Modern Clinical Trials Research Articles

Sequential Multiple Assignment Randomized Trials: An Opportunity for Improved Design of Stroke Reperfusion Trials

Modern clinical trials in stroke reperfusion fall into 2 categories: alternative systemic pharmacological regimens to alteplase and "rescue" endovascular approaches using targeted thrombectomy devices and/or medications delivered directly for persistently occluded vessels. Clinical trials in stroke have not evaluated how initial pharmacological thrombolytic management might influence subsequent rescue strategy. A sequential multiple assignment randomized trial (SMART) is a novel trial design that can test these dynamic treatment regimens and lead to treatment guidelines that more closely mimic practice. To characterize a SMART design in comparison to traditional approaches for stroke reperfusion trials. We conducted a numerical simulation study that evaluated the performance of contrasting acute stroke clinical trial designs of both initial reperfusion and rescue therapy. We compare a SMART design where the same patients are followed through initial reperfusion and rescue therapy within 1 trial to a standard phase III design comparing 2 reperfusion treatments and a separate phase II futility design of rescue therapy in terms of sample size, power, and ability to address particular research questions. Traditional trial designs can be well powered and have optimal design characteristics for independent treatment effects. When treatments, such as the reperfusion and rescue therapies, may interact, commonly used designs fail to detect this. A SMART design, with similar sample size to standard designs, can detect treatment interactions. The use of SMART designs to investigate effective and realistic dynamic treatment regimens is a promising way to accelerate the discovery of new, effective treatments for stroke.

Focusing on the “Person” in Personalized Medicine: The Future of Patient-Centered Care in Radiation Oncology

Numerous efforts in radiation oncology aim to improve the value of clinical care. To evaluate the success of these efforts, outcome measures must be well defined and incorporate the beliefs of the patients they affect. These outcomes have historically centered on rates of tumor control, overall survival, and adverse events as perceived and reported by providers. However, the future of patient-centered care in radiation oncology is increasingly focusing on the “person” in the population and the individual in the studies to more closely reflect the ideals of personalized medicine. Formally known as patient-centered outcomes, this metric encompasses parameters of patient satisfaction, engagement, and treatment compliance. Evaluations that investigate the safety and efficacy of treatments are increasingly soliciting participation from patients within a model of shared decision making that improves patients’ knowledge, satisfaction, physical and emotional well-being, and trust in providers. Modern clinical trials that embrace this approach may even focus on patient-reported outcomes as the primary end point, as opposed to time-honored physician-reported events. The authors explore the growing role of patient-centered care, the incorporation of shared decision making, and the relevant body of existing and developing literature on this topic in radiation oncology. The authors report recent discoveries from this area of study and describe how they can not only support high-quality, high-value patient care but also enhance recruitment to clinical oncology trials, both of which are challenging to achieve in today’s relatively resource-strapped environment.

Psychedelics in the treatment of unipolar mood disorders: a systematic review.

Unipolar mood disorders, including major depressive disorder and persistent depressive disorder (dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden. Current treatment is suboptimal in most cases and there is little of note in the pharmaceutical development pipeline. The psychedelic drugs, including lysergic acid diethylamide and psilocybin, were used extensively in the treatment of mood disorders, and other psychiatric conditions, before their prohibition in the late 1960s. They are relatively safe when used in medically controlled environments, with no reported risk of dependence. Here, we present a systematic review of published clinical treatment studies using psychedelics in patients with broadly defined UMD, and consider their place in psychiatry. Whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics. A recently completed pilot study in the UK favours the use of psilocybin with psychological support in treatment resistant depressive disorder. The evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis.

PurposeThe purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC).Materials and MethodsA systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson’s correlation coefficient (R) and the coefficient of determination (R2).ResultsTwenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, –2.4 to 3.4) for the median PFS and 0.7 months (range, –5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident.ConclusionTargeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

Implementing optimal allocation in clinical trials with multiple endpoints

Modern clinical trials are often complex, with multiple competing objectives and multiple endpoints. Such trials should be both ethical and efficient. In this paper, we overcome the obstacles introduced by the large number of unknown parameters and the possible correlations between the multiple endpoints. We obtain the optimal allocation proportions for the following two optimization problems: (1) maximizing the power of the test of homogeneity with a fixed sample size, and (2) minimizing the expected weighted number of failures with a fixed power. Further, we implement these optimal allocations through response-adaptive randomization procedures. Our theoretical results provide the foundation for the implementation and further investigation of the procedure, and our numerical studies demonstrate its ability to achieve diverse objectives.

Clinical Research Informatics for Big Data and Precision Medicine.

To reflect on the notable events and significant developments in Clinical Research Informatics (CRI) in the year of 2015 and discuss near-term trends impacting CRI. We selected key publications that highlight not only important recent advances in CRI but also notable events likely to have significant impact on CRI activities over the next few years or longer, and consulted the discussions in relevant scientific communities and an online living textbook for modern clinical trials. We also related the new concepts with old problems to improve the continuity of CRI research. The highlights in CRI in 2015 include the growing adoption of electronic health records (EHR), the rapid development of regional, national, and global clinical data research networks for using EHR data to integrate scalable clinical research with clinical care and generate robust medical evidence. Data quality, integration, and fusion, data access by researchers, study transparency, results reproducibility, and infrastructure sustainability are persistent challenges. The advances in Big Data Analytics and Internet technologies together with the engagement of citizens in sciences are shaping the global clinical research enterprise, which is getting more open and increasingly stakeholder-centered, where stakeholders include patients, clinicians, researchers, and sponsors.

Molecular Diagnostics and Anaplastic Thyroid Carcinoma: The Time has come to Harvest the High Hanging Fruit

Targeted therapies have played a major role in cancer therapeutics, starting with the discovery of a drug against BCR–ABL rearrangements in chronic myelogenous leukemia. This led to the first approval of a targeted agent in cancer and since, many others have followed. Anaplastic thyroid cancer (ATC) is an aggressive carcinoma with few curative options. Although previous cytotoxic chemotherapy and kinase inhibitor therapies have not proven efficacious in ATC, some of the newer drugs appear to be promising. A case report and a comprehensive review of the current standard of care, genetics, modern therapeutic drugs and clinical trials are presented, in order to outline where we currently stand and where the future lies in the quest for a cure for ATC.

Drug discovery in advanced prostate cancer: translating biology into therapy

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs.

In Memoriam: John F. Kurtzke, MD (1926-2015): A Founding Father of Neuroepidemiology and Pioneer of Modern Clinical Trial Design.

On December 1, 2015, we lost one of the most influential contributors to the field of medical epidemiology, and in particular the man who is credited for performing the most systematic exploration of the geographic distribution patterns for the most common disabling neurologic disorder of young people, multiple sclerosis (MS). John F. Kurtzke, MD, graduated from the Cornell Medical College in 1952, and by 1956 he had ascended to the position of chief of neurology for the Veterans Administration in Coatesville, Pennsylvania. He would later serve as professor of neurology at Georgetown University from 1963 to 1995, during which time he conducted some of the most seminal investigations that collectively helped to establish the field of neuroepidemiology. The role of one ormore environmental factors, including infections, as a critical factor in thepathogenesis ofMS is now widely recognized. It was Kurtzke’s pioneering work that brought forth some of the most persuasive evidence to date supporting a putative role for an infectious agent as a contributing factor in MS. When the presence of the disorder was nearly unheard of on the remote Faeroe Islands and in Iceland, the recording of many cases of MS following the occupation of these territories by the British troops during World War II fostered Kurtzke’s exploration into the infectious etiologic hypothesis as a contributing factor in the development of MS.1-8 The contemporary framework for thepathobiological underpinnings ofMS is nowmost consistentwith that of an epigenetic disorder predicatedongenetic, environmental, nutritional, and behavioral factors, in conjunction with a factor acting as a trigger or “ignition switch.” Kurtzke’s observations and interpretive conclusions resonate with contemporary thinking, particularly given his hypothesis that a modifying etiological factor for developing MS appeared to be influenced by the location, with respect to equatorial latitude, of early life development,withmounting evidence that corroborates thepostulated role of vitaminDas a criticalmitigating influence potentially linked to its relationship to immune regulatorynetworks and thederivative achievement of self-tolerance. Kurtzke’s secondmajor accomplishmentwas thedevelopment of the disability status scale score, which catapulted the clinical assessment within clinical trials from the reporting of the assessor’s subjective impressions to the establishment of anobjective, reproducible, andstereotypedgold-standardneurological examination and status ascertainment.9,10 This formidable contribution to the field of medical therapeutics resulted in the transformation of clinical trial design for MS in particular and set forth objective standards for the characterization of clinical outcomes to be emulated for disabling neurologic disorders in general. Originally proposed in 1955 and 1961, Kurtzke formulated anordinal scale for the application inMSdrug trials (initially for the assessment of isoniazid as a treatment forMS) as a means to objectify the effects of putative therapies on the clinical disposition of neurologic disability in MS.9 Initially conceived as a scale from0 (no evidence of signs, symptoms, or report of disabling changes in neurologic functioning or status) to 10 (death due toMSor its complications), the scale was later transformed into 0.5-point steps (the Expanded Disability Status Scale score) to account for the functional integrity of eachof the functional systemscales such as abnormalities affiliated with each of the components of the neurological examination: vision, brainstem functions, pyramidal functions (strength, reflexes, tone), cerebellar functions, sensory functions, bowel-bladder-sexual functions, cerebral functions (depression, euphoria, reduced mentation), and ambulation.10 The scale is an ordinal scale, heavily weighted on the impact anddeterioration inwalking, othermotor functions, and, toadegree, sensoryandvisual functions.Notwithstanding the ordinal nature of the scale, theheavybias on ambulation, and John F. Kurtzke, MD

Individual Patient Data Analysis of Randomized Clinical Trials: Impact of Black Race on Castration-resistant Prostate Cancer Outcomes

BackgroundPopulation data suggest that black men have a higher risk of dying from prostate cancer (PCa) than other racial ethnicities. ObjectiveTo examine the impact of black race on progression-free survival (PFS) and overall survival (OS) among men with metastatic castration-resistant PCa (mCRPC) enrolled in randomized controlled trials (RCTs). Design, setting, and participantsA pooled analysis was performed on individual patient data from five modern PCa RCTs available from Project Data Sphere. Outcome measurements and statistical analysisAdjusted hazard ratios (HRs) were calculated to compare black and white race regarding PFS and OS. Subgroup analyses of mCRPC trials were performed based on the control arm treatments (mitoxantrone or docetaxel). Relevant covariates were used for adjustment in all analyses. Results and limitationsA total of 1613 patients were included; 77 were black (4.7%). No significant differences between black and white men's baseline characteristics were noted regarding age, performance status, or pretreatment prostate-specific antigen. The pooled HRs for black race for OS and PFS were 1.01 (95% confidence interval [CI], 0.73–1.35) and 1.29 (95% CI, 0.95–1.76), respectively. The median OS for black compared with white men was 254 versus 238 d (p=0.92), respectively, with mitoxantrone and 581 versus 546 d (p=0.53), respectively, with docetaxel. The primary limitation was the relatively small number of black men enrolled in mCRPC clinical trials. ConclusionsIn the context of RCTs, in which patients receive generally uniform treatment, a significant difference in OS for black men could not be detected in mCRPC. Black men continue to be dramatically underrepresented in RCTs, and efforts are needed to increase minority accrual to these trials. Patient summaryWe looked at the outcomes of men treated in randomized controlled trials to determine the impact of black race on survival. We found that in the context of modern clinical trials, there does not appear to be a significant difference in survival between black and white races; however, a trend for greater progression in black men was noted.

Can rheumatoid arthritis (RA) registries provide contextual safety data for modern RA clinical trials? The case for mortality and cardiovascular disease.

We implemented a novel method for providing contextual adverse event rates for a randomised controlled trial (RCT) programme through coordinated analyses of five RA registries, focusing here on cardiovascular disease (CVD) and mortality. Each participating registry (Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (East Europe, Latin America, India) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan)) defined a main cohort from January 2000 onwards. To address comparability and potential bias, we harmonised event definitions and defined several subcohorts for sensitivity analyses based on disease activity, treatment, calendar time, duration of follow-up and RCT exclusions. Rates were standardised for age, sex and, in one sensitivity analysis, also HAQ. The combined registry cohorts included 57 251 patients with RA (234 089 person-years)-24.5% men, mean (SD) baseline age 58.2 (13.8) and RA duration 8.2 (11.7) years. Standardised registry mortality rates (per 100 person-years) varied from 0.42 (CORRONA) to 0.80 (NOAR), with 0.60 for RCT patients. Myocardial infarction and major adverse cardiovascular events (MACE) rates ranged from 0.09 and 0.31 (IORRA) to 0.39 and 0.77 (SRR), with RCT rates intermediate (0.18 and 0.42), respectively. Additional subcohort analyses showed small and mostly consistent changes across registries, retaining reasonable consistency in rates across the Western registries. Additional standardisation for HAQ returned higher mortality and MACE registry rates. This coordinated approach to contextualising RA RCT safety data demonstrated reasonable differences and consistency in rates for mortality and CVD across registries, and comparable RCT rates, and may serve as a model method to supplement clinical trial analyses for drug development programmes.

Bias in a Randomized Controlled Trial and how these can be Minimised

Randomized Controlled Trial, involving random assignments of participants to interventions, is seen as gold standard to study the effectiveness of an intervention, and has been the most powerful method of research for centuries, with the first recorded clinical trial dated back to 600 B.C by Daniel of Judah [1]. While Sir Bradford Hill is known to be the pioneer of modern day clinical trials for his study on treatment of tuberculosis, it was the French study on treatment of pneumonia by P. C. A. Louis which really marked the beginning of major advances in clinical trial [2,3].

The modern view on the problem of joint pathology rehabilitation

The article provides literature review that reflect a modern view on the problem of articular pathology treatment and rehabilitation. Step-by-step osteoarthritis management schemes, published in the leading recommendations (NICE, OARSI, HKOA) are presented. The results of modern clinical trials, systematic reviews and meta-analyzes on the use of various methods of physical therapy for joints diseases treatment from the standpoint of evidence-based medicine are analyzed. Etiopathogenetic and clinical substantiation for inclusion of physiotherapy measures in rehabilitation programs were given to help maximizing the impact on all links of the pathological process chain. The use of different methods and techniques of physical therapy for osteoarthritis is currently debated, because of the contradictory literature data. Low level of evidence does not allow including physical therapy in the leading guidelines of osteoarthritis management. The reasons for low level of evidence might be small samples and insufficient degree of randomization in the majority of studies. Different sensitivity of patients to physical therapy and presence of associated diseases necessitate individualization of rehabilitation program that makes further large-scale assessment of impact of the physical factors difficult. However, considering physical therapy infinite possibilities, scientists continue to actively explore, constantly improve and implement a lot of new, highly effective methods of physiotherapy in rehabilitation process of osteoarthritis, proving the prospects of this type of conservative therapy.

Cross cultural adaptation of the English version of the IOF-QLQ to Polish, to assess the health-related quality-of-life of patients after a distal radius fracture.

BackgroundA distal radius fracture (DRF) is a common injury that can cause significant pain and lead to a prolonged decrease in physical, emotional, and social functioning. In modern randomized clinical trials, assessing outcomes after a DRF, health-related quality-of-life (HRQoL) is a “must-be” endpoint. Additionally, HRQoL assessments are essential in the clinical decision-making process. The aim of this study to cross-culturally adapt the International Osteoporosis Foundation Quality of Life Questionnaire (IOF QLQ) for patients with a DRF to Polish.MethodsA standard forward-backward translation procedure and pilot-testing were used to prepare the Polish version of the IOF QLQ for use in this case–control study. Patients were eligible if they were between 18–80 years and were within 1–3 days after a non-comminuted DRF. The study group was gender and aged matched with healthy controls. All DRF patients filled out the Polish version of the IOF QLQ, the SF-36 and a demographic questionnaire. Assessment points were set as soon as possible after the fracture, 7 days, 6 weeks, 3, 6, 12, and 18 months after the fracture. Standard validity and reliability analyses were performed.ResultsNinety-seven patients (73 women – 75.3 %) with a mean age of 62.4 ± 7.1 years agreed to take part in the study. The control group consisted of 81 patients (60 women – 74.1 %) with a mean age 63.9 ± 8.2 years. No significant differences were found between the mean age of patients and controls (p = 0.19). Cronbach’s alpha coefficients showed positive internal consistency (0.79–0.89). The interclass correlations for the IOF QLQ domains and the overall score ranged from 0.85 to 0.92. Satisfactory convergent and discriminant validity of the IOF QLQ was seen.ConclusionsThe Polish version of the IOF QLQ for patients with a DRF is a reliable and valid tool for measuring HRQoL. It can be fully recommended for use in clinical settings in the Polish population. When combined with the SF-36 the IOF QLQ allows to obtain a comprehensive HRQoL assessment in patients with a DRF.

New medical therapies for heart failure.

Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics.

Tragedies in Clinical Trials - A History Wrapped Up

Today foremost emphasis is being given to the protection of patient's safety and ethics during the conduct of clinical trials. Serious considerations by regulatory authorities are taken to safeguard the patient's right, safety and wellbeing involved in a clinical trial. In addition considerations like International Conference on Harmonization (ICH) guidelines, Investigational New Drug (IND) application, New Drug Application (NDA), Post Marketing Surveillance (PMS) and Periodic Benefit-Risk Evaluation Report (PBRER) formerly known as Periodic Safety Update Report (PSUR) submissions to different regulatory authorities has also been framed to strengthen ethics and patient's safety. However modern clinical trials have evolved through serious consequences and tragedies like Thalidomide Tragedy, Sulfanilamide Disaster, Clioquinolol Tragedy, etc. associated with high morbidity and mortality. Potential reasons behind these tragedies include unethical clinical practices, inadequate preclinical safety and efficacy data, non-scientific conduct, lack of attentiveness for patient care, misinterpretation of safety data, lack of pharmaco-vigilance, slow withdrawal of drug from market etc. Hence toiling efforts have been made and should be made in investigating lacunas in national as well as international systems that encourage launch of such spurious drugs that needed withdrawals after 10-20 years of public use. This manuscript intends to collect and present data on tragic clinical trials, highlight the tragedies that occurred during the dark era of clinical trials and enumerate various corrective actions taken in response to the lessons learnt during those clinical trials.

You may have worked on more adaptive designs than you think.

According to the clinicaltrials.gov (accessed March 29, 2014), there are >1500 open clinical trials in the field of stroke. During the design of a clinical trial, several important design decisions must be made. Although study success depends on their accuracy, there may be limited information to guide the decisions. Adaptive designs address this uncertainty by allowing a review of accumulating data during an ongoing trial, and modifying trial characteristics accordingly if the interim information suggests that some of the original decisions may not be valid. Correspondingly, adaptive designs have received a great deal of recent attention in the statistical, pharmaceutical, and regulatory fields. However, it is well known that implementing many of the proposed adaptations will require the clinical trials community to address several statistical, logistical, and operational hurdles.1,2 For that reason, although some recent stroke trials have used adaptive methods, it may appear on first glance that adaptive designs are not being widely used. Yet, nearly all current stroke trials use group sequential methodology (interim monitoring) to some extent. Many researchers might think that these group sequential methods are a separate concept from adaptive designs. However, there is a close connection between the 2. I give a brief description of each of these methods and explain how these 2 statistical approaches are related. Having a periodic review of interim efficacy and safety data by an oversight group has become an integral part of modern clinical trials. For the purposes of this article, we will refer to these groups of individuals as a Data and Safety Monitoring Board (DSMB). However, other terms are also used to describe these groups (Data Monitoring Committees, Data Safety Monitoring Committees, etc). The decision to stop a trial early for efficacy (interim data suggest a clear difference between groups) or futility (interim …

Development of High Performance Liquid Chromatography and Mass Spectrometry: a Key Engine of TCM Modernization

Traditional Chinese Medicine (TCM) has been popular for thousand years in prevention and treatment of chronic diseases synergistically with Western medicine while producing mild healing effects and lower side effects. Although many TCMs have been proven effective by modern pharmacological studies and clinical trials, their bioactive constituents and the remedial mechanisms are still not well understood. Researchers have made great efforts to explore the real theory of TCM for many years with different strategies. Development of high performance liquid chromatography (HPLC) and mass spectrometry within recent decade can provide scientists with robust technologies for disclosing the mysterious mask of TCM. In this paper, important innovations of HPLC and mass spectrometry are reviewed in the application of TCM analysis from single compound identification to metabolomic strategy.

The effects of cognitive behavioral therapy as an anti-depressive treatment is falling: A meta-analysis.

A meta-analysis examining temporal changes (time trends) in the effects of cognitive behavioral therapy (CBT) as a treatment for unipolar depression was conducted. A comprehensive search of psychotherapy trials yielded 70 eligible studies from 1977 to 2014. Effect sizes (ES) were quantified as Hedge's g based on the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HRSD). Rates of remission were also registered. The publication year of each study was examined as a linear metaregression predictor of ES, and as part of a 2-way interaction with other moderators (Year × Moderator). The average ES of the BDI was 1.58 (95% CI [1.43, 1.74]), and 1.69 for the HRSD (95% CI [1.48, 1.89]). Subgroup analyses revealed that women profited more from therapy than did men (p < .05). Experienced psychologists (g = 1.55) achieved better results (p < .01) than less experienced student therapists (g = 0.98). The metaregressions examining the temporal trends indicated that the effects of CBT have declined linearly and steadily since its introduction, as measured by patients' self-reports (the BDI, p < .001), clinicians' ratings (the HRSD, p < .01) and rates of remission (p < .01). Subgroup analyses confirmed that the declining trend was present in both within-group (pre/post) designs (p < .01) and controlled trial designs (p = .02). Thus, modern CBT clinical trials seemingly provided less relief from depressive symptoms as compared with the seminal trials. Potential causes and possible implications for future studies are discussed. (PsycINFO Database Record

Kidney transplantation in patients with history of malignancy: Time to rethink the guidelines?

A history of malignancy is often considered a contraindication for kidney transplantation. While the desire to transplant a 'cancer-free' patient is understandable, the current approach neglects the heterogeneity in the natural history of cancers, even within a given tumor type. The information used to formulate current guidelines are dated and fail to reflect the vast resource of modern oncology clinical trials data that should more accurately predict the expected overall survival and recurrence risk of cancer patients. The expected survival for many cancer patients excluded by current guidelines compares favorably with other conditions considered acceptable for transplantation. This review will suggest that close collaboration between transplant teams and oncologists can increase the appropriate use of renal transplantation in cancer patients.