Diagnostic utility of Sudoscan for detecting bortezomib-induced painful neuropathy: a study on 18 patients with multiple myeloma.

Introduction: In the past few years, treatment of multiple myeloma has undergone a deep change for the employment of novel treatment comprising proteasome inhibitors. Bortezomib is a first-line drug in therapy of multiple myeloma. The onset of peripheral neuropathy is a dose-limiting collateral effect of the drug. This neuropathy is a distal symmetric neuropathy that affects both large and small fibers. Nerve conduction study (NCS) can be used for the diagnosis of bortezomib neuropathy, but this technique demonstrates alterations of the large nerve fibers. Sudoscan is a novel technique utilized to offer an evaluation of sudomotor function. The main objective of this study was to compare the sensitivity and diagnostic specificity of Sudoscan with respect to the nerve conduction study after bortezomib treatment. Material and methods: A total of 18 multiple myeloma patients were studied, 10 (55.5%) men and 8 (44.5%) women. Patients were analyzed at baseline and after 6 months of treatment with bortezomib. Subjects were submitted to nerve conduction study and electrochemical skin conductance evaluation with the Sudoscan device. Patients were also submitted to a clinical measure of pain and neuropathy. Results: At baseline NCS showed that only the mean sural SAP amplitude was below the 2SD lower limit of normal in 3 (16.7%) patients, while at same time we found an alteration of Sudoscan profiles in 2 (11.1%) patients. After 6 months of treatment, the NCS profiles were altered in 13 (72.2%) patients, and the Sudoscan profiles were modified in 11 (61.1%) subjects. Conclusions: Our results suggest that Sudoscan can be considered for the diagnosis of bortezomib-induced neuropathy. It is objective, reproducible, and surely easier than the traditional nerve conduction study. Sudoscan may be a useful help to manage the therapeutic interventions in multiple myeloma.

Anticancer Activity of Curcumin and Its Analogues: Preclinical and Clinical Studies.

Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways. Curcumin is a promising molecule for the prevention and treatment of cancer.

Possible Role of Interleukin-31/33 Axis in Imatinib Mesylate-Associated Skin Toxicity.

Imatinib mesylate is a small-molecule tyrosine kinase inhibitor (TKi) designed to target c-ABL and BCR-ABL, approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Adverse cutaneous reactions induced by imatinib are frequent, generally moderate, and dose-dependent. The aim of this work was to investigate the possible contribution of interleukin (IL)-33 and IL-31, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in a patient undergoing imatinib mesylate treatment. His IL-31 and IL-33 serum levels were significantly higher than in the control group (respectively 96.6 pg/mL vs. 7.623±7.681 pg/mL and 27.566 pg/mL vs. 6.170±7.060 pg/mL). In light of these findings, imatinib mesylate-related symptoms of dermatologic toxicities might be related to the release of IL-31 and IL-33. In particular, it is supposable that TKi usage could cause keratinocyte injury, the release of IL-33, and the consequent interaction with its receptor on mast cells that induces the secretion of several factors capable of causing skin manifestations, including IL-31, a known pruritus-inducing cytokine. This report, to the best of our knowledge, is the first work describing the possible involvement of the IL-31/IL-33 axis in the pathogenesis of skin side effects related to imatinib mesylate treatment.

Effect of therapeutic plasma exchange on plasma levels of oxidative biomarkers in a patient with thrombotic thrombocytopenic purpura.

BACKGROUND: The role of oxidative stress in the initiation and progression of endothelial damage in thrombotic thrombocytopenic purpura (TTP) syndrome has been the subject of much speculation in the recent past. OBJECTIVES: The aim of this study was to measure the concentration of plasma advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and carbonyl groups (CG) as markers of oxidative stress in plasma of a patient with TTP during the course of the disease until recovery and to evaluate the effect of plasmapheresis (PE) on these biomarkers. MATERIALS AND METHODS: The study consisted of plasma analysis of the patient, and 23 healthy subjects served as controls. In the patient with TTP, AOPP, AGE, and CG analysis was performed before and after each PE at the days +1 (Tα), +2, +4, +6, +10, +9, and +17 after the last plasmapheresis (Tω). RESULTS: Plasma concentrations of AOPPs were increased in the acute phase of TTP, and at Tα, the patient had AOPPs levels higher than 99°‰ of controls. AOPPs decreased in the recovery phase, and at Tω, their values were between 84° and 85°‰ of controls. No significant difference was found in AOPP levels before and after each PE. No significant differences for AGEs or CG concentrations were found at Tα with respect to the control group, while only a trend was observed for reduction of plasma AGEs after each plasmapheresis. CONCLUSION: Our data seem to confirm the hypothesis that oxidative stress is a critical component of the pathogenesis of TTP.

The cancer stem cell hypothesis: a guide to potential molecular targets.

Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.

MiRNome expression is deregulated in the peripheral lymphoid compartment of multiple myeloma.

MicroRNAs (miRNAs) are short non-coding RNAs involved in the regulation of gene expression. Selected groups of miRNAs are differentially expressed in various types of cancers. Alterations in miRNAs gene expression have been shown in cells from the B-cell malignancy, multiple myeloma (MM). However, although MM is a disease of plasma cells, abnormalities have been detected in the peripheral blood of the patients. The goal of our study was to analyse the entire miRNome in peripheral lymphocytes of MM patients using reverse transcription quantitative polymerase chain reaction. Using in silica analysis, we also evaluated some of the most interesting and significant pathways. Analysis revealed that MM samples had a distinct miRNA profile compared to the controls. This resulted in the identification of 203 miRNAs, 85 of which were over-expressed and 118 under-expressed. Of these, 184 possessed validated or highly predicted mRNA targets. We identified 12 354 mRNA targets of the transcriptome: 36·4% of the related proteins are involved in death processes while the 21% are required for growth and cell proliferation. We have demonstrated that miRNAs are differentially expressed in the peripheral blood of MM patients compared to controls, affecting some pathways involved in the anti-apoptotic process, cell proliferation and maybe anti-angiogenesis.

New orally active proteasome inhibitors in multiple myeloma.

Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Although Bortezomib has renovated the treatment of MM, a considerable proportion of subjects fail to respond to Bortezomib treatment and almost all patients relapse from this drug either alone or when used in combination therapies. However, the good clinical outcome of Bortezomib treatment in MM patients gave impulsion for the development of second generation proteasome inhibitors with the ambition of improving efficacy of proteasome inhibition, enhancing antitumor activity, and decreasing toxicity, as well as providing flexible dosing schedules and patient convenience. This review provides an overview of the role of oral proteasome inhibitors including Marizomib, Oprozomib, Delanzomib, chemical proteasome inhibitors, and cinnabaramides, in the therapy of MM, focusing on developments over the past five years. These emerging drugs with different mechanisms of action have exhibited promising antitumor activity in patients with relapsed/refractory MM, and they are creating chances to target multiple pathways, overcome resistance, and improve clinical outcomes, mainly for those subjects who are refractory to approved agents. Future steps in the clinical development of oral inhibitors include the optimization of the schedule and the definition of their antitumor activity in MM.

Association of osteonecrosis of the jaws and POEMS syndrome in a patient assuming rituximab.

POEMS syndrome, is a rare condition characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinaemia, and skin lesions. We report a rare case of a patient affected by Waldenström macroglobulinemia, who developed POEMS syndrome and who presented at the time of diagnosis with oral manifestations of the lymphoma and an osteonecrosis of the jaw (ONJ) after rituximab treatment. Although the etiology of ONJ is not known, it is likely that several factors are at play, including endothelial cell damage, decreased angiogenesis, and microvascular compromise. Our patient was treated with rituximab for a long period, and recent studies have demonstrated the possibility that rituximab, a monoclonal antibody directed against the CD20 can exert part of its anti-tumor action, through its action on angiogenesis. Although our report does not allow identification of rituximab as a new risk factor for the onset of the ONJ, further studies seem necessary to exclude a role of the antibody in the alterations of angiogenesis that could lead to the development of the syndrome after rituximab treatment.

Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma.

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma (MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies (MoAbs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that MoAbs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, MoAbs have shown the ability to overcome resistance to these therapies. It remains to be defined how MoAb therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short-term induction therapy, frontline therapy in patients ineligible for ASCT, or long-term maintenance treatment.

Evaluation of interleukin-23 plasma levels in patients with polycythemia vera and essential thrombocythemia.

Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis share the same acquired genetic lesion, JAK2V617F. It is believed that cytokines participate in the activation of JAK2V617F. In this study, we analyzed the plasma levels of interleukin (IL)-23, IL-10 and IL-22 in patients with PV and ET. In the same subjects we also performed analysis of the JAK2(V617F) mutation, and evaluated a possible relationship between interleukin levels and thrombotic complications or with the symptom pruritus. Plasma levels of IL-23 were significantly increased in all patients with MPN in comparison to controls. Moreover, there was a significant difference between the levels of IL-23 in patients affected by PV and those measured in controls (8.57±3.69pg/mL vs. 6.55±4.125pg/mL; p<0.03). No difference was found between IL-23 levels in ET patients and controls. No statistically significant differences were found between the levels of IL-23, Il-22 or IL-10 in PV or ET subjects with or without thrombosis, in patients with or without pruritus, or according the JAK2V617F burden. In PV patients the JAK2 burden and Hb levels correlated with occurrence of pruritus. Our study seems to point out a possible involvement of IL-23 in the pathogenesis of PV.

Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review).

MicroRNAs (miRNAs) are small non-coding, endogenous, single-stranded RNAs. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and cancer. However, while the majority of miRNAs are found intracellularly, a significant number of miRNAs have been observed outside of cells, including various body fluids. Circulating miRNAs function as 'extracellular communication RNAs' that play an important role in cell proliferation and differentiation. MiRNA regulation is essential to many cellular processes, and escape from this regulatory network seems to be a common characteristic of several disease processes and malignant transformation. The interest in circulating miRNAs reflects in fact their central role in regulation of gene expression and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, metabolic, neurologic, immune-related diseases as well as others. In our review we aimed to summarize the data related to the action of cellular miRNAs on the onset of various diseases, thus bringing together some of the latest information available on the role of circulating miRNAs. Additionally, the role of circulating miRNAs could be particularly relevant in the context of neoplastic diseases. At least 79 miRNAs have been reported as plasma or serum miRNA biomarkers of solid and hematologic tumors. Circulating miRNA profiling could improve the diagnosis of cancer, and could predict outcome for cancer patients, while the profiling of alterations in circulating miRNA that may signal a predisposition to cancer, could also be a therapeutic target in these patients.

Changes in advanced oxidation protein products, advanced glycation end products, and s-nitrosylated proteins, in patients affected by polycythemia vera and essential thrombocythemia.

OBJECTIVES: Oxidative stress has a clear pro tumoral effect in myeloproliferative neoplasms (MPDs). In this study, we analyzed oxidative stress in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Design and methods We analyzed serum levels of advanced oxidation protein products (AOPPs) degradation, advanced glycation end products (AGEs), and protein nitrosylation in ET and PV patients. We also evaluated neutrophil gelatinase-associated lipocalin (NGAL) levels, an acute phase protein isolated in human neutrophils, the activation status of platelets and leukocytes, and the JAK2 (V617F) mutation status. RESULTS: AOPPs and s-nitrosylated proteins were significantly higher in PV and ET subjects as compared to healthy volunteers, while AGEs were higher in ET subjects with respect to controls. Moreover, in PV patients we found a correlation between s-nitrosylated proteins and Hb value. In ET patients AGEs were significantly higher in patients with thrombosis compared with those without thrombotic events. CONCLUSIONS: Our results suggest that oxidative stress could play a role in the physiopathology of MPDs and in the onset of myeloproliferative associated thrombotic risk.

Increase of novel biomarkers for oxidative stress in patients with plasma cell disorders and in multiple myeloma patients with bone lesions.

OBJECTIVES: Protein oxidation plays a key role in the pathogenesis of oncological diseases. In this study, we analyzed the oxidative stress in untreated multiple myeloma (MM) patients and in patients affected by monoclonal gammopathy of uncertain significance (MGUS). METHODS: We evaluated serum levels of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and protein nitrosylation in patients with monoclonal gammopathy and in control subjects. RESULTS: Serum levels of AOPPs and S-nitrosylated proteins were significantly increased in MM patients in comparison to controls and to MGUS subjects. Moreover, in MM patients the levels of AOPPs, AGEs and S-nitrosylated proteins were significantly higher in patients with bone lesions compared with those without lytic bone lesions. CONCLUSIONS: MM is closely associated with oxidative stress and further investigation might provide an insight to understand a putative causal link between oxidative stress and MM disease onset and progression or MM complications.

Relationship between advanced oxidation protein products, advanced glycation end products, and S-nitrosylated proteins with biological risk and MDR-1 polymorphisms in patients affected by B-chronic lymphocytic leukemia.

The aim of our study was to analyze the serum levels of advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEs), and protein nitrosylation in patients with B-chronic lymphocytic leukemia (B-CLL). AOPPs, AGEs, and S-nitrosylated were increased in B-CLL patients. The mutation of IgVH gene, CD 38, and Zap 70 expression were not associated with increased oxidative stress. The mutant 2677GT genotype was found to be associated with higher AGEs levels with respect to wild-type genotype, while as far the C3435T MDR1 polymorphism is concerned, subjects presenting wild-type genotype showed higher values of AOPPs with respect to heterozygous genotype. Our results suggest that B-CLL is associated with oxidative stress.

Imatinib mesylate therapy induces reduction in neutrophil gelatinase-associated lipocalin serum levels and increase in leptin concentrations in chronic myeloid leukemia patients in molecular remission.

The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.