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.

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.

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.

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.

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.

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.

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.

High-dose hydroxyurea in the treatment of poor-risk myeloid leukemias.

The aim of the study was to evaluate the antileukemic effectiveness and toxicity of high-dose hydroxyurea (HHY) and to assess its acute toxicity. Between August 1997 and October 1998, 12 consecutive adult patients (>18 years) with high-risk acute myeloid leukemia (AML) (four patients in first early relapse, seven patients with secondary AML, and one patient with de novo AML concomitant to a lymphoproliferative disorder) were enrolled to receive a single course of HY (100 mg/kg per day) until bone marrow aplasia or for a maximum of 30 days. Of the 12 patients, 5 (41.6%) achieved complete remission (CR), 1 achieved partial remission (PR), 4 were resistant to treatment, and 2 died during induction from infection. No patient with relapsed AML achieved CR, while it was achieved by five of eight patients with secondary AML at diagnosis; five of six MDR1+ patients achieved CR. As concerns follow-up of the CR patients, one did not receive any further treatment and died in CR from pulmonary aspergillosis, and one with a concomitant chronic lymphocytic leukemia (CLL) received two courses of FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor) regimen with disappearance of the clonal Ig rearrangement, but relapsed after 11 months and died from pneumonia. The remaining three patients were consolidated with two courses of high-dose cytosine arabinoside (AraC), followed by peripheral blood stem cell transplantation (PBSCT) in one patient. One of them relapsed after 3 months, while the other two are still in continuous complete remission (CCR) after 16 and 28 months, respectively. This study has demonstrated the safety and efficacy of HHY in inducing CR in AML patients with unfavorable prognosis. Despite the small number of patients, these encouraging results warrant further studies.

Melphalan treatment in patients with myelofibrosis with myeloid metaplasia.

Between January 1985 and December 1992, 104 consecutive patients with symptomatic myelofibrosis with myeloid metaplasia (MMM) [splenic enlargement >5 cm and/or transfusional requirement or Hb < 10 g/dl and/or white blood cell (WBC) count >20 x 10(9)/l and/or platelets >1.0 x 10(9)/l] received low-dose Melphalan (2.5 mg/3 times/week) to evaluate the efficacy and toxicity of this approach. Among 99 evaluable patients, 66 (66.7%) achieved a response after a median time of 6.7 months: 26 (26.3%) had a normalization of all clinical and haematological parameters (complete response, CR) and 40 (40.4%) showed an improvement >50% (partial response, PR). Thirty-three patients (33.3%) were resistant. Reversible haematological toxicity was the most common complication. Median durations of CR and PR were 28.4 and 26 months respectively: median survival of CR + PR patients was 71.2 months (95%CI: 33.8-108.7) versus 36.5 months (95%CI: 24.5-48.5) for the non-responders (log-rank test, P =0.002). In the multivariate analysis, the following variables were significantly associated with a shorter survival: anaemia [hazard risk (HR) = 2.7], WBC count >20 x 10(9)/l (HR = 2.4) and not achieving any type of response, either partial or complete (HR = 3.9). In conclusion, Melphalan could be a promising first-line option for MMM patients with clinical or haematological symptoms requiring treatment.

Spontaneous remission in adult patients with de novo myelodysplastic syndrome: a possible event.

BACKGROUND AND OBJECTIVES: Spontaneous remission (SR) in de novo myelodysplastic syndromes (MDS) is a rare event, which has been so far described only in children with monosomy 7. The phenomenon is extremely heterogeneous, perhaps depending on different pathogeneses of the disease. DESIGN AND METHODS: We retrospectively evaluated the outcome of 564 consecutive adult patients with primary MDS diagnosed at our Institution in a 12-year period. SR was defined as an unexpected improvement lasting more than 1 year without concomitant treatments other than vitamins or low-dose steroids (in patients with platelets < 50 x 10(9)/L). RESULTS: Nine cases of SR were observed in 3 males and 6 females (median age 38.7 years). At diagnosis, all patients had Hb levels < 10 g/dL and 8/9 required packed red cell transfusions. The median time from diagnosis to SR was 18 months (range 4-46) and all patients had normalization of peripheral blood parameters: in 2 out of 3 patients with karyotypic abnormalities at onset, a cytogenetic remission was documented. The median duration of SR was 56 months; 5 patients are still in SR and 4 patients have relapsed (1 as MDS and 3 as acute myeloid leukemia). INTERPRETATION AND CONCLUSIONS: SR is a rare (less than 2% in our experience) but possible event also in adult MDS patients. It should be kept in mind in the evaluation of experimental treatments for MDS in which very low rates of complete responses are expected.

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.

[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.

A case-control study of the effects of hydroxyurea on circulating cortisol levels in patients with acute myelogenous leukemia and chronic myeloproliferative disorders.

We have shown previously that the antitumor drug, hydroxyurea (HU) is able to induce dose-dependent increases in plasma corticosterone levels in the rat. The drug was administered early in the morning, when the levels of circulating glucocorticoids are low in this species. Normally, in humans under physiological conditions, cortisol levels are elevated early in the morning, to which a sharp decrease follows between 09:00 and 11:00 hours. In a group of healthy volunteers, HU significantly attenuated the decrease in cortisol levels occurring between 09:00 and 11:00 hours with respect to the same subjects receiving placebo. Given the different circadian rhythms of the two species, such an effect of HU in man appeared to be the counterpart of the increase in serum corticosterone occurring in the rat. In the present study, we have attempted to ascertain whether HU is also able to influence adrenocortical function in patients with acute and chronic myeloproliferative disorders undergoing treatments with high doses of the drug. We found that the rate of decline in circulating cortisol observed in patients during the time interval 09:00-11:00 hours was overlapping to that previously found in healthy volunteers treated with HU. In patients, serum cortisol was still elevated at 15:00 hours, since average hormone levels were near to the upper normal limit of the assay. However, in the absence of a control group treated with placebo, we could not draw any clear-cut conclusion as to whether HU was able to modify significantly the pattern of cortisol release in the study population.

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.

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.

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.

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.

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.