Cutaneous manifestations of systemic non-Hodgkin lymphomas (NHL): study and review of literature.

Systemic non-Hodgkin lymphomas are often accompanied by cutaneous manifestations, which are not always looked out for. Nevertheless, these alterations can be very important because their presence is lied to the clinical behaviour of the underlying malignancy, with an early recognition being fundamental. The aim of this study was to make order in this topic and propose a preliminary classification of the cutaneous manifestations associated with non-Hodgkin lymphomas. We performed a retrospective chart review of 62 haematological patients affected by non-Hodgkin systemic lymphomas with dermatological manifestations, who were evaluated from January 2007 to December 2011, and combined these results with a systematic review of Pub medical literature from 1937 to 2011 on this topic. A preliminary classification of these manifestations has been proposed, dividing them in specific and non-specific ones, along with a description of the clinical features and those cases observed in our department. A preliminary approach has been proposed for the study of these manifestations that could be helpful in understanding the biological behaviour and aid early recognition of a flare up in systemic non-Hodgkin lymphomas.

Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story.

BACKGROUND: Improved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers. DESIGN AND METHODS: To evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL. RESULTS: Our results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival. CONCLUSIONS: A new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.

Upper and lower gastrointestinal causes of iron deficiency anemia in elderly compared with adult outpatients.

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.

Unawareness of gastrointestinal symptomatology in adult coeliac patients with unexplained iron-deficiency anaemia presentation.

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.

Acute myeloblastic leukemia with t(8;21) following Philadelphia positive acute lymphoblastic leukemia.

A patient with Philadelphia positive (Ph'+) acute lymphoblastic leukemia (ALL), in remission for over 4 years, developed an acute myeloblastic leukemia (AML), M2-type. During the second disease, the blast cells displayed a typical t(8;21)(q22;q22) translocation, in the absence of the Ph' chromosome. This is the first observation in the same patient of two leukemias displaying different cell phenotypes and each associated to one of the most characteristic chromosome changes. Cytogenetic characteristics and clinical aspects of the diseases are suggestive for the occurrence of two independent leukemic processes.

In vivo effect of granulocyte-macrophage colony-stimulating factor on the kinetics of human acute myeloid leukemia cells.

Granulocyte-macrophage colony-stimulating factor, (GM-CSF) was given at 8 micrograms/kg daily by continuous i.v. infusion for 72 h to six patients with acute myeloid leukemia (AML) in expansion and one with chronic myeloid leukemia in blastic crisis to determine whether it was possible to augment the proliferative activity of the neoplastic population. The percentage of marrow blasts in S phase (labeling index, LI) was increased in five patients (1.3-, 1.5-, 1.9-, 2.3- and 3.2-fold change). The increase in LI was similar 24 and 48 h after beginning GM-CSF. The RNA Index also increased in patients who showed an increased LI, suggesting that GM-CSF had recruited quiescent neoplastic cells into the cell cycle. Forty eight hours after beginning GM-CSF, chemotherapy was started. The fate of S phase cells, labeled in vivo with bromodeoxyuridine (BrdU) immediately before cytostatic treatment, was monitored. BrdU positive cells were identified by fluorescent antibody for up to 28 days. A preferential killing of BrdU (S phase) cells was observed in 5/7 patients who obtained a complete remission, whereas this was not apparent in the two patients who achieved only a partial remission. Chemotherapy induced a rapid and profound aplasia; its duration, however, was not significantly different from that observed in historical controls. GM-CSF may have a potential role in the treatment of AML, as this study shows that it recruits leukemic cells into the cell cycle without adversely prolonging aplasia after cycle-specific therapy.

Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia.

A total of 74 patients with poor risk AML (median age 36.7 years, range 4.5-60.6) received a single course of a regimen including mitoxantrone (6 mg/m2 intravenous bolus daily, days 1 to 6), etoposide (80 mg/m2 intravenous over 1 h, daily, days 1 to 6) and intermediate-dose Ara-C (1 g/m2 over 6 h, daily days 1 to 6). 28 patients had failed initial remission induction with daunorubicin and conventional doses of Ara-C, 16 patients had secondary AML and 30 patients had relapsed from initial remission (five within six months, 15 over six months and ten after autologous or allogeneic bone marrow transplantation). Overall 41/74 patients (55%) achieved complete remission, 26 (35%) had resistant disease and seven (10%) died of infection during marrow hypoplasia. A 4-day course of the same regimen was given as consolidation to patients in complete remission. Subsequent antileukemic therapy was individualized. Profound myelosuppression and pancytopenia were universal resulting in fever or documented infections in almost 100% of patient; major hemorrhagic complications occurred in 39% of patients. Extrahematologic toxicity was mild to moderate consisting mostly of nausea and vomiting, oral mucositis and transient liver and cardiac dysfunction. We conclude that the MEC combination chemotherapy program seems to be an effective antileukemic regimen for secondary and advanced AML, with acceptable toxicity.

Is aggressive chemotherapy the best choice for patients with acute nonlymphocytic leukemia after myelodysplastic syndromes?

Myelodysplastic syndromes (MDS) evolve in overt acute nonlymphocytic leukemia (ANLL) in about 40% of patients: the treatment of ANLL-MDS is not yet well clarified. To identify the role for aggressive and conservative approaches in ANLL-MDS, we evaluated retrospectively 78 patients in a 7-year period. Thirty-one patients (16 males and 15 females, median age 57.5 years, median MDS duration 5.5 months) were eligible for aggressive chemotherapy; 17 patients (54.8%) achieved complete remission (CR), 10 (32.3%) were resistant and 4 (12.9%) died during induction from infective complications. All patients that achieved CR relapsed, with a median CR duration of 6 months (range 2-28 months); median survival of the whole group was 8.5 months, while median survival of responders was 9 months. No prognostic factor revealed a statistical significance in the outcome, due to the small number of patients in each subgroup. Forty-seven patients (27 male and 20 female, median age 71.8 years, median MDS duration 10.1 months) were not eligible for aggressive chemotherapy; 16 patients (34.2%) received supportive care only, 31 patients (65.8%) needed conservative chemotherapy for disease progression. Median survival of the conservatively treated group was 5.5 months, without statistical difference from the aggressively treated group; 10/47 conservatively treated patients (21%) survived for longer than 12 months. In conclusion, aggressive chemotherapy may play a role only in a selected population of ANLL-MDS patients, while further studies could be helpful to identify the optimal conservative approach.

Unbalanced 6p translocation as primary karyotypic anomaly in secondary acute nonlymphocytic leukemia.

A case of acute nonlymphocytic leukemia after radiochemotherapy for Hodgkin's disease, with a rearrangement of 6p23 region, is described. This chromosome change, which has been previously reported in secondary leukemias or myelodysplastic syndromes, was an isolated karyotypic anomaly in our case, which strongly supports the nonrandom involvement of chromosome 6p in induced leukemias.

Molecular remission following high-dose hydroxyurea and fludarabine plus cytarabine in a patient with simultaneous acute myeloid leukemia and low-grade lymphoma.

The occurrence of acute myeloid leukemia (AML) as a secondary tumor has been frequently reported in patients who received various chemotherapy regimens for hematologic malignancies wile the concomitant development of chronic lymphoproliferative diseases (CLD) and AML in previously untreated patients is extremely rare. We report a case with an apparently spontaneous occurrence of AML and non Hodgkin low-grade lymphoma diagnosed by immunological, cytogenetical and molecular analyses. In particular genetic studies allowed to identify the coexistence of a clonal lymphoid population and a myeloid blast component characterized by inv(16) marker and CBFbeta-MYH11 gene fusion. Complete remission of AML and the CLD was obtained following high doses of hydroxyurea and two consolidation cycles of fludarabine plus intermediate dose cytarabine.

Is recombinant human erythropoietin treatment in myelodysplastic syndromes worthwhile?

It has been recently demonstrated that erythropoietin increases the haemoglobin levels in anemia secondary to chronic renal failure. Moreover some recent experiences also suggested a possible role in the treatment of MDS. From April 1990 to April 1992, 23 patients (16 males and 7 females, median age 63.5 years) affected with low risk myelodysplastic syndrome (MDS) were treated with recombinant human erythropoietin (rHuEPO) to ameliorate Hb levels and transfusional requirement. All patients received high doses of rHuEPO (800 U/Kg weekly s.c. in 2-3 divided doses, for 3 months). A complete remission, defined as stable normalization of Hb level, was achieved in 1/23 patients. This patient had refractory anemia, by FAB criteria. A partial response, defined as stable increase of Hb levels > or = 1 g/dl and/or reduction of transfusional requirement > or = 50% lasting at least 3 months, was achieved in 7/23 patients. Patients with a partial response received rHuEPO at increased dosages (1200 U/Kg weekly s.c. 2-3 times): 1/7 achieved a complete response, 4/7 remained stable and 2/7 decreased to pre-therapy Hb value. These results suggest that rHuEPO may be a promising therapeutic tool for some MDS patients.

Acute myeloblastic leukemia secondary to myelodysplasia (MDS-AML): a comparison of remission induction with three drugs versus standard two-drugs induction.

To evaluate the addition of a third drug to standard induction chemotherapy in patients with MDS-AML, 23 patients (males/females 13/10, median age 54.3 years, range 24-74 years, median MDS duration 9.8 months, range 2-39 months) who received a standard 2-drugs induction were compared with 23 patients (males/females 11/12, median age 45.6 months, range 21-60 years, median MDS duration 8.3 months, range 2-29 months) who received an intensified 3-drugs induction with etoposide. CR rate, median CR duration and median OS were similar in both groups (48% vs 56%, 4.8 vs 5.9 months, 6.5 vs 7.0 months respectively). Among responding patients, all but one, who underwent allogeneic bone marrow transplantation, relapsed. In conclusion, addition of a third drug (etoposide) does not seem to significantly improve the poor prognosis of MDS-AML patients.

[Use of erythropoietin in hematologic oncology]. / Impiego dell'eritropoietina in onco-ematologia.

Erythropoietin (EPO) is a glycoprotein synthesized by the kidney, which has a stimulating effect on bone marrow erythroid precursors. It has been identified many years ago, but its clinical use has been developed only since 1985 with the introduction of recombinant molecle (rHuEPO). In the past decade, rHuEPO has been employed in neoplastic as well as in chronic inflammatory diseases associated with anemia, that recognizes a multifactorial pathogenesis: defective endogenous EPO production, impaired erythroid proliferation due to excessive release of inflammatory cytokines, intrinsic abnormalities of erythroid precursors, reticulo-endothelial blockage with reduced erythroid uptake of iron. Anemia of neoplastic diseases, moreover, may be induced or worsened by marrow toxicity of chemotherapy. The efficacy of rHuEPO in these conditions is still unclear.

Histological recovery and gluten-free diet adherence: a prospective 1-year follow-up study of adult patients with coeliac disease.

BACKGROUND: Adequate gluten-free diet (GFD) is the only treatment for coeliac disease (CD). However, no agreement has been reached on either how and when to assess patient adherence to GFD or its effectiveness on villous atrophy. AIM: To assess, in a prospective study, patient adherence to and efficacy of GFD on histological recovery after 1-year of GFD. METHODS: Between 2009 and 2012, we enrolled 65 consecutive newly-diagnosed adult patients (median age 38 years, 18-70) with biopsy-proven atrophic CD. Patients were re-evaluated after 1 year of GFD with duodenal histology, serological assays, symptoms and a dietary interview based on a validated questionnaire. Complete histological recovery was defined as the absence of villous atrophy and ≤30/100 intraepithelial lymphocytes. RESULTS: Overall, 81.5% of patients had adequate adherence (ADA) to GFD, whereas 18.5% had an inadequate adherence (IADA); 66% of ADA patients and no IADA patients achieved complete histological recovery (P < 0.00001). Among ADA patients, antibody seroconversion and symptoms were not significantly different between patients who achieved complete histological recovery and those who achieved partial histological recovery with P = 0.309 and P = 0.197, respectively. Multivariate analysis showed that Marsh 3C was a risk factor for incomplete histological recovery in ADA patients (OR 8.74, 95% CI: 1.87-40.83). CONCLUSIONS: This study shows that complete histological recovery after 1-year of GFD in adult patients, who are assessed as adherent to the GFD, can be obtained in 66% of patients. Patients with severe histological damage at diagnosis are at risk for incomplete histological recovery 1 year later.

Benefit of concomitant gastrointestinal and gynaecological evaluation in premenopausal women with iron deficiency anaemia.

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.

Impact of a new dosing regimen of epoetin alfa on quality of life and anemia in patients with low-risk myelodysplastic syndrome.

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.

Combination chemotherapy for marrow relapse in children and adolescents with acute lymphocytic leukaemia.

38 children with acute lymphocytic leukaemia (ALL) in haematologic relapse were retreated with vincristine, daunomycin and prednisone (VPD) together with intrathecal methotrexate and prednisone, followed by asparaginase in those patients not in complete remission after 4 weeks. The overall complete remission (CR) rate was 79%; asparaginase was needed to achieve CR in 7 of the 30 responding patients. The median duration of second remission was only 36 weeks, but 6 out of 15 children receiving the COAP-POMP-CART consolidation regimen remain in continuous second remission after 37-260 weeks; 3 of them are currently off all therapy. It is concluded that a prolonged second remission can be achieved in children with ALL in bone marrow relapse by combining intensive chemotherapy with the prevention of meningeal leukaemia.

Polycythaemia vera and cerebral blood flow: a preliminary study with transcranial Doppler.

OBJECTIVES: The purpose of this study has been to investigate by ultrasonographic methods the flow velocities of cerebral arteries because increased blood viscosity due to haematocrit elevation can cause neurological symptoms in polycythaemia vera patients, because of the resulting decrease in cerebral flow. SUBJECTS AND DESIGN: Twenty newly diagnosed patients, with haemoglobin values of > 18 g dl-1 and/or an haematocrit of > 50%, were examined by transcranial Doppler. Recordings were performed in basal conditions and after pharmacological and/or phlebotomic treatment, when haematocrit values were < or = 50%. Blood velocities were evaluated in middle (MCA), anterior (ACA), posterior (PCA) cerebral arteries and in the basilar (BA) artery. RESULTS: Basal recordings showed decreased velocities (MCA: 39.40 +/- 9.34 cm s-1; ACA: 34.05 +/- 10.25 cm s-1; PCA: 31.46 +/- 5.97 cm s-1; and BA: 27.47 +/- 7.42 cm s-1); pre- and post-treatment value differences observed in MCA, ACA and BA were highly significant (P < 0.001). CONCLUSIONS: A decrease in cerebral flow could be a risk for multifocal micro-ischaemic cerebral infarctions leading, after several years, to a multi-infarct dementia; an early reduction in erythrocyte burden should be very useful in polycythaemic patients in preventing lacunar lesions.

Treatment of high-risk myelodysplastic syndromes with lymphoblastoid alpha interferon.

UNLABELLED: Seventeen patients with high-risk myelodysplastic syndromes (HR-MDS) received lymphoblastoid-interferon alpha (Ly-IFN alpha) for 3 months at escalating doses from 0.5 to 3 MU s.c. 3 times per week. Three patients stopped the treatment after 2 months because of cardiac failure (one patient) and cerebral haemorrhage (two patients); six had a partial response (PR) and continued Ly-IFN alpha; six were resistant and stopped Ly-IFN alpha; two evolved to acute myelogenous leukaemia (AML). Among the six partial responders, four achieved a complete response (CR) during subsequent Ly-IFN alpha treatment (CR duration 3, 4+, 15+ and 29 months) and two did not achieve any further improvement (PR duration 3 and 9 months). Two resistant patients had an unexpected clinical improvement soon after Ly-IFN alpha discontinuation and achieved a PR of 6+ and 14+ months respectively. No toxicity related to Ly-IFN alpha treatment was observed and no reduction of dosage was needed. IN CONCLUSION: (1) Ly-IFN alpha seems to be effective in some patients with HR-MDS; (2) the best treatment duration seems to be of a least 6 months.