Publications by authors named "Annarosa Cuccaro"

30 Publications

  • Page 1 of 1

The prognostic role of end-of-treatment FDG-PET/CT in diffuse large B cell lymphoma: a pilot study application of neural networks to predict time-to-event.

Ann Nucl Med 2021 Jan 22;35(1):102-110. Epub 2020 Oct 22.

Institute of Nuclear Medicine, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Roma, Italia.

Purpose: To evaluate the prognostic role of end-of-treatment (EoT) FDG-PET/CT parameters in diffuse large B cell lymphoma (DLBCL), and then to explore a pilot application of Neural Networks (NN) in predicting time-to-relapse.

Methods: For conventional survival analysis, parameters as Deauville score (DS) and quantitative extension of DS (qPET) were correlated to adverse events as relapse or progression in the follow-up. To build NN and conventional multi-regression models (MM) for time-to-event prediction, patients with residual FDG uptake (DS ≥ 2) and an adverse event were divided into a training and a test group. Models developed on the training group were evaluated in the test group. Pearson correlation coefficient (R) and mean relative error between observed and forecasted time-to-event were calculated.

Results: FDG-PET/CT data of 308 patients with DLBCL were analyzed. DS and qPET were prognostic factors in conventional univariate analysis. Positive and negative predictive values, respectively, were 55% and 83% for DS 4-5, 89% and 82% for positive qPET. Focusing on 37 relapsed patients with a residual FDG uptake, R between observed and forecasted time-to-event was of 0.63 in the NN model and 0.49 in the MM. Mean relative error in predicting time-to-event was of 58% for NN and 67% for MM.

Conclusions: EoT FDG-PET/CT visual score (DS) is a strong outcome predictor in DLBCL in a large monocentric cohort. The semi-quantitative parameter qPET may increase this prognostic performance. A pilot NN model applied on residual FDG uptake parameters seems to predict time-to-event in the follow-up.
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http://dx.doi.org/10.1007/s12149-020-01542-yDOI Listing
January 2021

Ruxolitinib Rapidly Reduces Acute Respiratory Distress Syndrome in COVID-19 Disease. Analysis of Data Collection From RESPIRE Protocol.

Front Med (Lausanne) 2020 4;7:466. Epub 2020 Aug 4.

Hematology Unit, Università of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.

The Coronavirus disease (COVID-19) pandemic is causing millions of infections and hundreds of thousands of deaths worldwide. Cumulative clinical and laboratory evidence suggest that a subset of patients with severe COVID-19 may develop a cytokine storm syndrome during the course of the disease, with severe respiratory impairment requiring ventilatory support. One field of research nowadays is to identify and treat viral-induced hyperinflammation with drugs used in other clinical conditions characterized by an hyperinflammation status. These drugs might help to reduce COVID19 mortality. Ruxolitinib, a JAK1 and JAK2 inhibitor, has been successfully used to treat severe immune-mediated diseases, such as graft vs. host disease and Hemophagocytic lymphohistiocytosis. We used ruxolitinib in 18 patients with clinically progressive COVID-19 related acute respiratory distress syndrome, with a primary endpoint to rapidly reduce the degree of respiratory impairment and as a secondary endpoint to rapidly restore the PaO/FiO ratio, as an evaluation of clinical status, and monitoring of drug related Adverse Events. Parameters of inflammation responses and organ functions were assessed and monitored. The treatment plan was ruxolitinib 20 mg bid for the first 48 h and subsequent two-step de-escalation at 10 mg bid and 5 mg bid for a maximum of 14 days of treatment. Our data collection shows a rapid clinical response with no evolution from to mechanical ventilation in 16/18 patients and no response in two patients (overall response rate-ORR 89%). Already after 48 h of ruxolitinib treatment 16/18 patients showed evident clinical improvement, and after 7 days of treatment 11/18 patients showed fully recovered respiratory function (pO > 98% in spontaneous breathing), 4/18 patients had minimal oxygen requirement (2-4 L/m), 1/18 patient showed stable disease, and 2/18 patient showed progressive disease. After 14 days, 16/18 patients showed complete recovery of respiratory function (ORR 89%). Compliance to ruxolitinib planned treatment was 100% and no serious adverse event was recorded. In our case series of 18 critically ill patients with COVID-19 and ARDS, administration of ruxolitinib resulted in a clinical improvement that concurred to modify the standard course of disease. Ruxolitinib can be a therapeutic option for patients with respiratory insufficiency in COVID-19 related ARDS. RESPIRE Study (uxolitinib for the treatment of acute rratory distss syndrome, ClinicalTrials.gov Identifier: NCT04361903).
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http://dx.doi.org/10.3389/fmed.2020.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417512PMC
August 2020

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study.

Lancet Haematol 2020 Oct 13;7(10):e737-e745. Epub 2020 Aug 13.

Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milano.

Background: Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19.

Methods: This multicentre, retrospective, cohort study included adult patients (aged ≥18 years) with diagnosis of a WHO-defined haematological malignancy admitted to 66 Italian hospitals between Feb 25 and May 18, 2020, with laboratory-confirmed and symptomatic COVID-19. Data cutoff for this analysis was June 22, 2020. The primary outcome was mortality and evaluation of potential predictive parameters of mortality. We calculated standardised mortality ratios between observed death in the study cohort and expected death by applying stratum-specific mortality rates of the Italian population with COVID-19 and an Italian cohort of 31 993 patients with haematological malignancies without COVID-19 (data up to March 1, 2019). Multivariable Cox proportional hazards model was used to identify factors associated with overall survival. This study is registered with ClinicalTrials.gov, NCT04352556, and the prospective part of the study is ongoing.

Findings: We enrolled 536 patients with a median follow-up of 20 days (IQR 10-34) at data cutoff, 85 (16%) of whom were managed as outpatients. 440 (98%) of 451 hospitalised patients completed their hospital course (were either discharged alive or died). 198 (37%) of 536 patients died. When compared with the general Italian population with COVID-19, the standardised mortality ratio was 2·04 (95% CI 1·77-2·34) in our whole study cohort and 3·72 (2·86-4·64) in individuals younger than 70 years. When compared with the non-COVID-19 cohort with haematological malignancies, the standardised mortality ratio was 41·3 (38·1-44·9). Older age (hazard ratio 1·03, 95% CI 1·01-1·05); progressive disease status (2·10, 1·41-3·12); diagnosis of acute myeloid leukaemia (3·49, 1·56-7·81), indolent non-Hodgin lymphoma (2·19, 1·07-4·48), aggressive non-Hodgkin lymphoma (2·56, 1·34-4·89), or plasma cell neoplasms (2·48, 1·31-4·69), and severe or critical COVID-19 (4·08, 2·73-6·09) were associated with worse overall survival.

Interpretation: This study adds to the evidence that patients with haematological malignancies have worse outcomes than both the general population with COVID-19 and patients with haematological malignancies without COVID-19. The high mortality among patients with haematological malignancies hospitalised with COVID-19 highlights the need for aggressive infection prevention strategies, at least until effective vaccination or treatment strategies are available.

Funding: Associazione italiana contro le leucemie, linfomi e mieloma-Varese Onlus.
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http://dx.doi.org/10.1016/S2352-3026(20)30251-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426107PMC
October 2020

Peyronie's disease in patients with Hodgkin lymphoma.

Leuk Res 2020 09 23;96:106427. Epub 2020 Jul 23.

Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Roma, Italy.

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http://dx.doi.org/10.1016/j.leukres.2020.106427DOI Listing
September 2020

Venous Thromboembolism in Lymphoma: Risk Stratification and Antithrombotic Prophylaxis.

Cancers (Basel) 2020 05 20;12(5). Epub 2020 May 20.

Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Lymphoma is listed among the neoplasias with a high risk of venous thromboembolism (VTE). Risk factors for VTE appear to differ from risk factors in solid tumors. We review the literature of the last 20 years for reports identifying these risk factors in cohorts consisting exclusively of lymphoma patients. We selected 25 publications. The most frequent studies were analyses of retrospective single-center cohorts. We also included two reports of pooled analyses of clinical trials, two meta-analyses, two analyses of patient registries, and three analyses of population-based databases. The VTE risk is the highest upfront during the first two months after lymphoma diagnosis and decreases over time. This upfront risk may be related to tumor burden and the start of chemotherapy as contributing factors. Factors consistently reported as VTE risk factors are aggressive histology, a performance status ECOG ≥ 2 leading to increased immobility, more extensive disease, and localization to particular sites, such as central nervous system (CNS) and mediastinal mass. Association between laboratory values that are part of risk assessment models in solid tumors and VTE risk in lymphomas are very inconsistent. Recently, VTE risk scores for lymphoma were developed that need further validation, before they can be used for risk stratification and primary prophylaxis. Knowledge of VTE risk factors in lymphomas may help in the evaluation of the individual risk-benefit ratio of prophylaxis and help to design prospective studies on primary prophylaxis in lymphoma.
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http://dx.doi.org/10.3390/cancers12051291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281118PMC
May 2020

Progressive multifocal leukoencephalopathy in patients with follicular lymphoma treated with bendamustine plus rituximab followed by rituximab maintenance.

Br J Haematol 2020 05 9;189(4):e140-e144. Epub 2020 Mar 9.

Area of Hematology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

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http://dx.doi.org/10.1111/bjh.16563DOI Listing
May 2020

Comorbidity assessment to determine prognosis in older adult patients with classical Hodgkin lymphoma.

Hematol Oncol 2020 Apr 3;38(2):153-161. Epub 2020 Feb 3.

Istituto di Ematologia, Università Cattolica del Sacro Cuore, Rome, Italy.

The clinical management of older adult patients with Hodgkin lymphoma (HL) remains a major challenge. The aim of this study was to evaluate the impact of comorbidity assessment according to a standardized approach, the Cumulative Illness Rating Scale (CIRS), on prognosis in patients with classical HL aged 60 years and older. We studied 76 consecutive older adult patients with HL (median age 69 y, range 60-84) who had been treated in our institution between 1999 and 2018. Comorbidity was assessed at diagnosis according to CIRS. Anthracycline-containing chemotherapy with curative intent was administered in 59 (78%) patients. We identified 41 (54%) patients with at least one severe comorbidity rated on CIRS grade ≥ 3. Patients with severe comorbidity were more likely to have advanced-stage disease (P = .003), to have an International Prognostic Score (IPS) > 3 (P = .03), and to not receive anthracycline-containing chemotherapy (P = .008). The probability of overall survival (OS) at 3 years was 88% (95% CI, 71%-95%) in patients without severe comorbidities, while it was only 46% (95% CI, 29%-62%) in patients with a comorbidity CIRS grade ≥ 3 (P = .0001). The impact of comorbidity on prognosis was also evident when restricting the analysis to patients treated with anthracycline-containing therapy. The 3-year OS was 93% (95% CI, 76%-98%) (P = .004) in patients without severe comorbidity and 72% (95% CI, 47%-87%) in patients with severe comorbidity (P = .004). In a multivariate analysis, presence of comorbidity, but not age, was a significant factor for OS. Therefore, we conclude that a significant proportion of older adult patients with HL has severe comorbidity on the CIRS scale, which impacts more importantly than age on prognosis.
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http://dx.doi.org/10.1002/hon.2715DOI Listing
April 2020

The prognostic impact of monoclonal immune globulin and free light chain secretion in diffuse large B cell lymphoma (DLBCL).

Leuk Lymphoma 2020 05 31;61(5):1133-1139. Epub 2019 Dec 31.

Area di Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.

We analyzed the prognostic impact of levels of free light chains (FLC) in 106 patients with DLBCL, selecting 61 patients with a monoclonal (M) protein in serum, and 45 patients without a M protein as an IPI-matched control group. Patients with a M protein had higher levels of FLC, but these were not of prognostic significance in this group. The presence of a M protein nullified associations of κ-FLC with several laboratory parameters indicating immune system activation observed in patients without a M protein. Patients without M protein and κ-FLC >50 mg/L had a significant inferior event-free survival ( = .004). The presence of M protein of an IgM type at diagnosis was a negative outcome predictor ( = .008), while a non-IgM M protein did not significantly impact on prognosis. In conclusion, the prognostic performance of the FLC assay is altered by the presence of a M protein.
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http://dx.doi.org/10.1080/10428194.2019.1706731DOI Listing
May 2020

The Role of 18F-FDG PET/CT in Staging and Prognostication of Mantle Cell Lymphoma: An Italian Multicentric Study.

Cancers (Basel) 2019 11 21;11(12). Epub 2019 Nov 21.

Institute of Nuclear Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with poor prognosis in which 18F-FDG-PET/CT role in treatment response evaluation and prediction of outcome is still unclear. The aim of this multicentric study was to investigate the role of 18F-FDG-PET/CT in staging MCL and the prognostic role of Deauville criteria (DC) in terms of progression-free survival (PFS) and overall survival (OS). We retrospectively enrolled 229 patients who underwent baseline and end-of-treatment (eot) 18F-FDG-PET/CT after first-line therapy. EotPET/CT scans were visually interpreted according to DC. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for evaluation of bone marrow (BM) were 27%, 100%, 100%, 48% and 57%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for evaluation of the gastrointestinal (GI) tract were 60%, 99%, 93%, 90% and 91%, respectively. At a median follow-up of 40 months, relapse occurred in 104 cases and death in 49. EotPET/CT results using DC significantly correlated with PFS, not with OS. Instead, considering OS, only MIPI score was significantly correlated. In conclusion, we demonstrated that MCL is an FDG-avid lymphoma and 18F-FDG-PET/CT is a useful tool for staging purpose, showing good specificity for BM and GI evaluation, but suboptimal sensitivity. EotPET/CT result was the only independent significant prognostic factor that correlated with PFS.
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http://dx.doi.org/10.3390/cancers11121831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966583PMC
November 2019

Preliminary results of a counselling programme for fertility preservation in female cancer patients: The experience of the GEMME DORMIENTI network.

Eur J Cancer Care (Engl) 2020 Jan 30;29(1):e13174. Epub 2019 Sep 30.

UOC Oncoematologia Fondazione Policlinico Tor Vergata, Rome, Italy.

Objective: To describe a population of patients referred for fertility preservation (FP), how to efficiently provide FP care, and how FP care changed over time.

Methods: This longitudinal observational study enrolled 281 female cancer patients referred between 2013 and 2016 to the non-profit organisation Gemme Dormienti ONLUS (GD) for FP care. All patients underwent the same battery of instrumental and laboratory diagnostic tests. GnRHa therapy was started at least seven days before CTh treatment.

Results: From 2013 to 2016, we observed a progressive increase in the number of patients referred for FP care. Out of 251 eligible patients, 135 patients were treated with GnRHa only, and 72 patients underwent GnRHa therapy and cryopreservation. The median time from GD referral to oocyte and ovarian tissue cryopreservation was 11 and 5 days respectively. Tissue cryopreservation requests increased during our study period (from four cases in 2013 to 17 cases in 2016). During follow-up, 17β-estradiol and FSH levels were significantly increased (p < .0001), and AMH levels were significantly decreased (p < .0001).

Conclusion: The rapid increase in the number of patients who requested FP care and in the complexity of FP procedures overtime reflects the need to improve quality of life for cancer patients.
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http://dx.doi.org/10.1111/ecc.13174DOI Listing
January 2020

The neutrophil/lymphocyte ratio ≥3.5 is a prognostic marker in diffuse large B-cell lymphoma: a retrospective analysis from the database of the Italian regional network 'Rete Ematologica del Lazio per i Linfomi' (RELLI).

Leuk Lymphoma 2019 12 1;60(14):3386-3394. Epub 2019 Jul 1.

Ematologia, Azienza Ospedaliera Universitaria, Sant'Andrea, Rome, Italy.

In solid tumors and lymphomas, the neutrophil/lymphocyte (N/L) ratio at diagnosis has been shown to be a prognostic factor. The aim of our study was to validate the originally reported N/L ratio cut-point of 3.5 in patients with diffuse large B-cell lymphoma (DLBCL) registered in an Italian real-life database. The prognostic role of the N/L ratio at diagnosis on event-free survival (EFS) and overall survival (OS) was assessed in 505 patients with DLBCL. Patients with an N/L ratio <3.5 ( = 249) had a 4-year EFS probability of 76% and OS probability of 86%, significantly higher than the 4 year EFS rate of 48% and OS rate of 64% in patients with N/L ratio ≥3.5 ( = 256, both <.0001). The N/L ratio was an independent prognostic factor in the multivariate analysis including the IPI score, and could separate patients with a low/intermediate risk IPI (IPI <3).
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http://dx.doi.org/10.1080/10428194.2019.1633628DOI Listing
December 2019

Muscle hypertrophy in amyloid myopathy.

Neuromuscul Disord 2019 02 21;29(2):150-151. Epub 2018 Dec 21.

Unità Operativa Complessa di Neurologia, Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS - Istituto di Neurologia, Università Cattolica del Sacro Cuore, Roma, Italy.

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http://dx.doi.org/10.1016/j.nmd.2018.12.010DOI Listing
February 2019

Bronchial Mucosa-Associated Lymphoid Tissue Lymphoma Staged by 11C-Methionine.

Clin Nucl Med 2018 Aug;43(8):e276-e277

Hematology, and.

A 57-year-old man had a diagnosis of a bronchial mucosa-associated lymphoid tissue lymphoma in the left lung and monoclonal gammopathy. The patient underwent whole-body C-methionine PET/CT, in order to evaluate the amino acid avidity of the lesion and to stage the bronchial mucosa-associated lymphoid tissue lymphoma. C-methionine uptake was detected in the lung lesion and in the mediastinal lymph nodes.
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http://dx.doi.org/10.1097/RLU.0000000000002160DOI Listing
August 2018

Risk factors for venous thromboembolism in patients with lymphoma requiring hospitalization.

Blood Cancer J 2018 06 7;8(6):54. Epub 2018 Jun 7.

Institute of Hematology, IRCCS Policlinico Gemelli Foundation, Catholic University of the Sacred Heart, Rome, Italy.

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http://dx.doi.org/10.1038/s41408-018-0096-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993802PMC
June 2018

FDG-PET/CT at the end of immuno-chemotherapy in follicular lymphoma: the prognostic role of the ratio between target lesion and liver SUV (rPET).

Ann Nucl Med 2018 Jun 20;32(5):372-377. Epub 2018 Feb 20.

Institute of Nuclear Medicine, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy.

Aim: To retrospectively investigate the prognostic role of the ratio between target lesion and liver SUV (rPET) in patients with follicular lymphoma (FL) submitted to FDG-PET/CT at the end of immuno-chemotherapy (PI-PET), and to compare rPET with International Harmonization Project criteria (IHP), Deauville Score (5p-DS) and FL International Prognostic Index at diagnosis (FLIPI).

Methods: Eighty-nine patients with FL undergoing PI-PET were evaluated. The receiver operating characteristic (ROC) approach was applied to identify the optimal cut-point of rPET with respect to 5-years progression free survival (PFS). The prognostic significance of rPET was compared with IHP, DS and FLIPI. Positive predictive value (PPV) and negative predictive value (NPV) were calculated using the presence of adverse events as gold standard.

Results: The ROC analysis for rPET as predictor of progression showed an optimal rPET cut-point of 0.98. Patients with positive values of IHP, DS and rPET had a PFS of 50, 30 and 31%. PPV were of 56, 80 and 80%, NPV of 83, 86 and 88%, respectively. DS and rPET differed only in two patients. FLIPI was not predictive of progression and relapse.

Conclusions: rPET is a prognostic factor in patients with FL submitted to PI-PET. Although it has a similar prognostic power as DS, it can have methodological advantages over visual analysis. PI-PET with different evaluation systems has a stronger prognostic power than FLIPI at diagnosis, so it could be useful to identify patients with FL at risk for early relapse after immuno-chemotherapy.
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http://dx.doi.org/10.1007/s12149-018-1243-2DOI Listing
June 2018

Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma.

Blood 2018 05 15;131(22):2413-2425. Epub 2018 Feb 15.

Institute of Oncology Research, Bellinzona, Switzerland.

The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying as the most frequently mutated gene in ∼40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL.
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http://dx.doi.org/10.1182/blood-2017-11-812073DOI Listing
May 2018

Vitamin D deficiency and supplementation in patients with aggressive B-cell lymphomas treated with immunochemotherapy.

Cancer Med 2018 01 22;7(1):270-281. Epub 2017 Dec 22.

Institute of Hematology, Università Cattolica del Sacro Cuore, Rome, Italy.

Vitamin D deficiency has been reported to be a negative prognostic factor in elderly patients with aggressive B-cell lymphomas. In vitro data suggest that vitamin D supplementation may enhance rituximab-mediated cytotoxicity. We prospectively assessed 25-hydroxyvitamin D [25(OH)D] levels at diagnosis in a cohort of 155 patients with aggressive B-cell lymphomas of whom 128 had diffuse large B-cell lymphoma (DLBCL) not otherwise specified. 25(OH)D levels were deficient (<20 ng/mL) in 105 (67%), insufficient (20-29 ng/mL) in 32 (21%), and normal (≥30 ng/mL) in 18 (12%) patients with a seasonal variation. Patient characteristics associated with lower 25(OH)D levels were poor performance status, overweight, B-symptoms, elevated LDH, lower albumin and hemoglobin levels. As a result of a change in practice pattern, 116 patients received vitamin D3 (cholecalciferol) supplementation that included a loading phase with daily replacement and subsequent maintenance phase with a weekly dose of 25,000 IU until end of treatment. This resulted in a significant increase in 25(OH)D levels, with normalization in 56% of patients. We analyzed the impact of 25(OH)D levels on event-free survival in patients treated with Rituximab-CHOP. 25(OH)D levels below 20 ng/mL at diagnosis and IPI were independently associated with inferior EFS. Moreover, patients with normalized 25(OH)D levels following supplementation showed better EFS than patients with persistently deficient/insufficient 25(OH)D levels. Our study provides the first evidence that achievement of normal 25(OH)D levels after vitamin D3 supplementation is associated with improved outcome in patients with DLBCL and deficient/insufficient 25(OH)D levels when receiving rituximab-based treatment.
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http://dx.doi.org/10.1002/cam4.1166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773978PMC
January 2018

Interleukin-31 and thymic stromal lymphopoietin expression in plasma and lymph node from Hodgkin lymphoma patients.

Oncotarget 2017 Oct 28;8(49):85263-85275. Epub 2017 Jul 28.

Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy.

Hodgkin Lymphoma (HL) is a tumor of B-cell origin characterized by Hodgkin and Reed-Stenberg (H/RS) cells embedded in an inflammatory tissue where numerous cytokines/chemokines contribute to shape the microenvironment, leading to the typical clinical symptoms. We investigated: i) the expression of Interleukin-IL-31 (IL-31) and Thymic Stromal Lymphopoietin (TSLP), two Th2-related cytokines with tumor-promoting and pruritogenic functions, and of the respective receptors in HL invaded lymph nodes by flow cytometry, and ii) the potential association of IL-31/TSLP plasma concentrations with clinical characteristics by ELISA. H/RS cells and the major immune cell types infiltrating HL lymph nodes expressed intracytoplasmic and surface IL-31/TSLP, and their receptors. A subgroup of patients showing at diagnosis elevated IL-31 and TSLP plasma levels had an International Prognostic Score>2, indicative of high risk of relapse, and a subsequent positive interim PET-scan, indicative of insufficient response to chemotherapy. No correlation was found between IL-31/TSLP plasma levels and overall or event-free survival. In conclusion, IL-31/TSLP and their receptors are expressed in HL cells and in immune cells infiltrating affected lymph nodes, where both cytokines may contribute to local immune suppression. The clinical impact of IL-31 and TSLP plasma levels has to be further defined in larger patient cohorts.
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http://dx.doi.org/10.18632/oncotarget.19665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689608PMC
October 2017

Dural MALT Lymphoma Detected by 11C-Methionine PET/CT.

Clin Nucl Med 2017 Dec;42(12):962-963

From the Institutes of *Nuclear Medicine and †Hematology, Università Cattolica del Sacro Cuore, Rome, Italy.

A 53-year-old man had a diagnosis of mucosa-associated lymphoid tissue lymphomas of the dura in the left tentorium. The patient underwent whole-body F-FDG PET/CT and C-methionine PET/CT in order to complete the staging of dural mucosa-associated lymphoid tissue lymphoma. C-methionine uptake was detected in multiple meningeal sites, including left tentorium, with no significant FDG uptake in the same regions.
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http://dx.doi.org/10.1097/RLU.0000000000001843DOI Listing
December 2017

11C-Methionine-Avid Plasmablastic Lymphoma.

Clin Nucl Med 2017 Nov;42(11):872-873

From the Institutes of *Nuclear Medicine, and †Hematology, Università Cattolica del Sacro Cuore, Rome, Italy.

A 73-year-old woman had a diagnosis of a plasmablastic lymphoma by the excision of the right parotid gland. Two years after the diagnosis, the patient underwent a whole-body C-methionine PET/CT in order to evaluate the amino acid avidity of a scalp metastasis and for plasmablastic lymphoma restaging. C-methionine uptake was detected in the scalp, in several bone sites, and in the cricoid cartilage. Plasmablastic lymphoma is a subtype of B-cell lymphoma with an aggressive behavior and a poor prognosis. C-methionine appears to be a promising tracer for paraprotein-producing neoplasms.
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http://dx.doi.org/10.1097/RLU.0000000000001803DOI Listing
November 2017

Heavy chain disease: our experience.

Clin Chem Lab Med 2017 11;56(1):e10-e12

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http://dx.doi.org/10.1515/cclm-2017-0254DOI Listing
November 2017

Interim FDG-PET/CT in Hodgkin lymphoma: the prognostic role of the ratio between target lesion and liver SUVmax (rPET).

Ann Nucl Med 2016 Oct 31;30(8):588-92. Epub 2016 May 31.

Institute of Nuclear Medicine, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy.

Objective: To evaluate the prognostic role of the ratio between target lesion and liver SUVmax (rPET) in patients with Hodgkin lymphoma (HL) undergoing interim FDG-PET/CT and to compare rPET with the 5-point Deauville Score (5p-DS).

Methods: Sixty-eight patients with HL undergoing interim FDG-PET/CT after first courses of chemotherapy were evaluated. The receiver operating characteristic (ROC) approach was applied to identify the optimal cutpoint of rPET with respect to progression free survival (PFS). The prognostic significance of rPET was compared with 5p-DS (scores 4 and 5 considered as positive). Positive predictive value (PPV) and negative predictive value (NPV) were calculated using the presence of an adverse event as the gold standard.

Results: The ROC analysis for rPET as a predictor of progression showed an optimal rPET cutpoint of 1.14. Both 5p-DS and rPET were strong outcome predictors (p < 0.001). Patients with negative 5p-DS and patients with rPET <1.14 had a similar two-year PFS (86 and 87 %, respectively). Patients with a positive 5p-DS had a 2-year PFS of 27 %, while patients with rPET >1.14 had a 2-year PFS of 15 %. 5p-DS and rPET cutoff of 1.14 showed a PPV of 58 versus 70 %, and a NPV of 85 versus 86 %, respectively.

Conclusions: rPET could be considered an accurate prognostic factor in patients with HL undergoing interim FDG-PET/CT. Larger prospective studies are needed to confirm these data.
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http://dx.doi.org/10.1007/s12149-016-1092-9DOI Listing
October 2016

CD68+ cell count, early evaluation with PET and plasma TARC levels predict response in Hodgkin lymphoma.

Cancer Med 2016 Mar 13;5(3):398-406. Epub 2016 Jan 13.

Institute of Hematology, Catholic University of the Sacred Heart, Rome, Italy.

Early response evaluation with [(18) F]fluordeoxyglucose (FDG) positron emission tomography after 2 cycles of chemotherapy (interim PET) has been indicated as the strongest predictor for outcome in classical Hodgkin lymphoma (HL). We studied the prognostic role of the number of tumor-infiltrating CD68+ cells and of the plasma levels of TARC (thymus and activation-regulated chemokine) in the context of interim PET in 102 patients with classical HL treated with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD). After 2 ABVD cycles, interim PET according to Deauville criteria was negative (score 0-3) in 85 patients and positive (score 4-5) in 15 patients (2 patients technically not evaluable). TARC levels were elevated in 89% of patients at diagnosis, and decreased after 2 cycles in 82% of patients. Persistently elevated TARC levels in 18% of patients were significantly associated with a positive PET result (P = 0.007). Strong predictors for progression-free survival (PFS) were a negative interim PET (85% vs. 28%, P < 0.0001) and CD68+ cell counts <5% (89% vs. 67%, P = 0.006), while TARC levels at diagnosis and at interim evaluation had no prognostic role. In multivariate analysis, interim PET, CD68+ cell counts and presence of B-symptoms were independently associated with PFS. We conclude that although TARC levels are a biomarker for early response evaluation, they cannot substitute for interim PET as outcome predictor in HL. The evaluation of CD68 counts and B-symptoms at diagnosis may help to identify low-risk patients regardless positive interim PET.
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http://dx.doi.org/10.1002/cam4.585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4799945PMC
March 2016

Prognostic factors in hodgkin lymphoma.

Mediterr J Hematol Infect Dis 2014 5;6(1):e2014053. Epub 2014 Jul 5.

Institute of Hematology, Catholic University S. Cuore, Rome, Italy.

Hodgkin lymphoma (HL) is among the neoplastic diseases that has the best long-term outcome after cytotoxic treatment. Cure rates approach 80-90%; however, 15-20% of patients will be resistant to therapy (primary refractory) or relapse after treatment. Prognostic factors should help to stratify treatment according to the risk profile and identify patients at risk for failure. Significance of prognostic factors partly depends on the efficacy of the treatments administered, since new effective therapies can variably counterbalance the adverse effects of some unfavorable clinical determinants. As a consequence, some prognostic factors thought to be important in the past may become meaningless when modern successful therapies are used. Therefore, the value of prognostic factors has to be updated periodically, and then adapted to new emerging biomarkers. Besides the prognostic role of PET imaging, tissue and circulating biomarkers, as the number of tumor-infiltrating macrophages, cytokine and chemokine levels and profiling of circulating nucleic acids (DNA and microRNAs) have shown promise.
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http://dx.doi.org/10.4084/MJHID.2014.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103502PMC
July 2014

Iron in Hodgkin's lymphoma.

Crit Rev Oncog 2013 ;18(5):463-9

Institute of Hematology, Catholic University S. Cuore, Rome, Italy.

Anemia is a frequent finding of Hodgkin's lymphoma (HL) diagnosis. It is usually mild, with hemoglobin levels between 10 and 12 g/dl; it is rarely (<10% of cases) a result of bone marrow infiltration; and it displays the characteristics of the anemia of chronic disease due to abnormalities in iron metabolism. The inflammatory cytokine IL-6 is frequently up-regulated in Hodgkin's lymphoma, and IL-6 levels are strongly associated with hepcidin, the main regulator of iron metabolism. Elevated hepcidin levels result in iron restriction and signs of anemia of chronic disease. In addition, the abundant microenvironment surrounding the neoplastic Hodgkin's and Reed-Sternberg cells may contribute to alterations in iron metabolism. Tumor-infiltrating macrophages can sequester iron using scavenger receptors. Iron-restricted anemia at HL diagnosis can be aggravated by intensive chemotherapy, and iron overload may become clinically relevant in heavily treated patients with relapsed or refractory disease undergoing high-dose chemotherapy and stem cell transplantation.
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http://dx.doi.org/10.1615/critrevoncog.2013007765DOI Listing
December 2013

Epstein-Barr Virus (EBV)-Associated Haemophagocytic Syndrome.

Mediterr J Hematol Infect Dis 2012 25;4(1):e2012008. Epub 2012 Jan 25.

Department of Hematology, Catholic University, Rome, Italy.

We describe the case of a 17- year old female who developed fatal haemophagocytic syndrome (HPS) one month following acute infection caused by Epstein-Barr virus (EBV). Despite initiation of treatment and reduction of EBV load, laboratory signs of HPS as severe cytopenia, hypofibrinogenemia, hyperferritinemia and hypertriglyceridemia persisted, and the patient died of multiorgan failure. HPS is a rare, but life-threatening complication of EBV infection.
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http://dx.doi.org/10.4084/MJHID.2012.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279323PMC
October 2012

The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma.

Clin Cancer Res 2011 May 8;17(9):2885-92. Epub 2011 Apr 8.

Institute of Hematology, Microbiology, and Pathological Anatomy, Catholic University S Cuore, Rome, Italy.

Purpose: The Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of 20% to 40% cases of Hodgkin lymphoma (HL) in Western countries. We were interested in the detection and quantification of cell-free plasma EBV-DNA as an indicator of biological and clinical characteristics in EBV-associated HL.

Experimental Design: EBV was detected in peripheral blood compartments (whole blood, plasma, and mononuclear cells) at diagnosis by real-time PCR for the EBNA (EB nuclear antigen) region (n = 93) and in HRS cells by in situ hybridization for EBV-encoded small RNAs (EBER; n = 63). These data were correlated to histological and clinical characteristics, EBV serology, circulating cell-free DNA, and interleukin (IL)-6 levels.

Results: Detection of EBV-DNA in plasma had a high specificity (90%), but a relatively low sensitivity (65%) to predict for EBV association. The viral load was higher in patients with advanced stage disease, older age in the presence of B-symptoms, and international prognostic score more than 2. The presence of EBV in HRS cells and higher plasma EBV-DNA copy numbers correlated to an increased frequency of tumor-infiltrating CD68+ macrophages in lymph node biopsies. Plasma EBV-DNA load correlated to circulating cell-free DNA and IL-6 levels, and inversely correlated to lymphocyte counts and EBNA1 antibody titers.

Conclusion: Although the presence of EBV-DNA in peripheral blood cannot be regarded as a surrogate marker for EBER, the plasma EBV-DNA load at HL diagnosis is an indicator of disease activity and biological characteristics associated with negative prognosis. Moreover, the inverse correlation to EBNA1 antibody titers and lymphocyte counts may indicate a reduction in immunosurveillance, favoring the expansion of EBV-HRS cells in HL.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-3327DOI Listing
May 2011

Anemia in Hodgkin's lymphoma: the role of interleukin-6 and hepcidin.

J Clin Oncol 2010 May 20;28(15):2538-43. Epub 2010 Apr 20.

Institute of Hematology, Catholic University S. Cuore, Rome, Italy.

Purpose: Cytokines play a pivotal role in Hodgkin's lymphoma (HL). Because interleukin-6 (IL-6) induces expression of hepcidin, one of the principal regulators of iron metabolism, we studied the contribution of hepcidin in anemia in HL at diagnosis.

Patients And Methods: Plasma samples from 65 patients with HL were analyzed for hepcidin levels using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry; cytokine levels were analyzed using enzyme-linked immunosorbent assays and parameters of iron metabolism and acute-phase reaction.

Results: Hepcidin plasma levels were significantly higher in HL patients when compared with controls, independent of the presence of anemia (P = .001). In the subset of patients with anemia, hepcidin levels inversely correlated with hemoglobin levels (P = .01). Analyzing parameters of iron metabolism, hepcidin levels showed a positive correlation with ferritin (P < .001) and an inverse correlation to iron and iron-binding capacity. Hepcidin strongly correlated to IL-6 levels (P < .001) but not to IL-10 or thymus and activation-regulated cytokine (TARC)/chemokine (C-C motif) ligand 17 (CCL17) levels. In a multivariate regression analysis, IL-6 and fibrinogen levels were independently associated with hepcidin. Higher hepcidin levels were observed in patients with more aggressive disease characteristics: stage IV disease (P = .01), presence of B symptoms (P = .03), and International Prognostic Score > 2 (P = .005).

Conclusion: Our findings suggest that in HL, hepcidin is upregulated by IL-6. Elevated hepcidin levels result in iron restriction and signs of anemia of chronic inflammation, although hepcidin-independent mechanisms contribute to development of anemia in HL.
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http://dx.doi.org/10.1200/JCO.2009.27.6873DOI Listing
May 2010