An advanced system to support cognitive rehabilitation in multiple sclerosis

Recent studies demonstrate the benefits of cognitive rehabilitation (CR) showing that it reduces cognitive impairment in Multiple Sclerosis (MS) improving performance of patients in memory and attention. However, CR procedures are still in a germinal stage and have not been accepted worldwide as a standard therapy yet. In this scenario, the use of computerized training systems has several advantages with respect to pen-and-paper based exercises (such as flexibility and immediate feedback), but the use of information technology is currently limited to provide general purpose tools (i.e., not tailored for specific diseases) that support rehabilitation exercises for single patients only. On the contrary, CR for MS patients must be considered as a part of a comprehensive and complex care process that involves many aspects that must be deeply analyzed to build an effective therapy program. In this paper, we argue that a computerized system, able to integrate the various phases of cognitive rehabilitation processes, may have an essential role in improving CR procedures, optimizing them for routine clinical use in MS. To illustrate our claim, we present MS-rehab, an advanced system specific for MS, highlighting its main features and comparing it with other computerized tools for CR

Focal nodular hyperplasia and hepatic regenerating nodules in pediatric oncology patients: how much invasive approach is necessary?

Introduction. Hepatic regenerating nodules (HRN) and focal nodular hyperplasia (FNH) are benign regenerating lesions of the liver that rarely occur in children. An increased incidence of these lesions is reported in children treated for cancer.Material and methods. Eight children who developed FNH and HRN after treatment for malignancies in the Oncology unit at the “Bambino Gesu” Pediatric Hospital in Rome, were retrospectively analyzed.Results. The lesions, considered in the differential diagnosis with metastatic relapse of the primitive disease, have been monitored with US or other available imaging techniques. Evolution of the lesions was observed in only 1 patient three years after the initial diagnosis of FNH.Conclusion. In conclusion serial monitoring with imaging techniques is sufficient to rule out liver metastasis and to monitor the evolution of the lesions. Surgery is suggested only in the case of complications

Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization

Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome mostly encompassing Long Interspersed Nuclear Element1 (LINE-1) have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. LINE-1 activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy

Integrated ligand-receptor bioinformatic and in vitro functional analysis identifies active TGFA/EGFR signaling loop in papillary thyroid carcinomas.

BACKGROUND: Papillary thyroid carcinoma (PTCs), the most frequent thyroid cancer, is usually not life threatening, but may recur or progress to aggressive forms resistant to conventional therapies. A more detailed understanding of the signaling pathways activated in PTCs may help to identify novel therapeutic approaches against these tumors. The aim of this study is to identify signaling pathways activated in PTCs. METHODOLOGY/PRINCIPAL FINDINGS: We examined coordinated gene expression patterns of ligand/receptor (L/R) pairs using the L/R database DRLP-rev1 and five publicly available thyroid cancer datasets of gene expression on a total of 41 paired PTC/normal thyroid tissues. We identified 26 (up) and 13 (down) L/R pairs coordinately and differentially expressed. The relevance of these L/R pairs was confirmed by performing the same analysis on REarranged during Transfection (RET)/PTC1-infected thyrocytes with respect to normal thyrocytes. TGFA/EGFR emerged as one of the most tightly regulated L/R pair. Furthermore, PTC clinical samples analyzed by real-time RT-PCR expressed EGFR transcript levels similar to those of 5 normal thyroid tissues from patients with pathologies other than thyroid cancer, whereas significantly elevated levels of TGFA transcripts were only present in PTCs. Biochemical analysis of PTC cell lines demonstrated the presence of EGFR on the cell membrane and TGFA in conditioned media. Moreover, conditioned medium of the PTC cell line NIM-1 activated EGFR expressed on HeLa cells, culminating in both ERK and AKT phosphorylation. In NIM-1 cells harboring BRAF mutation, TGFA stimulated proliferation, contributing to PI3K/AKT activation independent of MEK/ERK signaling. CONCLUSIONS/SIGNIFICANCE: We compiled a reliable list of L/R pairs associated with PTC and validated the biological role of one of the emerged L/R pair, the TGFA/EGFR, in this cancer, in vitro. These data provide a better understanding of the factors involved in the biology of PTCs and would be useful in developing combination therapeutic approaches against these cancers

Gefitinib in combination with oral topotecan and cyclophosphamide in relapsed neuroblastoma: Pharmacological rationale and clinical response

Aim. Activity and toxiciy of gefitinib in combination with topotecan and cyclophosphamide (CPA) were evaluated in a case-series of relapsed neuroblastoma (NB) patients. The in vitro activity of the combination was also assessed. Procedure. Gefitinib (250 mg/ day), topotecan (0.8 mg/m2/day), and CPA (50 mg/m2/day) (GTC) were administered orally for 14 consecutive days out of 28 days. Antitumor activity of gefitinib as single agent and in combination with either topotecan or CPA was assessed in a panel of NB cell lines. Results. Ninety-two courses were given in 10 patients. Grade 4 neutropenia was observed in 7/92 courses (8%) and grade 4 thrombocytopenia in 8/92 (9%). Two patients had a grade 2 liver toxicity, four a grade 1/2 skin toxicity, and two a grade 1/2 diarrhea. Dose reduction of topotecan and/or CPA was required in eight patients. After four courses, three patients were in partial response (PR) and four with a stable disease (SD), while three experienced a progressive disease (PD). Time to progression (TTP) was 9 months (range, 1-27). After a median follow-up of 16 months (range 5-54), seven patients are died of disease (DOD) and three alive with disease (AWD). All but one patient discontinued oral chemotherapy because of a PD, whilst one patient stopped chemotherapy after 27 months with a SD. In vitro, gefitinib was synergistic with topotecan and additive with CPA. Conclusion. The GTC combination was well tolerated and the TTP was encouraging. These promising results, also supported by in vitro evidence, should be further confirmed in a phase II study. © 2009 Wiley-Liss, Inc

Tumor-infiltrating T cells and PD-L1 expression in childhood malignant extracranial germ-cell tumors

Although pediatric malignant extracranial germ-cell tumors (meGCTs) are among the most chemosensitive solid tumors, a group of patients relapse and die of disease. To identify new markers predicting clinical outcome, we examined the prognostic relevance of tumor-infiltrating T lymphocytes (TILs) and the expression of PD-1 and PD-L1 in a cohort of pediatric meGCTs by in situ immunohistochemistry. MeGCTs were variously infiltrated by T cell-subtypes according to the tumor subtype, tumor location and age at diagnosis. We distinguished three different phenotypes: i) tumors not infiltrated by T cells (immature teratomas and half of the yolk sac tumors), ii) tumors highly infiltrated by CD8+ T cells expressing PD-1, which identifies activated tumor-reactive T cells (seminomas and dysgerminomas), iii) tumors highly infiltrated by CD8+ T cells within an immunosuppressive tumor microenvironment characterized by CD4+FOXP3+ Treg cells and PD-L1-expressing tumor cells (embryonal carcinomas, choriocarcinomas and the remaining yolk sac tumors). Tumor subtypes belonging mixed meGCTs were variously infiltrated, suggesting the coexistence of multiple immune microenvironments either facilitating or precluding the entry of T cells. These findings support the hypothesis that TILs influence the development of meGCTs and might be of clinical relevance to improve risk stratification and the treatment of pediatric patients