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Point-of-care rapid testing is one of the strategies to increase HIV screening. We present data on over 14 years of the "EASY Test Program", an ongoing cross-sectional collaborative project that provides free and anonymous rapid HIV testing in the metropolitan city of Milan, Italy. Overall, 22,186 HIV tests were performed, with a 0.52% prevalence of HIV infection; 100% of those diagnosed with HIV were linked to care. The "EASY Test Program" is an appropriate test-and-treat strategy, allowing a fast HIV assessment (24 hours). Motivated clinicians, in partnership with community associations, can perform an easy HIV screening out of hospitals in alternative settings, among individuals who in the majority of cases had never tested for HIV, ultimately providing an effective linkage to care.

Introduction Chronic obstructive pulmonary disease (COPD) is associated with increased lung and systemic inflammation. We aimed to identify associations between easy-to-obtain blood biomarkers and the frequency and severity of exacerbations. Methods Cross-sectional, multicentre study performed in four centres in Spain, Italy, Bulgaria, and Slovenia. Blood samples were obtained for blood cell count, C-reactive protein (CRP), alpha-1 antitrypsin (AAT) and fibrinogen analysis. The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and eosinophil/basophil ratio (EBR) were calculated. Firstly, patients were divided into clinical phenotypes according to the Spanish guidelines of COPD, and secondly, patients were classified into 2 groups: non-exacerbators (≤1 ambulatory exacerbation in the previous year) and exacerbators (≥2 ambulatory exacerbations or 1 hospitalisation in the previous year). A multivariate stepwise logistic regression model was performed to identify laboratory parameters associated with exacerbators. Results A total of 355 patients with a mean age 66 years (SD=8.9) were included, and 64% were male. The mean FEV1% (forced expiratory volume in the first second) was 55% (SD=20%), and the mean COPD Assessment Test (CAT) score was 15.6 (SD=7.9). One hundred ninety-six (55.2%) patients were classified in the non-exacerbator group, and 159 (44.8%) were exacerbators. Patients in the exacerbators group presented lower haemoglobin levels (p=0.019) and ERB (p= 0.023) but higher CRP levels (p=0.001). In the multivariate analysis, females, higher levels of CRP, lower FEV1% and low EBR were independently related to exacerbators. Conclusion Female sex, having a more severe impairment of lung function, higher CRP levels and a lower EBR are associated with an exacerbator phenotype in COPD.

Purpose Inflammation and immunity play a pivotal but yet unclear role in idiopathic pulmonary fibrosis (IPF), a chronic disorder characterized by progressive damage of lung parenchyma and severe loss of lung function despite optimal treatment. However, the pathophysiological and predictive role of combined blood cell count indexes of inflammation in IPF is uncertain. Methods Seventy-three patients with IPF and 62 healthy subjects matched for age, gender and smoking status were included in this cross-sectional study. Results We found significant differences in neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), systemic inflammation response index (SIRI) and aggregate index of systemic inflammation (AISI) between IPF patients and healthy controls. In logistic regression, all combined blood inflammation indexes, barring PLR, were independently associated with the presence of IPF after adjusting for age, gender, body mass index and smoking status. Furthermore, significant associations between FVC% and NLR, LMR, SIRI and AISI, and between DLCO% and NLR, dNLR, LMR, SIRI and AISI, were observed. Conclusions In conclusion, our data indicate significant alterations of combined blood cell count indexes of inflammation in IPF.

Understanding the risk factors for exacerbations of COPD may help provide a more personalised approach to exacerbation prevention.Observational, prospective, international, multicentre study aimed at identifying risk factors for exacerbations of COPD. Clinical variables, lung function and CAT scores were collected at baseline. In addition, routine blood biomarkers were also obtained, and patients were followed for 12 months.A total of 326 patients were included. Of these, 155 (47.5%) presented at least one exacerbation. The median time to the first exacerbation was 147 days. Exacerbators had more respiratory symptoms, more impairment in FEV1(%), FVC(%) and a worse CAT score. Regarding biomarkers, only C-reactive protein was significantly higher in exacerbators (2.8 (standard deviation (SD):3.8) mg/dL vs. 1.9 (SD:2.6) mg/dL; p = 0.037). In multivariate analysis, only CAT scores, FEV1(%) and previous exacerbations were significantly associated with having an exacerbation during follow-up. In the equation of risk, patients with a CAT score ≥15, FEV1(%)55% and at least one exacerbation the previous year had a probability of 76% of having an exacerbation during the next year, compared with 17% in patients who had none of the previous variables. No biomarkers showed a significant association in multivariate analysis.Less than half of the patients presented an exacerbation during the one-year follow-up. CAT scores, FEV1(%) and previous exacerbations were the only variables associated with increased risk of exacerbations. Routine biomarkers did not provide additional information to evaluate the risk of exacerbations.

Introduction Chronic obstructive pulmonary disease (COPD) is associated with increased lung and systemic inflammation. We aimed to identify associations between easy-to-obtain blood biomarkers and the frequency and severity of exacerbations. Methods Cross-sectional, multicentre study performed in four centres in Spain, Italy, Bulgaria, and Slovenia. Blood samples were obtained for blood cell count, C-reactive protein (CRP), alpha-1 antitrypsin (AAT) and fibrinogen analysis. The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and eosinophil/basophil ratio (EBR) were calculated. Firstly, patients were divided into clinical phenotypes according to the Spanish guidelines of COPD, and secondly, patients were classified into 2 groups: non-exacerbators (≤1 ambulatory exacerbation in the previous year) and exacerbators (≥2 ambulatory exacerbations or 1 hospitalisation in the previous year). A multivariate stepwise logistic regression model was performed to identify laboratory parameters associated with exacerbators. Results A total of 355 patients with a mean age 66 years (SD=8.9) were included, and 64% were male. The mean FEV1% (forced expiratory volume in the first second) was 55% (SD=20%), and the mean COPD Assessment Test (CAT) score was 15.6 (SD=7.9). One hundred ninety-six (55.2%) patients were classified in the non-exacerbator group, and 159 (44.8%) were exacerbators. Patients in the exacerbators group presented lower haemoglobin levels (p=0.019) and ERB (p= 0.023) but higher CRP levels (p=0.001). In the multivariate analysis, females, higher levels of CRP, lower FEV1% and low EBR were independently related to exacerbators. Conclusion Female sex, having a more severe impairment of lung function, higher CRP levels and a lower EBR are associated with an exacerbator phenotype in COPD.

Background: Approximately 500,000 migrants work in the agricultural sector in Italy. Many of them live in shantytowns, wrongly called “ghettos”, far away from city centers, with no water, proper hygienic conditions or health services. The aim of this study is to assess general health conditions and HIV prevalence by giving hygienic and sanitary sustenance. Methods: Between June 2019 and February 2020, we performed a screening campaign for HIV–diabetes–hypertension, involving migrants living in three Apulian establishments: ghetto Pista, “Sankara House” and “Arena House”. Results: Overall, 321 migrants were enrolled in the study. In the medical screening, one HIV test resulted positive. Hypertension was found in 12% of the migrants visited, diabetes in 2% and TB symptoms in 17%. Among others symptoms explored, muscle and joint pain/fatigue resulted in being the most frequent, and was reported by 34% of the migrants, followed by cough (10%). Significant predictors of muscle and joint pain/fatigue were: low BMI values (OR = 1.32, 95% CI 1.19–1.99), the absence of education (OR = 1.85, 95% CI 1.02–2.95), being employed with a regular contract (OR = 2.64, 95% CI 2.39–2.83) and living in the ghettos since &gt, 12 months (OR = 1.74, 95% CI 1.24–2.21). Conclusions: Our experience suggests that, in this population, the health condition is mainly linked to the specific working activities in the agricultural fields, as well as to the hygienic and living conditions, and that all of this is due to the lack of social protection in their life and job.

Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk-and age-adapted protocol (Programa Espanol de Tratamientos en Hematologia (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged >= 60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P = 0.15), 7 vs 12% (P = 0.23), 87 vs 69% (P = 0.04) and 74 vs 60% (P = 0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.

Introduction: Chronic obstructive pulmonary disease is associated with increased lung and systemic inflammation. As part of a multicenter, international study, we aimed to identify associations between easy-to-obtain blood biomarkers and frequency and severity of exacerbations. Methods: Cross-sectional and multicentre study performed in four centers in Spain, Italy, Bulgaria and Slovenia. Patients with COPD according to GOLD criteria were included and blood samples were obtained for blood cells, C-reactive protein (CRP), alpha-1 antitrypsin and fibrinogen. A multivariate stepwise logistic regression model was performed to identify laboratory parameters associated with history of exacerbations. Results: A total of 355 patients were included (mean age 66 years (SD=8.9) and 64% male). Mean FEV1% was 55% (SD=20%) and mean CAT 15.6 (SD=7.9). 208 patients presented ≥1 exacerbation in the previous year, of them 121 (58%) required hospitalization. Patients with exacerbations had only higher CRP (p=0.007), but those with hospitalizations had a higher platelet count (p=0.031) and platelet/lymphocyte ratio (p=0.031), lower hemoglobin (p=0.017) and lower eosinophil/basophil ratio (p= 0.013). Neutrophil to lymphocyte ratio was also higher but not significantly. However, in multivariate analysis only lower FEV1% was identified as independently related to previous exacerbations (OR=0.970, p=0.012). Conclusion: Only CRP was higher in patients with exacerbations, but several routine blood biomarkers were significantly increased in patients who suffered hospital admissions. However, multivariate analysis identified FEV1 as the only significantly associated variable to previous exacerbations.

Highlights • The diagnostic approach to patients with mediastinal pathology is not always simple. • Mediastinal masses should always be considered to be potentially malignant. • Surgical biopsy could be the only way to correctly diagnose mediastinal mass., Introduction The diagnostic approach to patients with mediastinal pathology is not always simple and an improper diagnostic work-up can lead to significant diagnosis delay. Presentation of case : We report on the case of a young woman who was admitted to the Emergency Department complaining of thoracic pain, dyspnoea, fever and productive cough. The physical examination showed a painful swelling over the sternum’s upper left margin, which had become evident 4 months earlier. A Computer Tomography showed the presence of a retrosternal oval lesion (5.5 x 4 cm) infiltrating the thoracic wall and showed the presence of discretely enlarged mediastinal lymph nodes in several mediastinal stations. Discussion The Multidisciplinary Team decided to perform an ultrasound-guided biopsy of the retrosternal mass that showed an inflammatory pattern, whereas microbiology tests proved negative. The lack of improvement with medical therapy (non steroideal anti-inflammatories and antibiotics) and the clinical suspicion of malignancy led us to perform a surgical biopsy of the mass that finally proved to be diagnostic for Hodgkin’s lymphoma. Conclusions Mediastinal masses with an aggressive behavior, should always be considered to be potentially malignant. Surgical biopsy, sometimes, can be the only way to correctly diagnose the pathological process, especially in the case of Hodgkin’s lymphoma in which few diagnostic cells (Reed-Sternberg cells) are generally embedded in an abundant inflammatory background tissue.

Humility was perceived in the Christian Middle Ages as a fundamental moral and intellectual quality, opening the way for access to the divine. How this access occurred, and for what kind of people, was dependent on different theological and philosophical presuppositions. The role of humility was thus moulded according to different anthropological and noetical models. By the end of the 13th century, the «question de l’humilite», as Alain de Libera posed it, had also become a locus for confrontation and definition between different intellectual identities. This study focuses on the role that the secular master Henry of Ghent (ca. 1217-1293) assigned to humility for approaching and transmitting divine truth, both from the perspective of the single individual and of the Christian community. Some topical categories describing essential features of humility – low/high, the ladder, interior/exterior, empty/full – aid in the analysis of some passages from the works of this theologian.

This article investigates three major contexts in which Henry of Ghent’s Summa quaestionum ordinariarum was received from the thirteenth to the fifteenth century. The study takes into account the material features of a group of relevant manuscripts of the Summa: (1) Paris, where the Summa was copied and annotated by Godfrey of Fontaines and his socii; (2) the Dominican convent in Bologna at the beginning of the fourteenth century, to which Aimericus de Placentia gave a copy of the Summa corrected against the very manuscript of Godfrey of Fontaines; (3) the Roman Papal Court, where the Summa attracted the special attention of the humanist Pope Nicholas V, who employed the manuscript from the Bolognese convent for producing new copies of the work. In this study, I endeavour to present a late-medieval history of the Summa as a book, and to contribute to the debate about the mutual relationships among some of the most important witnesses of the text. I pay particular attention to the marginal annotations in the manuscripts.

The Infectious Diseases Department and the Department of Dentistry of San Raffaele Scientific Institute in Milan conducted a screening and prevention program, the "EASY HCV-test Program," at a dental clinic to increase the identification of unrecognized infections. Using a cross-sectional community-based study design, hygienists in the dental clinic offered patients a hepatitis C virus (HCV) rapid salivary test (OraQuick ADVANCE® Rapid HCV Antibody Test) with pre- and post-test counseling prior to initiation of their oral hygiene routine. From April 2015 to November 2015, the EASY HCV test was offered to 2650 patients visiting the Center of Oral Health and Prevention at the Department of Dentistry at San Raffaele Hospital in Milan. Among them, 2077 eligible volunteers were tested. The test showed positive reactivity in 22 cases; of these, 21 subjects were known to suffer from HCV, and the test confirmed their status. One subject was newly diagnosed with HCV infection. The results of this study suggest EASY HCV test screening conducted in dental clinics may constitute an effective strategy for increasing HCV testing among people at risk for infection.

Chronic obstructive pulmonary disease (COPD) is a disabling condition that is characterised by poorly reversible airflow limitation and inflammation. Acute exacerbations of COPD are a common cause of hospitalisation and death among COPD patients. Several biochemical markers have been studied as outcome predictors in COPD; however, their measurement often requires significant time and resources. Relatively simple biomarkers of inflammation calculated from routine complete blood count tests, such as the neutrophil to lymphocyte ratio (NLR), might also predict COPD progression and outcomes. This review discusses the available evidence from studies investigating the associations between the NLR, COPD exacerbations and death in this patient group.

An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction failure in a series of 732 patients of all ages (range, 2-83 years) with newly diagnosed APL who received all-trans retinoic acid (ATRA) plus idarubicin as induction therapy in 2 consecutive studies of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group. Complete remission was attained in 666 patients (91%). All the 66 induction failures were due to induction death. Hemorrhage was the most common cause of induction death (5%), followed by infection (2.3%) and differentiation syndrome (1.4%). Multivariate analysis identified specific and distinct pretreatment characteristics to correlate with an increased risk of death caused by hemorrhage (abnormal creatinine level, increased peripheral blast counts, and presence of coagulopathy), infection (age >60 years, male sex, and fever at presentation), and differentiation syndrome (Eastern Cooperative Oncology Group [ECOG] score >1 and low albumin levels), respectively. These data furnish clinically relevant information that might be useful for designing more appropriately risk-adapted treatment protocols aimed at reducing the considerable problem of induction mortality in APL.

Aim of this study was to evaluate the efficacy and the retention-in-care of individuals diagnosed during six years of salivary HIV testing (EASY-test project). Among those linked-to-care at the Infectious Diseases Department of San Raffaele Hospital (Milan, Italy), the proportion of patients engaged, retained in care and virologically suppressed after the antiretroviral treatment was 96%, 100% and 95.2%, respectively. Results from our study suggest that salivary HIV testing may help bring to light cases of HIV infection otherwise undiagnosed, and thus favour a more rapid and wider reduction of the HIV infection burden at the population level.

All- trans -retinoic acid (ATRA) increases the efficacy of chemotherapy when used for induction and maintenance treatment of acute promyelocytic leukemia (APL), but its role in consolidation is unknown. Since November 1996, 426 patients with newly diagnosed APL have received induction therapy with ATRA and idarubicin. Before November 1999 (LPA96 study), consolidation therapy consisted of 3 courses of anthracycline monochemotherapy. After November 1999 (LPA99 study), patients with intermediate and high risks of relapse received consolidation therapy with ATRA and increased doses of anthracyclines. Of the 384 patients who achieved complete remission (90%), 382 proceeded to consolidation therapy. Seven patients died in remission (1.8%). The 3-year cumulative incidence of relapse for patients in the LPA96 and LPA99 studies was 17.2% and 7.5%, respectively ( P = .008). Patients treated with ATRA in consolidation therapy showed an overall reduction in the relapse rate from 20.1% to 8.7% ( P = .004). In intermediate-risk patients the rate decreased from 14.0% to 2.5% ( P = .006). This improved antileukemic efficacy also translated into significantly better disease-free and overall survival. A risk-adapted strategy combining anthracycline monochemotherapy and ATRA for induction and consolidation therapy of newly diagnosed APL results in improved antileukemic efficacy and a high degree of compliance.

Over the last few years, hepatitis C virus (HCV) infection has emerged as one of the most significant causes of chronic liver disease worldwide, with an estimated prevalence ranging from 2.2 to 3.0%. In Italy, approximately 2% of subjects are infected with HCV. Considering that acute HCV infection is usually asymptomatic, early diagnosis is rare. Those people who develop chronic infection, even though undiagnosed, may suffer serious liver damage, making chronic HCV infection a major health problem. New initiatives are needed to identify a submerged portion of patients with chronic viral hepatitis and to propose controls and antiviral treatments to avoid the progression to liver cirrhosis or hepatocellular carcinoma (HCC). Since January 2011, the Infectious Diseases Department of San Raffaele Scientific Institute in Milan has been carrying out a prevention program called "EASY test project", using a new oral test, the OraQuick® HCV rapid antibody test (OraSure technologies, Inc.). The main objective of the project is to evaluate the acceptability of an alternative, free and anonymous HCV test offer, available in different settings (Points of Care, STDs Prevention clinics and General Practitioner clinics). From January 2011 to April 2014, 29,600 subjects were approached to inform them about HCV infection and other sexually transmitted diseases; 4,507 (15.2% of the contacted subjects) of them, total eligible volunteers, performed HCV tests on saliva and completed the interview in the alternative POCTs. Twenty-seven subjects (0.6% of the total) turned HCV oral test reactive (27/4.507) during the evaluation period; all of them were confirmed by conventional test. All 27 patients were asymptomatic and without a history of HCV-re- lated symptoms. The results from this analysis suggest that the promotion of alternative HCV test screening has not yet been fully developed as a strategy to increase levels of HCV testing among people at risk for HCV infection. Increasing awareness of these alternative tests among individuals at risk and providers may be an appropriate strategy to increase the number of people who know their serological status. The recent introduction of rapid oral HCV antibody test could completely change the HCV diagnosis approach by facilitating the possibility of testing millions of people worldwide (in particular in the developing countries).

We present the clinical case of a 54 years old man who accessed for dyspnea and severe anemia. After being transfused, he underwent to gastroscopy, which showed an erosive gastritis with large hiatal hernia. The hernia was surgically reduced with laparoscopic hiatoplastic and Nissen-Rossetti fundoplication. In conclusion, dyspnea is not merely a medical competence but also a surgical one.

The submerged portion of undiagnosed HIV infection in Italy is about 30% of subjects found seropositive. This fact represents one of the most important public health problems hindering the control of infection progression. This means we need to fight unawareness and social stigma and promote easy and friendly access to HIV test. We developed a Prevention Program called “EASY test Project”, offering a new rapid HIV test on oral fluid, to evaluate the acceptability of an alternative, free and anonymous test available in different settings (on board a “Motor Home” at public events, Points of Care, STDs outpatient prevention units and GP surgeries). From December 2008 to December 2012 we performed 7,865 HIV saliva tests, with 50 new infections found (0.6% of the total) out of 140,000 informed subjects. From the self-reported characteristics of respondents, the population approaching the EAST test project was represented by males (70%) aged between 20 and 50 years, 61% with a medium-high education level, 62% homosexuals (MSM), 88% reported unsafe sexual behaviours, and 48% had never undergone an HIV screening test. In five years of the Prevention Program, 100% of subjects interviewed gave a general favorable consent in approaching rapid and not invasive screening, immediate return of the result, and a timely specialized approach and treatment of HIV positive subjects. Results from our study confirm that the rapid and alternative test may contribute to HIV prevention strategies and to the control of the spread of infection and HIV disease progression by reaching a larger population, particularly when and where regular screening procedures are difficult to obtain or are not preferred.

A 61-year-old woman underwent celiac trunk stenting to treat abdominal angina. Three months later, she was readmitted for recurrent symptoms. Computed tomography control revealed the migration of the stent into the splenic artery. No sign of vessel injury or end-organ ischemia was detected. Repeat stenting of the celiac trunk was performed; the postoperative course was uneventful. 12 months later, the patient was asymptomatic with the second stent in its correct position, and she was asymptomatic for mesenteric ischemia.

Background The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. Design and Methods Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy-with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. Results Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. Conclusions This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors.

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

HCT is the only potentially curative approach that may provide long-term disease control for patients con relapsed and/or refractory acute leukemia (Re/Ref AL). However, active disease burden at HCT is associated with high relapse rates and dismal outcomes. Recently, promising results in this way have been reported using sequential treatment schedules. We performed a retrospective multicentre analysis to investigate the safety and efficacy of clofarabine (CLO) cytoreduction prior to HCT for Re/Ref AL. Spanish Agency Qualification was obtained (AAH-CLO-2013-01/EPA-OD). A total of 50 patients from 14 Spanish centres (AML 33; ALL 17) who received CLO and had an HLA-matched donor were included. Median age was 37 years (18-64); sex: 26 M, 24 F. High risk cytogenetic/molecular profile in 31.4%, Intermediate 54%, and low risk 14.6%. Patients received first-line chemotherapy (ct) regimens based on cooperative national groups (PETHEMA, CETLAM and SHOP) and 2nd lines with fludarabine-based regimens in 85%. Prior to CLO, 56.3% of patients had received 2 CT lines and 35.5% ≥ 3 lines including 6 auto-HCT and 12 allogeneic HCT. Disease status at CLO administration was primary refractoriness (29.2%) secondary refractoriness (33.3%), first relapse (10%) and ≥2nd relapse (27%). CLO was administered at 20-40 mg/m2/day for 5 consecutive days combined with ARA-C in AML cases and Citoxan-Etoposide in ALL cases. Response was assessed by IWG-2006 criteria and toxicity evaluated according to CTCAE v3. Out of 50 included patients, 16 did not underwent allogeneic HCT due to early toxic deaths (N=6) or due to lack of disease control (N=10) 1.- Response was valuable in 44 cases, achieving 11 CR and 7 PR. Effective Cytoreduction (defined as 2.- Most frequent toxicity was haematological gr.4 in 100% of cases, mucositis gr.≥ 3 in 15%, liver toxicity with bilirrubin and/or SGOT elevation gr.≥3 in 23%, infections gr.≥3 in 50% and skin toxicity gr.2 in 4% 3.- Eventually, HCT was performed in 34 patients (22 AML and 12 ALL); 19 form HLA-matched sibling donor, 7 HLA-matched unrelated donor, 4 HLA-matched umbilical cord and 4 HLA-haploidentical donor. Conditioning regimen was fludarabine-based reduced-intensity in 19 patients and myeloablative in 15 patients. Median elapsed time from CLO administration and HCT was 37 days (range: 6-105). 4.-Transplant-related mortality (TRM)at day +100 and +365 was 20.6% and 41% respectively. Acute GVHD was developed in 16 patients (grades III-IV in 6 cases) and chronic GVHD was observed in 6 patients. With a median follow-up of 14.3 months after HCT, Overall Survival was 28.5% for the global series, 39.6% for AML patients and 15% for ALL patients. Patients achieving effective cytoreduction with CLO had a significantly superior Relapse Free Survival (48% vs. 0%, P=.002). Similarly, patients receiving CLO at earlier disease status (first relapse or primary refractoriness) had a significantly better OS than those treated at more advanced disease (48% vs. 5%). Elapsed time from CLO administration and HCT shorter than 50 days was also associated to a better OS (40.2% vs. 12.2%, P =.14) ) although no statistical difference was reached. Salvage CLO-based regimens as bridge to HCT in patients with Re/Ref AL can be administered with an acceptable toxicity profile and are followed by an acceptable TRM. Achievement of effective cytoreduction and no delayed HCT procedure could identify patients with less leukemic burden capable to achieve long-lasting sustained disease control. Disclosures: No relevant conflicts of interest to declare.

Abstract 4279 Introduction: Clofarabine (CLF) is a purine nucleoside analog approved by FDA and EMA in refractory pediatric ALL patients. Phase I and II studies have reported Clofarabine activity in AML. Aims: To evaluate the experience in Spain with (CLF) in the treatment of adult AML patients, analyzing effectiveness and toxicity profile. Method: This is a multicenter retrospective study including AML patients treated in Spain with CLF by compassionate use. Main points were complete remission as IWRv2003 criteria and toxicity as CTCAE v3.0 of NCI scale. Result: Between July 2007 ans April 2011 a total of 76 AML patients were treated with CLF based chemotherapy in Spain. We obtained clinical data from 64 cases. Median age at CLF treatment 52.4 years (18–77). Male/Female: 31/33. Previous Myelodisplastic syndrome 12 (18%). Cytogenetic data was available in 58 patients (90%), and 28 of them had high-risk cytogenetic. CLF treatment: 56 patients received CLF as salvage therapy (23 in AML relapse and 33 in refractory disease), median previous lines 2 (0–7), were the remaining 8 patients were untreated patients. CLF was administered in combination with AraC in 94% patients and the 91% received a five days schedule. The most frequents CLF dose/day were: 40 mg/m2/day in 39 patients, 30 mg/m2/day in 11 patients, and 20 mg/m2/day in 9 patients. Response and outcome: Nineteen (35.8%) patients achieved complete remission and 64.1% had resistant disease. Mean survival time 14.3 ± 1.4 months. The statistical analysis shows a significant difference in the CR rate between first line therapy (CR 82%) and savage therapy in relapsed (CR 45%) and salvage therapy in refractory (CR 18%), (p0.012). Neither adverse cytogenetics nor previous MDS did influence CR. (p0.57 and p0.53 respectively). Toxicity: All patients presented grade IV hematological toxicity with grade IV neuthopenia, grade IV trombopenia and transfusion depend anemia. The incidence of extra hematological toxic effects were low, creatinine >3 mg/dL: 4 cases (6%); bilirrubine > 3mg/dL: 9 cases (14%). Eleven (17%) patients died during Induction. Conclusions(opcion1): The revised experience in Spain with CLF as compassionate used in AML confirms the effectiveness of Clofarabine as a salvage regimen. Of note was that CLF could potentially overcome some adverse known factors as cytogenetics. Disclosures: Off Label Use: Clofarabine in AML is an off-label use.

Background: A first report of the PETHEMA LPA99 trial in acute promyelocytic leukemia (APL) showed that a risk-adapted treatment strategy combining ATRA and anthracycline alone for induction and consolidation results in high antileukemic efficacy and low toxicity. We report here an updated analysis of this trial including a significantly higher number of patients and longer follow-up. Methods: From November 1999 to July 2005, 564 patients (median age 40 years, range 2–83) with APL received induction with ATRA (45 mg/m2/d) until CR and idarubicin (12 mg/m2/d) on days 2, 4, 6 and 8. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: “low-risk” patients (WBC 40×109/l), idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); “intermediate-risk “ (WBC 10×109/l) patients received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3). Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 45 mg/m2/d ATRA for 15 days every 3 months. Results: CR was achieved in 511 patients (91%). Except for three cases labelled as resistant, of the remaining 50 patients 56%, 24%, 16% and 4% died due to hemorrhage, infection, retinoic acid syndrome, and acute myocardial infarction, respectively. Multivariate analysis showed that WBC >10×109/l, age >60 years, male gender, and serum creatinine >1.4 mg/dl at presentation had independent predictive value of death during induction. The median follow-up of the cohort was 57 months (range 20–94 months). Thirteen patients (median age 72 years, range 4–81) died in remission and 99% of patients completed the entire assigned therapy. Thirty-six patients presented haematological relapse, 16 molecular relapse, and 8 secondary myelodysplastic syndrome or acute myeloid leukemia. Overall, the 5-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 11%, 85%, and 84%, respectively. The 5-year CIR for low-, intermediate- and high-risk patients were 4%, 7% and 28%, respectively. Conclusions: A risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation therapy results in high antileukemic efficacy, low toxicity and a high degree of compliance in newly diagnosed APL.

ATRA combined to anthracycline based chemotherapy is the reference treatment of newly diagnosed APL and a role for maintenance treatment is supported by many studies, but some controversies remain, like the role of AraC. Methods: We performed a joint analysis of pts < 65 yrs included in studies LPA99 (Spanish PETHEMA) and APL 2000 (French -Belgian-Swiss APL group) to address some of those issues. In LPA99, pts received ATRA combined to Idarubicin (IDA) for induction, followed by 3 consolidation courses, 2 with IDA and 1 with mitoxantrone (MTZ, at cumulative dose of 50 mg/m2), and maintenance with intermittent ATRA and continuous 6MP + MTX during 2 years. Pts with high (WBC > 10000/mm3) and intermediate (WBC < 10000/mm3, platelets < 40000/mm3) Sanz score also received ATRA during consolidation courses and higher cumulative dose of IDA (100 mg/m2), vs low risk pts (no consolidation ATRA, cumulative IDA: 80 mg/m2). No AraC was administered in LPA99 trial. For APL 2000, we restricted the analysis to treatment groups that received AraC: pts with low or intermediate Sanz score received induction with ATRA and DNR (60 mg/m2/d x 3) + AraC (200 mg/m2/d x 7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d x 3) + AraC (1 g/m2/12h x 8) course and the same maintenance as in LPA99. High risk patients received the same treatment, but with intrathecal CNS prophylaxis and, in pts < 60 years, AraC 2g/m2/12h x 8 during the last course. Median follow up was 30 and 22 months in LPA99 (412 pts) and APL 2000 (180 pts), respectively. Comparisons were adjusted on age, gender, WBC and platelet counts. Results: In low and intermediate risk patients (308 LPA99 pts, 97 APL 2000 pts), the CR rates, 2 year cumulative incidence of relapse (CIR), EFS and survival were 96% and 99% (p = 0.2), 2.5% and 6.9% (p = 0.05), 93% and 91% (p = 0.6), 95% and 97% (p = 0.3) in LPA99 and APL 2000 trials, respectively. In high risk patients (104 LPA99 pts, 83 APL 2000 pts), the CR rate, 2 year CIR, EFS and survival were 84% and 95% (p = 0.02), 16.0% and 3.3% (p = 0.06), 69.2% and 88.0% (p = 0.01), 82.4% and 91.2% (p = 0.04) in LPA 99 and APL 2000, respectively. Four relapses in high risk pts involved the CNS in LPA99, vs. none in APL 2000. Three and 5 pts in LPA99 and APL 2000 respectively, died in CR, from treatment toxicity. Conclusion: This analysis suggests than in pts with WBC < 10000/mm3, the current PETHEMA approach yields even fewer relapses than a classical ATRA + DNR + AraC regimen, while being less myelosuppressive. This may be due to the anthracyclines used (IDA and MTZ instead of DNR) and/or to the higher cumulative dose of anthracyclines used in LPA99 trial, and possibly also to consolidation ATRA for intermediate risk pts. On the other hand, in pts with high WBC counts, APL 2000 results yielded better EFS and survival and a strong trend for fewer relapses (including relapses involving the CNS), suggesting a beneficial role for AraC, possibly at high dose, in this subset of patients

6515 Background: A first report of the PETHEMA LPA99 trial in acute promyelocytic leukemia (APL) showed that a risk-adapted treatment strategy combining ATRA and anthracycline alone for induction a...

The simultaneous combination of ATRA and anthracycline-based chemotherapy has resulted in a major improvement in remission induction rate and long term survival in patients with APL. This benefit is mainly due to an increased antileukemic efficacy, leading to a virtual absence of leukemic resistance and to a favorable impact on the coagulopathy and on the retinoic acid (RA) syndrome. One of the most successful regimens for induction is the combination of ATRA plus idarubicin (AIDA). In this study we analyze the causes of induction failure observed in two consecutive studies using the AIDA regimen (PETHEMA LPA96 and LPA99). Treatment consisted of oral ATRA (45 mg/m2/d ) until complete hematological remission and idarubicin (12 mg/m2/d) iv on days 2, 4, 6 and 8. In the LPA99 study, the dose of idarubicin on day 8 was omitted for patients older than 70 years of age and all patients received prednisone (0.5 mg/kg/day po for 14 days) for RA syndrome prophylaxis, as well as tranexamic acid (100 mg/kg/day iv) if the platelet count was below 50 × 109/L, in an attempt to improve the control of coagulopathy. The whole series included 642 genetically diagnosed APL patients, 174 in LPA96 and 468 in LPA99 studies, respectively. There were no differences in patient characteristics at presentation between the two groups. Induction results were virtually identical for LPA96 and LPA99 studies with an overall CR rate of 91%. Fifty-two patients (8.4%) failed to achieve CR due to early death. Four additional patients were considered as “resistant” because of persistence of a variable proportion of atypical promyelocytes on days 30 to 41. The distribution of causes of early death was as follows: hemorrhage 30/52 (58%); infection 16/52 (31%); and RA syndrome 5/52 (10%). Mortality due to hemorrhage and infection was significantly different in patients >60 years than in younger patients (37.5% and 56% vs. 72% and 16%, respectively; p=0.01). Neither the addition of prednisone nor tranexamic acid in the LPA99 study had an impact in early death rate. With respect to the chronology of deaths due to hemorrhage, nearly a half (14/30; 47%) occurred during the first week of induction therapy. Central nervous system and pulmonary hemorrhage (17 and 11 patients, respectively) were the only documented sites of lethal bleeding. Univariate analysis showed that age older than 70 years, high WBC counts, clinical and/or laboratory signs of coagulopathy, and abnormally increased level of serum creatinine were associated with an increased risk of lethal bleeding. Multivariate analysis showed that only WBC > 10 × 109/l and serum creatinine > 1.4 mg/dl at presentation retained an independent predictive value of lethal bleeding. In conclusion, despite outcome improvement provided by modern ATRA plus chemotherapy combination, hemorrhagic death remains the primary cause of induction failure in APL. The prophylactic use of prednisone and tranexamic acid failed to reduce the rate of early deaths in newly diagnosed APL. In particular, our study shows that patients presenting with hyperleukocytosis or renal dysfunction are of increased risk of lethal bleeding and should be early managed with more aggressive supportive measures to prevent hemorrhagic death.