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Il viaggio implica un’andata e un ritorno, anche se non sempre nei testi di viaggio il ritorno trova ampio svolgimento: è la fine del viaggio, segna la conclusione della trattazione e appare come un traguardo. In alcuni resoconti di viaggio del XIX secolo, che hanno come meta l’Europa, il capitolo dedicato al ritorno è spesso l’occasione per l’autore di inserire brani poetici, suoi o di altri autori, classici e moderni, attraverso cui esprimere i propri sentimenti. Ma il ritorno nell’amata patria è anche il momento per trarre le conclusioni del viaggio, come nel caso di Tahtawi, che nel suo rinnovato sguardo verso gli Egiziani li trova molto simili ai Francesi. Il ritorno implica un ritorno in sé, ma in un sé trasformato dalle esperienze del viaggio, in un processo di perdita e acquisizione che, come tale, comporta ansie e inquietudini. Del resto il distacco dalla propria comunità consente a ogni individuo di capire ciò che a essa lo unisce. Lo studio intende infatti guardare al concetto di ruju‘ ritorno, così come viene diversamente declinato in alcune Rihle del XIX secolo, dove l’intera narrazione è pervasa dal confronto con l’Altro e il ritorno stesso sembra configurarsi come la realizzazione di tale confronto: tornare per essere un egiziano moderno, un siriano moderno, ecc., così da poter dar vita a una nazione moderna.

Background: Although recent high-resolution genome-wide profiling analysis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) samples has contributed to the identification of many novel somatic genetic alterations, a deep molecular characterization of adult ALL is still challenging, especially for those cases lacking recurrent fusion genes. Aims: In order to better molecularly dissect this ALL subgroup, we performed an integrative molecular approach including gene-candidate high-resolution screening and genome-wide profiling analyses. Methods: We retrospectively analyzed 28 newly diagnosed BCR-ABL1- negative BCP-ALL subjects (19 males/9 females; median age 41.5 years; negative for known fusion genes) and 28 BCR-ABL1-positive BCP-ALL subjects as a comparison group. In BCR-ABL1-negative ALL karyotype was normal in 10/28 (36%). Copy number alterations (CNA) of know leukemiarelated genes, such as IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, and genes within PAR1: CRLF2, CSF2RA, IL3RA have been assessed by the SALSA MLPA kit P335 IKZF1 (MRC Holland). In addition, sequence mutations have been investigated in TP53, CRLF2, JAK2, LEF1, PAX5 and IL7R by nextgeneration deep-sequencing (NGS) (Roche Applied Science; IRON-II study oligonucleotide primer plates). Positivity for newly described BCR-JAK2, PAX5- JAK2, ETV6-ABL1, EBF1-PDGFRB, NUP-ABL1 gene fusions occurring in BCR-ABL1-like ALL (Roberts KG et al., Cancer Cell. 2012) was assessed by PCR amplification and sequencing. Finally, SNP arrays (SNP 6.0, Affymetrix), gene expression profile analyses (GeneChip® Human Transcriptome Array 2.0) and whole exome sequencing (Illumina) were performed to more fully assess genomic complexity. Results: Overall, 76% of BCR-ABL1-negative subjects showed an abnormality of at least one of the analyzed known leukemia genes: 7 (25%) had one, 4 (14%) had two, 6 (21%) had three, and 6 (21%) had four or more alterations. In subjects showing no abnormalities, SNP arrays analysis revealed amplifications of chromosome 1q in 2/6 cases (33%). Deletions of CDKN2A/B were the most frequent (39%) and in 73%, they occurred together with other abnormalities, suggesting that multiple events are needed to induce the full leukemia phenotype. Other common CNA included: deletions of IKZF1 (25%), ETV6 (25%), PAX5 (14%), EBF1 (11%), PAR1 region (11%) and RB1 (7%). NGS showed mutations of JAK2 and CRLF2 in 7% (R683S/G) and 4% (F232C), respectively. No positivity for newly described fusion genes activating tyrosine kinase was confirmed. Importantly, subjects with no abnormalities showed better survival rates compared to those with one or more molecular alterations (p

Introduction. Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. The recent WHO classification (2008) includes an indolent form (ISM), an aggressive form (ASM) and a leukemic subvariant (MCL). The c-kit mutation D816V is detectable in most adult patients with SM. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Methods. From 2008, 22 patients (male/female=11/11) affected by SM have been referred to our Institution. Among these, 12 (55%) presented with systemic symptoms associated with signs of organ involvement (skeletal lesions, ascites, liver function impairment or bon marrow disfunction), thus identifying an ASM. Therefore, since a first line therapy (IFNalfa, Imatinib and 2CdA in 56%, 11% and 33% of the patients, respectively) and supportive care with histamine receptor antagonists weren’t followed by a significant benefit, a personalized use of PKC412 was asked and obtained for 9 out of 12 ASM patients. Thus, from March 2011 9 (M/F =3/9) patients with ASM have been treated with PKC412, administered orally, at the dosage of 100 mg twice daily, without rest periods. The median age was 60 years (range 39-75); the median time from diagnosis was 6 months (range 2-53). Median serum tryptase level was 100 mcg/L(range 19.3-1160). C-kit mutation D816V was present in 8 out of 9 patients. Cytogenetic analysis was normal in all the patients. Results. Seven out of nine patients were evaluable for response. The median duration of therapy was 517 days (range 327-970+). According to European Criteria, a Major response was observed in one patient, and a partial response in 6 patients. Overall, the drug was well tolerated, and no serious adverse events were observed. All the patients obtained a quick and prolonged improvement of clinical symptoms, in terms of weight gain, bowel function and skeletal pain. At the bone marrow evaluation, the persistence of the D816V c-kit mutation was observed, despite a significant decrease of mast cell marrow involvement. Conclusions. In a small cohort of ASM patient, the prolonged therapy with PKC412 is safe and effective, mainly on symptoms improvement and haematological profile. Nevertheless, the persistence of the D816V c-kit mutation, despite significant responses, suggests that many other oncogenic factors may be responsible for the pathogenesis of the disease. UDS approaches are needed in order to clarify this issue. Acknowledgments. Work supported by European LeukemiaNet, AIRC, AIL, PRIN 2010-2011, University of Bologna, FP7 NGS-PTL project. Introduction. Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. The recent WHO classification (2008) includes an indolent form (ISM), an aggressive form (ASM) and a leukemic subvariant (MCL). The c-kit mutation D816V is detectable in most adult patients with SM. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Methods. From 2008, 22 patients (male/female=11/11) affected by SM have been referred to our Institution. Among these, 12 (55%) presented with systemic symptoms associated with signs of organ involvement (skeletal lesions, ascites, liver function impairment or bon marrow disfunction), thus identifying an ASM. Therefore, since a first line therapy (IFNalfa, Imatinib and 2CdA in 56%, 11% and 33% of the patients, respectively) and supportive care with histamine receptor antagonists weren’t followed by a significant benefit, a personalized use of PKC412 was asked and obtained for 9 out of 12 ASM patients. Thus, from March 2011 9 (M/F =3/9) patients with ASM have been treated with PKC412, administered orally, at the dosage of 100 mg twice daily, without rest periods. The median age was 60 years (range 39-75); the median time from diagnosis was 6 months (range 2-53). Median serum tryptase level was 100 mcg/L(range 19.3-1160). C-kit mutation D816V was present in 8 out of 9 patients. Cytogenetic analysis was normal in all the patients. Results. Seven out of nine patients were evaluable for response. The median duration of therapy was 517 days (range 327-970+). According to European Criteria, a Major response was observed in one patient, and a partial response in 6 patients. Overall, the drug was well tolerated, and no serious adverse events were observed. All the patients obtained a quick and prolonged improvement of clinical symptoms, in terms of weight gain, bowel function and skeletal pain. At the bone marrow evaluation, the persistence of the D816V c-kit mutation was observed, despite a significant decrease of mast cell marrow involvement. Conclusions. In a small cohort of ASM patient, the prolonged therapy with PKC412 is safe and effective, mainly on symptoms improvement and haematological profile. Nevertheless, the persistence of the D816V c-kit mutation, despite significant responses, suggests that many other oncogenic factors may be responsible for the pathogenesis of the disease. UDS approaches are needed in order to clarify this issue. Acknowledgments. Work supported by European LeukemiaNet, AIRC, AIL, PRIN 2010-2011, University of Bologna, FP7 NGS-PTL project.

Additional chromosome abnormalities (ACAs) occur in less than 10% of cases at diagnosis of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). In some cases, on the basis of the persistence of the ACAs in Ph-negative cells after response to imatinib, a secondary origin of the Ph chromosome has been demonstrated. In this study, the possible prognostic value of this phenomenon was evaluated. Thirty-six Ph-positive CML patients were included in the study. In six patients, ACAs persisted after the disappearance of the Ph. A complete cytogenetic response (CCR) was obtained in five of these six patients, and five of six also had a high Sokal score. In all the other cases, ACAs disappeared together (in cases of response to therapy with imatinib) or persisted with the Ph (in cases of no response to imatinib). In the former cases, the primary origin of the Ph was demonstrated. CCR was obtained in 22 cases (17 with low to intermediate Sokal scores), while no response was observed in 8 patients (5 with a high Sokal score). Sokal score seems to maintain its prognostic value for patients in whom the Ph occurs as a primary event, but not in those in whom it occurs as a secondary one.

Introduction. Acute myeloid leukemia (AML) is a heterogeneous disease with various chromosomal aberrations. The karyotype at diagnosis provides important prognostic information that influences therapy and outcome of this disease. However, using conventional chromosome banding techniques alone, karyotype abnormalities are detected in only half of all AML cases. Aims.We sought to identify novel genomic regions of interest in normal karyotype AML and to identify novel candidate regions and disease-related genes in patients with complex karyotypes using genome-wide high resolution SNP-array. Patients and Methods. Samples from 57 AML patients with FAB-M0, M1, M2, M3, M4, M5, miscellaneous cytogenetic abnormalities and normal karyotype were examined. Genomic DNA was isolated from mononuclear AML cells and applied to GeneChip® Human Mapping 250K NspI and Genome-Wide Human SNP 6.0 array microarrays (Affymetrix, Santa Clara, CA) following the manufacturer’s instructions. Copy number aberrations were scored using the Hidden Markov Model and the segmentation approach available within the Partek software package as well as by visual inspection. All aberrations were calculated with respect to a set of 270 Hapmap normal individuals and a set of samples obtained from acute leukaemia cases in remission in order to reduce the noise of raw copy number data. When available, in order to exclude inherited copy number variants a comparison to paired constitutional DNA and to paired remission DNA was performed. Fluorescence in situ hybridization, quantitative PCR and nucleotide sequencing were used to confirm genomic alterations. Results. A wide spectrum of different genetic lesions (gains/losses) involving complete chromosome arms (del 16q, i(13q10), del 3p, del 7p, monosomy 9) or submicroscopic genomic intervals were identified in a substantial proportion of cases (55%) without differences in the frequency of losses or gains. Focal genetic alterations were detected at the breakpoints of previously cytogenetically identified chromosomal translocations, such as t(2;3)(p22-23)(q26-27) and t(1;11)(p32;q23). Hemizygous deletions were identified at 2q33.3-q34 involving ERBB4 (verb-a erythroblastic leukemia viral oncogene homolog 4 avian), at 9p21.3- p21.2 (CDKN2A-2B), at 12p13 (ETV6), at 17q12 (NF1) and 21q21.2 (RUNX1). Most frequent alterations affected the oncogene MYC at 8q24.13 - q24.21 (4.33 Mb), the ABC transporters genes ABCA8, ABCA9, ABCA6, ABCA5, ABCA10 at 17q24, PTPRM at 18p11.31-p11.23 and ERG at 21q22. Other recurring genetic lesions were uncommon and were identified only in single cases. Some lesions affected regions with a single gene, such as: ETAA1, FIGN, STK32B, PRAGMIN, PCM1, GLIS3, MRGPRX1, SESN3, BCL2L14 or lacking annotated genes. Marked differences in the combination of copy number anomalies were identified across the different genetic subtypes of AML. Patients with normal karyotype showed no relevant genetic alterations. Conclusions. These data demonstrated that, in contrast to adult acute lymphoblastic leukaemia (ALL), AML is characterized by relatively few recurring copy number alterations, and that spectrum of genetic anomalies is significantly associated with AML disease subtype. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, PIO project 2007, Strategico di Ateneo.

The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1–positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (Δ4-7) and by removal of exons 2 through 7 (Δ2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the Δ4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the Δ2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronic-phase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAG-mediated recombination.

Aḥmad Bašīr al-‘Aylah is one of the most prolific and versatile authors of Contemporary Palestinian literary landscape. He is probably best known for his poetical collections, but he is also a journalist, a novelist, a script editor, a radio producer and a short story writer. In 2016 he published his first short story collection entitled Al-ḥabl allaḏī tadallà min al-samā’ (The rope hanging from the sky), that has never been translated into European languages. The stories included in this work are mainly set in Benghazi, which is the city where the author lives since he was a child, and they focus on the tragedy of war and its disasters, first of all the loss and destruction of houses and buildings. Through an in-depth critical analysis of the work – with a special attention to the methodological introduction and the first short story that gives its name to the whole collection (and here provided, for the first time, with an Italian translation) – the author of the present article examines the main features of Aḥmad Bašīr al-‘Aylah’s narrative experience with regard both to the themes he deals with and to his language and narrative style.

The translocation t(5;12)(q31;p13)/ETV6::ACSL6 is a rare cytogenetic abnormality, although it is reported in various myeloid malignancies. To date, only 16 cases of t(5;12) and ETV6::ACSL6 rearrangement, confirmed by either molecular or Fluorescence In Situ Hyridization (FISH) analysis, have been reported. Eosinophilia is a distinctive and common feature associated with this rearrangement. Although few cases have been described, the prognosis of patients with ETV6::ACSL6 is considered poor. We report two additional cases of t(5;12)(q31;p13)/ETV6::ACLS6 rearrangement and eosinophilia. Unusually, in our cases, the ETV6::ACSL6 rearrangement occurred at the relapse of Acute Myeloid Leukemia (AML) patients who had t(6;9)(p23;q34)/DEK::NUP214 rearrangement at disease onset. The concurrence of these two rare abnormalities has never been reported and may suggest a cooperative role of t(5;12) and t(6;9), leading to disease relapse. Moreover, at relapse, both cases presented with eosinophilia, further strengthening the association of t(5;12) with eosinophilia in myeloid malignancies. Given the poor prognosis and the non-responsiveness to tyrosine kinase inhibitors of cases of ETV6::ACSL6 rearrangement, in contrast to cases of ETV6::PDGFRB rearrangement, we recommend the introduction of testing for this abnormality in myeloid malignancies with eosinophilia.

Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a “warning” for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a “warning” category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.