Publications by authors named "Chiara Pagani"

32 Publications

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Jan 22;8(1):e34-e44. Epub 2020 Dec 22.

Department of Translational and Precision Medicine, Sapienza University of Rome, Roma, Italy.

Background: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).

Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.

Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.

Funding: Fondazione Italiana Linfomi and Celgene.
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http://dx.doi.org/10.1016/S2352-3026(20)30358-6DOI Listing
January 2021

Validation of the "fitness criteria" for the treatment of older patients with acute myeloid leukemia: A multicenter study on a series of 699 patients by the Network Rete Ematologica Lombarda (REL).

J Geriatr Oncol 2020 Oct 20. Epub 2020 Oct 20.

Department of Hematology, ASST Spedali Civili of Brescia, Brescia, Italy.

Objectives: Treatment of older patients with acute myeloid leukemia (AML) is still controversial. To facilitate treatment decisions, the "fitness criteria" proposed by Ferrara et al. (Leukemia, 2013), including age > 75 years, performance status and comorbidities, were verified retrospectively in 699 patients with AML (419 de-novo, 280 secondary AML), diagnosed at 8 Hematological Centers (REL).

Methods: Patients were categorized in FIT to intensive chemotherapy (i-T) (292, 42.5%), UNFIT to i-T (289, 42.1%), or unfit even to non-intensive therapy (non i-T) (FRAIL) (105, 15.3%). Biological characteristics and treatment actually received by patients [i-T, 274 patients (39.2%); non i-T, 134 (19.2%), best-supportive care (BSC), 291 (41.6%)] were recorded.

Results: "Fitness criteria" were easily applicable in 98.1% of patients. Overall concordance between "fitness criteria" and treatment actually received by patients was high (79.4%), 76% in FIT, 82.7% in UNFIT and 80% in FRAIL patients. Fitness independently predicted survival (median survival: 10.9, 4.2 and 1.8 months in FIT, UNFIT and FRAIL patients, respectively; p = 0.000), as confirmed also by multivariate analysis. In FRAIL patients, survival with any treatment was no better than with BSC, in UNFIT non i-T was as effective as i-T and better than BSC, and in FIT patients i-T was better than non i-T or BSC. In addition, a non-adverse risk AML, an ECOG PS <2, and receiving any treatment other than BSC had a favorable effect on survival (p < 0.001).

Conclusion: These simple "fitness criteria" applied at the time of diagnosis could facilitate, together with AML biologic risk evaluation, the choice of the most appropriate treatment intensity in older AML patients.
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http://dx.doi.org/10.1016/j.jgo.2020.10.004DOI Listing
October 2020

Postremission therapy with repeated courses of high-dose cytarabine, idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia.

Hematol Oncol 2020 Dec 29;38(5):754-762. Epub 2020 Sep 29.

Hematology Department, ASST Spedali Civili, Brescia, Italy.

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.
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http://dx.doi.org/10.1002/hon.2806DOI Listing
December 2020

Clinical characteristics and risk factors for mortality in hematologic patients affected by COVID-19.

Cancer 2020 12 10;126(23):5069-5076. Epub 2020 Sep 10.

Hematology Department, ASST Spedali Civili, Brescia, Italy.

Background: Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID-19) pandemic. However, there are still few data on COVID-19 occurring in hematologic patients.

Methods: One hundred two patients with COVID-19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID-19 were analyzed by comparisons of patients with COVID-19 and the standard hematologic population managed at the same institutions in 2019. Thirty-day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID-19.

Results: Male sex was significantly more prevalent in patients with COVID-19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID-19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive-related treatments. The 30-day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID-19 (23.5%; P = .02) and uninfected hematologic controls (3%; P < .001). The severity of the respiratory syndrome at presentation and active hematologic treatment were independently associated with a worse prognosis. Neither diagnosis nor disease status affected the prognosis. The worst prognosis was demonstrated among patients on active hematologic treatment and those with more severe respiratory syndrome at COVID-19 presentation.

Conclusions: During the COVID-19 pandemic, patients should be advised to seek medical attention at the earliest signs of dyspnea and/or respiratory infection. Physicians should perform a risk-benefit analysis to determine the impact of temporarily deferring nonlifesaving treatments versus the risk of adverse outcomes associated with COVID-19.

Lay Summary: Coronavirus disease 2019 (COVID-19) infection occurs across all different types of hematologic disease; however, the risk of acquiring it is lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive treatment. The 30-day mortality rate is 39.2%, which is far higher than the rates for both uninfected hematologic controls (3%; P < .001) and nonhematologic patients with COVID-19 (23.5%; P = .02) despite matching for age, sex, comorbidities, and severity of disease. Variables independently associated with a worse prognosis are the severity of the respiratory syndrome at presentation and any type of active hematologic treatment. Neither diagnosis nor disease status influence the prognosis.
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http://dx.doi.org/10.1002/cncr.33160DOI Listing
December 2020

Clinical and prognostic role of interim 18F-FDG PET/CT in elderly Hodgkin lymphoma: a dual-center experience.

Leuk Lymphoma 2020 12 24;61(13):3209-3216. Epub 2020 Jul 24.

Nuclear Medicine, University of Brescia and Spedali Civili Brescia, Brescia, Italy.

Hodgkin lymphoma (HL) has a bimodal age distribution curve, with a second peak in people aged more than 60 years. Interim PET/CT (iPET/CT) is highly predictive for PFS and OS in young HL, but it has not been sufficiently studied in the elderly. In this retrospective dual-center study, 82 patients with HL and aged 65 or more who performed iPET/CT were included. At iPET/CT, 60 patients had a complete metabolic response, 18 partial responses, and 4 progressions of disease. Baseline PET/CT metabolic features were not significantly correlated with the metabolic response at interim. In patients with interim complete metabolic response, PFS and OS were significantly longer than in patients without complete response( < 0.001 and  = 0.004). Patients with negative iPET had 2-year PFS and OS rates of 57 and 88% compared with 24 and 58% in patients with positive iPET ( < 0.001). iPET/CT results demonstrated to be independent prognostic factors for PFS and OS.
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http://dx.doi.org/10.1080/10428194.2020.1797012DOI Listing
December 2020

Prognostic role of baseline 18F-FDG PET/CT metabolic parameters in elderly HL: a two-center experience in 123 patients.

Ann Hematol 2020 Jun 24;99(6):1321-1330. Epub 2020 Apr 24.

Nuclear Medicine, University of Brescia and Spedali Civili, Brescia, Italy.

Elderly Hodgkin lymphoma (HL) is an aggressive lymphoma subgroup with high 18F-FDG avidity at 18F-FDG-PET/CT but no shared criteria for PET/CT in treatment evaluation and prediction of outcome are available. The aim of our bicentric study was to investigate whether the metabolic baseline PET/CT parameters can predict treatment response and prognosis in elderly HL. We retrospectively included 123 patients who underwent baseline 18F-FDG-PET/CT and end of treatment PET/CT scans. The PET images were analyzed visually and semi-quantitatively by measuring the lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Survival curves were plotted according to the Kaplan-Meier method. At a median follow-up of 40 months, the median PFS and OS were 29 and 37 months. L-BP SUV R, L-L SUV R, MTV, and TLG were significantly higher in patients with no complete response compared with complete response group at end of treatment. Moreover, these parameters were demonstrated to be independent prognostic factors for PFS together with tumor stage, while only L-L SUV R and L-BP SUV R for OS. End of treatment PET/CT results using Deauville criteria were significantly correlated with outcome survival. End of treatment PET/CT results (using Deauville criteria) and semiquantitative baseline PET/CT parameters were significantly correlated with response to treatment and long-term outcome.
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http://dx.doi.org/10.1007/s00277-020-04039-wDOI Listing
June 2020

Isavuconazole in Hematological Patients: Results of a Real-Life Multicentre Observational Seifem Study.

Hemasphere 2019 Dec 4;3(6):e320. Epub 2019 Nov 4.

Fondazione Policlinico Universitario A. Gemelli-IRCCS Roma, Italy.

Invasive fungal diseases (IFDs) remain a major clinical issue in patients with hematological malignancies (HMs). To confirm the efficacy and safety of the new azole isavuconazole (ISV) in a clinical care setting, we planned a multicenter retrospective study; we collected data on all possible/probable/proven IFDs in patients with HMs treated with ISV in 17 centers. Between July 2016 and November 2018, 128 patients were enrolled, and 122 were fully evaluable. ISV was employed as the 1 line therapy in 43 (35%) patients and as a subsequent therapy in 79 (65%) patients. The response rate was 82/122 patients (67.2%); it was similar when using ISV as a 1st or 2nd line treatment (60.5% vs 70.9%, respectively; p = 0.24). In multivariate analysis, both female sex (OR: 2.992; CI: 1.22-7.34) and induction phase of treatment (OR: 3.953; CI: 1.085-14.403) were predictive of a favorable response. At a median follow-up of 5 months, 43 (35.2%) patients were dead; the 1-year overall survival (OS) was 49.9%. In multivariate analysis, the response to ISV (OR: 0.103; CI: 0.041-0.262) and IFD refractoriness to previous antifungals (OR: 3.413; CI: 1.318-8.838) were statistically significant for OS. Adverse events (AEs) were reported in 15/122 patients (12.3%); grade 3-4 AEs were reported in 5 (4%) and led to ISV discontinuation. Our study confirms the safety and tolerability of ISV, also in diseases other than acute leukemia. Phase of hematological disease, gender and refractoriness to previous antifungals are the main predictive factors for the aforementioned response and outcome.
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http://dx.doi.org/10.1097/HS9.0000000000000320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924559PMC
December 2019

The classic prognostic factors in advanced Hodgkin's lymphoma patients are losing their meaning at the time of Pet-guided treatments.

Ann Hematol 2020 Feb 23;99(2):277-282. Epub 2019 Dec 23.

Policlinico S.Orsola-Malpighi, Istituto di Ematologia "Seragnoli", Bologna, Italy.

The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.
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http://dx.doi.org/10.1007/s00277-019-03893-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976582PMC
February 2020

Clinical characteristics of interim-PET negative patients with a positive end PET from the prospective HD08-01 FIL study.

Ann Hematol 2020 Feb 23;99(2):283-291. Epub 2019 Dec 23.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (e-PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18-4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative i-PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET.
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http://dx.doi.org/10.1007/s00277-019-03889-3DOI Listing
February 2020

An increase in copy number has a progressive negative prognostic impact in patients with diffuse large B-cell and high-grade lymphoma, who may benefit from intensified treatment regimens.

Haematologica 2020 05 8;105(5):1369-1378. Epub 2019 Aug 8.

Department of Hematology, ASST Spedali Civili di Brescia.

translocations, a hallmark of Burkitt lymphoma, occur in 5-15% of diffuse large B-cell lymphoma, and have a negative prognostic impact. Numerical aberrations of have also been detected in these patients, but their incidence and prognostic role are still controversial. We analyzed the clinical impact of increased copy number on 385 patients with diffuse large B-cell lymphoma screened at diagnosis for , , and rearrangements. We enumerated the number of copies, defining as amplified those cases with an uncountable number of extra-copies. The prevalence of translocation, increased copy number and amplification was 8.8%, 15%, and 1%, respectively. Patients with 3 or 4 gene copies, accounting for more than 60% of patients with copy number changes, had a more favorable outcome compared to patients with >4 copies or translocation of MYC, and were not influenced by the type of treatment received as first-line. Stratification according to the number of extra-copies showed a negative correlation between an increasing number of copies and survival. Patients with >7 copies or the amplification of had the poorest prognosis. Patients with >4 copies of MYC showed a similar, trending towards worse prognosis compared to patients with translocation. The survival of patients with >4 copies, translocation or amplification of seemed to be superior if intensive treatments were used. Our study underlines the importance of fluorescence hybridization testing at diagnosis of diffuse large B-cell lymphoma to detect the rather frequent and clinically significant numerical aberrations of .
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http://dx.doi.org/10.3324/haematol.2019.223891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193495PMC
May 2020

Invasive pulmonary aspergillosis in acute leukemia: a still frequent condition with a negative impact on the overall treatment outcome.

Leuk Lymphoma 2019 12 23;60(12):3044-3050. Epub 2019 May 23.

Hematology, ASST-Spedali Civili, Brescia, Italy.

We evaluated the impact of invasive pulmonary aspergillosis (IPA) on epidemiology and outcome in acute leukemia (AL), analyzing all acute myeloid (AML) and acute lymphoblastic leukemia (ALL) consecutively admitted to our Institution during a 5-year period of observation. Only AML patients received anti-mold prophylaxis. Among 175 AL patients (136 AML/39 ALL), possible and proven/probable IPA were diagnosed in 28 (16%). Frequency of IPA was similar in AML (16.2%) and in ALL (15.4%). Two-year overall survival (OS) was significantly affected by IPA (no IPA: 69.8% vs IPA: 31.7%  = .002). OS was similar in patients with proven/probable (28.2%) and possible IPA (36.4%) ( = .003 and .065, respectively). When censoring patients at transplant, IPA still affected 2-year survival (49.6% vs 79.2%,  = .02), but only proven/probable IPA was associated with lower survival (34.7%,  = .0003). IPA negatively impacts on long-term survival of leukemia patients; antifungal prophylaxis should be adopted also during induction in ALL and in AML beyond induction therapy.
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http://dx.doi.org/10.1080/10428194.2019.1613535DOI Listing
December 2019

Prognostic role of baseline 18F-FDG PET/CT metabolic parameters in mantle cell lymphoma.

Ann Nucl Med 2019 Jul 30;33(7):449-458. Epub 2019 Mar 30.

Nuclear Medicine, University of Brescia and Spedali Civili Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.

Objective: Mantle cell lymphoma (MCL) is an aggressive lymphoma sub-type with poor prognosis and high 18F-FDG avidity at PET/CT; nowadays, no validated criteria for PET/CT in treatment response evaluation and prediction of outcome are present. The aim of study was to investigate whether the metabolic PET/CT features may predict treatment evaluation and prognosis in MCL.

Methods: We retrospectively enrolled 87 patients who underwent baseline 18F-FDG PET/CT and 85 end-of-treatment (eot) PET/CT. The baseline PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), lesion-to-liver SUVmax ratio (L-L SUV R), lesion-to-blood pool SUVmax ratio (L-BP SUV R), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). EotPET/CT was visually interpreted according to the criteria of the Deauville 5-point scale (DC). Survival curves were plotted according to the Kaplan-Meier method.

Results: At a median follow-up of 40 months, relapse/progression occurred in 47 and death in 23 patients. Median PFS and OS were 30 and 41 months. Baseline MTV and TLG were significantly higher in patients with progressive metabolic response compared to complete/partial response group. EotPET/CT results using DC significantly correlated with PFS, not with OS. MTV and TLG were demonstrated to be independent prognostic factors for PFS; instead the other metabolic parameters were not related to outcome survival. Considering OS, no variable was significantly associated.

Conclusions: EotPET/CT results (using DC), MTV and TLG were significantly correlated with response to treatment and PFS.
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http://dx.doi.org/10.1007/s12149-019-01354-9DOI Listing
July 2019

Outcome of transformed follicular lymphoma worsens according to the timing of transformation and to the number of previous therapies. A retrospective multicenter study on behalf of Fondazione Italiana Linfomi (FIL).

Br J Haematol 2019 05 21;185(4):713-717. Epub 2019 Feb 21.

Haematology, ASST Spedali Civili di Brescia, Brescia, Italy.

Optimal treatment for transformed follicular lymphoma (tFL) is not fully defined. Clinical characteristics and treatments that impact on post-transformation outcome of 176 biopsy-proven tFL were analysed. Transformation occurred at initial diagnosis in 52% (Group 1) and after a FL diagnosis in 48% (Group 2). Five-year overall survival was 84% for Group 1 and 51% for Group 2 (P < 0·001). In Group 1, 5-year progression-free survival was superior after rituximab maintenance compared to observation only (94% vs. 53%, P = 0·024). In Group 2, an inverse trend was found between survival and both a higher number of pre-transformation treatment lines and a short time-to-transformation.
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http://dx.doi.org/10.1111/bjh.15816DOI Listing
May 2019

The e13a2 BCR-ABL transcript negatively affects sustained deep molecular response and the achievement of treatment-free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors.

Cancer 2019 05 1;125(10):1674-1682. Epub 2019 Feb 1.

Department of Hematology, Local Social Health Authority (ASST) Spedali Civili Brescia, Brescia, Italy.

Background: Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment-free remission (TFR).

Methods: The potential predictive role of BCR-ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors' center.

Results: Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second-generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second-generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript.

Conclusions: The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML.
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http://dx.doi.org/10.1002/cncr.31977DOI Listing
May 2019

Prognostic role of baseline 18F-FDG PET/CT metabolic parameters in Burkitt lymphoma.

Eur J Nucl Med Mol Imaging 2019 01 2;46(1):87-96. Epub 2018 Oct 2.

Nuclear Medicine, University of Brescia and Spedali Civili Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.

Purpose: Burkitt's lymphoma (BL) is an aggressive lymphoma subtype with high 18F-FDG avidity at 18F-FDG-PET/CT, but no validated criteria for PET/CT in treatment evaluation or prediction of outcome in BL are available. The aim of our study was to investigate whether the metabolic baseline PET/CT parameters can predict treatment response and prognosis in BL.

Materials And Methods: We retrospectively enrolled 65 patients who underwent baseline 18F-FDG-PET/CT, interim and end of treatment PET/CT. The PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value body weight (SUVbw), the maximum standardized uptake value lean body mass (SUVlbm), the maximum standardized uptake value body surface area (SUVbsa), lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), total metabolic tumor volume (tMTV) and total lesion glycolysis (TLG). Survival curves were plotted according to the Kaplan-Meier method.

Results: At a median follow-up of 40 months, the median PFS and OS were 34 and 39 months. MTV and TLG were significantly higher in patients with partial response compared to complete response group at end of treatment, while no significant differences were found at interim. Other metabolic PET/CT parameters were not related to treatment response. MTV and TLG were demonstrated to be independent prognostic factors for both PFS and OS; instead SUVbw, SUVlbm, SUVbsa, L-L SUV R and L-BP SUV R were not related to outcome survival.

Conclusions: Metabolic tumour features (MTV and TLG) were significantly correlated with response to treatment and long-term outcome.
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http://dx.doi.org/10.1007/s00259-018-4173-2DOI Listing
January 2019

Metabolic behavior and prognostic value of early and end of treatment 18F-FDG PET/CT in adult Burkitt's lymphoma: the role of Deauville and IHP criteria.

Leuk Lymphoma 2019 02 3;60(2):326-333. Epub 2018 Jul 3.

c Nuclear Medicine , University of Brescia and Spedali Civili Brescia , Brescia , Italy.

Burkitt's lymphoma is a lymphoma with unclear metabolic behavior at 18F-FDG-PET/CT and no validated criteria in treatment evaluation and prediction of outcome exist. Sixty-five patients were retrospectively included: all underwent baseline 18F-FDG-PET/CT, 56 interim PET/CT (iPET/CT) and 54 end of treatment PET/CT (eotPET/CT) after chemotherapy. Interim and eotPET/CT results were visually interpreted according to the criteria of the IHP and Deauville-five-point-scale. Results were correlated with PFS and OS to assess and to compare the predictive value of iPET and eotPET according to each criterion. All baseline PET/CT showed increased 18F-FDG uptake in nodal and extranodal lesions. The median PFS and OS were 44.6 and 48.2 months with 3-year and 5-year PFS of 76% and 62% and 3-year and 5-year OS of 71% and 57%, respectively. EotPET/CT results using DC and IHP significantly correlate with OS and PFS; while iPET/CT did not correlated with OS and PFS.
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http://dx.doi.org/10.1080/10428194.2018.1482541DOI Listing
February 2019

Ultrasound detection of aortoenteric fistula in a patient with sepsis.

J Ultrasound 2017 Jun 4;20(2):157-159. Epub 2017 May 4.

IRCSS Policlinico San Matteo, Pavia, Italy.

We report a case of an 81-year-old man, hospitalized for sepsis unresponsive to targeted antibiotic therapy, who underwent abdominal aortic aneurysmectomy with stent placement before 12 years. Point-of-care ultrasound examination showed the presence of a voluminous and inhomogeneous lesion adjacent to the anterior wall of aortic bifurcation with pulsatile flow from the aorta into the lesion, highlighted by Color-Doppler, and peripheral (closely with intestinal loops) floating hyperechoic spots marked by posterior comet tail artifact, suggestive for the presence of air bubbles. The presence of an aortoenteric fistula not excluding in differential diagnosis and the possibility of an abscess of aneurysmatic sac with colonization of gas-producing bacteria were suspected; an abdominal contrast-enhanced computed tomography was requested and it confirmed the suspicion of an aortoenteric fistula. The patient underwent emergency surgical intervention with good technical success (evidence of aorto-appendicular fistula), but he died the day after of cardiac arrest.
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http://dx.doi.org/10.1007/s40477-017-0249-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440338PMC
June 2017

Still a role for surgery as first-line therapy of splenic marginal zone lymphoma? Results of a prospective observational study.

Int J Surg 2017 May 30;41:143-149. Epub 2017 Mar 30.

Division of Hematology, Brescia Civic Hospital, Brescia, Italy.

Aim: Assessment of hematologic improvement, survival and peri-operative morbidity after first-line splenectomy for splenic marginal zone lymphoma (SMZL).

Methods: Forty-three patients undergoing open splenectomy were prospectively analyzed. Perioperative clinical course, overall and progression-free survival (OS-PFS) were evaluated. Risk factors analyzed were gender, age, ASA-grade, ECOG performance status, presence of B-symptoms, body mass index, steroidal treatment, serum albumin concentration, IIL-score, operative time, spleen size and weight.

Results: The median follow-up was 31 months (IQR 15-76; range 24-154). Anemia and thrombocytopenia resolved in 80% of patients at 6 months; in 60% at 2 years. The 5-year and 10-year PFS were 35% and 13% respectively, with a median of 35 months (shorter in patients with ECOG performance status ≥2 and B-symptoms). Nineteen cases (44.2%) had a progression of disease within 2 years. Of these, 14 (32.6%) received adjuvant chemotherapy (mainly R-FC or R-CVP). Progression was attributed to high-grade B lymphoma in 7 (16.3%) patients. The median time between diagnosis and progression to aggressive lymphoma was 25.5 months (range 18.8-81.8). The median time to next treatment was 83.5 months (95% CI 49-118). The 5-year and 10-year OS were 75% and 53% respectively. Mortality was due to disease progression and histological transformation in high-grade B lymphoma in 50% of cases, myelodisplastic syndrome in 15%, recurrence of hemolytic anemia in 15%, Hodgkin lymphoma in 7% and to infections (mainly pulmonary) in the remaining 13% of cases. Post-operative morbidity was 2.3% (1 patient with grade-3 complication). Overall grade ≥2 complication rate was 32.5% (mainly hemorrhagic and pulmonary complications). Spleen weight was the only independent risk factor for morbidity. Mortality was nil.

Conclusion: Splenectomy is safe and effective as regards cytopenia resolution and OS, although disease progression is frequently observed at follow-up. Such results are strictly linked to accurate pre- and post-operative clinical management and optimal anesthesiologic approach.
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http://dx.doi.org/10.1016/j.ijsu.2017.03.077DOI Listing
May 2017

Postremission sequential monitoring of minimal residual disease by WT1 Q-PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk-adapted therapy in acute myeloid leukemia patients.

Cancer Med 2016 Feb 29;5(2):265-74. Epub 2015 Dec 29.

Division of Hematology, AO Spedali Civili di Brescia, Brescia, Italy.

Risk stratification in acute myeloid leukemia (AML) patients using prognostic parameters at diagnosis is effective, but may be significantly improved by the use of on treatment parameters which better define the actual sensitivity to therapy in the single patient. Minimal residual disease (MRD) monitoring has been demonstrated crucial for the identification of AML patients at high risk of relapse, but the best method and timing of MRD detection are still discussed. Thus, we retrospectively analyzed 104 newly diagnosed AML patients, consecutively treated and monitored by quantitative polymerase chain reactions (Q-PCR) on WT1 and by multiparametric flow cytometry (MFC) on leukemia-associated immunophenotypes (LAIPs) at baseline, after induction, after 1st consolidation and after 1st intensification. By multivariate analysis, the factors independently associated with adverse relapse-free survival (RFS) were: bone marrow (BM)-WT1 ≥ 121/10(4) ABL copies (P = 0.02) and LAIP ≥ 0.2% (P = 0.0001) (after 1st consolidation) (RFS at the median follow up of 12.5 months: 51% vs. 82% [P < 0.0001] and 57% vs. 81%, respectively [P = 0.0003]) and PB-WT1 ≥ 16/10(4) ABL copies (P = 0.0001) (after 1st intensification) (RFS 43% vs. 95% [P < 0.0001]) Our data confirm the benefits of sequential MRD monitoring with both Q-PCR and MFC. If confirmed by further prospective trials, they may significantly improve the possibility of a risk-adapted, postinduction therapy of AML.
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http://dx.doi.org/10.1002/cam4.593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735778PMC
February 2016

Peri-operative complications and hematologic improvement after first-line splenectomy for splenic marginal zone lymphoma.

Leuk Lymphoma 2016 15;57(6):1467-70. Epub 2015 Oct 15.

a Department of Medical & Surgical Sciences, 2nd Division of General Surgery , Brescia Civic Hospital , Brescia , Italy .

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http://dx.doi.org/10.3109/10428194.2015.1092529DOI Listing
January 2017

Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre "real-world" experience.

Leuk Lymphoma 2015 12;56(11):3129-34. Epub 2015 May 12.

a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.

"Real life" data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3-164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML.
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http://dx.doi.org/10.3109/10428194.2015.1034703DOI Listing
September 2016

Peripheral blood WT1 expression predicts relapse in AML patients undergoing allogeneic stem cell transplantation.

Biomed Res Int 2014 17;2014:123079. Epub 2014 Aug 17.

Unit of Blood Disease and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, AO Spedali Civili di Brescia, P.le Ospedali Civili 1, 25123 Brescia, Italy.

To evaluate if WT1 expression may predict relapse after allo-SCT, we analyzed WT1 levels on peripheral blood (PB) and bone marrow (BM) before and after allo-SCT in 24 AML patients with WT1 overexpression at diagnosis. Five copies of WT1/ABL × 10(4) from PB were identified as the threshold value that correlated with relapse after allo-SCT. The same correlation was not identified when WT1 expression was assessed from bone marrow (BM). Eight out of 11 (73%) patients with a pre-allo-SCT PB-WT1 ≥ 5 and 4/13 (31%) patients with a pre-allo-SCT PB-WT1 < 5 relapsed, respectively (P = 0.04). The incidence of relapse was higher in patients with PB-WT1 ≥ 5 measured after allo-SCT, at the 3rd (56% versus 38%; P = 0.43) and at the 6th month (71% versus 20%; P = 0.03). Patients with pretransplant PB-WT1 < 5 had significantly better 2-year OS and LFS than patients with a PB-WT1 ≥ 5 (81% versus 0% and 63% versus 20%) (P = 0.02). Our data suggest the usefulness of WT1 monitoring from PB to predict the relapse in allotransplanted AML patients and to modulate the intensity of conditioning and/or the posttransplant immunosuppression in an attempt to reduce the posttransplant relapse risk.
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http://dx.doi.org/10.1155/2014/123079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150519PMC
June 2015

Relapsing bloodstream infections during treatment of acute leukemia.

Ann Hematol 2014 May 28;93(5):785-90. Epub 2013 Nov 28.

Department of Hematology, Spedali Civili, 25123, Brescia, Italy,

Acute leukemia (AL) patients may experience more than one episode of bloodstream infection (BSI) caused by the same pathogen during the entire chemotherapy program. In order to identify factors influencing BSI recurrence (R-BSI) during subsequent phases of treatment, we analyzed all BSIs occurring to consecutively treated AL patients during a period of active epidemiologic surveillance at our institution between 2004 and 2011. Two hundred and fifty BSIs were observed in 138 patients receiving more than 1 cycle of chemotherapy. BSI due to the same pathogen recurred in 39/138 (28.3 %) patients. Gram-negative rods (GNRs) accounted for 59.6 % and Gram-positive cocci (GPCs) for 34.4 % of BSI. Four pathogens were involved in R-BSI: Escherichia coli, Pseudomonas aeruginosa, coagulase-negative staphylococci, and Streptococcus viridans. GNRs were significantly more frequent among R-BSI compared to non-relapsing BSI (nR-BSI) [69/94 (73.4 %) vs 70/156 (50.6 %), p < 0.0001]; in particular, E. coli accounted for 67 % of R-BSI vs 32.1 % of nR-BSI (p < 0.0001). Receiving more than four chemotherapy courses and having an extended spectrum β-lactamase (ESBL)-producing E. coli BSI at any time of treatment were significantly associated to R-BSI. A trend toward a higher mortality among R-BSI patients in comparison with nR-BSI was observed (17.9 and 7.1 %, respectively, p = 0.12). Among AL patients, R-BSI is a frequent phenomenon, which may contribute to the shift of epidemiology toward GNR and to a higher mortality. This should significantly impact the strategies of antibiotic prophylaxis and treatment in patients with AL.
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http://dx.doi.org/10.1007/s00277-013-1965-0DOI Listing
May 2014

High cure rates in Burkitt lymphoma and leukemia: a Northern Italy Leukemia Group study of the German short intensive rituximab-chemotherapy program.

Haematologica 2013 Nov 10;98(11):1718-25. Epub 2013 Jun 10.

We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (≤ versus >60 years) and performance status (0-1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval ≤ 25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged ≤ 60 years with performance score 0-1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120.
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http://dx.doi.org/10.3324/haematol.2013.086827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815172PMC
November 2013

Lack of the lectin-like domain of thrombomodulin worsens Shiga toxin-associated hemolytic uremic syndrome in mice.

J Immunol 2012 Oct 31;189(7):3661-8. Epub 2012 Aug 31.

Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Parco Scientifico Tecnologico Kilometro Rosso, 24126 Bergamo, Italy.

Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TM(wt/wt)) and mice that lack the lectin-like domain of TM (TM(LeD/LeD)), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TM(LeD/LeD) mice exhibited more severe thrombocytopenia and renal dysfunction than TM(wt/wt) mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TM(LeD/LeD) than in TM(wt/wt) mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TM(LeD/LeD) mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TM(LeD/LeD) mice with HUS had a higher mortality rate than TM(wt/wt) mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx-HUS.
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http://dx.doi.org/10.4049/jimmunol.1102118DOI Listing
October 2012

Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes.

Am J Physiol Renal Physiol 2011 Nov 3;301(5):F1114-23. Epub 2011 Aug 3.

Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.

Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ET(A) receptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were prominent abnormalities of ZDF myocardium. Myocyte volume was reduced by ramipril and sitaxsentan, which also ameliorated heart capillary density. Drug combination restored myocardial structure and reestablished an adequate capillary network in the presence of increased cardiac expression of VEGF/VEGFR-1, and significant reduction of oxidative stress. In conclusion, in type 2 diabetes concomitant blockade of ANG II synthesis and ET-1 biological activity through an ET(A) receptor antagonist led to substantial albeit not complete renoprotection, almost due to the ACE inhibitor. The drug combination also showed cardioprotective properties, which however, were mainly dependent on the contribution of the ET(A) receptor antagonist through the action of VEGF.
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http://dx.doi.org/10.1152/ajprenal.00122.2011DOI Listing
November 2011