Reviews on Recent Clinical Trials | Year: 2016
The introduction of novel drugs in multiple myeloma therapy has changed disease survivals in last 15 years. Besides to be more effective in this disease new agents have been utilized in novel strategies such as consolidation and maintenance therapy. Lenalidomide has been one of the favourite in clinical trials because of its oral administration, and bortezomib has been utilized too after the drug has been proved to be effective subcutaneously. Advances in the understanding of disease biology and genetics could give a risk stratification to identify those patients who can benefit more and to better drive maintenance therapy in the future. © 2016 Bentham Science Publishers.
Zhang K.,Surgery |
Hao F.,Pathology |
Wang M.,Qingdao University |
Wang M.,Sun Yat Sen University |
And 3 more authors.
Cellular Physiology and Biochemistry | Year: 2014
Background/Aims: Several studies have shown secreted clusterin (sCLU) silencing directed against sCLU mRNA in sCLU-rich lung cancer cell lines sensitized cells to chemotherapy. However, the molecular mechanisms underlying the effect of sCLU silencing on lung cancer cell chemosensitivity is not known. In the present study, we aimed to determine that vector expressing short hairpin RNA against sCLU RNA (sCLU-shRNA) enhances the chemosensitivity in human small cell lung cancer A549 cells in vitro by inhibition of phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt). Methods: The pCDNA3.1-sCLU and control scrambled pCDNA3.1 plasmid was constructed. We investigated the effects of sCLU overexpression by pCDNA3.1-sCLU transfection on chemosensitivity to cisplatin (DDP) in A549 cells in vitro. We down-regulated sCLU expression by short hairpin RNA against sCLU RNA (sCLU-shRNA) and investigated the effects on chemosensitivity to DDP in A549 cells and A549DDPin vitro. In order to confirm the correlation between sCLU and AKT and ERK1/2 signals, cells were treated with wortmannin and U0126. Results: We found the chemotherapeutic agent DDP activated sCLU. Overexpression of sCLU increased cellular DDP chemoresistance in the A549DDP and pCDNA3. 1-sCLU transfected A549 cells via inhibition DDP-induced apoptosis. Whereas sCLU knockdown induced chemosensitization in the S549 and A549DDP cells via increase of DDP-induced apoptosis. sCLU overexpression activated pAKT Ser473 and pERK1/2Thr202/Tyr204, and vice versa. Inhibition of pAKT Ser 473 and pERK1/2Thr202/Tyr204 was sufficient to induce significant recover y in chemosensitivity to DDP in A549DDP in the presence of sCLU overexpression. The DDP activated sCLU, which directly regulated pAKT and pERK1/2. Conclusions: This novel finding suggests that therapies directed against sCLU and its downstream signaling targets pAKT and pERK1/2 may have the potential to enhance the efficacy of DDP-based chemotherapy. © 2014 S. Karger AG, Basel.
Oren A.,University of Toronto |
Benoit M.A.,University of Toronto |
Murphy A.,University of Toronto |
Schulte F.,Hematology |
Hamilton J.,University of Toronto
Journal of Clinical Endocrinology and Metabolism | Year: 2012
Context: Adolescents with differentiated thyroid cancer (DTC) require lifelong monitoring with a high possibility of reoperation or radioactive iodine. Although adult DTC survivors have similar or slightly worse quality of life (QOL), this has not been evaluated in the pediatric population. Objective: Our objective was to compare QOL and anxiety in adolescents with DTC to patients with acquired autoimmune hypothyroidism. Design, Setting, and Patients: In this cross-sectional pilot study, three validated questionnaires were administered to 16 adolescents with DTC and 16 controls for assessment of QOL and anxiety levels. These included teen and parent PedsQL, Multidimensional Anxiety Scale for Children, and Coddington Life Events Scales for Adolescents. The contribution of age, time since diagnosis, and biochemical variables were compared with the outcome measures. Results: There were 16 DTC patients (seven males); 13 had papillary carcinoma, one had follicular carcinoma, and two had mixed type. At diagnosis, five DTC patients had lymph node involvement and two had lung metastases, although at time of assessment, only one DTC patient had lymph node involvement. DTC patients were older than control subjects (P = 0.004) and had lower TSH levels than control subjects at time of assessment (P = 0.013). QOL and anxiety levels did not differ between DTC patients compared with control subjects and with previously reported scores in a healthy cohort.QOLand anxiety level parameters were not influenced by age, time since diagnosis, or free T4 levels measured at the time of assessment. Conclusions: Adolescents with DTC have similar QOL and anxiety levels compared with autoimmune hypothyroidism patients and with a healthy normative population. Copyright © 2012 by The Endocrine Society.
Gozzetti A.,Hematology |
Cerase A.,Unit NINT Neuroimaging and Neurointervention
Central Nervous System Agents in Medicinal Chemistry | Year: 2014
Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM. Treatment is still unsatisfactory. Many treatments have been described in the literature: chemotherapy (CHT), intrathecal therapy (IT), and radiotherapy (RT), with survivals reported between one month and six months. Recent drugs such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib) have changed the treatment of patients with MM, both younger and older, with a significant improvement in response and survival. The activity of new drugs in CNSMM has been reported but is still not well known. Bortezomib does not cross the blood brain barrier (BBB), and IMID’s seem to have only a minimal crossover. The role of novel agents in CNS MM management will be discussed as well as the potential role of other new immunomodulatory drugs (pomalidomide) and proteasome inhibitors that seem to cross the BBB and hold promise into the treatment of this rare and still incurable localization of the disease. © 2014 Bentham Science Publishers.
Vitolo U.,Hematology |
Chiappella A.,Hematology |
Franceschetti S.,University of Piemonte Orientale |
Carella A.M.,University of Genoa |
And 21 more authors.
The Lancet Oncology | Year: 2014
Background: Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. Methods: REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m2 intravenous rituximab, 750 mg/m2 intravenous cyclophosphamide, 50 mg/m2 intravenous doxorubicin, and 1·4 mg/m2 intravenous vincristine on day 1, and 40 mg/m2 oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by 18F-fluorodeoxyglucose (18F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. Findings: 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. Interpretation: Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. Funding: Fondazione Italiana Linfomi and Celgene. © 2014 Elsevier Ltd.