Search

The importance of T cell-dependent immune responses in achieving long-term cure of chemoimmunotherapy-treated cancer patients is underscored by the recently described "vaccinal effect" exerted by therapeutic mAbs. In accordance, pre- and post-therapy peripheral blood lymphopenia represents a well-established negative prognostic factor in DLBCL. We analyzed the phenotypic and functional (IFNγ production, and Granzyme B (GrzB) cytotoxic granule marker expression) profile of peripheral blood T lymphocyte subsets ("conventional" CD4 + and CD8 + , FOXP3 + CD25 bright Treg, and "innate-like" CD56 + ) in DLBCL patients at diagnosis, and assessed the long-term impact of R-CHOP chemoimmunotherapy, in a prospective study. At diagnosis, DLBCL patients showed lower lymphocyte counts, due to selective decrement of CD4 + T (including Treg) and B lymphocytes. While all T cell subsets transiently decreased during therapy, CD4 + T cell and Treg remained significantly lower than controls, up to 1 year after R-CHOP. Phenotypically skewed profile of CD4 + and CD8 + T cell subsets associated with higher frequencies of IFNγ + and GrzB + cells at diagnosis, that transiently decreased during therapy, and re-attained persistently elevated levels, till up to 1 year after therapy. Differently, the pre-therapy elevated levels of circulating monocytes, and of plasma IL-6 and IL-10 rapidly normalized upon R-CHOP. In sum, we describe a quantitatively and functionally altered status of the peripheral blood T cell compartment in DLBCL patients at diagnosis, that persists long-term after tumor eradication, and it is only transiently perturbed by R-CHOP chemoimmunotherapy. Moreover, data suggest the association of selected T cell functional features with DLBCL phenotype, and with therapy outcome.

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56 dim and CD16 + NK cells, and a higher frequency of GrzB + cells in CD56 dim , CD56 bright , and CD16 + NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon γ (IFNγ) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower "natural" cytotoxicity. A marked and prolonged therapy-induced reduction of both "natural" and CD16-dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56 dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNγ production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies.

Hepatitis B virus (HBV) reactivation strongly affects the practice of physicians dealing with hematological malignancies. In this respect, in collaboration with the Italian Lymphoma Foundation we developed a descriptive study of the real-life approach of physicians caring for patients with these diseases. A questionnaire was designed to explore the perception of HBV reactivation-related issues. Fifty-nine Italian Lymphoma Foundation-affiliated institutions participated, and 504 questionnaires were sent out. Forty institutions (67.8%) returned 154 (30.5%) completed questionnaires. The largest majority (91.5%, 141/154) were aware of possible HBV reactivation as a consequence of immunosuppression. Most of the participants providing an answer (93.3%; 126/135) performed universal screening, and were aware of strategies for managing reactivation (96.4%, 132/137). Specialists treating lymphoma show a high level of awareness concerning the management of HBV reactivation under immunosuppression. However, uncertainties regarding the issue of HBV reactivation still emerge in this setting, and thus continuing collaborative effort between hepatologists and hematologists is necessary.

Recently, diffuse-large-B-cell lymphoma (DLBCL) associated with serum IgM monoclonal component (MC) has been shown to be a very poor prognostic subset although, detailed pathological and molecular data are still lacking. In the present study, the clinicopathological features and survival of IgM-secreting DLBCL were analyzed and compared to non-secreting cases in a series of 151 conventional DLBCL treated with R-CHOP. IgM MC was detected in 19 (12.5%) out of 151 patients at disease onset. In 17 of these cases secretion was likely due to the neoplastic clone, as suggested by the expression of heavy chain IgM protein in the cytoplasm of tumor cells. In IgM-secreting cases immunoblastic features (p<.0001), non-GCB-type (p = .002) stage III-IV(p = .003), ≥ 2 extra nodal sites (p<.0001), bone-marrow (p = .002), central-nervous-system (CNS) involvement at disease onset or relapse (p<.0001), IPI-score 3-5 (p = .009) and failure to achieve complete remission (p = .005), were significantly more frequent. FISH analyses for BCL2, BCL6 and MYC gene rearrangements detected only two cases harboring BCL2 gene translocation and in one case a concomitant BCL6 gene translocation was also observed. None of the IgM-secreting DLBCL was found to have L265P mutation of MYD88 gene. Thirty-six month event-free (11.8% vs 66.4% p<.0001), progression-free (23.5% vs 75.7%, p<.0001) and overall (47.1% vs 74.8%, p<.0001) survivals were significantly worse in the IgM-secreting group. In multivariate analysis IgM-secreting (p = .005, expB = 0.339, CI = 0.160-0.716) and IPI-score 3-5 (p = .010, expB = 0.274, CI = 0.102-0.737) were the only significant factors for progression-free-survival. Notably, four relapsed patients, who were treated with salvage immunochemotherapy combined with bortezomib or lenalidomide, achieved lasting remission. Our data suggests that IgM-secreting cases are a distinct subset of DLBCL, originating from activated-B-cells with terminally differentiated features, prevalent extra nodal dissemination and at high risk of CNS involvement.

The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In diffuse large B-cell lymphoma (DLBCL), the response to first-line immunochemotherapy remains somewhat unpredictable. Interim [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET) (PET-int) analysis could be an important tool in the prompt shift to intensified regimens. We prospectively evaluated the effectiveness of PET-int carried out at mid-treatment with standard immunochemotherapy in predicting relapse in a series of 85 consecutive patients with DLBCL. PET-int results were dichotomized as positive or negative using the recently validated five-point scale scoring system. This examination was also compared with interim computed tomography (CT-int) and final PET (PET-fin). End-points were: complete remission (CR), positive predictive value (PPV) of refractoriness and relapse, negative predictive value (NPV), overall survival (OS) and progression-free survival (PFS). Observation time was fixed to 24 months unless preceded by a DLBCL-related event. The PPV of PET-int was 58% and the NPV was 77%. CR was correlated with both PET-int and CT-int (p < 0.0001), but in multivariate analysis only CT-int was correlated with CR (p = 0.002). CT-int and PET-fin were predictive of both OS and PFS, whereas PET-int was predictive only of OS (p = 0.013). In Cox regression only PET-fin was predictive for both OS (p = 0.004) and PFS (p = 0.005). PET-int was unable to discriminate those chemosensitive patients who would later relapse. We therefore believe that the use of this expensive radioactive tool is not justified as an interim analysis.

The long natural history of early stage mycosis fungoides (MF) makes its management a difficult problem. Skin lesions are sensitive to different therapies and a variety of treatment modalities have been used, such as topical nitrogen mustard, puvatherapy, UV-B, retinoids, radiation therapy, extracorporal photopheresis and systemic chemotherapy. For patients with refractory early stage MF, treatment selection is made by clinical parameters such as the age, sex and performance status of the patients, as well as the institutional expertise and the toxicity profiles of the different therapeutic approaches. We report radiation therapy in a relapsed/resistant stage IB patient with mycosis fungoides treated with local radiation therapy for symptomatic progression unresponsive to bexarotene therapy. Total skin electron beam therapy has been employed in early stage and for limited skin failure MF, while the role of local radiation therapy in MF is less defined. In our experience local radiotherapy has proved to be a very efficient, tolerable and cost effective approach in patients with MF unresponsive to systemic approaches.

Background: Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin's lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with rituximab-containing regimens., Aim: to evaluate the liver-related effects of rituximab-containing regimens on HCV-positive CD20-positive B-cell NHL patients., Patients and Methods: Retrospective analysis of 104 consecutive patients. HCV status was determined, and development of hepatitis flares analysed., Results: Nine patients (8.6%) were HCV-positive. No correlation was shown between viral load and alanine transaminase levels. Three of the 9 HCV-positive, and none of the 95 HCV-negative developed hepatitis flares (p<0.001). At the 12-month follow-up hepatitis flare patients were alive and in remission for their haematological disease and no hepatitis flares, liver-related death had developed., Conclusions: HCV-positive status may represent a risk factor for the development of hepatic flares in B-cell NHL patients receiving rituximab-containing regimens. Despite the increase in liver function tests, there were no major clinical events., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Aim: In the elderly, prevalence of bleeding- and/or iron malabsorption-related gastrointestinal (GI) causes of iron deficiency anemia (IDA) has not been addressed yet. The aim of this study was to assess the occurrence of malabsorptive diseases and bleeding lesions of the upper and lower GI tract in early (65-74 year-old) and late (over 75 year-old) elderly group compared with adult (50-64 year-old) outpatients., Methods: The study enrolled 136 consecutive adult (N.=31), early (N.=48) and late elderly (N.=57) IDA outpatients who were referred to the Gastroenterology Department for IDA evaluation and underwent gastroscopy/histology and colonoscopy., Results: Bleeding lesions were significantly less frequent in adult patients than in elderly patients (29% vs. 49.5%, P=0.0252). The most common bleeding lesions were large hiatal hernia (14.7%) and colon cancer (12.5%). Iron malabsorption diseases (Hp-related pangastritis, atrophic body gastritis and celiac disease) were more frequent in the adult group than in the early elderly group (80.6% vs. 56.2%, P=0.0367). In elderly patients, the observed prevalence of bleeding and iron malabsorption IDA causes was similar, whereas in adult patients iron malabsoptive diseases were more frequently detected (P<0.0001). The occurrence of concomitant IDA causes was not different among the three age-groups., Conclusion: In the early and late elderly, almost half of GI IDA causes are related to bleeding lesions which are more frequently observed respect to the adult patients. Iron malabsorption diseases affect almost 60% of early and late elderly groups. As for adult patients, an accurate upper and lower endoscopical/histological evaluation diagnoses IDA causes in the vast majority of the elderly outpatients.

The prognostic value of absolute lymphocytic count (ALC), has been a recent matter of debate in non-Hodgkin-lymphoma (NHL). We assessed prospectively the value of ALC at diagnosis and also after the completion of immuno-chemotherapy in 101 diffuse-large-B-cell-lymphoma (DLBCL). Analysis of prognostic factors with respect to overall survival (OS), event free survival (EFS) and progression free survival (PFS) was done by two-tailed log-rank test. The ALC cut-off value was calculated as <0.84 x 10(9)/L at diagnosis: this was a strong negative prognostic factor for OS (p = 0.0004), EFS (p < 0.00001) and PFS (p < 0.00001) and in multivariate analysis was independent from the revised-international-prognostic-index (R-IPI). ALC after chemo-immunotherapy was not of prognostic value. As R-IPI and ALC < 0.84 x 10(9)/L, were the factors better discriminating poor prognosis, a new trichotomous score (ALC/R-IPI) was built up: (1) low risk: R-IPI = very good or good and ALC < 0.84 x 10(9)/L; (2) intermediate risk: patients with at least one risk factor (R-IPI = poor or ALC < 0.84 x 10(9)/L). (3) high risk: patients with both risk factors. This new prognostic score was highly significant in univariate analysis for OS (p = 0.0002), EFS (p < 0.00001) and PFS (p < 0.00001). In multivariate analysis ALC/R-IPI was the most predictive factor for OS (OR = 2.954; p = 0.002) and EFS (OR = 2.381; p < 0.00001) and the only predictive factor for PFS (OR = 4.018; p < 0.00001). Our data, show that ALC at diagnosis has a strong prognostic relevance and is independent from the R-IPI. The new score including both values proved the most powerful predictor at multivariate analysis.

Background: Iron-deficiency anaemia (IDA) is common in premenopausal women and menorrhagia is often considered responsible. Aim To evaluate prospectively the occurrence of bleeding and iron malabsorption related gastrointestinal (GI) diseases likely responsible of IDA in premenopausal women regardless of their menstrual flow., Methods: One hundred and eighty-seven premenopausal women [median age 39 (20-56) years] irrespective of their menstrual flow underwent gastroscopy with gastric and duodenal biopsies and faecal occult blood test (FOBT). Patients over 50 years, positive 1st degree family history for colonic cancer and/or positive FOBT underwent colonoscopy too., Results: Menorrhagia was present in 67.4% of premenopausal women. A possible GI cause of IDA was found in 129/187 patients; in 65.2% the cause of IDA was possibly related to iron malabsorption diseases. GI bleeding as a cause of IDA was found in seven patients. An exclusive GI cause of IDA was found in 26.7% of premenopausal women, whereas a possible GI cause was observed in 34.2% of menorrhagic premenopausal women. The main risk factor for the presence of likely GI causes was the presence of upper GI symptoms (OR 5.2: 95% CI = 1.6-16.4)., Conclusions: Most premenopausal women had a possible upper GI cause of IDA because of diseases related to iron malabsorption. Menorrhagia and a GI cause coexist in one-third of women with iron-deficiency anaemia.

A patient with relapsed B cell non-Hodgkin lymphoma (NHL) infiltrating the Central nervous system (CNS) and resistant to chemotherapy was treated with intrathecal Rituximab (IT RTX), administered weekly for eight weeks at increasing doses, from 10 to 40 mg. After the second administration the patient showed significant clinical improvement and Cerebro spinal fluid (CSF) clearance of lymphomatous cells. A MRI scan performed after 30 days from the start of therapy showed full regression of lymphomatous infiltration. This report confirms the efficacy and safety of IT RTX in the treatment of CNS B-cell NHL.

Background: Most adults with coeliac disease have a subclinical form of the disease and iron-deficiency anaemia may be the sole presenting symptom., Aim: To evaluate demographic, clinical and biochemical characteristics of adult coeliac disease patients presenting with iron-deficiency anaemia., Patients: A total of 108 iron-deficiency anaemia patients in whom coeliac disease has been diagnosed were studied. As a control group 108 non-coeliac iron-deficiency anaemia patients, comparable for sex and age, were studied., Results: Of the 108 coeliac disease patients, 95 (88%) were female (mean age 34 years, range 19-72) and 13 (12%) were male (mean age 33 years, range 15-65). The median duration of iron-deficiency anaemia before diagnosis was 66 months in coeliac disease patients and 14 months in the iron-deficiency anaemia control group (P = 0.0001). The occurrence of at least one gastrointestinal symptom, not spontaneously reported, was observed in 92 (85%) patients with coeliac disease and in 67 (62%) patients in the control group (P = 0.001). The concomitant presence of diarrhoea, abdominal pain and abdominal bloating was detected in 14% patients with coeliac disease with respect to 3% in the control group (P = 0.005)., Conclusions: The vast majority of coeliac disease patients with iron-deficiency anaemia presentation were unaware of the gastrointestinal symptoms and this relationship is useful for diet compliance.

Aim: To investigate the possible relationships between gastric autoimmune phenomena and clinical presentations of this disorder, in consecutive atrophic body gastritis patients., Methods: A total of 140 atrophic body gastritis patients, diagnosed as consecutive outpatients presenting with macrocytic or iron deficiency anemia, or longstanding dyspepsia underwent gastroscopy with antral and body biopsies, assay of intrinsic factor, parietal cells and Helicobacter pylori (H pylori) antibodies. Gastritis was assessed according to Sydney System., Results: Parietal cell antibodies were equally distributed in all clinical presentations, whereas the positivity of intrinsic factor antibodies (49/140, 35%) was significantly higher in pernicious anemia patients (49.2%) than in iron deficiency (21.1%) and dyspeptic patients (27.8%). No specific pattern of autoantibodies was related to the clinical presentations of atrophic body gastritis. A positive correlation was obtained between the body atrophy score and the intrinsic factor antibody levels (r = 0.2216, P = 0.0085). Associated autoimmune diseases were present in 25/140 (17.9%) patients, but the prevalence of autoimmune diseases was comparable, irrespective of the clinical presentations., Conclusion: The so-called hallmarks of gastric autoimmunity, particularly in intrinsic factor antibody cannot be usefully employed in defining an autoimmune pattern in the clinical presentations of ABG.

This study evaluated the impact of a new epoetin alfa dosing regimen on quality of life (QOL), transfusion requirements, and hemoglobin (Hb) levels in 133 patients with low-risk myelodysplastic syndrome (MDS) and Hb < or =10 g/dl. Epoetin alfa 40,000 IU was given subcutaneously twice weekly; after 4 weeks, the dose could be reduced to 40,000 IU weekly in patients achieving erythroid response. QOL was assessed using the functional assessment of cancer therapy-anemia (FACT-An) questionnaire. FACT-An scores increased on average by 7.5 after 4 weeks and by 8.8 after 8 weeks compared with baseline. FACT-An scores were positively associated with Hb values (r=0.53, P<0.01). The mean FACT-An score increase at week 8 was 10.2 in responders and 5.6 in nonresponders. The overall erythroid response rate at week 8 was 68%: 74% in transfusion-independent patients and 59% in transfusion-dependent patients. Of all responders at week 8, response was maintained in 86% at week 12, 71% at week 16, 65% at week 20, and 54% at week 24. Treatment was generally well tolerated. Our data provide new and encouraging results regarding the benefits of 40,000 IU biweekly induction doses followed by 40,000 IU weekly in improving QOL, correcting anemia, and reducing transfusion requirements in low-risk MDS patients.

Laparoscopy seems to be playing an emerging role in the management of lymphoproliferative diseases. The aim of this study was to prospectively analyze personal experience evaluating the role and limits of laparoscopy in the management of lymphomas. From July 1993 to December 2000, 131 consecutive patients were referred to our institution for primary diagnosis (group A, n = 70), suspected relapse (reassessment) (group B, n = 54), or staging/restaging of lymphoproliferative diseases (group C, n = 7). Diagnostic and/or operative laparoscopy was performed in all patients. To assess the accuracy of laparoscopy, the results were analyzed according to the indications for surgery. In all, 128 procedures were completed laparoscopically (95.5%). Conversion was required in 7 cases (5.1%). Causes of the conversions were severe obesity (body mass index 62.5), uncontrolled intraoperative bleeding (HIV+), nondiagnostic tissue sampling (2 cases), perisplenic inflammation and perisplenic abscesses (3 cases). The results of this study highlight the safety of diagnostic and staging laparoscopy and laparoscopic splenectomy in patients with lymphoproliferative diseases (major complications 2.9%, perioperative mortality 0%). In all, 96.4% of patients from group A and 100% of patients from group B were treated on the basis of laparoscopic findings. No false negative diagnosis occurred. Laparoscopy may become the "gold standard" in the management of lymphoproliferative disease in the following settings: for the differential diagnosis of hepatic and/or splenic focal lesions; when percutaneous needle biopsy fails and/or genetic analysis is needed for therapeutic decision; for the primary diagnosis and abdominal staging of patients with diffuse retroperitoneal lymphadenopathy in the absence of peripheral lymphadenopathy; for cases of abdominal restaging after concurrent chemoradiotherapy and in cases of suspected relapse when percutaneous biopsy is not technically possible; and for patients with lymphoproliferative disease when splenectomy is required. Marked splenomegaly with perisplenic inflammatory reaction and lymphadenopathy in HIV+ patients should be considered possible causes of failure of the laparoscopic approach.

Background: In premenopausal women, iron-deficiency anaemia is common and menstrual flow is often held responsible, but it is not clear whether these women should be submitted to gastrointestinal (GI) evaluation. We aim to prospectively investigate whether premenopausal women with iron-deficiency anaemia benefit from GI evaluation regardless of menstrual flow., Methods: The study population comprised 59 consecutive premenopausal women with iron-deficiency anaemia. Excluded were women with obvious or suspected causes of anaemia and those < or = 21 years. Heavy menstrual loss was not considered an exclusion criterion. All subjects had: complete blood count, ferritin, non-invasive testing by faecal occult blood (FOB), 13C-urea breath test (13C-UBT), anti-tissue transglutaminase antibodies (tTG) and gastrin levels. Gastroscopy with antral (n = 3), corporal (n = 3) and duodenal (n = 2) biopsies was performed in women with positive 13C-UBT or tTG titre or hypergastrinaemia., Results: Heavy menstrual loss was present in 50.8%. Non-invasive tests were positive in 40/59 (67.8%): 30 had positive 13C-UBT, 12 had hypergastrinaemia, 7 had positive tTG and 3 had positive FOB. Women tested positive were similar to those tested negative as far as concerned age, haemoglobin and ferritin levels and heavy menstrual flow (55% versus 42.1%). All 40 women tested positive underwent gastroscopy with biopsies. Four (10%) had bleeding-associated lesions and 34 (85%) had non-bleeding-associated lesions. As regards upper GI findings, no differences were observed between women with normal and those with heavy menstrual flow. No lower GI tract lesions were detected in the three women with positive FOB., Conclusions: Our data suggest that premenopausal women with iron-deficiency anaemia benefit from endoscopic evaluation of the upper GI tract irrespective of menstrual flow.

Background: In premenopausal women, iron-deficiency anaemia is common and menstrual flow is often held responsible, but it is not clear whether these women should be submitted to gastrointestinal (GI) evaluation. We aim to prospectively investigate whether premenopausal women with iron-deficiency anaemia benefit from GI evaluation regardless of menstrual flow., Methods: The study population comprised 59 consecutive premenopausal women with iron-deficiency anaemia. Excluded were women with obvious or suspected causes of anaemia and those ≤21 years. Heavy menstrual loss was not considered an exclusion criterion. All subjects had: complete blood count, ferritin, non-invasive testing by faecal occult blood (FOB), 13 C-urea breath test ( 13 C-UBT), anti-tissue transglutaminase antibodies (tTG) and gastrin levels. Gastroscopy with antral (n = 3), corporal (n = 3) and duodenal (n = 2) biopsies was performed in women with positive 13 C-UBT or tTG titre or hypergastrinaemia., Results: Heavy menstrual loss was present in 50.8%. Non-invasive tests were positive in 40/59 (67.8%): 30 had positive 13 C-UBT, 12 had hypergastrinaemia, 7 had positive tTG and 3 had positive FOB. Women tested positive were similar to those tested negative as far as concerned age, haemoglobin and ferritin levels and heavy menstrual flow (55% versus 42.1%). All 40 women tested positive underwent gastroscopy with biopsies. Four (10%) had bleeding-associated lesions and 34 (85%) had non-bleeding-associated lesions. As regards upper GI findings, no differences were observed between women with normal and those with heavy menstrual flow. No lower GI tract lesions were detected in the three women with positive FOB., Conclusions: Our data suggest that premenopausal women with iron-deficiency anaemia benefit from endoscopic evaluation of the upper GI tract irrespective of menstrual flow.

Background: The standard evaluation of a patient with iron deficiency anemia includes a complete evaluation of the gastrointestinal tract to identify a source of bleeding. However, even after a careful examination, many patients remain without a diagnosis. Because iron deficiency anemia results from iron loss or defective absorption, we sought to determine the prevalence of potential gastrointestinal sources for iron deficiency anemia in patients without gastrointestinal symptoms., Methods: Over a 10-month period, 668 outpatients were referred to the University Hematology Department with iron deficiency anemia, defined by a hemoglobin concentration less than 14 g/dL (less than 12 g/dL in women), mean corpuscular volume less than 80 fL, and ferritin level less than 30 microg/L. After excluding patients with obvious causes of blood loss, inadequate diet, chronic diseases, or malignancies, there were 81 eligible patients, 10 of whom refused investigation. The remaining 71 patients (51 women, median age 59 years) underwent colonoscopy, as well as gastroscopy with gastric (antrum and body) and duodenal biopsies., Results: A likely cause of iron deficiency anemia was detected in 60 patients (85%). Diseases associated with bleeding were found in 26 patients (37%), including colon cancer (10 patients), gastric cancer (2), peptic ulcer (7), hiatal hernia with linear erosions (5), colonic vascular ectasia (3), colonic polyps (2), and Crohn's disease (1). Causes not associated with bleeding were found in 36 patients (51%), including 19 with atrophic gastritis, 4 with celiac disease, and 13 with Helicobacter pylori gastritis. Six (8%) patients had coincident gastrointestinal findings, and 11 (15%) had no cause identified. Patients with an identified nonbleeding-associated cause were younger than those with a bleeding-associated cause (median, 56 vs 70 years; P = 0.001) and included 59% of women (n = 30) versus 30% of men (n = 6) (P = 0.04). Hemoglobin level was not related to the site and severity of disease., Conclusion: Gastrointestinal diseases that do not usually cause bleeding are frequently associated with iron deficiency anemia in patients without gastrointestinal symptom or other potential causes of gastrointestinal bleeding.

Objective: Iron deficiency anemia has been reported as the most frequent extraintestinal symptom in adult celiac disease. Prospective studies on the effect of gluten-free diet on recovery from iron deficiency anemia are lacking. The aim of this study was to verify in adult patients with celiac disease the efficacy of and the time course of recovery from iron deficiency anemia by a gluten-free diet alone., Methods: We studied 190 consecutive adult patients with iron deficiency anemia, screened for celiac disease by duodenal biopsies. New diagnosed celiac patients were invited to follow a gluten-free diet alone without iron supplementation. After 6 months of diet, duodenal biopsies were performed and hematological tests were repeated at 6, 12, and 24 months., Results: Celiac disease was diagnosed in 26 (24 women, 2 men; 13.7%) adult patients. After 6 months of gluten-free diet 14 of 18 (77.8%) female patients recovered from anemia, but only 5 of 18 (27.8%) reversed from iron deficiency. At 12-month control all but one patient (94.4%) recovered from anemia and 9 patients (50%) from iron deficiency. After 24 months of diet, only the patient who did not recover from anemia at 12-month control was still anemic, whereas 10 patients (55.5%) reversed from iron deficiency. A significant inverse correlation (r = -0.7141, p = 0.0003) between increase of Hb concentrations and decrease of individual histological scores of duodenitis was observed., Conclusions: A screening for celiac disease should be carried out in adult patients with iron deficiency anemia. Recovery from anemia occurs between 6 and 12 months on a gluten-free diet alone as a consequence of normalization of histological alterations of the intestinal mucosa.

Granulocytic sarcoma (GS) is a rare extramedullary tumor composed of immature myeloid cells. It is usually associated with leukemia or other myeloproliferative disorders, but can also occur without overt hematologic disease, i.e. in patients with a normal bone marrow and no history of acute myelogenous leukemia. This primary extramedullary lesion may indeed represent a diagnostic and therapeutic dilemma for both the hematopathologist and oncologist. We describe a case of GS diagnosed in a nonleukemic patient and review the literature regarding the pathologic features and treatment of this condition., (Copyright 2000 S. Karger AG, Basel)

Background: Iron deficiency anemia is the most common form of anemia worldwide. Recent studies have suggested an association between Helicobacter pylori infection and iron deficiency., Objective: To investigate the effects of eradicating H. pylori with combination antibiotic therapy on iron deficiency anemia in patients with H. pylori-associated gastritis., Design: Case series., Setting: University hospital., Patients: 30 patients with a long history of iron deficiency anemia in whom H. pylori-associated gastritis was the only pathologic gastrointestinal finding detected., Intervention: Eradication therapy with two antibiotics and discontinuation of iron replacement therapy., Measurements: Complete blood count, ferritin levels, and gastroscopy with biopsy to evaluate H. pylori status., Results: At 6 months, 75% of patients had recovered from anemia (P<0.001), ferritin values increased from 5.7+/-0.7 microg/L to 24.5+/-5.2 microg/L (95% CI, 8.85 to 29.97). After 12 months, 91.7% of patients had recovered from anemia., Conclusions: Cure of H. pylori infection is associated with reversal of iron dependence and recovery from iron deficiency anemia.

The relationships between acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), chronic myeloid leukaemia (CML) and refractory anaemia with excess of blasts (RAEB) and human herpes virus (HHV)-6 antibody level were investigated in a multicentre case-control study. An association between increased HHV-6 seropositivity and geometric mean titre ratio with AML was shown: P for trend = 0.022, adjusted odds ratio 1.20, 95% confidence interval 1.07-1.33 respectively. No association was found between HHV-6 and ALL, CML or RAEB.

Background: The treatment of lymphoproliferative diseases requires extensive histological, immunohistochemical, and cytogenetic diagnosis. The aim of this study was to analyze the results of 66 laparoscopic procedures in the diagnosis, staging, and restaging of hematological malignancies localized in the abdominal cavity., Methods: Between July 1993 and March 1998, 64 consecutive patients (28 male and 36 female; mean age 46.6 years, range 7 to 69) with diagnosed or suspected lymphoproliferative diseases were referred for primary diagnosis or reassessment and for staging/restaging., Results: Sixty-two out of 66 procedures (93.9%) were completed laparoscopically., Conclusions: The minimally invasive approach, in the management of lymphoproliferative diseases, is able not only to provide an adequate specimen for proper diagnostic techniques, but also, when compared with open surgery, to offer a large number of advantages.

Objective: Atrophic body gastritis (ABG) is characterized by atrophy of the gastric body mucosa, hypergastrinemia, and hypo/achlorhydria. Its association with pernicious anemia is well recognized. Gastric hypo/achlorhydria is known to affect iron absorption but ABG is rarely considered as a possible cause of iron deficiency (microcytic) anemia. The aims of this study were to validate a screening methodology for the detection of ABG in a consecutive series of patients with microcytic and macrocytic anemia and to investigate the clinical and gastric morphofunctional characteristics of the two hematological presentations of ABG., Methods: A two-part prospective study was carried out. Part A aimed to validate the screening methodology to detect the presence of ABG in patients with macrocytic and microcytic anemia who have no specific GI symptoms, by measuring their gastrin levels and verified by performing gastroscopy with biopsy. Part B aimed to detect the presence of ABG in a larger sample of anemic patients by our validated method and, by pooling the data of ABG patients, to determine the clinical, gastric histological, and functional characteristics pertaining to the macrocytic and microcytic presentations of ABG., Results: In part A, ABG was detected in 37.5% of patients with macrocytic and in 19.5% of those with microcytic anemia. Pooling the data of the ABG patients from part A and part B, microcytic ABG patients were on average 20 yr younger than those with macrocytic anemia. The majority of microcytic ABG patients were female, most of whom were premenopausal. H. pylori infection was widely represented in the microcytic ABG group (61.1%). They also had a lesser grade of body mucosal atrophy and lower hypergastrinemia levels, suggesting a less severe oxyntic damage of shorter duration., Conclusions: Macrocytic anemia is not the only hematological presentation of ABG. Physicians evaluating patients with unexplained iron deficiency anemia should consider ABG as a possible cause by determining fasting gastrin levels and performing gastroscopy with biopsies of the body mucosa.

During a 7-month period a prospective study of 71 anaemic patients (29 males and 42 females) over the age of 50 was undertaken in order to identify patients with myelodysplastic syndrome (MDS). The mean values of mean corpuscular volume (MCV), serum ferritin, folate, vitamin B12 and red cell folate (RCF) of patients grouped according to the diagnosis were compared to those observed in age-matched blood donors. Forty-four of the 71 elderly patients showed macrocytic anaemia: 21 of them had gastric disease and the remaining 23 MDS. Two further patients with MDS showed microcytic anaemia. The 25 patients diagnosed with MDS were subclassified according to the FAB nomenclature: 9 had a refractory anaemia with excess of blasts and 16 refractory anaemia. The mean values of MCV, serum folate, ferritin, vitamin B12 and RCF were statistically different between patients with macrocytic anaemia due to gastric disease and patients with MDS. Among patients with MDS, the RCF level pathologically high was inversely correlated to the haemoglobin level (r=-0.39; p<0.05). Thus the RCF and serum folate may represent useful parameters for the diagnosis of MDS in elderly anaemic patients.

Background: Very little information is presently available regarding risk factors for essential thrombocythemia (ET)., Methods: A case-control study was performed to study the possible association between ET and selected behavioral, occupational, and environmental exposures., Results: Thirty-nine patients aged 20 years or older and 156 controls were enrolled in 2 Italian Hematology Departments located in Rome and Pavia. Controls were recruited among outpatients seen in the same hospitals and matched 4:1 to the patients after stratification by age and sex. Odds ratio (OR) estimates suggest an association between ET and hair dye use (in particular the use of dark hair dye for periods longer than 10 years: OR - 5.3; 95% confidence interval [CI], 1.4-19.9), living in houses built with tuff (a material with a high concentration of gamma-emitting radionuclides and radon) for longer than 9 years (OR = 5.1; 95% CI, 1.2-22.1), and selected occupations (electrical worker and shoemaker, OR +infinity and 2.7; 95% CI, 0.5-16 respectively)., Conclusion: Behavioral exposures such as hair dyes, living in a tuff house, and working as an electrician are significantly associated with ET development. The data are consistent with those observed in acute leukemias.

Background: The estimated incidence of acute promyelocytic leukemia (APL) is approximately 6 cases per 10 million people per year with no apparent differences between sexes. The age of APL cases is younger than that of other acute myeloid leukemias (AML). Spatial and temporal clusters of APL have been reported. These observations suggest a possible selective role for environmental and/or occupational factors in APL development., Methods: A multicenter case-control study was carried out on risk factors for acute leukemias and preleukemias. In this report data related to APL are selectively analyzed from the larger study to identify specific risk factors., Results: The case-control study on 38 cases of APL showed a strong association with shoemaking (odds ration 6.3, 95% confidence interval 1.3-31.1). A moderate leukemogenic effect from living in houses built with tuff, a polous building material containing gamma-emitting radionuclides and having a high radon concentration, and from using hair dyes was also suggested., Conclusions: These data, together with the reported spatial and temporal clustering of APL, support the hypothesis of specific environmental and/or occupational risk factors for APL among other AML subtypes and indicate the need for additional ad hoc multicenter studies.

There is a wealth of experiences concerning cancer and leukemia induced in human populations by radiation. The contribution of the nuclear industry to the radiation exposure of the general population is small, but there is the risk of catastrophic accidents causing a large number of deaths. The authors describe the case of a 48 year old black man accidentally exposed to the effects of radiations during the nuclear disaster of Chernobyl in 1986. The patient showed, many years later, a predominantly cutaneous high-grade T cell lymphoma, which was refractory to traditional treatments but sensitive to high doses of a recombinant interferon. Unluckily the patient died, six months later, because of autoinfection overwhelming. The goal of the authors is again to ask to reflect on the risk of the use of nuclear power and to debate the possible choice of the still experimental treatments.

Background and Methods: A significant correlation between bone marrow (BM) histology, survival and disease progression (DP) probability has been observed by several authors in chronic lymphocytic leukemia (CLL). The prognostic value of BM histologic patterns on survival and disease progression probability was investigated in 335 B-CLL patients., Results: Actuarial survival probability estimated by univariate analysis proved to be significantly influenced by stage (p < 0.0001), BM histology (p = 0.01), and by the following parameters: anemia (p = 0.0005), splenomegaly (p < 0.001), CLL-related symptoms (p < 0.01), thrombocytopenia (p < 0.01), number of involved nodal areas (p = 0.01) and peripheral lymphocyte count over 30 x 10(9)/L (p < 0.05). In this series we did not detect a discriminating prognostic effect for BM histology within the individual stages. Cox multivariate regression analysis failed to demonstrate a significant value for BM histology, while stage and anemia emerged as the best prognostic variables. Actuarial DP free probability in 294 untreated patients with A and B stages was significantly related to stage (p < 0.00001) and to BM pattern (p = 0.01)., Conclusions: Despite the clear correlation between the D pattern of BM involvement and advanced and early progressive disease, we were unable to demonstrate an independent prognostic value for BM histology. These findings suggest that stage emerged as the best predictive factor of survival probability in our B-CLL patients.

Background: The use of fludarabine, an analog of vidarabine with significant lymphocytolytic activity, has provided encouraging results in the treatment of patients with non Hodgkin's lymphoma (NHL) and sometimes in phase II studies of solid tumors and acute leukemias. Fludarabine has also been shown to be effective in B-CLL. Some studies referred results using fludarabine in high-risk untreated or pretreated CLL patients., Methods: We report treatment results with fludarabine and prednisone in 22 pretreated B-CLL patients in progressive disease, refractory to CHL and other regimens., Results: One patient obtained a complete response (CR), 8 obtained a partial response (PR). Thirteen failed to respond to treatment. Among the partial responders, 1 patient had fatal pneumonia while neutropenic, another died of disease progression. Among the non responders, 7 died of progressive disease, and 3 evolved into high-grade NHL. Three are still alive in disease progression., Conclusions: We confirm the effectiveness of fludarabine in pretreated and resistant B-CLL, but in the light of the considerable toxicity observed in this series, we believe that the drug would be better employed as a first-line approach to "younger" untreated B-CLL patients.

Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) died of infection during induction, and nine (28%) had resistant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated.

Extramedullary blast crisis (EBC) with T-lymphoid phenotype has been reported rarely and generally associated with extremely poor prognosis. We describe a case of T-lymphoid EBC in which long-lasting remission was observed following intensive chemotherapy and allogeneic bone marrow transplantation (BMT). Characterization of bone marrow (BM) and lymph node (LN) cells was performed by means of morpho-cytochemical, cytogenetic, immunophenotypic and molecular analyses. These showed, together with a marrow picture consistent with typical Ph'+ chronic myelogenous leukemia, the expansion of an early T-lymphoid (CD7+/TdT+) LN cell population exhibiting the same bcr rearranged pattern and an additional Ph' chromosome. At the present time, 33 months after BMT, the patient is alive and well, with persistent clinical, hematological, cytogenetic and molecular evidence of complete remission.

We examined 245 lymph node biopsies of subjects possibly suffering from systemic lymphopathy, in which non-invasive means did not allow a certain diagnosis. The parameters considered are: histological finding, age of patients at the time of diagnosis, presence of general symptoms, location of the superficial lymph nodes concerned, collateral tests usually performed, familiarity. The significance of differences between the main disease groups has been checked by the usual statistical methods. Our data are generally consistent with the diagnostic criteria commonly accepted in the literature, except for some details: e. g. in Hodgkin's disease the distribution of patient ages at the time of first diagnosis shows a single peak (unimodal), instead of two, as described in other countries. The involvement of supraclavicular nodes in chronic aspecific lymphopathies is less frequent than in systemic lymphomas. Our experience has widely confirmed the indications and usefulness of lymph node biopsy for hematological diagnosis.

A case of warm autoimmune hemolytic anemia due to IgA antibody is described. The patient had clinical and hematologic signs of hyperhemolysis, but all specific tests were negative. The direct antiglobulin test was positive only when it was performed with anti-IgA monospecific antiserum. The autoantibody eluted from the patient's red cells showed anti-e specificity. The sensitivity of broad-spectrum antiglobulin serum and the possible hemolytic mechanisms of IgA-coated red cells are discussed.

Thirty patients with advanced acute leukemia and lymphoma were treated with the sequential combination of high dose ARA-C (HiDAC 3 gm/m2 infused i.v. over 3 h at 0, 12, 24, 36 h) and asparaginase (ASP 6.000 IU/m2 i.m. at hour 42). The sequence was given on day 1 and 8 irrespective of the degree of myelosuppression. Of 22 patients with leukemia there was only one who was absolutely refractory to therapy. Complete remission was induced in 3 patients with ANLL (30%) and in 3 with ALL (30%). Three patients became hypoplastic but recovered with blasts and 12 died from infection, complicated by intracranial hemorrhage in 3, during hypoplasia. Of 8 patients with lymphoma, 2 were clearly refractory to therapy, one died from sepsis and the remaining 5 all entered remission (2 CR + 3 PR, 62%). Activity of HiDAC/ASP against CNS disease is suggested by the clinical response seen in patients with overt meningeal or intracerebral involvement. Toxicity associated with HiDAC/ASP was mainly hematologic. All but one patient experienced hypoplasia and severe pancytopenia; documented infections and major hemorrhages occurred in 80 and 20% of patients respectively. We conclude that HiDAC/ASP is a regimen with definite activity against acute leukemia and lymphoma including CNS disease. Alternate treatment schedules should be explored in order to reduce marrow toxicity.

The presence of Epstein-Barr virus antigens and genome was studied in lymph nodes from HIV + patients affected by PGL. Cryostat sections from 50 lymph nodes of HIV + patients were immunostained with EBV-VCA (viral capsid antigen), EBV-EA (early antigen) and p24 HIV major core protein monoclonal antibodies. In situ hybridization was performed using a biotin conjugated EBV DNA probe; the reaction product was demonstrated by immunohistochemical method. As positive controls, EBV producer B95-8 and HIV infected H9 cell lines were used. The majority of patients had circulating EBV antibodies mainly directed against the viral capsid antigen and only in few cases against early antigens. Positivity for HIV p24 protein was detected in 43 out of 50 lymph nodes within the germinal centers with a reticular pattern. Only 2 out of 50 lymph nodes presented very few positive cells for EBV antigens and none expressed detectable EBV genome. Our results suggest that EBV cellular expression does not correlate with serum positivity; furthermore the absence of EBV antigens and genome at tissue level might indicate that EBV is not directly involved in the pathogenesis of PGL.

Signet ring cell lymphoma is a non-Hodgkin's lymphoma, characterized by neoplastic lymphoid signet ring cells very similar to epithelial mucin producing cells. We describe here a case of signet ring cell lymphoma in which the immunophenotypic markers of signet ring cells parallel those of plasma cells, being intensively T10+ (CD 38), weakly HLA-DR+, and To15 (CD 22) and T200 (CD 45) negative. The morphologic and immunohistochemical features of the case and the main differential diagnosis are preceded by a review of the literature.

Quinolones are active against gram-negative strains. They are commonly used for selective intestinal decontamination in patients with hematologic malignancies and prolonged neutropenia due to chemotherapy. In our open study we used pefloxacin, a new fluoroquinolone, for the treatment of fifteen documented gram-negative infections in hematologic patients. Thirteen patients were mildly neutropenic, and in nine cases they received oral treatment as non-hospitalized patients. Cure was achieved in fourteen cases, with microbiological eradication of the offending pathogen.

A quantitative evaluation of terminal deoxynucleotidyl transferase (TdT) was performed using a highly sensitive enzyme immunoassay (EIA) in 72 previously untreated patients with acute myeloid leukemia (AML). Biological analysis of the leukemic cells included in all cases cytochemistry, search for Ph' chromosome and immunophenotyping with both anti-lymphoid and anti-myeloid monoclonal antibodies (MoAbs). Thirteen AML cases (18 per cent) were considered TdT+ by EIA. According to the FAB classification, almost all of them (12 out of 13) were within the M1 and M2 subgroups. A mixed lymphoid-myeloid phenotype was observed in one of the 13 TdT+ cases, while in none of the others were lymphoid features detected. Nine of the 10 EIA TdT+ cases studied in parallel were TdT positive with the conventional immunofluorescence assay. All patients received standard protocol chemotherapy and in 61 (13 TdT+, 48 TdT--) the response to induction treatment was analysable. Only 3/13 TdT+ patients (23 per cent) achieved a complete remission (CR), while in the TdT- group 38 patients had a CR (79 per cent) and 10 were resistant (p less than 0.01). It is suggested that the incidence, biological interest and prognostic significance of TdT+ AML should encourage the routine and more accurate search for this marker in all patients with AML.