokines play in human lymphoproliferative disorders, we investigated the possible involvement of tumor necrosis factor-alpha (TNF) in hairy cell leukemia (HCL). PATIENTS AND METHODS: The levels of TNF were measured in the serum of untreated patients, and in the culture supernatants of unstimulated and stimulated enriched hairy cells (HC). Furthermore, the presence of TNF mRNA transcripts in HC was analyzed. The possibility that HC could inhibit the in vitro growth of normal erythroid progenitors via the release of TNF was also investigated. Finally, in an attempt to correlate the circulating levels of TNF with the course of the disease, these were retested during and after treatment with interferon-alpha (IFN). RESULTS: Significantly increased levels of TNF were found in the sera of untreated HCL patients compared with normal control sera were seen from patients with other diseases (P less than .001), with values greater than 10 pg/mL in 21 of 42 samples tested. A significant decrease (P less than .01) of TNF levels was recorded following IFN-2a administration in 16 cases with detectable pretreatment serum levels of TNF. In two cases, an increase in TNF values was associated with persistence or progression of disease. The likelihood that the circulating levels of TNF were caused by the pathologic cells is supported by the evidence that purified HC may release TNF spontaneously. The values can be markedly increased following in vitro activation with the phorbol ester 12-0-tetradecanoylphorbol-13 acetate (PMA), with B-cell growth factor (BCGF), and, to a further extent, with the combination of PMA and BCGF. Furthermore, the constitutive mRNA for TNF was found in seven of eight HC samples analyzed. Although supernatants of enriched HC, were capable of reducing the growth of normal bone marrow erythroid progenitors by 50%, duplicate experiments using an anti-TNF antibody produced an almost complete disappearance of the inhibitory effect. CONCLUSION: The results of this study suggest that TNF plays an important role in the pathogenesis of the cytopenia(s) characteristically associated with HCL.

Long-term follow-up of idiotype vaccination in human myeloma as a maintenance therapy after high-dose chemotherapy.

The aim of this work was to evaluate the long-term immunological and clinical impact of idiotype (Id) vaccination in multiple myeloma (MM) patients in first remission after high-dose chemotherapy. A total of 15 patients received a series of subcutaneous (s.c.) injections of autologous Id, conjugated to keyhole limpet hemocyanin (KLH) and in association with low doses of GM-CSF. The median duration of follow-up was 110 months from diagnosis. The vaccine induced immune responses that lasted almost 2 years after the end of treatment. Antibody responses included anti-KLH IgM and IgG (90% of patients), anti-KLH IgE (30%), anti-GM-CSF IgG (20%), anti-Id IgG (20%), and anti-Id IgE (30%). Id-specific delayed type hypersensitivity skin tests were positive in 85% of tested patients. Following vaccination, a progressive recovery of T-cell receptor (TCR) diversity was observed and the loss of oligoclonality was significantly correlated with the remission duration. Although Id/KLH conjugates did not eliminate the residual tumor burden, the median progression-free survival, and overall survival were 40 and 82 months, respectively. A retrospective case-matched analysis showed similar results in patients treated with IFN-alpha alone or in association with steroids. This vaccine formulation can overcome Id-specific immune tolerance by inducing clinical responses that are worthy of further investigation.

Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs 200 mg/m(2)).

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m(2), MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m(2), MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.

Idiotypic vaccination as therapy for multiple myeloma.

Although advances in the treatment of multiple myeloma have been made using high-dose chemotherapy with subsequent autologous stem-cell transplantation, recurrence of the underlying disease almost invariably occurs. One proposed strategy to increase survival is tumor-specific activation of the immune system via idiotypic protein vaccination. Current issues to be resolved in the development of this approach include optimal vaccine formulation, appropriate assays to monitor treatment results, and timing of vaccine administration. Several clinical trials of idiotypic vaccines are currently being conducted in the United States and Europe. Initial results support the use of these vaccines as adjunct therapy in patients with multiple myeloma after high-dose chemotherapy and transplantation.

Serum levels of tumour necrosis factor-alpha in patients with B-cell chronic lymphocytic leukaemia.

Serum levels of tumour necrosis factor-alpha (TNF-alpha) have been evaluated in the peripheral blood of 91 patients with B-cell chronic lymphocytic leukaemia (B-CLL), and have been correlated with the clinical stage (according to Rai's staging system) and relevant haematological and immunological data. Increased values were detected, compared to 36 normal age-matched controls (36 pg/ml +/- 5 versus 0.11 pg/ml +/- 0.08; P < 0.05). An increase of TNF-alpha serum levels was observed in all stages including stage 0, with a progressive increase in relation to the stage of the disease. A significant relationship between serum TNF-alpha levels and the number of circulating monocytes (P < 0.002) and an inverse correlation with the level of the haemoglobin (P < 0.001) was established, as defined by the Pearson's correlation test. In contrast, no correlation was observed between TNF-alpha serum levels and the other parameters taken into account, including the white blood cell and platelet counts, the absolute number of peripheral blood (PB) lymphocytes, CD5+ B lymphocytes, CD57+ lymphocytes, serum levels of lactic dehydrogenase, total serum immunoglobulins and the serum levels of IgG, IgA and IgM. These data suggest that, in addition to the B-CLL neoplastic cells, the PB monocytes may be involved in the release of TNF-alpha.

5'nucleotidase, adenosine deaminase and purine nucleoside phosphorylase activities in acute leukaemia.

Three enzymes concerned in purine degradation, 5'nucleotidase (5'NT), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) have been measured biochemically in the bone marrow or peripheral blood blasts from 75 patients with acute leukaemia, from 18 patients with blast crisis of chronic granulocytic leukaemia and in the bone marrow and peripheral blood lymphocytes from 14 normal donors. Characteristic patterns among the different sub-types of acute leukaemia have been detected, with high ADA, low 5'NT and PNP in Thy-ALL, high 5'NT and ADA in c-ALL, high PNP and low ADA in AML. The cells in CGL blast transformation resembled the enzymatic pattern of either AML or c-ALL respectively. However, no significant correlation was found between any pair of enzymes in any group of leukaemia, normal bone marrow or peripheral blood lymphocytes studied here.

T cells in multiple myeloma: is this a reliable population to count on as antitumor effector cells?

Multiple Myeloma (MM) is still a long way from being cured. Disease evolution has been associated with a number of phenotypic and functional alterations in T cells, indicating that a progressive deterioration of cellular immunity might facilitate the negative outcome. Despite these correlations, specific interactions between tumor and T cells have been demonstrated indicating that a population liable to be exploited as antitumor effector cells exists in vivo. This review aims at recording some evidence obtained in our laboratory demonstrating that MM T cells, despite the variety of their alterations, can still generate potent antitumor activity. Adequate stimulation, however, is required to exploit this ability.

Clinical and immunological studies in advanced cancer patients sequentially treated with anti CD3 monoclonal antibody (OKT3) and interleukin-2.

CD3 engagement has been used as a surrogate for antigen-specific stimulation to trigger T cell effector functions. Exogenous IL-2 has been used to prolong and amplify CD3-induced T cell activation. Previous studies have been shown that CD3 reactivity is increased in cancer patients with preactivated (> 10% HLA-DR+) T cells in the peripheral blood. In this study, we report 9 courses of a single infusion of anti-CD3 mAb (OKT3) followed by continuous infusion of intermediate dose IL-2 in 4 cancer patients [2 multiple myeloma (MM), 1 B-cell lymphoma (NHL), 1 metastatic melanoma (ME)] with advanced disease and > 10% HLA-DR+ T cells in the peripheral blood. An increase of lymphocytes, equally distributed between CD4+ and CD8+ subsets, was observed during treatment. Activation was phenotypically documented by the emergence of CD25+ cells in the peripheral blood. Unexpectedly, functional studies [including proliferation to mitogens (PHA, OKT3) and cytotoxicity assays (NK and LAK activities)] did not parallel phenotypic data and a slight decrease of all functions was observed after OKT3 and IL-2 treatment. OKT3 and IL-2 infusions were well tolerated and no limiting toxicity was observed. The treatment did not revert tumor progression in the 2 patients with progressive disease (NHL, ME) and had only minimal effects in the 2 MM patients with stable disease. These data indicate that the sequential administration of OKT3 and IL-2 had no anti-tumor activity in this small series of patients with advanced cancer who were selected for treatment because of an increased number of HLA-DR+ T cells in the peripheral blood. A discrepancy was observed between the emergence of CD25+ T cells and the clinical outcome.

Usefulness of frequency analysis of cytotoxic T-lymphocytes precursors (CTL-p) for selection of HLA matched unrelated marrow donors.

A child with Sanfilippo syndrome and 5 potential unrelated marrow donors were typed serologically, tested in mixed lymphocyte reaction and typed by restriction fragment length polymorphism analysis in attempt to find a suitable donor. All donors were found to be identical with the recipient, however, these studies were not conclusive in identifying the best match donor. Therefore, recipient-donor pairs were examined by HLA-DR oligotyping. In addition we have studied the potential of cytotoxic T-lymphocytes precursors (CTL-p) analysis as a means of selection for matched unrelated donors. Low frequencies (1/10(5)) of pretransplant CTL-p correlated with oligotyping identity in all donor-recipient pairs evaluated. In one case oligotyping disclosed a previously unrecognized HLA-DRB1 disparity. This resulted in high frequencies of CTL-p (1/35,000). Based on this experience we can argue that CTL-p analysis may be used as an additional tool for selection of compatible unrelated marrow donors.

Hypernatremic dehydration in the elderly on admission to hospital.

Dehydration is the most common cause of fluid and electrolyte disturbances in the elderly. This condition is related to the lack of increase in water intake in the presence of an increased fluid loss. The aim of this study was to evaluate the prevalence of hypernatremic dehydration in elderly patients admitted to the hospital. We retrospectively studied 2,894 subjects admitted to the acute ward of the Geriatric Section of the Department of Medical and Surgical Disciplines of the University of Torino from January 1990 to July 1995. Among them 84 (2.9%) patients, mean age 77.3 +/- 9.8 years, had serum sodium levels and blood urea nitrogen greater than 145 mEq/L and 25 mg/dL respectively with serum creatinine below 3 mg/dL. The prevalence of hypernatremic dehydration increases with age. Only 1.6% of the subjects under 65 years old are affected by this condition, against 5.3% of those over 85 years. The mortality rate observed during hospitalization is 29.8%. Mortality is positively related to serum sodium levels. We found mortality rates of 33.3% and 71.4% respectively in subjects with serum sodium levels from 151 to 153 mEq/L and in those with values over 154 mEq/L. Both serum sodium levels and age are independent risk factors for mortality (O.R. 1.31 and 1.07 respectively).

Monoclonal immunoglobulin gene rearrangement in peripheral lymphocytes of a patient with multiple myeloma.

We analyzed the immunoglobulin (Ig) heavy chain gene rearrangement in the peripheral blood lymphocytes of a patient with multiple myeloma (MM). Although the morphological and immunological examination did not reveal the presence of circulating plasma cells, a monoclonal Ig gene rearrangement was detected. This observation indicates that a monoclonal expansion of circulating B cells was present in the peripheral lymphocytes of this patient.

Hemorheolocical and photoplethysmographical modifications with aging.

The association of hemorheological patterns with the common risk factors for atherosclerosis is widely known. There are only few data about hemorheological modifications with aging. The objective of our study was to evaluate the relationships of blood and plasma viscosity, the whole blood and red cell filterability, and the amplitude of photoplethysmographical wave to aging and to some risk factors for atherosclerosis. The study involved 278 healthy women, mean age 55.3 +/- 11.9 (SD) years. Blood viscosity was positively correlated to body mass index (BMI), total cholesterol/HDL ratio, triglyceridemia, glycemia and hematocrit. Plasma viscosity was positively correlated to age, systolic blood pressure, glycemia, and fibrinogen contents. Whole blood filterability was negatively correlated to diastolic blood pressure, triglyceridemia, glycemia, hematocrit, and fibrinogen contents. Red cell filterability was negatively correlated to age, hematocrit, and fibrinogen. The amplitude of photoplethysmographical wave is inversely correlated to age and systolic blood pressure. Our findings show an increase of plasma viscosity, a decrease of red cell filterability and of the amplitude of photoplethysmographical wave with advancing age. These modifications may contribute to the microcirculatory troubles often evident in aging individuals.

Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits.

The relevance of low folate levels as determinants of cognitive deficits and the usefulness of folate supplementation in the treatment of cognitive deficits was reviewed from the literature. Over 40 papers and book chapters published in English, French, German, Italian and Spanish were examined. This represents those papers published in the international literature in the last 10 years which were identified by various key words including folate, cognition and aging (or ageing). Among these papers, only 13 articles specifically addressed issues relevant to the criteria adopted for this review. The remaining papers were principally concerned with depression and or with other pathologies of the aged associated with folate deficiency. Although the specific role of low folate levels in the physiopathology of dementia is still under debate, a growing consensus is emerging in the literature where low folate as well as cobalamin levels in aged patients with cognitive deficits are being considered as a sign of functional problems in the absorption and utilization of vitamins, and not merely as a sign of bad eating habits. In studies where folate compounds were evaluated for treatment effects, the results of a majority of investigations indicated that folate treatment was effective in lessening cognitive deficits. Treatment efficacy, however, has not yet been sufficiently demonstrated by these results because there were no controlled studies and the methodology was heterogeneous for the evaluation of cognitive characteristics. An ad hoc double-blind, controlled versus placebo pilot study was undertaken to evaluate the efficacy of folic acid in 30 aged patients with abnormal cognitive decline and folate level below 3 ng/ml to better understand the value of this type of intervention. Our results from this preliminary study demonstrated that patients treated with folic acid for 60 days showed a significant improvement on both memory and attention efficiency when compared with a placebo group. The intensity of memory improvement was positively correlated with initial severity of folate deficiency. On the contrary, the severity of initial cognitive decline was unrelated to the degree of folate deficiency.