Luigia Simeone

Clinical and phenotypic features of CD5-negative B cell chronic lymphoproliferative disease resembling chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) B cells are phenotypically identified by surface expression of CD5 and CD23 antigens. Infrequently, patients with a monoclonal B cell lymphocytosis clinically resembling classic B-CLL have been found to harbor leukemic B cells lacking expression of the CD5 antigen. Little information is available concerning such CLL-like lymphoproliferative syndromes. Here, we provide phenotypic and clinical characteristics of 13 patients with CD5-negative chronic lymphoproliferative disorders selected from among 400 B-CLL patients followed up at a single academic center. Phenotypic analysis was carried out by flow cytometry using a broad panel of monoclonal antibodies including activation, costimulatory, adhesion, and growth factor receptor molecules. Moreover, intracellular staining and stimulation experiments were performed to investigate whether CD5 antigen was either retained in the cytoplasm of clonal B cells or not expressed due to defective cellular activation, respectively. Overall, CD5-negative leukemic cells were found to express significantly different levels of several membrane molecules, including CD95, CD69, CD23, CD25, CD80, and CD20, compared to “classic” CLL B cells. CD5 antigen was not detected in the cytoplasm of CD5-negative clonal B cells, nor could it be induced following in vitro activation. CD3+ T cell proportions were found to be less affected in CD5-negative patients than in classic B-CLL. Although these data suggest that CD5-negative clonal B cells are phenotypically different from classic B-CLL, clinical outcomes were similar to those shown by B-CLL patients, with most of the patients experiencing a long-lasting disease requiring chemotherapeutic intervention at some time during the disease course.

Role of ZNF224 in cell growth and chemoresistance of chronic lymphocitic leukemia

Chronic lymphocytic leukaemia (CLL) is associated with apoptosis resistance and defective control of cell growth. Our study describes for the first time a critical role in CLL for the KRAB-zinc finger protein ZNF224. High ZNF224 transcript levels were detected in CLL patients with respect to control cells. Moreover, ZNF224 expression was significantly lowered after conventional chemotherapy treatment in a subset of CLL patients. By in vitro experiments we confirmed that ZNF224 expression is suppressed by fludarabine and demonstrated that ZNF224 is involved in apoptosis resistance in CLL cells. Moreover, we showed that ZNF224 positively modulates cyclin D3 gene expression. Consistently, we observed that alteration of ZNF224 expression leads to defects in cell cycle control. All together, our results strongly suggest that in CLL cells high expression level of ZNF224 can lead to inappropriate cell growth and apoptosis resistance, thus contributing to CLL progression. Targeting ZNF224 could thus improve CLL response to therapy.

Impact on survival of early detection of recurrence in the follow‐up of high risk H odgkin lymphoma in first complete remission

mance status (ECOG > 1) (P = .01), stage IV disease (P = .01), and IPS (Hasenclever) score > 2 (P = .002). Furthermore, levels were lower in patients with hemoglobin below 10,5 g/dl (P = .06). No association was found with gender, albumin level, B symptoms. In addition, there was a significant seasonal variation, with 25(OH)D levels to be lowest in the first quarter and highest in the third quarter (P = .03). FDG‐PET evaluation after 2 cycles of chemotherapy according to the 5‐point Deauville scale was available in 66 patients. Vitamin D levels were not associated with interim PET response.With a median of 12 months follow‐up of patients is still short. Patients with deficient levels (n = 9) had a significantly worse PFS than patients with higher levels (n = 67) (P = .002). The probability of progression‐free survival at 12 months was 87% (95% CI, 75%‐94%) in patients with 25(OH)D levels >10 ng/ml, while patients with levels <10 ng/ml had a 12 months PFS of 47% (95% CI, 12%‐76%). We included 25(OH)D levels, IPS (that includes age, stage and hemoglobin level), ECOG, and season in a multivariate Cox analysis. Deficient 25(OH)D level had a borderline significance (HR, 5.65; 95% CI,0.98‐32.55; P = .05). Conclusions: 25(OH)Vitamin D serum levels are frequently low in patients with Hodgkin lymphoma and are associated with patient‐ related and disease‐related characteristics. Our preliminary analysis suggests that low 25(OH)D levels might be associated with worse prognosis.

Ultrasonography-driven combination antibiotic therapy with tigecycline significantly increases survival among patients with neutropenic enterocolitis following cytarabine-containing chemotherapy for the remission induction of acute myeloid leukemia

Neutropenic enterocolitis (NEC) is an abdominal infection reported primarily in patients with acute myeloid leukemia (AML) following chemotherapy, especially cytarabine, a notable efficacious cytotoxic agent for AML remission. Specific data regarding the impact of different cytarabine schedules and/or antibacterial regimens for NEC are sparse. The aim of the study was to identify the predictors of outcome within 30 days of NEC onset. NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our Institution, over a 10‐year period, for receiving chemotherapy protocols with 100–6000 mg/m2 daily of cytarabine. Two subgroups, survivors versus nonsurvivors, were compared by using logistic regression analysis. NEC was documented in 100 of 420 (23.8%) analyzed patients: 42.5% had received high‐dose cytarabine, whereas 19% and 15% intermediate‐dose and standard‐dose cytarabine, respectively (P < 0.001). The 30‐day NEC attributable mortality rate was 23%. In univariate analysis, antileukemic protocols containing robust dosages of cytarabine were significantly associated with high mortality (P < 0.001); whereas, standard‐dose cytarabine and prompt initiation (at the ultrasonographic appearance of intestinal mural thickening) of NEC therapy with antibiotic combinations including tigecycline were significantly associated with low mortality. In multivariate analysis, high‐dose cytarabine‐containing chemotherapy was the independent predictor of poor outcome (odds ratio [OR]: 0.109; 95% confidence interval [CI]: 0.032–0.364; P < 0.001), whereas ultrasonography‐driven NEC therapy with antibiotic regimens including tigecycline was associated with a favorable outcome (OR: 13.161; 95% CI: 1.587–109.17; P = 0.017). Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable. Vigorous antibacterial therapy, triggered off pathologic ultrasonographic findings, with drug combinations which have broad antimicrobial coverage and good gut penetration, specifically those also including tigecycline, may be effective in improving 30‐day survival rate after NEC onset.