Publications by authors named "Endri Mauro"

30 Publications

  • Page 1 of 1

Bosutinib in the real-life treatment of chronic myeloid leukemia patients aged >65 years resistant/intolerant to previous tyrosine-kinase inhibitors.

Hematol Oncol 2021 Feb 22. Epub 2021 Feb 22.

Hematology, Department of Translational and Precision Medicine, Policlinico Umberto I, Sapienza University, Rome, Italy.

To evaluate the role of bosutinib in elderly patients aged >65 years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500 mg/day in 25 patients (24.8%), 400 mg/day in 7 patients (6.9%), 300 mg/day in 33 patients (32.7%), 200 mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.
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http://dx.doi.org/10.1002/hon.2851DOI Listing
February 2021

Hepatitis C virus-related cryoglobulinemic vasculitis.

Minerva Med 2021 Apr 16;112(2):175-187. Epub 2020 Nov 16.

Unit of Clinical of Experimental Onco-Hematology, IRCCS Centro di Riferimento Oncologico (CRO), Aviano, Pordenone, Italy.

Introduction: Hepatitis C virus (HCV) infection affects about 170 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases, and it can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas (NHL). Cryoglobulinemic vasculitis (CV) varies, ranging from mild-moderate clinical symptoms (purpura on the legs, asthenia and arthralgias) and chronic hepatitis to severe symptoms (ulcers on the legs, peripheral neuropathy, glomerulonephritis, low-grade NHL to life threatening complications (rapid progressive glomerulonephritis, gastrointestinal vasculitis, acute hyper-viscosity).

Evidence Acquisition: CV is associated with significant morbidity and mortality. Some studies have shown kidney involvement, cirrhosis, central nervous system involvement, and heart involvement as unfavorable prognostic factors. Many studies have demonstrated that, after antiviral therapy, CV can disappear along with HCV. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned.

Evidence Synthesis: Several studies on new DAAs have reported remarkable 90% to 100% HCV eradication rates, regardless of genotype. Treatment with DAAs has comparable efficacy on viral eradication in CV patients but definite clinical improvements of vasculitis can be observed only in half the patients.

Conclusions: In patients with mild to moderate CV disease, DAAs therapy should be used as first line approach. In patients with severe vasculitis, DAAs therapy and a second-line treatment with RTX with or without aphaeresis are a required.
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http://dx.doi.org/10.23736/S0026-4806.20.07120-7DOI Listing
April 2021

Direct-acting antiviral agents for hepatitis C virus-mixed cryoglobulinaemia: dissociated virological and haematological responses.

Br J Haematol 2020 12 13;191(5):775-783. Epub 2020 Aug 13.

Clinical and Experimental Onco-Haematology Unit, CRO Aviano National Cancer Institute IRCCS, Aviano, Italy.

The hepatitis C virus-positive (HCV+) mixed cryoglobulinaemia (MC) is associated with haematological alterations such as monoclonal B-cell lymphocytosis or non-Hodgkin lymphomas (NHLs). Antiviral therapy for MC, based on interferon and ribavirin, has been shown to be able to eliminate the viral replication as well as the B-cell monoclonal alterations. Many studies have reported the efficacy of direct-acting antivirals (DAAs) in the treatment of HCV+ MC. However, some authors noticed the persistence of haematological diseases despite HCV eradication. To verify the effects of DAAs on B-cell proliferation, we evaluated 67 patients with HCV+ MC. Six patients had an overt NHL and 30% had monoclonal B-lymphocytosis. In 20% of the patients, the mutation L265P of the myeloid differentiation factor 88 (MYD88) gene was detected in peripheral blood. All patients had negative HCV viraemia at week 12; one had a breakthrough, while two cases relapsed. A complete clinical response of vasculitis was seen in 60% of the patients. Among the six patients with NHL, one showed a complete response, whereas in the others there were no changes in the number and size of the nodes. Among the patients carrying a clonal population in peripheral blood, only 22% became negative. These data indicate that DAAs are not able to eliminate the clonal alterations induced by HCV in a large proportion of cases.
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http://dx.doi.org/10.1111/bjh.17036DOI Listing
December 2020

Hepatitis C virus- related cryoglobulinemic vasculitis: A review of the role of the new direct antiviral agents (DAAs) therapy.

Autoimmun Rev 2020 Aug 12;19(8):102589. Epub 2020 Jun 12.

Clinical and Surgical Sciences, University of Trieste, Trieste, Italy.

Hepatitis C virus (HCV) infection affects about 70 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases and can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas. Many studies have demonstrated that, after antiviral therapy, MC can disappear along with HCV eradication. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. Several studies on new DAAs have reported remarkable 90% to 100% eradication rates, regardless of HCV genotype. Treatment with DAAs has comparable efficacy on viral eradication in patients with MC, but definite clinical improvements of vasculitis can be observed only in half the patients. On the contrary, the regression of renal disease and lympho-proliferative disorders, induced by HCV, appears to have a lower remission rate after viral eradication with DAAs and most cases need immunosuppressive treatments. In HCV related CV, the main clinical goal must be early eradication of HCV, to avoid organ complication and manifestation of lympho-proliferative diseases. This review focuses on the role of DAAs in treatment of HCV-related cryoglobulinemic vasculitis.
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http://dx.doi.org/10.1016/j.autrev.2020.102589DOI Listing
August 2020

Outcome of very elderly chronic myeloid leukaemia patients treated with imatinib frontline.

Ann Hematol 2019 Oct 7;98(10):2329-2338. Epub 2019 Aug 7.

Institute of Hematology, Università Cattolica SacroCuore, Rome, Italy.

Very elderly (> 75 years) chronic myeloid leukaemia (CML) patients at diagnosis are sometimes treated with different doses of imatinib (IM) based on concomitant diseases and physicians' judgement. However, data on long-term follow-up of these patients are still lacking. To investigate treatment response and outcome, we retrospectively revised an Italian database of 263 very elderly CML patients receiving IM from the time of diagnosis. Median age at diagnosis was 78.5 years and 56% of patients had 2 or 3 comorbidities. A complete haematological and cytogenetic response were achieved in 244 (92.8%) and 184 (69.9%) patients, respectively. In 148 cases (56.2%), a major molecular response was observed, which was deep in 63 cases (24%). A blastic phase occurred in 11 patients (4.2%). After a median follow-up of 45.0 months, 93 patients have died (9 from disease progression) and 104 (39.5%) are still in treatment with IM. Incidence of grades 3-4 haematological and non-haematological toxicity was similar to those reported in younger patients. Five-year event-free survival was 54.5% and 45.2% in patients ≤ 80 years and > 80 years, respectively (p = 0.098). Five years OS was 75.7% and 61.6% in patients ≤80 years and > 80 years, respectively (p = 0.003). These findings show that IM plays an important role in frontline treatment of very elderly CML patients without increased toxicity and any effort to treat these patients with standard doses should be made in order to achieve responses as in younger subjects.
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http://dx.doi.org/10.1007/s00277-019-03767-yDOI Listing
October 2019

Survival and Prognostic Factors in Mixed Cryoglobulinemia: Data from 246 Cases.

Diseases 2018 May 3;6(2). Epub 2018 May 3.

Department of Clinical and Surgical Sciences, University of Trieste, 34121 Trieste, Italy.

Introduction: The clinical and therapeutic management of mixed cryoglobulinemia (MC) remains a subject of controversy. In addition, most studies have not recorded the long-term follow-up and the outcome of these cases.

Material And Methods: We enrolled 246 patients affected by MC who were consecutively admitted to our Department from January 1993 to February 2013. Clinical and biological data had been recorded until June 2014.

Results: The median age (at diagnosis) was 60 years (range 26⁻83). The aetiology was HCV in 95% of patients, HBV in 3% and “essential” in 2%. HCV genotype was 1b in 57%, genotypes 2⁻3 in 43%. MC was Type II in 203 of the cases (87%) and Type III in 52 (13%). The most frequent clinical manifestations were purpura (72%), chronic liver disease (70%), glomerulonephritis (35%), arthralgias (58%), peripheral neuropathy (21%), non-Hodgkin lymphoma (15%) and cutaneous ulcers (3%). Purpura, arthralgias, peripheral neuropathy, glomerulonephritis and non-Hodgkin lymphoma were more frequently observed in Type II than in Type III MC ( 0.05). Treatments were interferon (IFN) or Pegilated-IFN (PEG-IFN) alone or plus Ribavirin (RIBA) in 101 cases, steroids with or without alkylating agents in 33 cases, Rituximab in 8 patients. The complete clinical, virological and immunological responses were associated with PEG-IFN plus RIBA. Severe infections were associated with renal failure. At 10 years, the overall survival rate was 71% in Type II MC and 84% in Type III ( 0.053).

Conclusions: From our data, antiviral therapy is the first-line therapy in HCV-related MC, whereas steroids, alkylating agents and Rituximab should be considered as a second-line therapy. Given the heterogeneity of the disease, the role of these different therapeutic strategies should be checked in randomized controlled trials.
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http://dx.doi.org/10.3390/diseases6020035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023473PMC
May 2018

Long-term effects of the new direct antiviral agents (DAAs) therapy for HCV-related mixed cryoglobulinaemia without renal involvement: a multicentre open-label study.

Clin Exp Rheumatol 2018 Mar-Apr;36 Suppl 111(2):107-114. Epub 2018 Feb 13.

Department Clinical and Surgical Sciences, University of Trieste, Italy.

Objectives: To investigate the long-term effects and safety of new direct anti-viral agents (DAAs) in patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC) without renal involvement.

Methods: The study enrolled 22 consecutive patients, 19 received sofosbuvir-based regimen and three patients received other DAAs, individually tailored according to latest guidelines. As of December 2016, the median length of follow-up was 17 months (range 13-21).

Results: Extra-hepatic manifestations at enrollment were: purpura and arthralgia (12 cases), peripheral neuropathy (10 cases) and marginal zone B- lymphomas (2 cases). After a four-week DAA therapy, all patients became HCV- negative. Moreover, after 48 weeks since the beginning of DAA treatment, sustained regression of purpura and arthralgias was observed respectively in eight and in nine cases; peripheral neuropathy improved in seven cases, and cryocrit median values decreased from three (1-20) at baseline to two (1-12) after 48 weeks. Two cases with indolent marginal zone lymphomas did not show any haematological response: size and number of the involved nodes remained unchanged. In addition, the monoclonal B-cell population found in the peripheral blood in four cases did not disappear after recovery from HCV- RNA. Mild side effects occurred in nine patients, but six patients developed ribavirin-related anaemia requiring reduction of ribavirin dose.

Conclusions: DAA therapy is safe and effective to eradicate HCV in MC, but seems associated with satisfactory clinical response in mild or moderate cryoglobulinaemic vasculitis and no response in B-NHL.
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July 2018

Bendamustine plus Rituximab Versus R-CHOP as First-Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study.

Oncologist 2018 04 9;23(4):454-460. Epub 2018 Jan 9.

Haematology Division, "Federico II" University Hospital, Naples, Italy.

Background: Rituximab plus bendamustine (R-B) has been demonstrated to improve outcomes and reduce toxicity compared with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma (FL). Nevertheless, in clinical practice, many centers still prefer R-CHOP to R-B in patients with FL grade 3A (FL3A). Therefore, we retrospectively assessed patients with FL3A treated with either R-CHOP or R-B in five European cancer centers and compared their outcomes.

Materials And Methods: We retrospectively assessed 132 patients affected by FL grade 3A treated with either R-B or R-CHOP in the first line and evaluated outcome and toxicity according to the type of treatment. This study included 101 patients who were a subgroup of a previously published cohort.

Results: R-B was less toxic and achieved a similar percentage of complete remissions compared with R-CHOP (97% vs. 96%,  = .3). During follow-up, 10 (16%) patients relapsed after R-B and 29 (41%) after R-CHOP ( = .001), leading to a median progression-free survival (PFS) of 15 versus 11.7 years, respectively ( = .03). Furthermore, R-B overcame the negative prognostic impact of BCL2 expression (15 vs. 4.8 years;  = .001). However, median overall survival was similar between both groups (not reached for both;  = .8).

Conclusion: R-B as a first-line treatment of FL3A is better tolerated than R-CHOP and seems to induce more profound responses, leading to a significantly lower relapse rate and prolonged PFS. Therefore, R-B is a valid treatment option for FL grade 3A.

Implications For Practice: Rituximab plus bendamustine (R-B) has shown to be less toxic and more effective than rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma grade 3A. Although both regimens can induce a complete remission in >95% of patients, relapses occur more frequently after R-CHOP than R-B, leading to a significantly longer progression-free survival in the latter. R-B is also able to overcome the impact of negative prognosticators, such as BCL2 expression. However, because of the indolent course of this disease and efficient salvage treatments, overall survival was similar in both treatment groups. Therefore, R-B is a valid treatment option in this patient setting.
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http://dx.doi.org/10.1634/theoncologist.2017-0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896707PMC
April 2018

Frontline Dasatinib Treatment in a "Real-Life" Cohort of Patients Older than 65 Years with Chronic Myeloid Leukemia.

Neoplasia 2016 09;18(9):536-40

Department of Hematology and Oncology "L. and A. Seràgnoli,", S. Orsola-Malpighi University Hospital, Bologna.

Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a "real-life" cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities.
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http://dx.doi.org/10.1016/j.neo.2016.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031865PMC
September 2016

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

Oncotarget 2016 Nov;7(48):80083-80090

Hematology and Transplants Unit, University of Bari, Bari, Italy.

Background: About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity.

Methods: 296 patients at 35 Italian hematological institutions were evaluated.

Results: Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity.

Conclusion: Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.
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http://dx.doi.org/10.18632/oncotarget.11657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346773PMC
November 2016

Hepatitis B virus related cryoglobulinemic vasculitis: A multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie - GISC.

Dig Liver Dis 2016 Jul 2;48(7):780-4. Epub 2016 Apr 2.

Department of Medical and Surgical Sciences, University of Trieste, Trieste, Italy.

Background: Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatment is ill-defined.

Aims: To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the efficacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine, was explored.

Methods: In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45-70) were enrolled.

Results: The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy (29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobulinemias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1-14), rheumatoid factor was 200U/L (range 20-5850), C4 was 12mg/dl (range 2-31), ALT 71U/L (range 36-114). All patients were HBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight), Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no disease progression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regression of purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidney failure and two of liver cirrhosis.

Conclusion: NUC therapy appeared to be safe and effective in CV-related HBV.
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http://dx.doi.org/10.1016/j.dld.2016.03.018DOI Listing
July 2016

Bendamustine plus rituximab versus R-CHOP as first-line treatment for patients with indolent non-Hodgkin's lymphoma: evidence from a multicenter, retrospective study.

Ann Hematol 2016 Jun 22;95(7):1107-14. Epub 2016 Apr 22.

Internal Medicine V: Hematology & Oncology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

The optimal first-line treatment for advanced low-grade non-Hodgkin lymphomas (LG-NHL) is still highly debated. Recently, the StiL and the BRIGHT trials showed that the combination of rituximab and bendamustine (R-B) is non-inferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a better toxicity profile. Utilizing a retrospective analysis, we compared the efficacy and safety of both regimens in clinical practice. From November 1995 to January 2014, 263 LG-NHL patients treated with either R-B or R-CHOP were retrospectively assessed in seven European cancer centers. Ninety patients were treated with R-B and 173 with R-CHOP. Overall response rate was 94 and 92 % for the R-B and the R-CHOP group, respectively. The percentage of complete response was similar for both groups (63 vs. 66 % with R-B and R-CHOP, respectively; p = 0.8). R-B was better tolerated and less toxic than R-CHOP. The median follow-up was 6.8 and 5.9 years for the R-CHOP and the R-B group, respectively. Overall, no difference in progression-free survival (PFS) (108 vs. 110 months; p = 0.1) was observed in the R-B group compared to the R-CHOP cohort. Nevertheless, R-B significantly prolonged PFS in FL patients (152 and 132 months in the R-B and R-CHOP group, respectively; p = 0.05). However, this result was not verified in multivariate analysis probably due to the limits of the present study. We confirm that the R-B regimen administered in patients with LG-NHL is an effective and less toxic therapeutic option than R-CHOP in clinical practice.
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http://dx.doi.org/10.1007/s00277-016-2668-0DOI Listing
June 2016

Hepatitis C virus and non-Hodgkin's lymphomas: Meta-analysis of epidemiology data and therapy options.

World J Hepatol 2016 Jan;8(2):107-16

Gabriele Pozzato, Francesca Zorat, Giulia Moratelli, Department of Medical and Surgical Sciences, University of Trieste, 34100 Trieste, Italy.

Hepatitis C virus (HCV) is a global health problem affecting a large fraction of the world's population: This virus is able to determine both hepatic and extrahepatic diseases. Mixed cryoglobulinemia, a B-cell "benign" lymphoproliferative disorders, represents the most closely related as well as the most investigated HCV-related extrahepatic disorder. Since this virus is able to determine extrahepatic [non-Hodgkin's lymphoma (NHL)] as well as hepatic malignancies (hepatocellular carcinoma), HCV has been included among human cancer viruses. The most common histological types of HCV-associated NHL are the marginal zone, the lymphoplasmacytic and diffuse large cell lymphomas. The role of the HCV in the pathogenesis of the B-cell lymphoproliferative disorders is confirmed also by the responsiveness of the NHL to antiviral therapy. The purpose of this review is to provide an overview of the recent literature and a meta analysis of the epidemiology data, to explain the role of HCV in the development of NHL's lymphoma. Furthermore, the possibility to treat these HCV-related NHL with the antiviral therapy or with other therapeutic options, like chemotherapy, is also discussed.
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http://dx.doi.org/10.4254/wjh.v8.i2.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716526PMC
January 2016

Efficacy and safety of pegylated interferon plus ribavirin for the treatment of hepatitis C virus-positive cryoglobulinemic glomerulonephritis.

Dig Liver Dis 2015 Jul 31;47(7):613-6. Epub 2015 Mar 31.

Clinical Department of Medical and Surgical Sciences, University of Trieste, Trieste, Italy. Electronic address:

Background: The most frequent form of renal involvement in patients with hepatitis C infection is cryoglobulinemic membrano-proliferative glomerulonephritis. Nonetheless, some reports indicate that the eradication of the hepatitis C virus may also lead to the remission of this renal disease.

Methods: The virological, immunological and nephrological response to pegylated interferon α plus ribavirin (48 weeks in patients infected with genotype 1, and 24 weeks for patients infected with genotypes 2 and 3) was evaluated retrospectively in 10 patients with cryoglobulinemic glomerulonephritis.

Results: 6 patients obtained end of treatment virological response (60%); during follow-up, 2 relapsed, and 4 patients maintained a sustained virological response (40%). At the end of follow-up, three patients obtained a significant nephrological response and decrease in cryoglobulin levels (p<0.05). No significant changes in clinical and biological parameters were observed in non-responders/relapsers.

Conclusions: Eradication of hepatitis C may be associated with the regression of cryoglobulinemic glomerulonephritis.
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http://dx.doi.org/10.1016/j.dld.2015.03.020DOI Listing
July 2015

Recombinant Human Erythropoietin (RHuEpo) and Granular Colony Stimulating Factor (G-CSF) in hepatitis C virus (HCV) related to mixed cryoglobulinaemia associated to membranoproliferative glomerulonephritis type I: a case report description.

Infez Med 2014 Dec;22(4):337-41

Department of Internal Medicine, Pordenone General Hospital; Clinical and Experimental Onco Haematology, CRO, IRCCS, Aviano, Pordenone, Italy.

HCV infection is related to hepatic disease and mixed cryoglobulinaemia (MC). Renal involvement is reported in one third of cryoglobulinaemic patients. The combination of HCV related MC with renal involvement has been associated with poor survival and identified as Hepatitis C Virus Risk Syndrome (HCV RS). Here we describe antiviral treatment and management of side effects (anaemia and neutropenia) with RHuEpo and G CSF in a rare case of HCV RS.
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December 2014

Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival.

Leuk Res 2014 Oct 7;38(10):1173-6. Epub 2014 Jul 7.

Ematologia, Polo Universitario ASO San Luigi Gonzaga, Orbassano, Italy.

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75-93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ≥ 1. Imatinib standard dose was reduced at start of therapy (200-300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ≥ 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ≥ 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ≥ 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ≥ 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ≥ 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ≥ 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ≥ 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients.
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http://dx.doi.org/10.1016/j.leukres.2014.06.020DOI Listing
October 2014

Imatinib in very elderly patients with chronic myeloid leukemia in chronic phase: a retrospective study.

Drugs Aging 2013 Aug;30(8):629-37

Dipartimento di Biotecnologie Cellulari ed Ematologia, Università, La Sapienza, Via Benevento 6, 00161, Rome, Italy.

Background: A large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries.

Patients And Methods: To describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75 years were retrospectively analyzed using data collected from 31 institutions in Italy.

Results: The median age at imatinib start was 78.6 years [interquartile range (IR) 76.3-81.4], median time from diagnosis to imatinib start was 1.2 months (IR 0.5-3.7). The starting dose of imatinib was 400 mg/day in 144 patients (68.2 %), >400 mg/day in 4 patients (2.0 %), and <400 mg/day in 63 patients (29.8 %); overall, 94 patients (44.5 %) needed a dose reduction and 27 (12.7 %) discontinued imatinib for toxicity. Grade 3-4 hematologic and extrahematologic toxicities were observed in 40 (18.9 %) and 45 (21.3 %) patients, respectively. After a median observation of 29.8 months (IR 13.0-55.6), 203/211 patients had at least 6 months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2 %) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4 %) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5 %). Among the 129 patients with CCyR, 95 (46.7 %) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase (p = 0.001) and grade 3-4 extrahematologic toxicity (p = 0.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase (p = 0.026), grade 3-4 extrahematologic toxicity (p = 0.007), and lower initial dose of imatinib (p = 0.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6 % (95 % CI 88.7-96.5) and 78.0 % (95 % CI 71.2-84.8), respectively.

Conclusions: Results from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies.
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http://dx.doi.org/10.1007/s40266-013-0088-6DOI Listing
August 2013

Differential diagnosis of lung nodules: breast cancer metastases and lung tuberculosis.

Infez Med 2010 Mar;18(1):39-42

Department of Medicine, Operative Unit of Medicine 2, Azienda Ospedaliera Santa Maria degli Angeli, Pordenone City Hospital, Pordenone, Italy.

In a follow-up a 74-year-old woman with breast cancer (clinical stage T4N1M0 at onset, treatment by surgical resection and tamoxifen) presented a combination of two distinct diseases in the lung: breast cancer metastasis and tuberculosis. A CT scan showed multiple pulmonary nodular lesions and in only one lesion fine needle aspiration cytology (FNAC) diagnosed tuberculosis. After specific antibiotic therapy, isoniazide and rifampin, a CT scan highlighted disappearance of tubercular lesion. Because occurrence of tuberculosis during chemo or hormone therapy for metastatic breast cancer is rare, the present case is noteworthy. Indeed, it is worth pointing out the differential diagnosis of pulmonary nodular lesions in patients with cancer and the possible reactivation of tuberculosis even in patients without specific symptoms, without typical tubercular radiological features.
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March 2010

Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival.

Haematologica 2007 Apr;92(4):478-85

Department of Biomedical Sciences and Advanced Therapies, Section of Haematology, Center Study Haemostasis and Thrombosis, University of Ferrara, Italy.

Background And Objectives: Common methylenetetrahydrofolate reductase gene variants (MTHFR C677T and A1298C) have been described to have opposite effects on cancer patients. They may reduce cancer susceptibility and increase drug-related toxicity when folate antagonists (e.g. methotrexate) are utilized. We analyzed 110 patients with high-grade non-Hodgkin's lymphoma (NHL), 68 of whom were eligible for a chemotherapy combination containing methotrexate (MACOP-B) and 42 for chemotherapy without methotrexate (CHOP).

Design And Methods: Patients were genotyped by polymerase chain reaction and stratified by MTHFR variants. These data were related to the toxicity (WHO grade GO-4) that the patients suffered and their survival. Overall 64 cases (58.2%) developed some form of toxicity and 23 (20.9%) had grade 3/4 toxicity.

Results: When considering toxicity of any grade (grade 1-4), the 677TT genotype was significantly over-represented among cases with mucositis (OR=4.85; 95% CI, 1.47-15.97; p=0.009) and those with hepatic toxicity (OR=3.43; 95% CI, 0.99-11.86; p=0.052). Sub-analyses in the group treated with MACOP-B showed a slight increase in the risk of developing mucositis (OR=5.22; 95% CI, 1.20-27.27; p=0.03), and a strong increase in the risk of hepatic toxicity (OR=7.08; 95% CI, 1.38-36.2; p=0.019) and thrombocytopenia (OR=7.69, 95% CI 1.0-58.94; p=0.05). Interestingly, compared to the risk of developing toxicity of any grade, the risk of developing severe (grade 3/4) mucositis was almost doubled in the whole group of cases with 677TT (OR=8.13; 95% CI 1.61-41.04; p=0.011) and dramatically increased in the MACOP-B-treated cases with this gene variant (OR=24.6; 95% CI 2.49-87.41; p=0.001). There were significant results for 1298CC cases exclusively for mucositis (any grade, OR=5.33; 95% CI, 1.25-22.70; p=0.023 and OR=9.15; 95% CI, 1.14-73.41; p=0.037; for the whole group and the MACOP-B-treated group, respectively). Similarly, the risk of 1298CC patients developing severe mucositis increased (OR=9.24; 95% CI, 1.47-58.0; p=0.017 and OR=11.53; 0.93-143.18; p=0.057; in the whole group and in the MACOP-B-treated group, respectively). Event-free survival analysis revealed a lower probability of event-free survival at 5 years for 677T-carriers (log-ranks, p=0.05 and p=0.07 in the whole group and in the MACOP-B-treated group, respectively). More significant results were obtained when 1298CC cases were excluded from the reference group (log-ranks, p=0.03 and p=0.04, respectively). No significant associations were found in the CHOP-treated group.

Interpretation And Conclusions: Our data suggest that MTHFR gene variants play a critical role in NHL outcome, possibly by interfering with the action of methotrexate with significant effects on toxicity and survival. Genotyping of folate pathway gene variants might be useful to enable reduction of chemotherapy toxicity and/or to improve survival by indicating when dose adjustments or alternative treatments are necessary.
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http://dx.doi.org/10.3324/haematol.10587DOI Listing
April 2007

Neoplastic circulating endothelial-like cells in patients with acute myeloid leukaemia.

Eur J Haematol 2007 May 28;78(5):365-73. Epub 2007 Mar 28.

Haematology Section, Department of Biomedical Sciences, Azienda Ospedaliero-Universitaria Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.

Accumulating evidence suggests that angiogenesis may play a key role in the pathogenesis of leukaemic disorders. Several studies have shown that bone marrow-derived endothelial cells (EC) may contribute to tumour angiogenesis and that in the peripheral blood of cancer patients there is an increased amount of circulating ECs (CECs) that may participate to new vessel formation. In this report, we showed that, in seven acute myeloid leukaemia (AML) patients with known cytogenetic abnormalities, CEC levels were significantly increased in comparison with controls and that a significant proportion of these CECs carried the same chromosomal aberration as blast cells (20-78%, mean value 42.1% of CECs). Most of CECs (mean value 74.4%) displayed immunophenotypic features of endothelial progenitor cells as they expressed CD133, a marker gradually lost during EC differentiation and absent on mature EC. These findings suggest a possible direct contribution of AML-related CECs to tumour vasculogenesis and possibly to the spreading and progression of the disease.
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http://dx.doi.org/10.1111/j.1600-0609.2007.00839.xDOI Listing
May 2007

Mobilization of endothelial progenitor cells in patients with hematological malignancies after treatment with filgrastim and chemotherapy for autologous transplantation.

Eur J Haematol 2007 May 27;78(5):374-80. Epub 2007 Feb 27.

Section of Haematology, Azienda Ospedaliero Universitaria Arcispedale S. Anna, Department of Biomedical Sciences, University of Ferrara, Ferrara, Italy.

In recent years, endothelial progenitor cells (EPCs), gave rise to increasing interest because of their possible use as a therapeutic tool in the treatment of vascular lesions in ischemic tissues or as a target for anti neoplastic therapy. It has been shown that several drugs can increase the number of EPCs into the peripheral blood (PB). However, there is insufficient data concerning the mobilization and collection of EPCs during CD34+ cell mobilization. In this study, we have evaluated EPC mobilization and collection in a series of 47 patients affected by lymphoid neoplasms [31 non Hodgkin lymphoma and 16 multiple myeloma] undergoing CD34+ cell mobilization with cyclophosphamide (4000 mg/m2) and Filgrastim (5 microg/kg). PB EPCs identified by flow cytometry as CD34+/VEGFR2+/CD133+ cells showed a peak on day +10. This peak paralleled that of PB CD34+/CD45+ cells. A direct correlation was observed between CD34+ and CD34+/VEGFR2+/CD133+ cells (r = 0.99 P < 0.0001). An average of 23.7 x 10e6 CD34+/VEGFR2+ CD133+ cells have been collected (range 12.1-41.76 x 10e6). These findings showed that in hematological diseases, cyclophosphamide in combination with filgrastim allows the mobilization and collection of large numbers of EPCs which may be used for reparative medicine studies in these patients.
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http://dx.doi.org/10.1111/j.1600-0609.2007.00831.xDOI Listing
May 2007

Neoplastic circulating endothelial cells in multiple myeloma with 13q14 deletion.

Blood 2006 Mar 29;107(6):2531-5. Epub 2005 Nov 29.

Hematology Section, Department of Biomedical Sciences, University of Ferrara, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, Corso Giovecca 203, 44100 Ferrara, Italy.

In multiple myeloma (MM), circulating endothelial cells (CECs) represent a vascular marker of angiogenesis and may reflect tumor mass. In this report, we showed that, in 5 MM patients with 13q14 deletion, CECs carried the same chromosome aberration as the neoplastic plasma cells (11%-32% of CECs with 13q14 deletion). Most of the CECs displayed immunophenotypic features of endothelial progenitor cells as they expressed CD133, a marker gradually lost during endothelial differentiation and absent on mature endothelial cells. To the contrary, in 3 patients with monoclonal gammopathy of undetermined significance and 13q14 deletion, CECs were cytogenetically normal and had a mature immunophenotype. In MM CECs, immunoglobulin genes were clonally rearranged. These findings suggest a possible origin of CECs from a common hemangioblast precursor that can give rise to both plasma cells and endothelial cells and point to a direct contribution of MM-derived CECs to tumor vasculogenesis and possibly to the spreading and progression of the disease.
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http://dx.doi.org/10.1182/blood-2005-04-1768DOI Listing
March 2006

A case of advanced Hodgkin lymphoma with breast involvement treated with a combination of gemcitabine and pegylated liposomal doxorubicin.

Eur J Haematol 2005 Dec;75(6):515-7

Section of Hematology, Department of Biochemical Sciences, University of Ferrara, University of Ferrara, Ferrara, Italy.

Gemcitabine in combination with pegylated liposomal doxorubicin has been recognized as an effective treatment in patients with refractory solid tumors. To our knowledge, this is the first case of relapsed Hodgkin lymphoma with breast involvement successfully treated with this association.
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http://dx.doi.org/10.1111/j.1600-0609.2005.00558.xDOI Listing
December 2005

Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile.

Eur Heart J 2005 Sep 28;26(18):1838-45. Epub 2005 Apr 28.

Section of Cardiology, University of Ferrara and Cardiovascular Research Centre, Arcispedale S. Anna C.rso Giovecca 203, 44100 Ferrara, Italy.

Aims: There is increasing evidence that stem cell (SC) mobilization to the heart and their differentiation into cardiac cells is a naturally occurring process. We sought to assess the safety and feasibility of granulocyte-colony stimulating factor (G-CSF) administration in humans to enhance SC mobilization and left ventricle (LV) injury repair during myocardial infarction (MI).

Methods And Results: Twenty patients with STEMI (mean age, 61+/-10 years), of whom 14 were submitted to primary percutaneous coronary intervention, were randomized to G-CSF (5 microg/kg/day s.c. for 4 consecutive days) or placebo. At entry and then at months 3 and 6, (99m)Tc-sestamibi gated-SPECT was performed to estimate extension of perfusion defect (PD) and LV function. The study drug was well tolerated and induced a significant increase of white blood count, CD34(+) cells, and CD34(+) cells coexpressing AC133 and VEGFR-2. At follow-up, treated and placebo groups did not differ for the angiographic coronary late loss and showed a similar pattern of PD recovery, whereas in the former at 6 months LVEF and especially LVEDV tended to be relatively higher (P=0.068) and lower (P=0.054), respectively.

Conclusion: G-CSF administration in acute MI patients was feasible and did not lead to any clinical or angiographic adverse events and resulted in CD34(+) and CD34(+)AC133(+)VEGFR2(+) cell mobilization.
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http://dx.doi.org/10.1093/eurheartj/ehi289DOI Listing
September 2005

Flow cytometric detection of accelerated telomere shortening in myelodysplastic syndromes: correlations with aetiological and clinical-biological findings.

Eur J Haematol 2004 Nov;73(5):351-8

Section of Haematology, Department of Biomedical Sciences, University of Ferrara, Ferrara, Italy.

Using quantitative fluorescence in situ hybridisation and flow cytometry (flow-FISH), we investigated the biological and clinical relevance of telomere length in 55 patients affected by myelodysplastic syndromes (MDS) compared with 55 sex- and age-matched controls. We found that telomere fluorescence in MDS granulocytes, and CD34+ cells did not decline with age as in normal controls and that MDS granulocytes and CD34+ cells had significantly shorter telomeres than healthy controls. A significant higher incidence of cases with intermediate-unfavourable cytogenetics and International Prognostic Scoring System (IPSS) int-2/high-risk group was observed among patients with lower telomere fluorescence. We also found that apoptosis in CD34+ cells was significantly higher in IPSS int-1 low-risk patients when compared with IPSS int-2 high-risk cases and healthy controls and that CD34+ cell telomere fluorescence directly correlated with CD34+ cell apoptosis. Reduced telomere fluorescence was associated with a history of occupational exposure to toxic agents and with worse survival in univariate and multivariate analyses. Our results suggest that flow-cytometry assessment of telomere dynamics may represent a valuable tool in the biological and clinical-prognostic characterisation of MDS disorders.
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http://dx.doi.org/10.1111/j.1600-0609.2004.00305.xDOI Listing
November 2004

In patients with myelodysplastic syndromes response to rHuEPO and G-CSF treatment is related to an increase of cytogenetically normal CD34 cells.

Br J Haematol 2004 Aug;126(4):501-7

Section of Haematology, Department of Biomedical Sciences, University of Ferrara, Ferrara, Italy.

The in vivo effect of recombinant human erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) combined treatment on CD34(+) cells was evaluated by fluorescence in situ hybridization (FISH) in 13 myelodysplastic syndrome (MDS) patients with known cytogenetic abnormalities. After treatment, responsive patients presented a significantly lower proportion of FISH abnormal CD34(+) cells than before treatment (P = 0.003), and in comparison with unresponsive cases (P = 0.007). Response to treatment was associated with a reduced degree of apoptosis in CD34(+) cells (P = 0.021): however, no difference in telomere length was observed in responsive patients after growth factor administration. Although the number of patients analysed was relatively small, the present data suggest that, in MDS patients, response to rHuEpo and G-CSF may be related to the proliferation of karyotypically normal but potentially defective CD34(+) progenitor cells.
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http://dx.doi.org/10.1111/j.1365-2141.2004.05086.xDOI Listing
August 2004

CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure.

Circulation 2004 Sep 12;110(10):1209-12. Epub 2004 Jul 12.

University of Ferrara and Cardiovascular Research Center, Salvatore Maugeri Foundation, IRCCS, Gussago, Italy.

Background: Peripheral blood CD34(+) cells and circulating endothelial progenitor cells (EPCs) increase in myocardial infarction and vascular injuries as a reflection of endothelial damage. Despite the occurrence of endothelial dysfunction in heart failure (HF), no data are available on EPC mobilization in this setting. We investigated the pattern of CD34(+) cells and EPC mobilization during HF and their correlation with the severity and origin of the disease.

Methods And Results: Peripheral blood CD34(+) cells (n=91) and EPCs (n=41), assessed both as CD34(+) cells coexpressing AC133 and vascular endothelial growth factor (VEGF) receptor-2 and as endothelial colony-forming units, were studied in HF patients (mean age 67+/-11 years) and 45 gender- and age-matched controls. Tumor necrosis factor-alpha (TNF-alpha) and its receptors (sTNFR-1 and sTNFR-2), VEGF, stromal derived factor-1 (SDF-1), granulocyte-colony stimulating factor (G-CSF), and B-type natriuretic peptide were also measured. CD34(+) cells, EPCs, TNF-alpha and receptors, VEGF, SDF-1, and B-type natriuretic peptide were increased in HF. CD34(+) cells and EPCs were inversely related to functional class and to TNF-alpha, being decreased in New York Heart Association class IV compared with class I and II and controls. No role was found for the origin of the disease.

Conclusions: CD34(+) cells and EPC mobilization occurs in HF and shows a biphasic response, with elevation and depression in the early and advanced phases, respectively. This could be related to the myelosuppressive role of TNF-alpha.
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http://dx.doi.org/10.1161/01.CIR.0000136813.89036.21DOI Listing
September 2004