Publications

OBJECTIVE: To assess if commercially sponsored trials are associated with higher success rates than publicly-sponsored trials.

STUDY DESIGN AND SETTINGS: We undertook a systematic review of all consecutive, published and unpublished phase III cancer randomized controlled trials (RCTs) conducted by GlaxoSmithKline (GSK) and the NCIC Clinical Trials Group (CTG). We included all phase III cancer RCTs assessing treatment superiority from 1980 to 2010. Three metrics were assessed to determine treatment successes: (1) the proportion of statistically significant trials favouring the experimental treatment, (2) the proportion of the trials in which new treatments were considered superior according to the investigators, and (3) quantitative synthesis of data for primary outcomes as defined in each trial.

RESULTS: GSK conducted 40 cancer RCTs accruing 19,889 patients and CTG conducted 77 trials enrolling 33,260 patients. 42% (99%CI 24 to 60) of the results were statistically significant favouring experimental treatments in GSK compared to 25% (99%CI 13 to 37) in the CTG cohort (RR = 1.68; p = 0.04). Investigators concluded that new treatments were superior to standard treatments in 80% of GSK compared to 44% of CTG trials (RR = 1.81; p<0.001). Meta-analysis of the primary outcome indicated larger effects in GSK trials (odds ratio = 0.61 [99%CI 0.47-0.78] compared to 0.86 [0.74-1.00]; p = 0.003). However, testing for the effect of treatment over time indicated that treatment success has become comparable in the last decade.

CONCLUSIONS: While overall industry sponsorship is associated with higher success rates than publicly-sponsored trials, the difference seems to have disappeared over time.

In decades of clinical-trial data, new treatments are better than standard ones just over half the time. That's as it should be, say Benjamin Djulbegovic and colleagues.

Genome sequencing has overflowed the databases with huge amount of SNP data. Although the amount of detected single nucleotide polymorphisms (SNPs) is rising exponentially every day, we still lag behind in characterization techniques. Implementing computational platforms to determine the pathogenecity associated with the SNPs can provide a probable solution to this problem. To improve the prediction quality for SNP characterization methods, we implemented machine learning support vector classification method. Total 557 non-synonymous amino acid variants were collected from CENP family proteins, excluding CENPE. Multivariate simulation of associated changes in biological phenomena's for each SNPs was computed through available SNP analysis platforms. Support vector model was designed using training dataset and the raw classification data was subjected to the classification hyperplane. We observed multiple evidences of cancer associated genetic mutations in CENPI, CENPJ, CENPK, CENPL and CENPX protein. The former four proteins have showed positive hits in cosmic database for mutations in tumour samples, but CENPX has never been reported before for the cancer associated outcomes. Since CENPX has been recently classified and not much functional and pathological insight has been, the results obtained in this study will serve as a starting point for future investigation on cancer research in association to CENPX protein.

BACKGROUND: Despite advances in understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) and availability of more effective therapies, MM remains incurable. The autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy is based on combining cytoreduction from high-dose (chemo- or chemoradio)-therapy with adoptive immunotherapy. However, conflicting results have been reported when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT. A previously published meta-analysis has been reported; however, it suffers from serious methodological flaws.

METHODS: A systematic search identified 152 publications, of which five studies (enrolling 1538 patients) met inclusion criteria. All studies eligible for inclusion utilized biologic randomization.

RESULTS: Assessing response rates by achievement of at least a very good partial response did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87-1.09), p = 0.66]; but complete remission was higher in the auto-allo HCT arm [RR = 1.65 (1.25-2.19), p = 0.0005]. Event-free survival did not differ between auto-allo HCT group versus auto-auto HCT group using per-protocol analysis [hazard ratio (HR) = 0.78 (0.58-1.05)), p = 0.11] or using intention-to-treat analysis [HR = 0.83 (0.60-1.15), p = 0.26]. Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR = 0.88 (0.33-2.35), p = 0.79], or by intention-to-treat [HR = 0.80 (0.48-1.32), p = 0.39] analysis. Non-relapse mortality (NRM) was significantly worse with auto-allo HCT [RR (95%CI) = 3.55 (2.17-5.80), p < 0.00001].

CONCLUSION: Despite higher complete remission rates, there is no improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. At present, totality of evidence suggests that an auto-allo HCT approach for patients with newly diagnosed myeloma should not be offered outside the setting of a clinical trial.

Evidence regarding the efficacy of gemtuzumab ozogamicin (GO) addition to standard induction chemotherapy in newly diagnosed acute myeloid leukaemia (AML) is conflicting. This systematic review aimed to identify and summarize all evidence regarding the benefits and harms of adding GO to conventional chemotherapy for induction treatment of AML. A comprehensive literature search of two databases (PUBMED and Cochrane) from inception up to November 22, 2012, and 4 years of proceedings from four major haematology/oncology conferences was undertaken. Endpoints included benefits (complete remission, relapse-free, event-free, and overall survival), and harms (early mortality and incidence of hepatic veno-occlusive disease/sinusoidal obstructive syndrome). Seven trials (3942 patients) met all inclusion criteria. Addition of GO showed improved relapse-free [Hazard Ratio (HR) = 0·84 (95% confidence interval (CI) 0·71-0·99)] and event-free survival [HR = 0·59 (95%CI 0·48-0·74)] but not overall survival [HR = 0·95 (95%CI 0·83-1·08)]. Addition of GO resulted in higher rate of early mortality [Risk Ratio = 1·60 (95%CI 1·07-2·39)]. Improved overall survival was observed in studies using a lower cumulative GO dose (<6 mg/m(2) ) [HR = 0·89 (95%CI 0·81-0·99)]. Addition of GO to conventional chemotherapy as induction therapy may improve relapse-free and event-free survival, but does not impact overall survival and significantly increases early mortality in AML.

BACKGROUND: Lung cancer is considered a terminal illness with a five-year survival rate of about 16%. Informed decision-making related to the management of a disease requires accurate prognosis of the disease with or without treatment. Despite the significance of disease prognosis in clinical decision-making, systematic assessment of prognosis in patients with lung cancer without treatment has not been performed. We conducted a systematic review and meta-analysis of the natural history of patients with confirmed diagnosis of lung cancer without active treatment, to provide evidence-based recommendations for practitioners on management decisions related to the disease. Specifically, we estimated overall survival when no anticancer therapy is provided.

METHODS: Relevant studies were identified by search of electronic databases and abstract proceedings, review of bibliographies of included articles, and contacting experts in the field. All prospective or retrospective studies assessing prognosis of lung cancer patients without treatment were eligible for inclusion. Data on mortality was extracted from all included studies. Pooled proportion of mortality was calculated as a back-transform of the weighted mean of the transformed proportions using the random-effects model. To perform meta-analysis of median survival, published methods were used to pool the estimates as mean and standard error under the random-effects model. Methodological quality of the studies was examined.

RESULTS: Seven cohort studies (4,418 patients) and 15 randomized controlled trials (1,031 patients) were included in the meta-analysis. All studies assessed mortality without treatment in patients with non-small cell lung cancer (NSCLC). The pooled proportion of mortality without treatment in cohort studies was 0.97 (95% CI: 0.96 to 0.99) and 0.96 in randomized controlled trials (95% CI: 0.94 to 0.98) over median study periods of eight and three years, respectively. When data from cohort and randomized controlled trials were combined, the pooled proportion of mortality was 0.97 (95% CI: 0.96 to 0.98). Test of interaction showed a statistically non-significant difference between subgroups of cohort and randomized controlled trials. The pooled mean survival for patients without anticancer treatment in cohort studies was 11.94 months (95% CI: 10.07 to 13.8) and 5.03 months (95% CI: 4.17 to 5.89) in RCTs. For the combined data (cohort studies and RCTs), the pooled mean survival was 7.15 months (95% CI: 5.87 to 8.42), with a statistically significant difference between the two designs. Overall, the studies were of moderate methodological quality.

CONCLUSION: Systematic evaluation of evidence on prognosis of NSCLC without treatment shows that mortality is very high. Untreated lung cancer patients live on average for 7.15 months. Although limited by study design, these findings provide the basis for future trials to determine optimal expected improvement in mortality with innovative treatments.

AIMS: There is a perceived benefit associated with the administration of donor lymphocyte infusion (DLI) in patients with lymphoid malignancies relapsing after allogeneic hematopoietic cell transplantation. However, it is unclear if and how this benefit varies according to specific diseases. Because administration of DLI is not universally effective and could be associated with significant toxicities resulting in morbidity and mortality, it is imperative to identify cases where benefits outweigh harms of the procedure.

MATERIALS & METHODS: We conducted a systematic review of the published literature and extracted and pooled data independently for each disease cohort: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL).

RESULTS: In summary, 39 studies met inclusion criteria. The pooled proportion (95% CI) for complete response was 27% (16-40) in ALL, 55% (15-92) in CLL, 26% (19-33) in MM, 52% (33-71) in NHL and 37% (20-56) in HL.

CONCLUSION: Complete response rates appear higher when DLI is used for relapsed CLL and lymphomas (NHL and HL), and less pronounced in ALL or MM. Absence of data pertaining to disease-specific prognostic determinants, such as adverse genetic or molecular abnormalities, or quantitative disease burden when applicable, limit our ability to identify cases in whom benefits from DLI outweigh risks associated with the procedure within a particular disease.

AKT1, a serine/threonine-protein kinase also known as AKT kinase, is involved in the regulation of various signalling downstream pathways including metabolism, cell proliferation, survival, growth, and angiogenesis. The AKT kinases pathway stands among the most important components of cell proliferation mechanism. Several approaches have been implemented to design an efficient drug molecule to target AKT kinases, although the promising results have not been confirmed. In this paper we have documented the detailed molecular insight of AKT kinase protein and proposed a probable doxorubicin based approach in inhibiting miR-21 based cancer cell proliferation. Moreover, the inhibition of miR-21 activation by raising the FOXO3A concentration seems promising in reducing miR-21 mediated cancer activation in cell. Furthermore, the use of next generation sequencing and computational drug design approaches will greatly assist in designing a potent drug molecule against the associated cancer cases.

Centrosome forms the backbone of cell cycle progression mechanism. Recent debates have occurred regarding the essentiality of centrosome in cell cycle regulation. CEP family protein is the active component of centrosome and plays a vital role in centriole biogenesis and cell cycle progression control. A total of 31 proteins have been categorized into CEP family protein category and many more are under candidate evaluation. Furthermore, by the recent advancements in genomics and proteomics researches, several new CEP proteins have also been characterized. Here we have summarized the importance of CEP family proteins and their regulation mechanism involved in proper cell cycle progression. Further, we have reviewed the detailed molecular mechanism behind the associated pathological phenotypes and the possible therapeutic approaches. Proteins such as CEP57, CEP63, CEP152, CEP164, and CEP215 have been extensively studied with a detailed description of their molecular mechanisms, which are among the primary targets for drug discovery. Moreover, CEP27, CEP55, CEP70, CEP110, CEP120, CEP135, CEP192, CEP250, CEP290, and CEP350 also seem promising for future drug discovery approaches. Since the overview implicates that the overall researches on CEP proteins are not yet able to present significant details required for effective therapeutics development, thus, it is timely to discuss the importance of future investigations in this field.

BACKGROUND: Limited data have been reported describing the outcome and prognosis of patients with MDS in whom treatment with azanucleosides has failed. We report our single-institutional experience of patients with higher-risk MDS in whom therapy with azacitidine has failed.

PATIENTS AND METHODS: This was a retrospective study of MDS patients treated at the Moffitt Cancer Center in whom azacitidine treatment regimens had failed. Patients were identified through the Moffitt database, and clinical data were extracted. Azacitidine failure was defined as failure to achieve hematologic improvement or better after at least 4 cycles of therapy, loss of response, or disease progression during therapy. The objectives were to characterize response to salvage therapies after azacitidine failure and to estimate the overall survival. All responses were defined according to the International Working Group 2006 criteria, and survival was estimated using the Kaplan-Meier method.

RESULTS: A total of 59 patients in whom azacitidine treatment had failed were identified. The median age at treatment failure was 68 years, and most were Caucasian male patients. Thirteen patients received intensive chemotherapy with an overall response rate of 31%. Six patients were treated with decitabine, and none responded. Median overall survival of the entire cohort after azacitidine failure was 5.8 months (95% confidence interval, 1.3-10.3 months), with an estimated 12-month survival of 17%.

CONCLUSION: Patients with higher-risk MDS in whom azacitidine treatment has failed have a poor prognosis and low probability of response to salvage treatments. The standard of care after azanucleoside failure should be enrollment in clinical trials.