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Summary 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.

Introduction Delirium and sarcopenia are common, although underdiagnosed, geriatric syndromes. Several pathological mechanisms can link delirium and low skeletal muscle mass, but few studies have investigated their association. We aimed to investigate (1) the association between delirium and low skeletal muscle mass and (2) the possible role of calf circumference mass in finding cases with delirium. Methods The analyses were conducted employing the cross-sectional “Delirium Day” initiative, on patient 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes and hospices in Italy in 2017. Delirium was diagnosed as a 4 + score at the 4-AT scale. Low skeletal muscle mass was operationally defined as calf circumference ≤ 34 cm in males and ≤ 33 cm in females. Logistic regression models were used to investigate the association between low skeletal muscle mass and delirium. The discriminative ability of calf circumference was evaluated using non-parametric ROC analyses. Results A sample of 1675 patients was analyzed. In total, 73.6% of participants had low skeletal muscle mass and 24.1% exhibited delirium. Low skeletal muscle mass and delirium showed an independent association (OR: 1.50; 95% CI 1.09–2.08). In the subsample of patients without a diagnosis of dementia, the inclusion of calf circumference in a model based on age and sex significantly improved its discriminative accuracy [area under the curve (AUC) 0.69 vs 0.57, p Discussion and conclusion Low muscle mass is independently associated with delirium. In patients without a previous diagnosis of dementia, calf circumference may help to better identify those who develop delirium.

Objectives Delirium is commonly seen in older adults with multimorbidity, during a hospitalization, resulting from the interplay between predisposing factors such as advanced age, frailty, and dementia, and a series of precipitating factors. The association between delirium and specific multimorbidity is largely unexplored so far although of potential key relevance for targeted interventions. The aim of the study was to check for a potential association of multimorbidity with delirium in a large cohort of older patients hospitalized for an acute medical or surgical condition. Design This is a cross-sectional study nested in the 2017 Delirium Day project. Setting and Participants The study includes 1829 hospitalized patients (age: 81.8, SD: 5.5). Of them, 419 (22.9%) had delirium. Methods Sociodemographic and medical history were collected. The 4AT was used to assess the presence of delirium. The Charlson Comorbidity index was used to assess multimorbidity. Results The results identified neurosensorial multimorbidity as the most prevalent, including patients with dementia, cerebrovascular diseases, and sensory impairments. In light of the highest co-occurrence of 3 neurosensorial chronic conditions, we could hypothesize that a baseline altered brain functional and neural connectivity might determine the vulnerability signature for incipient overall system disruption in presence of acute insults. Conclusions and Implications Eventually, our findings moved a step forward in supporting the key importance of routine screening for sensory impairments and cognitive status of older patients for the highest risk of in-hospital delirium. In fact, preventive interventions could be particularly relevant and effective in preventing delirium in such vulnerable populations and might help refining this early diagnosis.

Background although frailty and delirium are among the most frequent and burdensome geriatric syndromes, little is known about their association and impact on short-term mortality. Objective to examine, in hospitalized older persons, whether frailty is associated with delirium, and whether these two conditions, alone or in combination, affect these patients’ 30-day survival. Design observational study nested in the Delirium Day project, with 30-day follow-up. Setting acute medical wards (n = 118) and rehabilitation wards (n = 46) in Italy. Subjects a total of 2,065 individuals aged 65+ years hospitalized in acute medical (1,484 patients, 71.9%) or rehabilitation (581 patients, 28.1%) wards. Methods a 25-item Frailty Index (FI) was created. Delirium was assessed using the 4AT test. Vital status was ascertained at 30 days. Results overall, 469 (22.7%) patients experienced delirium on the index day and 82 (4.0%) died during follow-up. After adjustment for potential confounders, each FI score increase of 0.1 significantly increased the odds of delirium (odds ratio, OR: 1.66 [95% CI: 1.45–1.90]), with no difference between the acute (OR: 1.65 [95% CI: 1.41–1.93]) and rehabilitation ward patients (OR: 1.71 [95% CI: 1.27–2.30]). The risk of dying during follow-up also increased significantly for every FI increase of 0.1 in the overall population (OR: 1.65 [95% CI: 1.33–2.05]) and in the acute medical ward patients (OR: 1.61 [95% CI: 1.28–2.04]), but not in the rehabilitation patients. Delirium was not significantly associated with 30-day mortality in either hospital setting. Conclusions in hospitalized older patients, frailty is associated with delirium and with an increased risk of short-term mortality.

Introduction. The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. Materials and Methods. In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. Results. At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( χ 2 10.4; p < 0.001 ), neutrophil-to-lymphocyte (NL) ratio ( χ 2 7.6; p = 0.006 ), and platelet count ( χ 2 5.39; p = 0.02 ), along with age ( χ 2 87.6; p < 0.001 ) and gender ( χ 2 17.3; p < 0.001 ), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality OR = 3.40 (2.40-4.82), while the OR for a RDW > 13.7 % was 4.09 (2.87-5.83); a platelet count > 166,000 /μL was, conversely, protective (OR: 0.45 (0.32-0.63)). Conclusion. Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.

Purpose Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. Patients and Methods The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification. Results Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). Conclusion Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

Extranodal non-Hodgkin's lymphomas constitute 20-25% of overall non-Hodgkin's lymphomas cases and can be managed with very different therapeutic strategies. Therefore, the Italian Society of Hematology and the two affiliate societies (the Italian Society of Experimental Hematology and the Italian Group of Bone Marrow Transplantation) appointed a panel of experts to produce clinical practice-guidelines for the management of these conditions. Primary lung and mediastinal lymphomas were the objective of this part of the project. The panel of experts produced the following key recommendations that were graded according to the strength of evidence and clinical judgement. The first-line therapy for non-MALT primary lung non-Hodgkin's lymphomas should include anthracycline-based chemotherapy with CHOP or CHOP-like, MACOP-B or MACOP-B-like regimens (grade D). Rituximab association with chemotherapy needs to be evaluated within approved clinical trials. Second-line therapy with high-dose chemotherapy and autologous stem cell transplantation is recommended (grade B). In patients with MALT primary lung non-Hodgkin's lymphomas, the recommended first-line therapy should include chlorambucil, CHOP, CHOP-like or fludarabine-containing regimens (grade B). Radiotherapy is to be reserved for patients with a unique, small lesion in a poorly mobile site and with contraindication to surgery (grade D). Rituximab should be administered only within approved clinical trials. For treatment of primary mediastinal large B-cell lymphomas, the recommended first-line therapy is a chemotherapy and radiotherapy association (grade B). An anthracycline-based chemotherapy with CHOP, MACOP-B or VACOP-B is recommended (grade B). Rituximab combination with chemotherapy is highly suggested but only for patients enrolled into approved clinical trials. Patients with an inadequate early response should be candidates for early intensification with high-dose chemotherapy (grade C). Patients with refractory or relapsed disease should undergo rescue programs including intensive, non-cross-resistant debulking treatment followed, in chemosensitive patients, by high-dose chemotherapy and autologous stem cell transplantation (grade B).

To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years ( P = .0002), equal to or more than 2 extranodal sites ( P = .0002), lactic dehydrogenase (LDH) value at normal levels or above ( P < .0001), performance status (PS) equal to or more than 2 ( P ≤ .0001), stage III or higher ( P = .0001), and bone marrow involvement ( P = .0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P < .0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P < .0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P < .0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P = .026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4, 3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively ( P ≤ .0001; log-rank, 66.79).

The possible prognostic value of the position of the breakpoint within the M-BCR in patients with Phl+ CML is still being debated. We analyzed the DNA rearrangements and the transcript types of 244 patients and tried to correlate the data obtained with prognostic features, defined according to Sokal's risk index, and with chronic phase and/or survival duration. The exact location of the breakpoint, either 5' or 3' to the Hind III restriction site within the M-BCR was identified. Moreover, the exact M-BCR subregion was also identified. As a whole, 150 pts were rearranged in the 5' part and 94 in the 3' part of the M-BCR. No correlation was observed between the site of rearrangement on the one hand and the Sokal's prognostic index and survival, on the other. Transcript analysis was performed in 130 patients; 59 carried an a2b2 and 69 an a2b3 pattern. Two patients carried both transcripts. Of the patients rearranged in the 5' area, according to Southern blotting, 29.2% showed an a2b3 transcript. Therefore, R...

Background: Optimal therapeutic management of intravascular lymphoma (IVL) lacks precise guidelines. Patients and methods: The clinico-pathological features of 38 HIV-negative patients with IVL were reviewed to define efficacy of chemotherapy in these malignancies. Clinical characteristics of 22 patients treated with chemotherapy and of 16 untreated patients were compared in order to understand better the impact and causes of potential patient selection. Results: Median age was 70 years (range 34-90), with a male/female ratio of 0.9; 23 (61%) patients had Eastern Cooperative Oncology Group performance status (ECOG-PS) >1; 21 (55%) had systemic symptoms. Cutaneous lesions and anemia were significantly more common among patients treated with chemotherapy; central nervous system (CNS) and renal involvement were significantly more common among untreated patients. Chemotherapy was associated with a response rate of 59% and a 3-year overall survival of 33 ± 11%. Five of six patients with CNS involvement received chemotherapy: four of them died early; only one patient, treated with adriamycin, cyclophosphamide, vincristine, methotrexate, bleomycin and prednisolone (MACOP-B) followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), was alive at 19 months. High-dose chemotherapy supported by ASCT was indicated at diagnosis in another patient (43 years of age, stage I), who was alive at 71 months, and at relapse after cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in two patients who died early after transplantation. PS ≤1, disease limited to the skin, stage I, and use of chemotherapy were independently associated with better outcome. Conclusions: Anthracycline-based chemotherapy is the standard treatment for IVL. However, survival is disappointing, with a relevant impact of diagnostic delay and lethal complications. More intensive combinations, containing drugs with higher CNS bioavailability, are needed in cases with brain involvement, and the role of high-dose chemotherapy supported by ASCT should be further investigated in younger patients with unfavorable features. © 2004 European Society for Medical Oncology.

In order to elucidate the role of anthracycline based combination chemotherapy regimens for the treatment of follicular lymphoma we conducted a retrospective study on a large series of patients with a histologically confirmed diagnosis of follicular lymphoma. The Italian lymphoma intergroup (ILI) promoted a retrospective study of patients with follicular lymphoma treated in cooperative trials between 1985 and 1996. Six hundred and thirty three cases were treated with an anthracycline-containing regimen and 128 patients were treated without anthracyclines. The two groups were prognostically comparable; in particular, no difference was observed according to both IPI and ILI prognostic index. Results showed a complete remission (CR) rate for patients treated with anthracyclines was 69.2% and overall response rate was 92.5%. After a median follow-up of 51 months (54 months for patients still alive), the 5- and 10-year overall survival (OS) rates were 80 and 66%, respectively. Disease-free survival (DFS) and failure-free survival (FFS) rates at 5 years were 61 and 49%, respectively. In the group of patients treated with combination chemotherapy not including anthracyclines, the CR rate was 67.5% and the overall response rate was 85.4%. A longer OS (80% at 5 years) was observed in patients treated with anthracyclines compared to 67% OS rate in patients treated without anthracyclines (p = 0.0004). FFS was significantly longer in patients treated with anthracyclines (49 vs. 34% p = 0.006). Patients treated with anthracyclines with low or intermediate risk according to ILI prognostic index showed a significantly longer OS (p = 0.0001 andp = 0.0009, respectively); those in the high-risk group showed a trend for a longer survival. In conclusion, this retrospective study shows that patients with follicular lymphoma treated with an anthracycline containing regimen had a better outcome compared to patients treated with other combination regimens non including anthracyclines in terms of CRs, OS and FFS. On the basis of these results anthracycline-containing regimens (ACR) should be considered as the standard treatment of patients with advanced follicular lymphoma.

Background: Surgery is the primary treatment for patients with stage I, II, or IIIA non-small-cell lung cancer (NSCLC). However, long-term survival of NSCLC patients after surgery alone is largely unsatisfactory, and the role of adjuvant chemotherapy in patient survival has not yet been established. Methods: Between January 1994 and January 1999, 1209 patients with stage I, II, or IIIA NSCLC were randomly assigned to receive mitomycin C (8 mg/m 2 on day 1), vindesine (3 mg/m 2 on days 1 and 8), and cisplatin (100 mg/m 2 on day 1) every 3 weeks for three cycles (MVP group; n = 606) or no treatment (control group; n = 603) after complete resection. Randomization was stratified by investigational center, tumor size, lymph-node involvement, and the intention to perform radiotherapy. The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment. Survival curves were analyzed using the log-rank test. All statistical tests were two-sided. Results: After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P = .589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P = .128). Only 69% of patients received the three planned cycles of MVP. Grades 3 and 4 neutropenia occurred in 16% and 12%, respectively, of patients in the MVP arm. Radiotherapy was completed by 65% of patients in the MVP arm and by 82% of patients in the control group. In the multivariable analysis, only disease stage and sex were associated with survival. Conclusion: This randomized trial failed to prospectively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. Given the poor compliance with the MVP regimen used in this study, future studies should explore more effective treatments.

PurposePromising new therapeutic options for follicular lymphoma (FL) include fludarabine plus mitoxantrone (FM) and the mouse/human anti-CD20 antibody, rituximab. We performed a randomized comparative trial of FM with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) front-line chemotherapy with and without sequential rituximab.Patients and MethodsAll previously untreated CD20+FL patients presenting in 15 Italian cooperative institutions from October 1999 were randomly allocated to FM or CHOP. Following clinical or molecular restaging, patients in complete remission (CR) with bcl-2/IgH negativity (CR−) received no further treatment; those in CR with bcl-2/IgH positivity (CR+) received rituximab, as did those in partial remission (PR) with bcl-2/IgH negativity (PR−) or positivity (PR+); nonresponders (NR subgroup) were off study.ResultsAfter chemotherapy, the FM arm achieved higher rates of CR (68% [49 of 72 patients] v 42% [29 of 68 patients]; P = .003) and CR−(39% [28 of 72 patients] v 13 of 68 patients [19%]; P = .001). Rituximab elicited CR−in 55 of 95 treated patients (58%). The final CR−rate was higher in the FM arm (71% [51 of 72 patients] v 51% [35 of 68 patients]; P = .01). However, with a median follow-up of 19 months (range, 9 to 37 months), no statistically significant difference was found among the various study arms in terms of both progression-free (PFS) and overall survival (OS).ConclusionThese results indicate that FM is superior to CHOP for front-line treatment of FL and that rituximab is an effective sequential treatment option. However, they also confirm that this superiority is unlikely to translate into either better PFS or OS.

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The number of HLA-haploidentical hematopoietic cell transplants continues to increase worldwide due to recent improvements in outcomes, allowing more patients with hematological malignancies and non-malignant disorders to benefit from this procedure and have a chance to cure their disease. Despite these encouraging results, questions remain as multiple donors are usually available for transplantation, and choosing the best HLA-haploidentical donor for transplantation remains a challenge. Several approaches to haploidentical transplantation havebeen developed over time and, based on the graft received, can be grouped as follows: T-cell depleted haploidentical transplants, either complete or partial, or withT-cell replete grafts, performed with post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, or G-CSF-primed bone marrow graft and enhanced GVHD prophylaxis. Carefully selecting the donor can help optimize transplant outcomes for recipients of haploidentical donor transplants. Variables usually considered in the donor selection include presence of donor-specific antibodies in the recipient, donor age, donor/recipient gender and ABO combinations, and immunogenic variables, such as natural killer cell alloreactivity or KIR haplotype. Here we provide a comprehensive review of available evidence for selecting haploidentical donors for transplantation, and summarize the recommendations from the European Society for Blood and Marrow Transplantation (EBMT) on donor selection for different transplant platforms.

ObjectivesThis study compared the burden of fatigue between treatment-naïve patients with newly diagnosed acute myeloid leukaemia (AML) and the general population and investigated patient factors associated with fatigue severity.MethodsPretreatment patient-reported fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire in a sample of 463 newly diagnosed patients with AML who were enrolled in a clinical trial. Multivariable linear regression models were used to estimate the adjusted mean differences in fatigue between patients with AML and adults from the general population (n=847) by AML disease risk categories. A clinically meaningful difference in fatigue was defined as ≥3 points. Univariable and multivariable linear regression models were used to identify sociodemographic, clinical and molecular correlates of worse fatigue in patients with AML.ResultsPatients with AML reported adjusted mean fatigue scores that were 7.5 points worse than the general population (95% CI −8.6 to −6.4, pConclusionsPatients with newly diagnosed AML reported worse fatigue than the general population, and mean differences exceeded twice the threshold for clinical significance. Our findings may help to identify patients with AML most likely to benefit from supportive care interventions to reduce fatigue.

BCR-ABL1 kinase domain mutation testing in tyrosine kinase inhibitor (TKI)-resistant Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) patients is routinely performed by Sanger sequencing (SS). Recently, next-generation sequencing (NGS)-based approaches have been developed that afford greater sensitivity and straightforward discrimination between compound and polyclonal mutations. We performed a study to compare the results of SS and NGS in a consecutive cohort of 171 Ph+ ALL patients. At diagnosis, 0/44 and 3/44 patients were positive for mutations by SS and NGS respectively. Out of 47 patients with haematologic resistance, 45 had mutations according to both methods, but in 25 patients NGS revealed additional mutations undetectable by SS. Out of 80 patients in complete haematologic response but with BCR-ABL1 ≥0·1%, 28 (35%) and 52 (65%) were positive by SS and NGS respectively. Moreover, in 12 patients positive by SS, NGS detected additional mutations. NGS resolved clonal complexity in 34 patients with multiple mutations at the same or different codons and identified 35 compound mutations. Our study demonstrates that, in Ph+ ALL on TKI therapy, NGS enables more accurate assessment of mutation status both in patients who fail therapy and in patients with minimal residual disease above 0·1%.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of KIT, together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: i) patients with mast cell-restricted KIT D816V; ii) patients with multilineage KIT D816V-involvement; iii) patients with “multi-mutated disease”. Thanks to these findings, new prognostic scoring systems combining clinical and molecular data have been developed. Finally, non-genetic SETD2 histone methyltransferase loss of function has recently been identified in advanced SM. Assessment of SETD2 protein levels and activity might provide prognostic information and has opened new research avenues exploring alternative targeted therapeutic strategies. This review discusses how progress in recent years has rapidly complemented previous knowledge improving the molecular characterization of SM, and how this has the potential to impact on patient diagnosis and management.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice., SCOPUS: re.j, info:eu-repo/semantics/published

Physical exercise is considered to be one of the beneficial factors of a proper lifestyle and is nowadays seen as an indispensable element for good health, able to lower the risk of disorders of the cardiovascular, endocrine and osteomuscular apparatus, immune system diseases and the onset of potential neoplasms. A moderate and programmed physical exercise has often been reported to be therapeutic both in the adulthood and in aging, since capable to promote fitness. Regular exercise alleviates the negative effects caused by free radicals and offers many health benefits, including reduced risk of all-cause mortality, sarcopenia in the skeletal muscle, chronic disease, and premature death in elderly people. However, physical performance is also known to induce oxidative stress, inflammation, and muscle fatigue. Many efforts have been carried out to identify micronutrients and natural compounds, also known as nutraceuticals, able to prevent or attenuate the exercise-induced oxidative stress and inflammation. The aim of this review is to discuss the benefits deriving from a constant physical activity and by the intake of antioxidant compounds to protect the body from oxidative stress. The attention will be focused mainly on three natural antioxidants, which are quercetin, resveratrol and curcumin. Their properties and activity will be described, as well as their benefits on physical activity and on aging, which is expected to increase through the years and can get favorable benefits from a constant exercise activity.

Cancer patients experience symptoms and adverse effects of treatments that may last even after the end of treatments. Exercise is a safe, non-pharmacological and cost-effective therapy that can provide several health benefits in cancer patient and survivors, reducing cancer symptoms and cancer treatment side effects. The purpose of this review is to describe how the physical exercise is capable to reduce cancer symptoms and cancer treatment side effects. We realized a pragmatic classification of symptoms, dividing them into physical, psychological and psycho-physical aspects. For each symptom we discuss causes, therapies, we analyse the effects of physical exercise and we summarize the most effective type of exercise to reduce the symptoms. This review also points out what are the difficulties that patients and survivors face during the practice of physical activity and provides some solutions to overcome these barriers. Related to each specific cancer, it emerges that type, frequency and intensity of physical exercise could be prescribed and supervised as a therapeutic program, like it occurs for the type, dose and duration of a drug treatment.

Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS–International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT01287741","term_id":"NCT01287741"}}NCT01287741.

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Eye charts are typically optimized to assess visual acuity (VA) with constant and controlled spacing, while close-to-acuity crowding limits letter identification in the normal fovea when adjacent letters are closely spaced. Here we developed a clinical tool that enables the assessment of acuity with different levels of crowding. In a cross-sectional study, we examined the developmental trajectories with our newly devised Milan Eye Chart (MEC). A total of 252 children of 1st, 3rd and 5th grade were assessed with the MEC using SLOAN letter optotypes with 100%, 50%, 25% and 12.5% inter-optotype spacing. Results show an interaction between spacing and grade. The performance to the 100% standard VA was not significantly different among grades, while the narrow spaced acuity (12.5% spacing) strongly improved with the grade. The different trajectories of acuity measured with high spaced and low spaced eye-charts suggest that the mechanisms able to reduce the crowding effects develops later than VA, and it is, at least in part, dissociated by the psychophysiological development of lower level visual mechanisms. The MEC charts are feasible and useful in assessing visual acuity with different level of crowding during the whole lifespan. The opportunity to assess crowding-limited acuity in early age is particularly relevant since it plays a significant role in amblyopia screening.

Purpose: To evaluate the accuracy and repeatability of a computer-generated Pelli–Robson test displayed on liquid crystal display (LCD) systems compared to a standard Pelli–Robson chart. Methods: Two different randomized crossover experiments were carried out for two different LCD systems for 32 subjects: 6 females and 10 males (40.5±13.0years) and 9 females and 7 males (27.8±12.2years), respectively, in the first and second experiment. Two repeated measurements were taken with the printed Pelli–Robson test and with the LCDs at 1 and 3m. To test LCD reliability, measurements were repeated after 1week. Results: In Experiment 1, contrast sensitivity (CS) measured with LCD1 resulted significantly higher than Pelli–Robson both at 1 and at 3m of about 0.20 log 1/C in both eyes (p&nbsp

A decreased physical fitness has been reported in patients and survivors of acute lymphoblastic leukemia (ALL). This is influenced by the negative effects of the disease and by the treatments of childhood cancer. In the past, children were advised to recover in bed, and to take as much relax as possible. Nowadays, it is considered that too much immobility may result in a further decrease of physical fitness and functioning. Exercise training for ALL children has frequently been reported to improve physical fitness and the well-being of the children, since it prevents the negative effects of a sedentary life-style, such as obesity and a poor skeletal health. In recent years, different studies and protocols on this subject has become available for children and young adults with cancer, both during and after treatment. The efficacy of recent physical exercise training interventions, that act on several ALL impairments in children such as skeletal, musculoskeletal, neuromuscular, cardiopulmonary and cardiovascular systems, fatigue, body balance disorders and metabolism alterations have been examined. These side effects might be prevented or significantly reduced by introducing a physical exercise program during or shortly after cancer treatment. Several interventions are discussed and presented for each impairment, reducing their level caused by the disease and thus suggesting the importance of physical training activity in ameliorating the children quality of life.

The Bruton tyrosine kinase inhibitor ibrutinib (IB) has attained an important role in the treatment of patients with chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenström macroglobulinemia, significantly improving clinical outcomes. However, IB therapy has been associated with an increased risk of atrial fibrillation (AF) and bleeding. We report on the expert opinion that a group of Italian haematologists, cardiologists, and pharmacologists jointly released to improve the practical management of patients at risk for AF and bleeding during treatment with IB. A proper pretreatment assessment to identify patients who are at a higher risk, careful choice of concomitant drugs, regular monitoring, and multispecialist approach were characterized as the main principles of clinical management of these patients. For patients developing AF, anticoagulant and antiarrhythmic therapy must be guided by considerations about efficacy, safety, and risk of pharmacokinetic interactions with IB. For patients experiencing bleeding or requiring procedures that increase the risk of bleeding, considerations about platelet turnover, IB-related platelet dysfunctions, and bleeding worsening by concomitant anticoagulants or antiplatelet agents provide clues to manage bleeding. Overall, AF and bleeding are manageable clinical events in patients receiving IB, not requiring drug interruption in most cases. Preexisting AF should not represent an absolute contraindication to IB therapy. For each patient candidate for IB, strategies of risk assessment and mitigation may allow to exploit the life-saving effects of in chronic lymphocytic leukaemia and mantle cell lymphoma.

Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults accounting for 31% of all NHL in Western Countries. Following, morphological, biological and clinical studies have allowed the subdivision of DLBCLs into morphological variants, molecular and immunophenotypic subgroups and distinct disease entities. However, a large number of cases still remain biologically and clinically heterogeneous, for which there are no clear and accepted criteria for subclassification; these are collectively termed DLBCL, not otherwise specified (NOS). DLBCL-NOS occurs in adult patients, with a median age in the seventh decade, but the age range is broad, and it may also occur in children. Clinical presentation, behaviour and prognosis are variable, depending mainly of the extranodal site when they arise. These malignancies present in localized manner in approximately 20% of patients. Disseminated extranodal disease is less frequent, and one third of patients have systemic symptoms. Overall, DLBCLs are aggressive but potentially curable malignancies. Cure rate is particularly high in patients with limited disease with a 5-year PFS ranging from 80% to 85%; patients with advanced disease have a 5-year PFS ≈ 50%. The International Prognostic Index (IPI) and age adjusted IPI (aaIPI) are the benchmarks of DLBCL prognosis. First-line treatment for patients with DLBCL is based on the individual IPI score and age, and three major subgroups should be considered: elderly patients (>60 years, aaIPI=0-3); young patients with low risk (

Selective attention, i.e. the ability to concentrate one's limited processing resources on one aspect of the environment, is a multifaceted concept that includes different processes like spatial attention and its subcomponents of orienting and focusing. Several studies, indeed, have shown that visual tasks performance is positively influenced not only by attracting attention to the target location (orientation component), but also by the adjustment of the size of the attentional window according to task demands (focal component). Nevertheless, the relative weight of the two components in central and peripheral vision has never been studied. We conducted two experiments to explore whether different components of spatial attention have different effects in central and peripheral vision. In order to do so, participants underwent either a detection (Experiment 1) or a discrimination (Experiment 2) task where different types of cues elicited different components of spatial attention: a red dot, a small square and a big square (an optimal stimulus for the orientation component, an optimal and a sub-optimal stimulus for the focal component respectively). Response times and cue-size effects indicated a stronger effect of the small square or of the dot in different conditions, suggesting the existence of a dissociation in terms of mechanisms between the focal and the orientation components of spatial attention. Specifically, we found that the orientation component was stronger in periphery, while the focal component was noticeable only in central vision and characterized by an exogenous nature.

Background and Objectives This study explored variations in the clinical manifestations of intravascular lymphoma (IVL) on the bases of the association with hemophagocytosis and the country where the diagnosis was made. Design and Methods The clinical features of 50 Western patients with IVL were compared with those of 123 patients with IVL diagnosed in Eastern countries (87 diagnosed in Japan and 36 in other Asian countries), previously reported in English literature, and collected by an electronic bibliographic search. Results Hemophagocytosis was absent in Western patients, but reported in 38 (44%) Japanese patients ( p =0.00001) and in seven (19%) patients from other Asian countries ( p =0.002). No clinical differences were evident between patients with hemophagocytosis-negative IVL diagnosed in Western countries, Japan and other Asian Countries. Conversely, Japanese and non-Japanese patients with hemophagocytosis-related IVL more frequently had stage IV disease, fever, hepato-splenic involvement, marrow infiltration, dyspnea, anemia, and thrombocytopenia, and rarely exhibited cutaneous or central nervous system involvement. Lymph node and peripheral blood involvement was uncommon in all subgroups. In Western patients, anthracycline-based chemotherapy was associated with a 52% remission rate, and a 2-year overall survival of 46%. Interpretation and Conclusions The clinical features of IVL vary according to the association with hemophagocytosis, regardless of the country in which the diagnosis is made. Western, Japanese and other Asian patients with hemophagocytosis-negative IVL display similar clinical characteristics and should be considered as having classical IVL. Patients with hemophagocytosis-related IVL show significantly different clinical features. Both forms have a poor prognosis. Extensive molecular studies are needed to explore whether these clinical differences might reflect discordant biological entities within IVL.

Purpose The quantitative assessment of Positron Emission Tomography (PET) scans using standardized uptake value and derived parameters proved to be superior to traditional qualitative assessment in several retrospective or mono-centric prospective reports. Since different scanners give different quantitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of quantitative PET in prospective multi-centre clinical trials and in every-day clinical life. Methods We set up, under the auspices of Italian Foundation on Lymphoma (FIL), a CTQ program consisting of the PET/CT scan acquisition and analysis of 18F and 68Ge NEMA/IEC image quality phantoms for the reduction of inter-scanner variability. Variability was estimated on background activity concentration (BAC) and sphere to background ratio (SBR). Results The use of a 68Ge phantom allowed reducing the inter-scanner variability among different scanners from 74.0% to 20.5% in BAC and from 63.3% to 17.4% in SBR compared to using the 18F phantom. The CTQ criteria were fulfilled at first round in 100% and 28% of PET scanners with 68Ge and 18F respectively. Conclusions The 68Ge phantom proved a reliable tool for PET scanner qualification, able to significantly reduce the potential sources of error while increasing the reproducibility of PET derived quantitative parameter measurement.

BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

We performed a multicenter study to validate the concept that a simple comprehensive geriatric assessment (CGA) can identify elderly, non-fit patients with diffuse large B-cell lymphoma (DLBCL) in whom curative treatment is not better then palliation, and to analyze potential benefits of treatment modulation after further subdividing the non-fit category by CGA criteria. One hundred and seventy-three patients aged > 69 treated with curative or palliative intent by clinical judgement only were grouped according to CGA into fit (46%), unfit (16%) and frail (38%) categories. Two-year overall survival (OS) was significantly better in fit than in non-fit patients (84% vs. 47%; p < 0.0001). Survival in unfit and frail patients was not significantly different. Curative treatment slightly improved 2-year OS in unfit (75% vs. 45%) but not in frail patients (44% vs. 39%). CGA was confirmed as very efficient in identifying elderly patients with DLBCL who can benefit from a curative approach. Further efforts are needed to better tailor therapies in non-fit patients.

Serum interleukin-6 (sIL6) is an acknowledged predictor of all-cause mortality in older age. A common G/C polymorphism has been identified at position −174 of the IL6 gene promoter (IL6−174G>C), but its associations with sIL6 and mortality are still unclear. Data from a population-based elderly cohort (n = 824) were used to study the associations of baseline sIL6 with the IL6−174 C-allele (C+) carrier status and all-cause mortality at 4 years, in the presence and absence of preexisting major diseases (PMD). Analyses were adjusted for socio-demographic factors and body-mass-index. Three-hundred-eighty-eight participants (47.1%) had PMD. Compared to the bottom sIL6 quartile, mortality increased both in presence [Hazard Ratio (HR) = 3.04; 95% confidence interval (CI): 1.48–6.25] and absence of PMD [HR = 3.91; 95%CI: 1.42–10.72] for the third higher sIL6 quartile, but only in presence of PMD for the top sIL6 quartile [HR = 2.30; 95%CI: 1.09–4.83]. In absence of PMD, C+ carrier status did not affect both sIL6 and mortality. In presence of PMD, C+ carrier status was associated with increased baseline sIL6 [odds ratio 2.01; 95%CI: 1.25–3.22, for all sIL6 quartiles above the bottom] but not with increased mortality risk. A survival advantage was even found for C+ carriers with PMD and sIL6 in the top quartile [HR = 0.31, 95%CI: 0.13–0.76]. In conclusion, although associated with increased sIL6 levels in presence of major diseases, the IL6−174 C-allele does not seem to have direct detrimental effects on survival in older age.

Background: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitiveimpairmentanddementia.Incidencestudiesofthisissuearefew and have produced conflicting results. Objective: We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population. Design: A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12. Results: Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy 15 mol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P 0.014), whereas the association was not significant for vitamin B-12.

The cross-sectional association of functional impairment with several peripheral blood inflammatory markers (increased C-reactive protein (CRP), fibrinogen and leucocyte count, decreased cholesterol and albumin) was studied in 739 elderly community-dwellers. Functional measures included Tinetti test for gait and balance, and basic and Instrumental Activities of Daily Living. When considering each marker individually, only increased CRP was inversely associated with all functional measures independently of demographics, lifestyle, and comorbidity (P0.05). When considering the sum of positive markers, having more than one marker was also inversely associated with all functional measures (P0.05), but no clear gradient of impairment was found across increasing numbers of markers. When considering specific combinations of markers, having both increased CRP and at least another positive marker had a stronger association with functional impairment (P0.01 for all measures) than increased CRP alone (P0.05), or other positive markers alone or in combination (P0.05). In conclusion, in elderly individuals, peripheral blood markers of inflammation are associated with functional impairment independently of potential confounders. A specific combination of CRP with other markers provides a better correlate of functional impairment than both individual markers or a simple count of positive markers.

The Greek region is characterized by intense geodynamic activity with widespread volcanic, geothermal and seismic activity. Its complex geology is reflected in the large variety of chemical and isotopic composition of its gas manifestations. Basing on their chemical composition the gases can be subdivided in three groups, respectively CO2, CH4 or N2-dominated. On oxygen-free basis these three gases make up more than 97% of the total composition. The only exceptions are fumarolic gases of Nisyros that contain substantial amounts of H2S (up to more than 20%) and one sample of Milos that contains 15% of H2. CO2-dominated gases with clear mantle contribution in their He isotopic composition (R/Ra corrected for air contamination ranging from 0.5 to 5.7) are found along the subduction-related south Aegean active volcanic arc and on the Greek mainland close to recent (upper Miocene to Pleistocene) volcanic centers. These areas are generally characterized by active or recent extensive tectonic activity and high geothermal gradients. On the contrary, gases sampled in the more external nappes of the Hellenide orogen have generally a CH4- or N2-rich compositions and helium isotope composition with a dominant crustal contribution (R/Ra corr < 0.2). The chemical and isotopic characteristics of the emitted gas display therefore a clear relationshipwith the different geodynamic sectors of the region. Gas geochemistry of the area contributes to a better definition of the crust-mantle setting of the Hellenic region.

Crowding is a phenomenon that characterizes normal periphery limiting letter identification when other letters surround the signal. We investigated the nature of the reading limitation of crowding by analyzing eye-movement patterns. The stimuli consisted of two items varying across trials for letter spacing (spaced, unspaced and increased size), lexicality (words or pseudowords), number of letters (4, 6, 8), and reading modality (oral and silent). In Experiments 1 and 2 (oral and silent reading, respectively) the results show that an increase in letter spacing induced an increase in the number of fixations and in gaze duration, but a reduction in the first fixation duration. More importantly, increasing letter size (Experiment 3) produced the same first fixation duration advantage as empty spacing, indicating that, as predicted by crowding, only center-to-center letter distance, and not spacing per se, matters. Moreover, when the letter size was enlarged the number of fixations did not increase as much as in the previous experiments, suggesting that this measure depends on visual acuity rather than on crowding. Finally, gaze duration, a measure of word recognition, did not change with the letter size enlargement. No qualitative differences were found between oral and silent reading experiments (1 and 2), indicating that the articulatory process did not influence the outcome. Finally, a facilitatory effect of lexicality was found in all conditions, indicating an interaction between perceptual and lexical processing. Overall, our results indicate that crowding influences normal word reading by means of an increase in first fixation duration, a measure of word encoding, which we interpret as a modulatory effect of attention on critical spacing.

This article focuses on the mathematical model of the pitch control mechanism for a marine controllable pitch propeller, with the aim of describing the dynamic behaviour of this kind of system and its influence on ship performance. Too great a load on the blades can result in high pressures in the actuating system, response delays and control system problems, which are ultimately responsible for most mechanism failures. The behaviour of the controllable pitch propeller actuating mechanism is considered in terms of blade position, oil pressures inside the controllable pitch propeller hub and magnitudes of the forces acting on the blades. In the proposed mathematical model, the forces acting on the propeller blade are evaluated taking into account the yaw motion of the ship, the propeller speed (including shaft accelerations and decelerations) and the turning of the blade during the pitch change. On the basis of the introduced procedure, a controllable pitch propeller numerical model as part of an overall propulsion and manoeuvrability simulator representing the dynamic behaviour of a twin-screw fast vessel is developed. The aim of this work is to represent the ship propulsion dynamics through time-domain simulation, based on which the designers can develop and test several design options, in order to avoid possible machinery overloads with their consequent failures and to obtain the best possible ship performances. In this aspect, the controllable pitch propeller model is an essential design tool.

Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyer's ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.

In the paper stator faults are analyzed by means of a procedure ba­ sed on the space-vector theory. The used approach, due to Stepina, allows to consider separately each conductor of every single slot and therefore to take easily into account the winding dissymmetry. The interactions among the different harmonic fields are studied by starting from the topological structure of windings and the harmonic ana­ lysis of the currents and of torque is carried out. The method is' tested to numerical computations of steady-state cur­ rents for an induction machine with different positions of stator short­ circuits. Finally the procedure is validated by using an experimental squirrel cage machine, having stator windings constructed so as to realize diffe­ rent short-circuits.

The impact of different treatment modalities and prognostic factors on the clinical course of primary thyroid diffuse large B-cell lymphoma (PTDLBCL) is still the subject of research. This study was conducted to clarify these clinical aspects of this disorder. The clinical parameters of 48 patients with PTDLBCL at time of diagnosis were comparable to those of previous studies. Patients underwent either radiotherapy (RT) ±° surgery (SX), chemotherapy (CHT) alone or in combination with local treatments (RT or SX), or SX followed by CHT and RT. A 90% complete remission (CR) rate was observed among patients who underwent combined treatment modalities (CTM), compared to 76% among the others. The 5-year progression-free survival differed significantly between both groups (p = 0.028). Poor performance status and advanced age correlated with decreased survival. PTDLBCL is a curable disease prevalent in elderly patients. Combined treatment modalities were able to induce an elevated rate of CR, improving long-term survival in younger patients. However, the outcome in elderly patients still remains unsatisfactory. © 2011 Informa UK, Ltd.

We retrospectively analyzed the data of 337 patients with cytogenetically normal (CN) acute myeloid leukemia (AML), aged ≤ 65 years (training set). A prognostic index score (PIS) was calculated by totaling the score derived from the regression coefficients of each clinical variable, significantly associated with prognosis by multivariate analysis. The variables that were independent prognostic factors for event-free survival (EFS) and overall survival (OS) in the training set were: age ≥ 50 years, secondary AML and white blood cell count (WBC) ≥ 20 × 10(9)/L. The patients of the training set were stratified into three groups: low-, intermediate- and high-risk. The median EFS was 25, 12 and 7 months in the low-, intermediate- and high-risk groups (p < 0.0001), respectively. The median OS was not reached in the low-risk group and was 19 and 10 months in the intermediate- and high-risk groups (p < 0.0001). This PIS was validated in a series of 193 patients with CN-AML. The median EFS was 66, 16, and 3 months (p < 0.0001) and the median OS was 66, 16, and 5 months in the three risk groups, respectively (p < 0.0001). This PIS may be useful for clinical decision-making in CN-AML and may be prospectively integrated with the newest biological markers which at present are not routinely assessed and need prognostic validation.

90-yttrium-ibritumomab-tiuxetan is approved for treatment of rituximab-relapsed/refractory CD20+ follicular B-cell lymphoma and as consolidation therapy in untreated follicular lymphoma. Recommendations on the use of 90-yttrium-ibritumomab tiuxetan were issued in a consensus conference, sponsored by the Italian Society of Hematology and the Italian Association of Nuclear Medicine. Current concepts and scientific evidence on the use of 90-yttrium-ibritumomab-tiuxetan were evaluated by a panel of seven experts. The following key recommendations were issued. The most important exclusion criteria are: bone marrow infiltration by lymphoma cells and platelet count or neutrophil count lower than 100 x 10 9 /L or 1.5 x 10 9 /L. The most relevant indication for 90 Y-ibritumomab-tiuxetan is as a single agent or following debulking chemotherapy for relapsed/refractory follicular lymphoma. 90 Y-ibritumomab tiuxetan as a single agent is effective in improving the quality and duration of the response in follicular lymphoma after primary chemotherapy or immunochemotherapy. 90 Y-ibritumomab-tiuxetan as a single agent has activity in relapsed/refractory mantle cell lymphoma and DLBCL, but the responses are of short duration. Its use after first line chemoimmunotherapy as consolidation therapy appears promising, particularly in elderly patients. The addition of 90 Y-ibritumomab-tiuxetan to high-dose chemotherapy, such as BEAM, is feasible and may be recommended for patients with high-risk relapsed/ refractory lymphoma. Subsequent lines of therapy can be successfully used in patients who relapse after radioimmunotherapy.

Purpose The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. Patients and Methods Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed. Results After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. β2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001). Conclusion Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.

Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin ( NPM1 ) in the same family