For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important ...part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus ...cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone R-CVP) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI 0.88 margin). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.
•The complete response rate for first-line bendamustine/rituximab was statistically noninferior to R-CHOP or R-CVP in indolent NHL or MCL.•The safety profile of bendamustine/rituximab is distinct from that of R-CHOP/R-CVP.
Regulation of microRNAs in cancer metastasis Bouyssou, Juliette M.C.; Manier, Salomon; Huynh, Daisy ...
Biochimica et biophysica acta,
04/2014, Letnik:
1845, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Metastasis is a phenomenon of crucial importance in defining prognosis in patients with cancer and is often responsible for cancer-related mortality. It is known that several steps are necessary for ...clonal cells to disseminate from their primary tumor site and colonize distant tissues, thus originating metastatic lesions. Therefore, investigating the molecular actors regulating this process may provide helpful insights in the development of efficient therapeutic responses. Recent evidences have indicated the role of microRNAs (miRNAs) in modulating the metastatic process in solid tumors. miRNAs are small regulatory non-coding RNAs that bind to specific target mRNAs, leading to translational repression. miRNAs are known to act as negative regulators of gene expression and are involved in the regulation of biological processes, including cell growth, differentiation and apoptosis, both in physiological conditions and during diseases, such as tumors. In the specific field of tumorigenesis, miRNAs play an important role in mediating oncogenesis and favoring tumor progression, as a result of their ability to modulate epithelial-to-mesenchymal transition (EMT) and other series of events facilitating the formation of metastasis. The role of miRNAs in cancer development has been widely studied and has helped elucidate events such as the change in expression of oncogenes, tumor-suppressors and cancer-related proteins. This review focuses on the mechanisms underlying the role of miRNAs as part of the metastatic process.
The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated ...with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival EFS) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval CI, 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.
•Ibrutinib was administered to 28 patients with BNS.•Ibrutinib showed rapid and durable symptomatic and radiologic responses in patients with BNS.
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We previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS ...relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkin's lymphoma (NHL).
The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients.
The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy.
These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.
Introduction
To assess the value of the Mini-Mental State Examination (MMSE)-score at baseline in predicting survival in adult primary central nervous system lymphoma (PCNSL) patients.
Methods
In the ...HOVON 105/ ALLG NHL 24 phase III study patients with newly-diagnosed PCNSL were randomized between high-dose methotrexate-based chemotherapy with or without rituximab. Data on potential (MMSE-score), and known baseline prognostic factors (age, performance status, serum LDH, cerebrospinal fluid total protein, involvement of deep brain structures, multiple cerebral lesions, and the IELSG-score) were collected prospectively. Multivariable stepwise Cox regression analyses were used to assess the prognostic value of all factors on progression-free survival (PFS) and overall survival (OS) among patients with available MMSE score at baseline. Age was analyzed as continuous variable, the MMSE-score both as a continuous and as a categorical variable.
Results
In univariable analysis, age, MMSE-score and whether the patient received rituximab were statistically significantly prognostic factors for PFS. Age and MMSE-score were statistically significantly associated with OS. In a multivariable analysis of the univariately significant factors only MMSE-score was independently associated with the survival endpoints, as a continuous variable (HR for PFS 1.04, 95% CI 1.01–1.08; OS 1.06 (95% CI 1.02–1.10) and as categorical variable HR (< 27 versus ≥ 27 for PFS 1.55 (1.02–2.35); OS 1.68 (1.05–2.70). In our population, performance status, serum LDH, and CSF protein level were not of prognostic value.
Conclusion
Neurocognitive disturbances, measured with the MMSE at baseline, are an unfavorable prognostic factor for both PFS and OS in adult PCNSL patients up to 70 years-old.
The CD‐20 antibody rituximab is a standard component of treatment of non‐Hodgkin B‐cell lymphomas, including diffuse large B‐cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also ...called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial‐level random‐effects meta‐analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression‐free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment‐related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52‐1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression‐free survival (HR 0.65; 95% CI, 0.45‐0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment‐related mortality (RR 0.53; 95% CI, 0.20‐1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate‐based chemotherapy may improve progression‐free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.
Cobalt(II) complexes of chiral bis-binaphthyl porphyrins were prepared, and their catalytic activity in the asymmetric cyclopropanation of alkenes with ethyl diazoacetate was examined. Good yields ...and enantioselectivities (up to 90% ee) were observed with cis/trans ratios reaching 11:89. UV−vis and 1H NMR studies suggest that the axial nitrogen ligand N-methylimidazole could play a role in changing the enantioselectivity of the reaction.
Autologous stem cell transplantation has greatly improved the prognosis of systemic recurrent non-Hodgkin's lymphoma. However, no prospective data are available concerning the feasibility and ...efficacy of this strategy for systemic lymphoma relapsing in the central nervous system. We, therefore, we performed an international multicenter retrospective study of patients with a central nervous system recurrence of systemic lymphoma to assess the outcome of these patients in the era of stem cell transplantation. We collected clinical and treatment data on patients with a first central nervous system recurrence of systemic lymphoma treated between 2000 and 2010 in one of five centers in four countries. Patient- and treatment-related factors were analyzed and compared descriptively. Primary outcome measures were overall survival and percentage of patients transplanted. We identified 92 patients, with a median age of 59 years and a median Eastern Cooperative Oncology Group/World Health Organization performance status of 2, of whom 76% had diffuse large B-cell histology. The majority (79%) of these patients were treated with systemic chemotherapy with or without intravenous rituximab. Twenty-seven patients (29%) were transplanted; age and insufficient response to induction chemotherapy were the main reasons for not being transplanted in the remaining 65 patients. The median overall survival was 7 months (95% confidence interval 2.6-11.4), being 8 months (95% confidence interval 3.8-5.2) for patients ≤ 65 years old. The 1-year survival rate was 34.8%; of the 27 transplanted patients 62% survived more than 1 year. The Memorial Sloan Kettering Prognostic Index for primary central nervous system lymphoma was prognostic for both undergoing transplantation and survival. In conclusion, despite the availability of autologous stem cell transplantation for patients with central nervous system progression or relapse of systemic lymphoma, prognosis is still poor. Long-term survival is, however, possible and more likely in patients able to undergo stem cell transplantation.
This paper addresses if and how excess debt can be considered as an early warning signal for banks and takes an additional dimension by comparing the excess leverage between Islamic and conventional ...banks in Indonesia before, during, and after the Global Financial Crisis (GFC). To do so, this research develops an empirical model of banks' capital structure and optimal and excess debt, and it conducts an empirical analysis on the overleveraging of eleven conventional and Islamic banks in Indonesia. Results show that all banks became vulnerable to the GFC in 2007-2009 while credit build-up, i.e., overleveraging, started in 2005. However, for most of the banks in the sample, Islamic banks performed better and leveraged less prior to the GFC, which made them more resilient to the crisis.
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