Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia

BACKGROUND: Rituximab in sequential combination with fludarabine (Flu) allowed patients with B-cell chronic lymphocytic leukemia (B-CLL) to achieve higher remission rates and longer response duration. Based on their recent experience in indolent non-Hodgkin lymphomas, in this study, the authors attempted to demonstrate whether consolidation/maintenance therapy with rituximab could prolong the response duration in this patient population. METHODS: This Phase II study was based on a consolidation/maintenance therapy with rituximab for patients in complete remission (CR) or partial remission (PR) who were positive for minimal residual disease (MRD), as determined by flow cytometry. Seventy-five symptomatic, untreated patients with B-CLL received 6 monthly cycles of Flu (25 mg/m(2) for 5 days) followed by 4 weekly doses of rituximab (375 mg/m(2)). Then, 28 patients who were positive for MRD were consolidated with 4 monthly cycles of rituximab (375 mg/m(2)) followed by 12 monthly low doses of rituximab (150 mg/m(2)). RESULTS: Based on National Cancer Institute criteria, 61 of 75 patients (81%) achieved a CR, 10 of 75 patients (13%) had a PR, and 4 of 75 patients (5%) had either no response or disease progression. MRD-positive patients in CR or PR who received consolidation therapy (n = 28 patients) had a significantly longer response duration (87% vs 32% at 5 years; P = .001) compared with a subset of patients who did not receive consolidation therapy (n = 18 patients). All patients experienced a long progression-free survival from the end of induction treatment (73% at 5 years). It was noteworthy that, within the subset of ZAP-70-positive patients, MRD-positive, consolidated patients (n = 12 patients) had a significantly longer response duration (69% vs 0% at 2.6 years; P = .007) compared with MRD-positive, unconsolidated patients (n = 11 patients). CONCLUSIONS: The addition of a consolidation and maintenance therapy with rituximab prolonged response duration significantly in patients with MRD-positive B-CLL.     

Neuroactive steroids and peripheral myelin proteins

The present review summarizes observations obtained in our laboratories which underline the importance of neuroactive steroids (i.e., progesterone (PROG), dihydroprogesterone (5α-DH PROG), tetrahydroprogesterone (3α, 5α-TH PROG), testosterone (T), dihydrotestosterone (DHT) and 5α-androstan-3α,17β-diol (3α-diol)) in the control of the gene expression of myelin proteins (i.e. glycoprotein Po (Po) and the peripheral myelin protein 22 (PMP22)) in the peripheral nervous system. Utilizing different in vivo (aged and adult male rats) and in vitro (Schwann cell cultures) experimental models, we have observed that neuroactive steroids are able to stimulate the mRNA levels of Po and PMP22. The effects of these neuroactive steroids, which are able to interact with classical (progesterone receptor, PR, and androgen receptor, AR) and non-classical (GABA_A receptor) steroid receptors is further supported by our demonstration in sciatic nerve and/or Schwann cells of the presence of these receptors. On the basis of the observations obtained in the Schwann cells cultures, we suggest that the stimulatory effect of neuroactive steroids on Po is acting through PR, while that on PMP22 needs the GABA_A receptor. The present findings might be of importance for the utilization of specific receptor ligands as new therapeutical approaches for the rebuilding of the peripheral myelin, particularly in those situations in which the synthesis of Po and PMP22 is altered (i.e. demyelinating diseases like Charcot–Marie–Tooth type 1A and type 1B, hereditary neuropathy with liability to pressure palsies and the Déjérine–Sottas syndrome, aging, and after peripheral injury).     

Atopy in childhood idiopathic nephrotic syndrome

AIM: Aim of the study was to evaluate the immunoallergic pattern and their modulating serum cytokines in children with primary manifestation of nephrotic syndrome, in order to analyse the correlation with disease activity and the outcome of childhood NS. MATERIALS AND METHODS: We have evaluated 72 children: 58 steroid-sensitive and 14 steroid-resistant; 42 subjects were the healthy controls. In all were measured serum: T cell-subset, cytokines by Th-1, Th-2, total IgE levels and specific IgE antibodies. RESULTS: Of the 72 children investigated, 35 (48.6%) had either a history of atopy and/or elevated serum IgE; 14 of these children (40%) had clinical sign of an atopic disease (asthma, rhinitis, dermatitis) and 21 (60%) had elevated sIgE. The atopy was more frequent among SS than SRNS patients (52% versus 36%, p<0.05). The CD19 were significantly increased in nephrotic patients compared with controls. IL-4 levels were not different from those in normal control both in SS and SRNS patients, either in relapse than in remission. There was no correlation between the sIgE and IL-4 levels. Therefore, IL-5 and Il-13 levels were significantly higher in SSNS compared to controls, in both pre than posttreatment, and higher in atopic patients. Interestingly, IL-6 and IL-10 levels were significantly increased in SRNS pretreatment compared to posttreatment and controls and, only for IL-10, significantly higher in atopic patients. CONCLUSION: In our study, only 40% of atopic children had a positive allergic history and 51.4% of the nephrotic children had normal sIgE levels, both pre and posttreatment, indicating different aetiologies, as immune mechanisms, in the pathogenesis of NS. Therefore, specific IgE antibodies were not related to disease activity, suggesting that IgE production might be co-incident in childhood NS. However, the increased production of IL-5 and IL-13 in atopic SSNS may indicate that these cytokines are involved in the enhanced production of sIgE while IL-4 have a role as controlling cytokine.     

Keratinocyte growth factor receptors

Modulation of the number of functional growth factor receptors on the epithelial cell surface that is exposed to the action of cognate ligands represents a key strategy in cellular physiology to regulate the proliferation rate and the differentiation process. The keratinocyte growth factor receptor (KGFR) and the epidermal growth factor receptor (EGFR), among the growth factor receptors expressed on keratinocytes, are believed to play a unique crucial role in controlling epithelial proliferation. KGFR and EGFR appear to also contribute to the cell differentiation process. Modulation of KGFR and EGFR on the proliferation rate and differentiation process has been reported either in in vivo or in vitro conditions. This article reviews the architecture, the ligand binding activated-signaling pathways, and the biologic effects of KGFR and EGFR on keratinocytes.     

Helicobacter pylori as cause of gastrointestinal disease in children with hemato-oncologic diseases

After documentation of a case of life threatening Helicobacter pylori (H. pylori) gastric ulcer in an adolescent girl on treatment for acute lymphoblastic leukaemia, we started to systematically look for gastro-intestinal symptoms due to H. pylori infection in our cancer patients at G. Gaslini Children's Hospital. During a period of 46 months, we observed 13 further cases of severe dyspepsia syndrome or gastro intestinal bleeding associated with presence of H. pylori faecal antigen. All patients recovered with appropriate therapy. H. pylori may represent a cause of severe gastrointestinal complications in children with cancer or following bone marrow transplant.     

Treatment-related transient splenial lesion of the Corpus Callosum in patients with neuropsychiatric disorders: a literature overview with a case report

ABSTRACT

Introduction: Transient-localized lesions of the splenium of the corpus callosum (SCC) have been described in various clinical conditions, some of them being attributed to the withdrawal of psychotropic drugs. The pathophysiology of the lesion reflects cytotoxic edema and reversible demyelination.

Areas covered: The present article aimed at reviewing cases of transient SCC lesion exclusively related to changes in pharmacotherapy. It also reports the original case of a patient receiving a complex psychopharmacological therapy who developed a transient SCC lesion investigated by magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and pharmacogenetic profiling.

Expert opinion: To date, only one review on the subject has been published, analyzing 22 cases of transient SCC lesion arising in epileptic patients on antiepileptic therapy. It hypothesized that the nature of the lesion is a cytotoxic edema and the cases described in the subsequent 14 years seem to support this hypothesis. The authors reported the case of an Italian-Egyptian patient who developed a transient SCC lesion after the rapid withdrawal of Carbamazepine and Lurasidone. The lesion completely disappeared from the MRI performed after 1 month. Patient’s ethnic group and its pharmacogenetic profile were considered as possible causes of altered drug metabolism and, likely, of the SCC lesion.     

Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism

In about 50% of sporadic cases of retinoblastoma, no constitutive RB1 mutations are detected by conventional methods. However, recent research suggests that, at least in some of these cases, there is somatic mosaicism with respect to RB1 normal and mutant alleles. The increased availability of next generation sequencing improves our ability to detect the exact percentage of patients with mosaicism. Using this technology, we re-tested a series of 40 patients with sporadic retinoblastoma: 10 of them had been previously classified as constitutional heterozygotes, whereas in 30 no RB1 mutations had been found in lymphocytes. In 3 of these 30 patients, we have now identified low-level mosaic variants, varying in frequency between 8 and 24%. In 7 out of the 10 cases previously classified as heterozygous from testing blood cells, we were able to test additional tissues (ocular tissues, urine and/or oral mucosa): in three of them, next generation sequencing has revealed mosaicism. Present results thus confirm that a significant fraction (6/40; 15%) of sporadic retinoblastoma cases are due to postzygotic events and that deep sequencing is an efficient method to unambiguously distinguish mosaics. Re-testing of retinoblastoma patients through next generation sequencing can thus provide new information that may have important implications with respect to genetic counseling and family care.