Generation Of Clinical Studies Research Articles

Weighing ependymoma as an epigenetic disease.

Ependymoma is the third most common malignant pediatric brain tumor. Although the biology that drives ependymoma is slowly being unraveled, the ability to translate these findings to clinical care remains an ongoing challenge. Epigenetic alterations appear to play a central role in the development of molecular classification of ependymoma. We reviewed the published literature available describing genetic and epigenetic underpinnings of ependymoma that have been reported to date and have summarized the information regarding genetic drivers of ependymoma that may point us toward therapeutic strategies. Ependymoma is a molecularly heterogeneous disease which has now been divided into at least nine distinct molecular subtypes based on DNA methylation and gene expression profiling. DNA methylation has emerged as an effective tool for classification of brain tumors alongside histopathology and other molecular diagnostics. There have been large retrospective cohorts describing molecular subgroup identity as a powerful independent predictor of outcome. There is limited published data on prospective trials to date however this is forthcoming which will lead to molecular stratification in the next generation of clinical studies. This is a review of recent advancements in our understanding of the epigenetic basis of ependymoma and discussion of how these findings reveal potential therapeutic opportunities.

Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence.

Purpose of reviewTo provide an overview of the mechanistic and clinical evidence for the use of nonspecific immunomodulators in paediatric respiratory tract infection (RTI) and wheezing/asthma prophylaxis.Recent findingsNonspecific immunomodulators have a long history of empirical use for the prevention of RTIs in vulnerable populations, such as children. The past decade has seen an increase in both the number and quality of studies providing mechanistic and clinical evidence for the prophylactic potential of nonspecific immunomodulators against both respiratory infections and wheezing/asthma in the paediatric population. Orally administered immunomodulators result in the mounting of innate and adaptive immune responses to infection in the respiratory mucosa and anti-inflammatory effects in proinflammatory environments. Clinical data reflect these mechanistic effects in reductions in the recurrence of respiratory infections and wheezing events in high-risk paediatric populations. A new generation of clinical studies is currently underway with the power to position the nonspecific bacterial lysate immunomodulator OM-85 as a potential antiasthma prophylactic.SummaryAn established mechanistic and clinical role for prophylaxis against paediatric respiratory infections by nonspecific immunomodulators exists. Clinical trials underway promise to provide high-quality data to establish whether a similar role exists in wheezing/asthma prevention.

The Next Generation of Clinical Studies with Antidepressants in Bipolar Disorder

Antidepressants are still widely used in the treatment for bipolar disorder (BD), but evidence do not support their extensive use during depressive episodes. Recently, an important systematic review was published after an extensive literature search on the use of antidepressants in bipolar depression (1). Based on the conclusions, in spite of a considerable number of clinical studies (more than 37 so far) and meta-analyses currently available, the authors did not make broad statements endorsing antidepressant use in BD, but acknowledge that individual bipolar patients may benefit from these agents. Other studies showed similar results (2). These publications also call attention to a wide range of methodological issues and discrepancies as well as to heterogeneous statistical approaches and conclusions. Also, studies have emphasized other limitations (2) including small samples, co-treatments, lack of adequate controls, and varied design, and therefore, current clinical evidence seems still inconclusive. Thus, the first generation of studies has not provided consistent clinical answers to ensure more generalizable conclusions and guidelines for clinicians. They focused primarily in answering two simple questions: first, testing “yes or no” for the use of antidepressants regarding efficacy and safety (switch risk) in bipolar depression. This linear paradigm still does not help to guide clinicians’ therapeutic decision. The second question aimed to address what agent (or class) would be more effective and safer in bipolar depression. These two main aspects still remain not fully elucidated and additional questions have arisen, described next. Also, the role of BD diagnosis (bipolar I or II), family history and the risk of cycle acceleration, suicidality, mixed episodes/rapid cycling as associated outcomes did not provide yet consistent guidance. These variables were evaluated as secondary analyses and did not present standardized definitions (e.g., switch process and cycle acceleration). In the same perspective, even though it is clear that antidepressant monotherapy is contraindicated in bipolar depression, some large studies used this approach to compare with new agents (e.g., EMBOLDEN II). Thus, this is an area where future studies critically require translational approach for the next generation of clinical trials (3). Only few trials with antidepressants in bipolar depression have systematically evaluated the potential clinical usefulness of biomarkers that may predict antidepressant response in BD and even less have thoroughly assessed the potential biological basis of switch risk. Most of the studies also have limitations including small samples, co-treatments, lack of adequate controls, and varied design. The identification of neurobiological substrates able to minimize sample heterogeneity may also help to identify potential enriched samples for further confirmatory studies with different classes of antidepressants would be a critical step forward. This may also provide evidence to support the use of antidepressants in specific subgroups and guide clinical decision in the personalized treatment paradigm. At the same time, the development of standardized conceptual definitions is essential to perform neurobiological studies and may be added to the evaluation of diverse constructs and dimensions across neurobiological systems. In the same context, the next generation of proof of concept studies is also expected to provide information on which clinical and neurobiological variables are associated with a subgroup that will likely respond to a specific antidepressant and address key questions including optimal duration of antidepressant treatment and presence (or not) of a dose- and/or time-dependent regulation of mood elevation using adequate methodology (e.g., more frequent rating scales, standard dose escalation design). These approaches may also help to define the lowest effective dose for the shortest time necessary for sustained remission. Future studies would also benefit from dimensional approaches and evaluation of new targets such as the glutamatergic system. Finally, it is also critical to better understand this complex and non-linear interaction, the study of specific domains such as early improvement, short and long-term response, cognition, role of compliance, duration of use, and dosage/response curve. These are important variables to be considered integrated with biomarkers such as predictors of response and surrogate outcomes. The next generation of studies is also expected to evaluate a broader risk–benefit equation, integrating generalizable data to discoveries on personalized treatments for those who need it most.

Integrating collection of biospecimens in clinical trials: the approach of the European organization for research and treatment of cancer.

Access to biospecimens and their derivatives, that is, human biological materials (HBM), for translational research (TR) is considered a major bottleneck hindering successful bench to bedside translation. Clinical trials offer a unique opportunity to collect HBM in a specialized setting that allows prospectively designed, high-quality TR that would be difficult to fulfill from community- or population-based HBM collections alone. Increasingly, as the field advances toward personalized treatment of cancer patients, access to HBM is becoming a necessity for patient enrollment in a new generation of clinical studies that are designed and driven by molecular hypotheses. The European Organization for Research and Treatment of Cancer (EORTC) is one of the largest networks for clinical trials in oncology. The EORTC is re-focusing its strategy, building on experiences and expertise gained over the years from specific initiatives such as EORTC Group activities and the EORTC Virtual Tumour Bank, by developing new mechanisms to support investigators with the practical aspects of HBM collection as part of EORTC clinical studies. Due to the complex, multidisciplinary nature of HBM collection and TR, integration of HBM collection into clinical trials warrants careful upfront planning and input from a range of expertise. To simplify HBM collection in clinical studies, the EORTC has developed a simple checklist containing the key elements of HBM collection setup and combines these into a simple tool for practical use. Through identifying and managing key risk areas, this can maximize the HBM collection success while achieving efficient clinical trial development. This article focuses on the key elements of HBM collection and the approaches of the EORTC for efficiently integrating this collection into clinical trial development.

Therapeutic prevention of colorectal carcinogenesis

An overwhelming amount of experimental and observational information about the basic processes underlying carcinogenesis obtained during the 1970s to 1990s, led to a series of translational and eventually definitive placebo-controlled, double blind randomized controlled trials (RCT), involving patients at increased risk for breast, prostate, non-melanoma skin, cervix, chronic myelogenous leukemia (CML), and colon cancer. Despite clear evidence of the favorable effects on the primary endpoints, regulatory approval has been low and usage of those compounds, which have been approved, has been minimal to non-existent. How come? And what can we do to improve this situation, as we move ahead to the next generation of clinical studies? For cervical cancer and CML, respectively, we have the good news that a highly effective vaccine and a targeted therapy (Imatinib) supplanted retinoids as the intervention of choice.[1,2] However, it is probably still worth looking into the vitamin A status of patients who develop cervical cancer, who have received the vaccine, or CML patients who relapse on Imatinib. For the remaining malignancies the issues are very similar. We have recently presented a comprehensive review of this topic, including for those interested, a discussion of regulatory and business challenges.[3] In this current perspective we will focus on the issues of particular concern to the audience being served at this symposium: Scientific, translational, and clinical issues related to colorectal cancer. The major questions that need to be asked and addressed regardless of the organ site are contained in these five areas: What relevance do cellular, animal studies, and epidemiological observations have to the cancer in ‘at-risk individuals′? How can we better identify those at true risk, to develop a more favorable risk-benefit profile? How can we better assess toxicity, and thus a potential risk-benefit in our preclinical experiments? How can we better convey the risks and benefits to trial participants in prevention studies? to regulatory bodies (FDA, EMA, etc.) after a positive RCT? or to potential future patients after a drug is approved? How should we move forward?

Molecular Biology of Medulloblastoma: Will It Ever Make a Difference to Clinical Management?

Over the last 10 years approximately 750 children with medulloblastoma have been treated on consortia based clinical trials at an estimated cost of over 150 million US dollars. Despite this enormous effort, no meaningful molecular data has been generated that will inform the next generation of clinical studies. It is imperative that the neuro-oncology community give greater priority to studies of medulloblastoma molecular biology: unless we do this our patients will face a bleak future in which there is no accurate disease-risk stratification tool and no effective new treatments. We review some of the reasons we have failed to translate knowledge of medulloblastoma disease biology to the clinic and look forward to the next generation of clinical and molecular studies that are seeking to correct this.

Towards a therapeutic breast cancer vaccine: the next steps

The genomic revolution has advanced our understanding of breast cancer biology and the molecular basis of antitumor immunity. Trastuzumab, the first monoclonal antibody for breast cancer, is now a routine part of clinical care. Breast cancer vaccines may be more effective by actively recruiting both humoral and cellular immunity to the therapeutic effort. However, immunization alone is unlikely to have significant activity against established breast cancers, where it is limited by potent mechanisms of immune tolerance and the immunobiology of breast cancer itself. The next generation of clinical studies should integrate breast cancer vaccines with standard breast cancer drugs or novel immunotherapeutics in strategic doses and schedules that abrogate immune tolerance and groom the tumor microenvironment for a productive immune response.

Platinums: Extending Their Therapeutic Spectrum

Three decades since the introduction of cisplatin into clinical cancer treatment, this drug and its second generation analogues, carboplatin and oxaliplatin, form an integral part of recent evolving achievements in the treatment of solid tumors. For example, landmark studies have established a role for cisplatin after resection in lung cancer, and improved survival from platinum-based chemoradiation in cancer of the uterine cervix and combination chemotherapy in mesothelioma, small cell lung, ovarian, and endometrial cancers. Colon cancer survival has improved with the addition of oxaliplatin to its treatment. Here we summarize how insights into the mechanism of action of platinum compounds and studies of their structure-activity relationships may identify platinums with unusual selectivity towards tumors such as melanoma, renal cell, and breast cancer and other cancers not usually treated with existing platinums. Both new drug development and mechanistic studies with established drugs should lead to the next generation of clinical studies with platinum compounds, and their integration with emerging ‘targeted therapies’.