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Language workbenches are tools that enable the definition, reuse and composition of programming languages and their ecosystem. This breed of frameworks aims to make the development of new languages easier and more affordable. Consequently, the comprehensibility of the language used in a language workbench (i.e., the meta-language) should be an important aspect to consider and evaluate. To the best of our knowledge, although the quantitative aspects of language workbenches are often discussed in the literature, the evaluation of comprehensibility is typically neglected. Neverlang is a language workbench that enables the definition of languages with a modular approach. This paper presents a preliminary study that intends to assess the comprehensibility of Neverlang programs, evaluated in terms of users' effectiveness and efficiency in a code comprehension task. The study also investigates the relationship between Neverlang comprehensibility and the users' working memory capacity. Furthermore, we intend to capture the relationship between Neverlang comprehensibility and users' acceptance, in terms of perceived ease of use, perceived usefulness, and intention to use. Our preliminary results on 10 subjects suggest that the users' working memory capacity may be related to the ability to comprehend Neverlang programs. On the other hand, effectiveness and efficiency do not appear to be associated with an increase in users' acceptance variables.

Deliverable D3.2.1 del progetto PNRR Ecosistemi ed innovazione - THE

Logic based (semi-)automatic contouring in Medical Imaging has shown to be a very promising and versatile technique that can potentially greatly facilitate the work of different professionals in this domain while supporting explainability, easy replicability and exchange of medical image analysis methods. In such a context there is a clear need of a prototype Graphical User Interface (GUI) support for professionals which is usable, understandable and which reduces unnecessary cognitive load to the minimum, so that the focus of attention can remain on the main, critical, tasks such as image segmentation in support of planning of radiotherapy. In this paper we introduce a first proposal for a graphical user interface for the segmentation of medical images via the spatial logic based analyser VoxLogicA. Since both the logic approach to image analysis and its application in medical imaging are completely new, this is the first step in an iterative development process that will involve various analysis and development techniques, including empirical research and formal analysis. In the current work we analyse the GUI with a focus on the cognitive and memory load aspects which are critical in this domain of application.

Spatial and spatio-temporal model checking techniques have a wide range of application domains, among which large scale distributed systems and signal and image analysis. In the latter domain, automatic and semi-automatic contouring in Medical Imaging has shown to be a very promising and versatile application that can greatly facilitate the work of professionals in this domain, while supporting explainability, easy replicability and exchange of medical image analysis methods. In recent work we have applied this model-checking technique to the (3D) contouring of tumours and related oedema in magnetic resonance images of the brain. In the current work we address the contouring of (2D) images of nevi. One of the challenges of treating nevi images is their considerable inhomogeneity in shape, colour, texture and size. To deal with this challenge we use a texture similarity operator, in combination with spatial logic operators. We apply our technique on images of a large public database and compare the results with associated ground truth segmentation provided by domain experts.

Although definite risk classes are well known, risk-adapted modulation of first-line therapy is seldom attempted in adult ALL. So, a prospective validation of the therapeutic efficacy of a protocol (or a component thereof) in specific risk groups is uncommon.From 1996-1999 a risk-oriented program (08/96) was evaluated in 102/121 unselected patients (median age 35 years, blast count 0-450 x 10(9)/l, 100 B(lin) (lineage), 21 T(lin)) responsive to induction therapy. The standard risk (SR) class was B(lin) CD10+ Ph- with blasts10 x 10(9)/l (prior studies: disease-free survival (DFS) rate 52% at five years with dose-intensive anthracycline-containing programs). The SR protocol was therefore anthracycline-rich (early consolidation cycles with total idarubicin 96 mg/m2), and comprised long-term maintenance. High-risk (HR) patients were eligible to the following three options: allogeneic hematopoietic stem cell transplantation (HSCT) from related family donor; short sequence with high-dose cyclophosphamide-cytarabine-methotrexate followed by melphalan/total body irradiation with autologous HSCT; or T(lin) ALL chemotherapy regimen inclusive of high-dose cytarabine and methotrexate.Treatment realization and three-year DFS rates according to risk class, HR subset and postremission treatment intensity were the following. SR group (n = 28): realization rate 93%, DFS 68.5%. HR group (n = 74): realization rate 80%, DFS 39% (P = 0.052 vs SR category). In HR group, three-year DFS rates by disease subtype were the following. B(lin) Ph- (n = 35) 43%; Ph+ (n = 19) 13% at 2.7 years (P = 0.006 vs other HR subtypes); T(lin) (n = 18) 59.5%. And DFS rates by treatment intensity were: allograft (n = 21) 40%; autograft (n = 28) 27%; shift to SR protocol (n = 13) 52% (P = ns vs allograft/autograft); T(lin) program (n = 10) 57%. Matched analyses of treatment protocols and disease subtypes suggested a possible therapeutic role of the autograft regimen in B(lin) Ph- ALL with a blast count25 x 10(9)/l, and of T(lin) protocol for T(lin) ALL. Comparisons with retrospective control cohorts were confirmatory of anthracycline activity in SR subclass.The intended strategy was applicable to the majority of study patients, confirming the value of anthracyclines in SR class and, preliminarily, the usefulness a T(lin)-specific treatment. Apart from the case of Ph+ ALL, the indications for high-dose procedures with HSCT remains largely undetermined in this study.

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Patients with severe aplastic anemia (SAA) and a neutrophil (PMN) count of less than 0.5 x 10(9)/L are exposed to a high risk of early mortality when treated with antilymphocyte globulin (ALG) and steroids, with the major problem being infectious complications. The addition of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to ALG may reduce early mortality by improving neutrophil counts in the short term. To test the feasibility of this approach, the SAA Working Party of the European Group for Blood and Marrow Transplantation (EBMT) designed a pilot study that included rhG-CSF (5 micrograms/kg/d, days 1 through 90), horse ALG (HALG; 15 mg/kg/d, days 1 through 5), methylprednisolone (2 mg/kg/d, days 1 through 5, then tapering the dose), and cyclosporin A (CyA; 5 mg/kg/d orally, days 1 through 180). Patients with newly diagnosed acquired SAA (untreated) and with neutrophil counts of < or = 0.5 x 10(9)/L were eligible. Forty consecutive patients entered this study and are evaluable with a minimum follow up of 120 days: the median age was 16 years (range, 2 to 72 years), the interval from diagnosis to treatment was 24 days, and the median PMN count was 0.19 x 10(9)/L. Twenty-one patients had hemorrhages, and 19 were infected at the time of treatment. Overall, treatment was well tolerated: the median maximum PMN count during rhG- CSF administration was 12 x 10(9)/L (range, 0.4 x 10(9)/L to 44 x 10(9)/L). There were three early deaths (8%) due to infection. Four patients (10%) showed no recovery, whereas 33 patients (82%) had trilineage hematologic reconstitution and became transfusion- independent at a median interval of 115 days from treatment. Median follow up for surviving patients is 428 days (range, 122 to 1,005). Actuarial survival is 92%: 86% and 100% for patients with PMN counts less than 0.2 x 10(9)/L or between 0.2 x 10(9)/L and 0.5 x 10(9)/L, respectively. This study suggests that the addition of rhG-CSF to ALG and CyA is well tolerated, is associated with a low risk of mortality, and offers a good chance of hematologic response. This protocol would appear to be an interesting alternative treatment for SAA patients with a low PMN count who lack an HLA-identical sibling.

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...

In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.

The objective of the study was to evaluate the incidence, characteristics, treatment and outcome of acute megakaryoblastic leukemia (AMeL) in patients enrolled in GIMEMA trials. Between 1982 and 1999, 3603 new consecutive cases of AML aged over 15 years were admitted to GIMEMA trials. Of them, 24 were AMeL. The incidence of AMeL among AML patients enrolled in GIMEMA trials was 0.6% (24/3603). Diagnosis was based on morphological criteria. Out of 11 cytogenetic studies performed two presented chromosome 3 abnormalities. Twelve patients (50%) reached a CR, five (21%) died in induction and seven (27%) were unresponsive. The median duration of CR was 35 weeks (range 10-441). Seven patients underwent transplantation procedures (1 BMT, 4 aBMT, 2 aPBSCT). Four patients died in CR due to chemotherapy-related complications. Comparing the CR rate between AMeL and the other cases of AML enrolled in GIMEMA trials, no differences were observed. These results were mirrored for different age groups. The median survival was 40 weeks. At present, after a follow-up of a minimum of 2 years, only two patients are alive in CR, all the others having died. A 5-year Kaplan-Meier curve shows a disease-free survival of 17% and an actuarial overall survival of 10%. AMeL is a rare form of AML. The CR duration and the overall survival in this group of patients are very poor, even if similar to those observed in other AML. Furthermore, a high number of deaths in CR were observed. On the basis of these data, a specific therapeutic approach, possibly with innovative treatments, should be evaluated.

Fludarabine (FAMP) is the most active single agent in relapsed and refractory patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear whether it should be used immediatly after failure of chlorambucil (CLB). We addressed such an issue retrospectively analyzing a series of patients in whom FAMP was used as third-line therapy after a sequential use of CLB and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like regimen, respectively.On a retrospective basis, 57 B-CLL patients fulfilling the above mentioned criteria and followed-up in seven different hematologic institutions, were evaluated.Of 57 patients who were evaluated for response, 3 (5.2%) achieved a complete response (CR), 30 (52.6%) had a partial response (PR) and the remaining 24 (42.1%) failed to respond to FAMP. Overall median survival from the start of FAMP therapy was 30 months. Survival by tumor response did not show any difference between responders and non-responders (p = 0.536). The survival was significantly shorter in the group of patients with progressive disease than in all other patients included in our study (p = 0.05). Using each patient as his own control (McNemar test) we attempted to evaluate the value of FAMP in inducing a therapeutic response after failure of previous therapies. Among the 37 patients resistant to CLB the response rate was 40.3% with FAMP (p = 0.037) and only 17.5% with CHOP (p = 1.0). Among 35 patients resistant to a CHOP-like regimen, the response rate was 29.8% (p = 0.066) after FAMP therapy.From our results, it seems that FAMP works better than a CHOP-like regimen in patients resistant to CLB although results do not translate into a survival advantage for responders.

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The outcome of a cohort of 218 consecutive patients who failed to respond to a single course of standard daunorubicin plus ARAC (three + seven) induction regimen has been retrospectively evaluated to assess the characteristics of this group of AML patients and the effectiveness of second-line induction programs. Seventy-four of the 218 patients (33.9%) attained complete remission with salvage chemotherapies. The multivariate analysis of pretherapy characteristics of the patients showed that peroxidase positivity and age were the most important factors in determining whether or not the patient would have a favorable response to second-line induction regimen. In addition, comparison of marrow characteristics at diagnosis with those of marrow after the first-line therapy (marrow leukemic index, MLI) provided the greatest differences between second-line CR and resistant patients. Finally, peroxidase positivity and MLI predicted for remission duration and overall survival. Allogeneic BMT, however, appeared the most important factor for survival and event-free survival of remitting patients. These results are of importance when considering that better defined prognostic factors provide an objective rationale for selecting appropriate strategies for the treatment of patients who do not respond to a single course of induction regimen.

In this study serum cholesterol was measured in different types of human hematologic malignancies characterized by a wide range of cell proliferation. In all tumoral types a significant decrease of HDL cholesterol was observed, whereas total serum cholesterol generally remained unchanged. Another interesting observation of our study was the apparent inverse correlation between the extent of cell proliferation in these neoplastic disorders and the level of HDL cholesterol. Since a decrease of HDL cholesterol was previously observed, in our laboratory, in different experimental models of normal and neoplastic cell proliferation, we suggest that the decrease of HDL cholesterol may be a generalized phenomenon related to massive cellular growth in normal and malignant processes.

In the present study, lipoprotein metabolism was investigated during compensatory hyperplasia of bone marrow after haemolysis induced by phenylhydrazine (20 mg/kg b.w.) administration in rats. The rats were sacrificed at different time intervals (0, 1, 2 and 5 days) after phenylhydrazine treatment. Analysis of the different fractions of lipoproteins has shown that during bone marrow hyperplasia there is an alteration of lipoprotein profiles, mainly due to a decrease of HDL2 and HDL3 subfractions.

At present major issues regarding optimal therapy of acute nonlymphocytic leukemia (ANLL) remain unresolved. Controversial areas include the importance of consolidation and the role of postconsolidation therapy (either conventional or intensive). To investigate these problems the Italian Cooperative Group GIMEMA designed a prospective treatment program based on standard induction therapy with daunorubicin (DNR) plus cytosine arabinoside (Ara-C) followed by intensive consolidation. There-after, patients were randomized in three arms to receive an aggressive postconsolidation treatment with sequential combinations of active agents given in short courses at myelosuppressive doses, conventional maintenance, or no treatment at all. This multi- center trial began in 1982 and was closed to patient entry in May 1987.