Cutaneous T-cell lymphomas (including rare subtypes) : current concepts. II

Background. Cutaneous T-cell lymphomas (CTCL) represent about the 80% of skin lymphomas and comprise a heterogeneous group of diseases with respect to clinical presentation, outcome, histologic and immunophenotypic features. In the recent years, data have been accumulated indicating that clinical and biological differences exists between primary nodal and primary extranodal lymphomas. Information Sources. On such bases, the cutaneous lymphoma classification by the EORTC (European Organization for Cancer Research and Treatment) but also the recent general lymphoma classification, by the WHO (World Health Organization), have dedicated special attentions to the cutaneous lymphomas including the T and NK-cell subtypes. This paper reviews the most significative subtypes of T-cell lymphoma that affect the skin primarily or secondarily. State of the Art. Apart from mycosis fungoides with its variants forms and the Sezary's syndrome, we have focused on the CD30(+) primary cutaneous lymphoproliferative disorders (PCLD) (25% of all CTCL), a fascinating spectrum of disease, extending from lymphomatoid papulosis (LyP) trough to CD30(+) large cell lymphoma. These disorders have in common large atypical CD30(+) cells and a frequent spontaneous regression of the skin lesions associated with a relatively favourable outcome (excellent in LyP). The identification of this group of skin disorders is crucial for the patients since most of CD30(+) PCLD are indolent diseases that do not warrant aggressive treatment. Others types of CTCL include the heterogeneous category of peripheral T-cell lymphoma not otherwise specified (NOS), subcutaneous panniculitis-like T-cell lymphoma and the still controversial group of the cytotoxic lymphomas. Perspectives. Notably, the latter two subtypes have special relevance to the clinicians because (i) subcutaneous panniculitis-like T-cell lymphoma may be associated with the hemophagocytic syndrome; (ii) skin lesions in cytotoxic lymphomas may represent the first mainifestation of an otherwise systemic disease

A practical algorithmic approach to mature aggressive B cell lymphoma diagnosis in the double/triple hit era. Selecting cases, matching clinical benefit. A position paper from the Italian Group of Haematopathology (G.I.E.)

An accurate diagnosis of clinically distinct subgroups of aggressive mature B cell lymphomas is crucial for the choice of proper treatment. Presently, precise recognition of these disorders relies on the combination of morphological, immunophenotypical, and cytogenetic/molecular features. The diagnostic workup in such situations implies the application of costly and time-consuming analyses, which are not always required, since an intensified treatment option is reasonably reserved to fit patients. The Italian Group of Haematopathology proposes herein a practical algorithm for the diagnosis of aggressive mature B cell lymphomas based on a stepwise approach, aimed to select cases deserving molecular analysis, in order to optimize time and resources still assuring the optimal management for any patient

Whole-genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent genetic defects (eg, single nucleotide changes, indels, large chromosomal aberrations) have been identified in BPDCN, none are disease-specific, and more importantly, none explain its genesis or clinical behavior. In this study, we performed the first high resolution whole-genome analysis of BPDCN with a special focus on structural genomic alterations by using whole-genome sequencing and RNA sequencing. Our study, the first to characterize the landscape of genomic rearrangements and copy number alterations of BPDCN at nucleotide-level resolution, revealed that IKZF1, a gene encoding a transcription factor required for the differentiation of plasmacytoid dendritic cell precursors, is focally inactivated through recurrent structural alterations in this neoplasm. In concordance with the genomic data, transcriptome analysis revealed that conserved IKZF1 target genes display a loss-of-IKZF1 expression pattern. Furthermore, up-regulation of cellular processes responsible for cell-cell and cell-ECM interactions, which is a hallmark of IKZF1 deficiency, was prominent in BPDCN. Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients

Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective B therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo

What factors influence training opportunities for older workers? Three factorial surveys exploring the attitudes of HR professionals

The core research questions addressed in this paper are: what factors influence HR professionals in deciding whether to approve training proposals for older workers? What kind of training are they more likely to recommend for older employees and in which organizational contexts? We administered three factorial surveys to 66 HR professionals in Italy. Participants made specific training decisions based on profiles of hypothetical older workers. Multilevel analyses indicated that access to training decreases strongly with age, while highly-skilled older employees with low absenteeism rates are more likely to enjoy training opportunities. In addition, older workers displaying positive performance are more likely to receive training than older workers who perform poorly, suggesting that training late in working life may serve as a reward for good performance rather than as a means of enhancing productivity. The older the HR professional evaluating training proposals, the higher the probability that older workers will be recommended for training. keywords: training; older workers; HR professionals; factorial survey; multilevel model

Splenic marginal zone lymphoma: a prognostic model for clinical use.

The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P < .001), albumin levels below 3.5 g/dL (P = .001), International Prognostic Index (IPI) scores of 2 to 3 (P < .001), lactate dehydrogenase (LDH) levels above normal (P < .001), age older than 60 years (P = .01), platelet counts below 100 000/μL (P = .04), HbsAg-positivity (P = .01), and no splenectomy at diagnosis (P = .006). Values that maintained a negative influence on CSS in multivariate analysis were hemoglobin level less than 12 g/dL, LDH level greater than normal, and albumin level less than 3.5 g/dL. Using these 3 variables, we grouped patients into 3 prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor, and high-risk group (25%) with 2 or 3 adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group, and 50% for the high-risk group. The cause-specific mortality rate (x 1000 person-years) was 20 for the low-risk group, 47 for the intermediate-risk group, and 174 for the high-risk group. This latter group accounted for 54% of all lymphoma-related deaths. In conclusion, with the use of readily available factors, this prognostic index may be an effective tool for evaluating the need for treatment and the intensity of therapy in an individual patient. © 2006 by The American Society of Hematology

Time of symptom onset and histologic findings in bladder pain syndrome/interstitial cystitis: new findings on useful correlations

The aim was to find out whether a correlation exists between denudation of urothelium and time of symptom onset in patients with bladder pain syndrome/interstitial cystitis (BPS/IC), and to search a correlation between impact of symptoms evaluated with ICSI-ICPI and the presence of comorbid conditions associated with BPS/IC. Ninety-seven consecutive patients underwent cystoscopy under general anesthesia to classify those cases suspected of being affected from BPS/IC. Three cold bladder biopsies were taken including detrusor muscle. Statistical analysis showed significant correlation between IC/BPS duration and the presence of Hunner's lesions (P<0.023). Hunner's lesion with cystoscopy and histological evidence of urothelial denudation with bladder biopsy appear to be items related to IC/BPS duration. Thus an early diagnosis allows to start an appropriate therapeutic approach and prevent a more severe evolution of this multifaceted painful syndrome. Our study shows a correlation between time of symptom onset and evidence of urothelial denudation and with detrusor mast cell count in the whole group of patients. IC/BPS duration seem to correlate with the presence of associated diseases