Negative Results Of Clinical Trials Research Articles

MP72-04 ASSOCIATION OF CLINICAL TRIAL ENROLLMENT AND MORTALITY AMONGST PATIENTS WITH ADVANCED PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP72-04 ASSOCIATION OF CLINICAL TRIAL ENROLLMENT AND MORTALITY AMONGST PATIENTS WITH ADVANCED PROSTATE CANCER Rodrigo R Pessoa, Thomas Flaig, Tyler Robin, BORIS Gershman, Michael Bronsert, Kayvon Kiani, Eric Ballon-Landa, Corbin Eule, Elizabeth Kessler, Marc C Smaldone, and Simon P Kim Rodrigo R PessoaRodrigo R Pessoa More articles by this author , Thomas FlaigThomas Flaig More articles by this author , Tyler RobinTyler Robin More articles by this author , BORIS GershmanBORIS Gershman More articles by this author , Michael BronsertMichael Bronsert More articles by this author , Kayvon KianiKayvon Kiani More articles by this author , Eric Ballon-LandaEric Ballon-Landa More articles by this author , Corbin EuleCorbin Eule More articles by this author , Elizabeth KesslerElizabeth Kessler More articles by this author , Marc C SmaldoneMarc C Smaldone More articles by this author , and Simon P KimSimon P Kim More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003340.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Publication bias has been raised as concern in reporting clinical trials with negative results. However, little is known about the degree of publication bias from clinical trials with negative results for prostate cancer. Thus, we sought to elucidate the association of enrollment into a clinical trial and all-cause mortality from a population-based cohort of men with advanced prostate cancer in the U.S. METHODS: From CancerLinQ, a large national database of community oncology practices, all men with N1 and/or M1 advanced prostate cancer were identified from 2011 to 2021. The primary outcome was all-cause mortality. Multivariable Cox Proportional Hazards were used to test the association of overall survival and clinical covariates including clinical trial enrollment. RESULTS: During the study interval, we identified 139,971 men diagnosed with advanced prostate cancer. With a median follow-up of 58 months, only 2.3% of patients were enrolled into a clinical trial (n=3,269). On multivariable analysis adjusting for disease features, Asian (HR: 0.61; p<0.001) race and Hispanic/Latino origin (HR: 0.68; p<0.001) were associated with lower risk of all-cause mortality. Higher ECOG performance status also correlated with higher risk of all-cause mortality (all p<0.001). However, patients enrolled into clinical trials had higher risk of all-cause mortality compared to those patients who were not enrolled (HR: 1.18; p<0.001). CONCLUSIONS: In this population-based cohort of advanced prostate cancer patients, clinical trial enrollment was associated with a higher risk of all-cause mortality. We controlled for pertinent prognostic variables, but it remains possible that poorer prognosis patients are triaged to clinical trials. However, an alternate explanation is that some trials do have worse outcomes than standard of care and these findings raise concern that negative clinical trial results are rarely disseminated. Source of Funding: Schramm Foundation © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1025 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rodrigo R Pessoa More articles by this author Thomas Flaig More articles by this author Tyler Robin More articles by this author BORIS Gershman More articles by this author Michael Bronsert More articles by this author Kayvon Kiani More articles by this author Eric Ballon-Landa More articles by this author Corbin Eule More articles by this author Elizabeth Kessler More articles by this author Marc C Smaldone More articles by this author Simon P Kim More articles by this author Expand All Advertisement PDF downloadLoading ...

Identification of a subpopulation of patients with gastric cancer responsive to PARP inhibitors.

432 Background: Treatment with PARP inhibitors (PARPi) has been approved in some tumors bearing a deficient Homologous Recombination (HR) system. Despite negative results of clinical trials conducted on the overall population of gastric cancer (GC) patients, we wondered whether a PARPi therapeutic strategy might represent a window of opportunity for a subpopulation of these patients. 7-12% of gastric cancers exhibit a mutational signature associated with HR failure, suggesting that these patients might benefit from PARPi. Methods: To analyze responsiveness to PARPi we exploited a proprietary human Gastro-Esophageal Adenocarcinoma (GEA) annotated platform of Patient-Derived Xenografts (PDXs) and PDX-derived primary cells on which we performed in vivo and in vitro experiments. Results: We selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that treatment with PARPi was effective in PDXs harbouring BRCA2 germline mutations and somatic inactivation of the second allele in a microsatellite stable background. PARPi responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency and mutational signatures efficiently stratified responder vs non-responder PDXs. A retrospective analysis on 57 GEA patients showed that those carrying BRCA2 inactivating variants had longer PFS upon platinum-based regimens (used as proxy). In 5 out of 7 BRCA2 germline mutated patients we identified the p.K3326* variant, currently classified as “benign”. However, familial history of cancer, the absence of RAD51 foci in the tumor cells and a high HR deficiency score suggest a deleterious effect for this mutation in gastric cancer. Conclusions: PARP inhibition could represent a new therapeutic perspective for BRCA2 mutated and/or high HRD score GEA patients, including familial intestinal gastric cancer patients.

Neo-adjuvant radiation therapy provides a survival advantage in T3-T4 nodal positive gastric and gastroesophageal junction adenocarcinoma: a SEER database analysis

BackgroundDue to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs.MethodsWe retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T1–2N−, T1–2N+, T3–4N−, and T3–4N+).ResultsOverall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T3–4N+ subgroup [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66–0.95; P = 0.01]. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P < 0.001), but not in diffuse type (P = 0.11) for T3–4N+ patients. In the multivariate competing risk model, NRT still showed survival advantage only in T3–4 N+ patients (subdistribution HR: 0.77; 95% CI: 0.64–0.93; P = 0.006), but not in other subgroups.ConclusionsNRT might benefit resectable gastric and GEJ cancer patients of T3–4 stages with positive lymph nodes, particularly for intestinal-type. Nevertheless, these results should be interpreted with caution, and more data from ongoing RCTs are warranted.

Prospective Role of Peptide-Based Antiviral Therapy Against the Main Protease of SARS-CoV-2.

The recently emerged coronavirus (SARS-CoV-2) has created a crisis in world health, and economic sectors as an effective treatment or vaccine candidates are still developing. Besides, negative results in clinical trials and effective cheap solution against this deadly virus have brought new challenges. The viral protein, the main protease from SARS-CoV-2, can be effectively targeted due to its viral replication and pathogenesis role. In this study, we have enlisted 88 peptides from the AVPdb database. The peptide molecules were modeled to carry out the docking interactions. The four peptides molecules, P14, P39, P41, and P74, had more binding energy than the rest of the peptides in multiple docking programs. Interestingly, the active points of the main protease from SARS-CoV-2, Cys145, Leu141, Ser139, Phe140, Leu167, and Gln189, showed nonbonded interaction with the peptide molecules. The molecular dynamics simulation study was carried out for 200 ns to find out the docked complex’s stability where their stability index was proved to be positive compared to the apo and control complex. Our computational works based on peptide molecules may aid the future development of therapeutic options against SARS-CoV-2.

Personalized therapeutic strategies in HER2-driven gastric cancer.

Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.

Pulmonary Hypertension Roundtable: Drug Development and Negative Clinical Trial Results

Pulmonary Hypertension Roundtable: Drug Development and Negative Clinical Trial Results

К вопросу о кетогенной диете при сахарном диабете 2-го типа

The article deals with the pressing issue of the medical use of the ketogenic diet in the type 2 diabetes mellitus treatment. Obesity has become one of the most acute worldwide problems. The medical community is concerned about a hike in the number of obese people in the world. This leads to heavy consequences, namely an increase in the incidence of diabetes and the development of further complications. The article highlights and reveals the features of the pathogenesis of obesity in adults and children; WHO statistics on this issue are provided. The purpose of this article is to study the latest basic research on the issue of ketogenic diet therapy of type 2 diabetes mellitus; identification of positive and negative results of clinical trials; summary of foreign practical experience. In conclusion, the author says that the issue of the medical use of the ketogenic diet stays open and requires further large-scale research both in Russia and abroad.

The Emergence of a New Conceptual Framework for Alzheimer's Disease.

The New Criteria for the diagnosis of Alzheimer’s disease (AD), published by a group of experts in 2007, have resulted in a revolution in the comprehension of the disease. Before 2007, the diagnosis of AD dementia was done through a process of exclusion: it was considered in the case of patients with a dementia syndrome without identified etiologies. This traditional algorithm had three major limitations that penalize the disease: 1) a low accuracy of the performance which may share responsibility for negative results in clinical trials; 2) a late identification of the patients only when they reach the threshold of dementia which may delay the activation of optimal care; and last but not least, 3) an absence of clear recognition of AD as a disease because of the lack of specific arguments for its identification. Since 2007, the disease has gained a clear definition based on positive evidence: a specific clinical phenotype (the amnestic syndrome of the hippocampal type) and the presence of biomarkers, considered as a biological signature of the disease. Thanks to these positive arguments, AD is a clinically and biologically well-delineated disease, no longer defined as “probable”. It is now possible to certify that a given patient has or does not have the disease. Like diabetes, cancer, hyperthyroidism or any other disorder, AD has now a clear definition with well-defined borders. The disease has entered the world of medicine with identified diseases with a biological fingerprint. This is the story of this adventure that we will present now.

Thoughts About the Negative Results of Clinical Trials in Rehabilitation Medicine

The last decade has witnessed an increase in the number of moderate to large-scale nonpharmacologic stroke recovery trials. While a majority, having tested the superiority of a particular evidence-based intervention, returned negative findings, the rehabilitation research community has gained an important perspective for future efforts. We offer our interpretation first, on why most of the past decade’s trials failed in the sense of not supporting the primary superiority hypothesis, and, second, we provide our perspective on how to solve this problem and thereby inform the next generation of neurorehabilitation clinical trials. The first large-scale randomized controlled trial (RCT) ever conducted in neurorehabilitation was the Extremity Constraint Induced Movement Therapy Evaluation (EXCITE) trial. The majority of stroke recovery trials that followed were based on a prevailing, but as yet immature science of brain-behavior mechanisms for recovery and limited practical know-how about how to select the most meaningful outcomes. The research community had been seduced by a set of preclinical studies, ignited by the 1990’s revolution in neuroscience and an oversimplified premise that high doses of task-oriented training was the most important ingredient to foster recovery. Here, we highlight recent qualitative and quantitative evidence, both mechanistic and theory-driven, that integrates crucial social and personal factors to inform a more mature science better suited for the next generation of recovery-supportive rehabilitation clinical trials.

Calcium channel modulation as a target in chronic pain control.

Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first‐in‐class synthetic version of ω‐conotoxin MVIIA, a peptide blocker of Cav2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use‐dependent block of Cav2.2 channels; activation state‐dependent blockers were hypothesized to circumvent the side effects of state‐independent blockers by selectively targeting high‐frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state‐dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans‐aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus‐evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant‐based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench‐to‐bedside translation of calcium channel modulators.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc

English

The results of published studies with various neuroprotectors seeking to preserve motor neuron function and improve survival in amyotrophic lateral sclerosis patients have poor evidence in humans, although there are several studies in animal models with positive results. A systematic review and meta-analysis of studies on drug treatment options and survival times in animal models and patients with amyotrophic lateral sclerosis from March, 2009 to March, 2015 was conducted. Four hundred eighty-nine (489) articles were found, and from these, we selected 30 preclinical &lsquo;in vivo&rsquo; studies, 18 randomized controlled trials, and four systematic reviews. A meta-analysis confirmed the effectiveness of various drugs in improving the life span in preclinical trials, in particular, Resveratrol, which had a mean difference of 10.8 days (95% CI: 9.57 to 12.02), whereas no drug showed efficacy in clinical trials. The positive results of preclinical studies should be interpreted with caution because there is a mismatch between those results and the negative results in clinical trials. Key words: Amyotrophic lateral sclerosis (ALS), motor neuron disease, drug, treatment.

Methodological Quality of Experimental Stroke Studies Published in the Stroke Journal: Time Trends and Effect of the Basic Science Checklist.

The translational roadblock, characterized by beneficial effects of treatments in experimental studies and subsequent neutral or negative results in clinical trials, is a major problem in cerebrovascular medicine.1 Growing evidence suggests that this may be due, at least in part, to low study quality of experiments resulting in a systematically reduced internal validity of animal studies. The lack of blinding and randomization in experimental studies, for instance, leads to an overestimation of treatment effects and may, therefore, contribute to different results of preclinical and clinical studies.2 As a consequence, the Stroke Therapy Academic Industry Roundtable was founded to develop recommendations on quality characteristics of animal stroke studies.3 Stroke is generally regarded as one of the most important journals in the area of cerebrovascular disease, publishing clinical and experimental studies with the latter focusing on basic mechanisms of cerebral ischemia and on the development of new stroke therapies. To insure the quality of experimental studies, authors need to declare in a checklist cornerstones of study conductance, such as randomization and blinding procedures, definition of inclusion and exclusion criteria, etc, when submitting an article to Stroke . However, whether implementation of the so-called Basic Science Checklist in the submission process in August 2011 improved the quality of preclinical studies is unknown so far. The aim of this study was to analyze time trends of quality and design of preclinical studies published in Stroke from January 2010 through December 2013 and whether implementation of the Basic Science Checklist in August 2011 had an effect on key quality measures. ### Retrieving Publications and Selection of Studies We used the journal’s Archive of All Online Issues4 for the identification of eligible articles published from January 2010 to December 2013. Publications were categorized according to the journal’s article categories as an …

The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

Therapy in pancreatic cancer - and still it moves along!

According to predictions pancreatic ductal adenocarcinoma will be the third most common cancer-related cause of death in 2030 due to its growing incidence and advances in prevention and treatment of other tumor entities. Pancreatic cancer is usually a (too) late diagnosed disease. Already at time of primary diagnosis nearly 80 % of patients have palliative disease due to local irresectability or distant metastases. Even after R0 resection of the primary tumor followed by adjuvant chemotherapy the 5-year overall survival rate does not exceed 20 %. Recently the treatment landscape has significanty changed in metastatic pancreatic cancer. For the first time, we have the opportunity to personalize our therapies in the field of pancreatic cancer. In addition, the range of therapeutic options after failure of first-line treatment expands more and more. After years of stagnation and negative results in clinical trials these advances inspire and dynamize the landscape of new clinical trials in this entity.

Nutri(meta)genetics and cardiovascular disease: novel concepts in the interaction of diet and genomic variation.

In addition to the interaction of nutrition and genetic variation on the genesis and natural history of cardiovascular disease, recent studies have revealed an entire new genome that resides in the trillions of microbes that exist in various human habitats, predominantly in the gut, that may also contribute to the pathogenesis of cardiovascular disease. This microbial genome and the proteins for which it codes have important functions in homeostatic adaptations to the past and present changes in diet and environment accompanying human civilization. Both preclinical and clinical investigations suggest the role of commensal microbiota in promoting adverse cardiovascular risk. Specifically, microbial metabolism of methylated amines leads to direct pro-atherogenic effects in humans. Further investigations are needed to understand the complex relationships among nutritional status, genetic variation, and the microbial genome, which may explain the recent negative results of clinical trials of nutritional interventions such as B vitamin therapy to lower plasma homocysteine levels. The results of such contemporary genomic investigations would allow us to utilize personalized nutritional interventions to reduce cardiovascular risk.

Mitochondria: a pathogenic paradigm in hypertensive renal disease.

Mitochondria were first described in 1840 as bioblasts, elementary organisms responsible for vital cellular functions, but were subsequently named mitochondria, from the Greek names mitos (thread) and chondros (granule), which describes their appearance during spermatogenesis.1 Their discovery generated substantial interest given their structure resembling bacteria, which led in subsequent years to important scientific discoveries positioning mitochondria as the energy powerhouse of the cell. The unique architecture of mitochondria, consisting of 2 membranes (outer and inner) and compartments (intermembrane space and matrix), is crucial for their vital functions. Mitochondria serve not only as primary sources of cellular energy, but also modulate several cellular processes, including oxidative phosphorylation, calcium homeostasis, thermogenesis, oxygen sensing, proliferation, and apoptosis.2 Therefore, mitochondrial injury and dysfunction might be implicated in the pathogenesis of several diseases. Hypertension accounts for nearly 30% of patients reaching end-stage renal disease.3 Renal injury secondary to hypertension or to ischemia associated with renovascular hypertension (distal to renal artery stenosis) may have significant and detrimental effect on health outcomes. Studies have highlighted several deleterious pathways, including inflammation, oxidative stress, and fibrosis that are activated in the hypertensive kidney, eliciting functional decline.4,5 However, the precise molecular mechanisms responsible for renal injury have not been fully elucidated. Over the past few years, increasing evidence has established the experimental foundations linking mitochondrial alterations to hypertensive renal injury (Table). Mitochondriopathies, abnormalities of energy metabolism secondary to sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA) genes, may contribute to the development and progression of hypertension and its complications. In addition, several studies have reported mitochondrial damage and dysfunction consequent to hypertensive renal disease. View this table: Table. Evidence of Renal Mitochondrial Damage in Models of Hypertension and Antihypertensive Treatment Importantly, hypertensive-induced renal injury is characterized by activation of several deleterious pathways, including oxidative stress, renin–angiotensin–aldosterone …

Effects of Chronic Methylphenidate on Cocaine Self-Administration under a Progressive-Ratio Schedule of Reinforcement in Rhesus Monkeys

It has been hypothesized that drugs that serve as substrates for dopamine (DA) and norepinephrine (NE) transporters may be more suitable medications for cocaine dependence than drugs that inhibit DA and NE uptake by binding to transporters. Previous studies have shown that the DA/NE releaser d-amphetamine can decrease cocaine self-administration in preclinical and clinical studies. The present study examined the effects of methylphenidate (MPD), a DA uptake inhibitor, for its ability to decrease cocaine self-administration under conditions designed to reflect clinically relevant regimens of cocaine exposure and pharmacotherapy. Each morning, rhesus monkeys pressed a lever to receive food pellets under a fixed-ratio 50 schedule of reinforcement; cocaine was self-administered under a progressive-ratio schedule of reinforcement in the evening. After cocaine (0.003-0.56 mg/kg per injection, i.v.) dose-response curves were determined, self-administration sessions were suspended and MPD (0.003-0.0056 mg/kg per hour, i.v.; or 1.0-9.0 mg/kg p.o., b.i.d.) was administered for several weeks. A cocaine self-administration session was conducted every 7 days. When a MPD dose was reached that either persistently decreased cocaine self-administration or produced disruptive effects, the cocaine dose-effect curve was re-determined. In most cases, MPD treatment either produced behaviorally disruptive effects or increased cocaine self-administration; it took several weeks for these effects to dissipate. These data are consistent with the largely negative results of clinical trials with MPD. In contrast to the positive effects with the monoamine releaser d-amphetamine under identical conditions, these results do not support use of monoamine uptake inhibitors like MPD as a medication for cocaine dependence.

Primary sclerosing cholangitis: a review and update on therapeutic developments

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease characterized by fibro-obliterative inflammation of the hepatic bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and in some cases, cholangiocarcinoma. Despite clinical trials of nearly 20 different pharmacotherapies over several decades, safe and effective medical therapy, albeit critically needed, remains to be established. PSC is pathogenically complex, with genetic, immune, enteric microbial, environmental and other factors being potentially involved and, thus, not surprisingly, it manifests as a clinically heterogeneous disease with a relatively unpredictable course. It is likely that this complexity and clinical heterogeneity are responsible for the negative results of clinical trials, but novel insights about and approaches to PSC may shift this trend. The authors herein provide a review of previously tested pharmacologic agents, discuss emerging fundamental concepts and present viewpoints regarding how identifying therapies for PSC may evolve over the next several years.

Letter by Fuentes et al Regarding Article, “J-Shaped Association Between Serum Glucose and Functional Outcome in Acute Ischemic Stroke”

Response: We thank Fuentes et al for their interest in our work1 and for their comments. We agree that hypoglycemic values occur only rarely at admission in stroke patients. To confirm this further, we performed an updated evaluation of our registry,2 which showed that between January 2003 and November 2010, there were only 4 patients (0.18%) and 10 patients (0.44%) with admission glucose levels of <3.7 and <4 mmol/L, respectively. The association of hypoglycemic values with unfavorable outcome as described by the J-curve1 seems to be of little clinical …

Negative Clinical Trial Results Less Likely to Be Published; Pfizer Said to Have Hidden Negative Trial Results

Negative Clinical Trial Results Less Likely to Be Published; Pfizer Said to Have Hidden Negative Trial Results