The Opioid Analgesic Reduction Study (OARS) Pilot: A Double-Blind Randomized Multicenter Trial.

BACKGROUND: With addiction rates and opioid deaths increasing, health care providers are obligated to help stem the opioid crisis. As limited studies examine the comparative effectiveness of fixed-dose combination nonopioid analgesia to opioid-containing analgesia, a comparative effectiveness study was planned and refined by conducting a pilot study. METHODS: The Opioid Analgesic Reduction Study (OARS) pilot, a stratified, randomized, multisite, double-blind clinical trial, was designed to test technology and procedures to be used in the full OARS trial. Participants engaged in the full protocol, enabling the collection of OARS outcome data. Eligible participants reporting to 1 of 5 sites for partial or full bony impacted mandibular third molar extraction were stratified by biologic sex and randomized to 1 of 2 treatment groups, OPIOID or NONOPIOID. OPIOID participants were provided 20 doses of hydrocodone 5 mg/acetaminophen 300 mg. NONOPIOID participants were provided 20 doses of ibuprofen 400 mg/acetaminophen 500 mg. OARS outcomes data, including pain experience, adverse effects, sleep quality, pain interference, overall satisfaction, and remaining opioid tablets available for diversion, were collected via surveys, electronic medication bottles, eDiary, and activity/sleep monitor. RESULTS: Fifty-three participants were randomized with 50 completing the OARS pilot protocol. Across all outcome pain domains, in all but 1 time period, NONOPIOID was better in managing pain than OPIOID (P < 0.05 level). Other outcomes suggest less pain interference, less adverse events, better sleep quality, better overall satisfaction, and fewer opioid-containing tablets available for diversion. DISCUSSION: Results suggest patients requiring impacted mandibular third molar extraction would benefit from fixed-dose combination nonopioid analgesia. KNOWLEDGE TRANSFER STATEMENT: Study results suggest fixed-dose nonopioid combination ibuprofen 400 mg/acetaminophen 500 mg is superior to opioid-containing analgesic (hydrocodone 5 mg/acetaminophen 500 mg). This knowledge should inform surgeons and patients in the selection of postsurgical analgesia.

Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

Patient mortality following alcohol use and trauma: a propensity-matched analysis.

OBJECTIVE: To examine the outcomes of trauma patients who tested positive for alcohol at the time of hospital arrival versus those who tested negative. METHODS: Data were pulled from the National Trauma Data Bank (2007-2010). All injured patients who were ≥14 years of age, sustained a "blunt" or "penetrating" injury, had complete systolic blood pressure (SBP) and heart rate (HR) records, were taken to a level 1 or 2 trauma center, and who received a confirmed blood alcohol test were included in the study. Any blood alcohol concentration (BAC) above the legal limit (≥0.08 g/dL) was considered "positive" for alcohol, and if no alcohol was identified it was considered "negative". Patients' demography and clinical information were compared across groups using Chi-square and Wilcoxon rank sum tests. Logistic regression, propensity score matching, and a follow-up paired analysis were also performed. RESULTS: Of 279,460 total patients, around one-third of the patients (92,960) tested positive for BAC. There were clear demographic differences found between the two groups regarding age, gender, race, and injury type. There was also a significantly higher mortality rate (4.3 vs. 3.1%, P < 0.001) and a longer hospital length of stay (4 vs. 3 days, P < 0.001) found in the alcohol-negative group. Propensity score matching was also performed resulting in 92,959 patients per group. Using the paired data, the overall mortality observed was 3.1 vs. 3.3% (P = 0.035) between the alcohol-positive and alcohol-negative groups, respectively. There was no significant difference noted in the total hospital length of stay (median: 3 vs. 4 days, P = 0.84). CONCLUSION: Patients who tested positive for alcohol following a traumatic injury showed no clinically significant reduction in mortality and no significant difference in total hospital length of stay.

Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA.

Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM).

A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the World Health Organization (WHO)-classification-based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features, and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that the WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS with the IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS versus IPSS-R model. Overall, both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant in formation for the implementation of risk-adapted strategies in MDS.

Monosomal karyotype in MDS: explaining the poor prognosis?

Monosomal karyotype (MK) is associated with an adverse prognosis in patients in acute myeloid leukemia (AML). This study analyzes the prognostic impact of MK in a cohort of primary, untreated patients with myelodysplastic syndromes (MDS). A total of 431 patients were extracted from an international database. To analyze whether MK is an independent prognostic marker in MDS, cytogenetic and clinical data were explored in uni- and multivariate models regarding overall survival (OS) as well as AML-free survival. In all, 204/431 (47.3%) patients with MK were identified. Regarding OS, MK was prognostically significant in patients with ≤ 4 abnormalities only. In highly complex karyotypes (≥ 5 abnormalities), MK did not separate prognostic subgroups (median OS 4.9 months in MK+ vs 5.6 months in patients without MK, P=0.832). Based on the number of abnormalities, MK-positive karyotypes (MK+) split into different prognostic subgroups (MK+ and 2 abnormalities: OS 13.4 months, MK+ and 3 abnormalities: 8.0 months, MK+ and 4 abnormalities: 7.9 months and MK+ and ≥ 5 abnormalities: 4.9 months; P<0.01). In multivariate analyses, MK was not an independent prognostic factor. Our data support the hypothesis that a high number of complex abnormalities, associated with an instable clone, define the subgroup with the worst prognosis in MDS, independent of MK.

Molecular and genetic features of myelodysplastic syndromes.

Multifactorial pathogenetic features underlying myelodysplastic syndromes (MDS) relate to inherent abnormalities within the hematopoietic precursor cell population. The predominant final common pathogenetic pathway causing ineffective hematopoiesis in MDS has been the varying degrees of apoptosis of the hematopoietic precursors and their progeny. A variety of molecular abnormalities have been demonstrated in MDS. These lesions are attributable to nonrandom cytogenetic and oncogenic mutations, indicative of chromosomal and genetic instability, transcriptional RNA splicing abnormalities, and epigenetic changes. Evolutionary cytogenetic changes may occur during the course of the disorder, which are associated with disease progression. These genetic derangements reflect a multistep process believed to underlie the transformation of MDS to acute myeloid leukemia. Recent findings provide molecular insights into specific gene mutations playing major roles for the development and clinical outcome of MDS and their propensity to progress to a more aggressive stage. Use of more comprehensive and sensitive methods for molecular profiling using 'next-generation' sequencing techniques for MDS marrow cells will likely further define critical biologic lesions underlying this spectrum of diseases.

Single-chain VαVß T-cell receptors function without mispairing with endogenous TCR chains.

Transduction of exogenous T-cell receptor (TCR) genes into patients' activated peripheral blood T cells is a potent strategy to generate large numbers of specific T cells for adoptive therapy of cancer and viral diseases. However, the remarkable clinical promise of this powerful approach is still being overshadowed by a serious potential consequence: mispairing of the exogenous TCR chains with endogenous TCR chains. These 'mixed' heterodimers can generate new specificities that result in graft-versus-host reactions. Engineering TCR constant regions of the exogenous chains with a cysteine promotes proper pairing and reduces the mispairing, but, as we show here, does not eliminate the formation of mixed heterodimers. By contrast, deletion of the constant regions, through use of a stabilized Vα/Vß single-chain TCR (scTv), avoided mispairing completely. By linking a high-affinity scTv to intracellular signaling domains, such as Lck and CD28, the scTv was capable of activating functional T-cell responses in the absence of either the CD3 subunits or the co-receptors, and circumvented mispairing with endogenous TCRs. Such transduced T cells can respond to the targeted antigen independent of CD3 subunits via the introduced scTv, without the transduced T cells acquiring any new undefined and potentially dangerous specificities.

Difficult physician-patient encounters.

Consultant physicians encounter patients, and families and carers of patients, who leave us feeling helpless, frustrated, irritated and even angry. There are limited opportunities for trainees and physicians to discuss how to recognize, manage, learn from and prevent these difficult physician-patient encounters. This paper addresses factors, including physician factors, that may contribute to making encounters difficult, categorizes the types of difficult encounters and provides generic and specific suggestions (based in part on published literature and in part on our personal experience) about prevention and management of many of them.

Cautionary tales in the interpretation of studies of tools for predicting risk and prognosis.

Assessing future risk or prognosis in individual subjects is an often difficult and humbling task for clinicians. In recent times numerous prediction tools have been developed to make the task more accurate and thereby render management decisions more appropriate. If these tools are to be used effectively, an understanding is needed of their method of development, performance characteristics, ease of use and applicability in clinical settings, and potential impact on clinical decision-making. In this fourth article in a series on critical appraisal, we discuss questions that need to be asked of any new risk prediction tool.

The risks and costs of multiple-generic substitution of topiramate.

OBJECTIVE: To investigate clinical and economic consequences following generic substitution of one vs multiple generics of topiramate (Topamax; Ortho-McNeil Neurologics, Titusville, NJ). METHODS: Medical and pharmacy claims data of Régie de l'Assurance-Maladie du Québec from January 2006 to October 2007 were used. Patients with epilepsy treated with topiramate were selected. An open-cohort design was used to classify the observation period into periods of brand, single-generic, and multiple-generic use. One-year generic-switch and switchback-to-brand rates were estimated using Kaplan-Meier methodology. Medical resource utilization and costs were compared among the three periods using multivariate regression analysis. RESULTS: In total, 948 patients were observed during 1,105 person-years of brand use, 233 person-years of single-generic use, and 92 person-years of multiple-generic use. A total of 23% of generic users received at least two different generic versions. Compared to brand use, multiple-generic use was associated with higher utilization of other prescription drugs (incidence rate ratio [IRR] = 1.27, 95% confidence interval [CI] = 1.24-1.31), higher hospitalization rates (0.48 vs 0.83 visit/person-year, IRR = 1.65, 95% CI = 1.28-2.13), and longer hospital stays (2.6 vs 3.9 days/person-year, IRR = 1.43, 95% CI = 1.27-1.60), but the effect was less pronounced in single-generic use (hospitalization: IRR = 1.08, 95% CI = 0.88-1.34, length of stay: IRR = 1.12, 95% CI = 1.03-1.23). The risk of head injury or fracture was nearly three times higher (hazard ratio = 2.84, 95% CI = 1.24-6.48) following a generic-to-generic switch compared to brand use. The total annualized health care cost per patient was higher in the multiple-generic than brand periods by C$1,716 (cost ratio = 1.21, p = 0.0420). CONCLUSION: Multiple-generic substitution of topiramate was significantly associated with negative outcomes, such as hospitalizations and injuries, and increased health care costs.

Cautionary tales in the clinical interpretation of studies of diagnostic tests.

The use of investigational tests in making a diagnosis is a core activity of physicians and one that requires an understanding of the accuracy and usefulness of specific tests in discriminating between several diagnostic possibilities. Studies of diagnostic tests are frequently methodologically flawed and their results are often not well understood or applied in clinical practice. This article defines the performance characteristics of diagnostic tests, describes several commonly encountered deficiencies in study design which may invalidate reports of new diagnostic tests, and explains a Bayesian approach to interpreting test results in terms of disease probability.

Chronic disease management: time for consultant physicians to take more leadership in system redesign.

There is a need for system redesign to meet the needs of individuals with chronic disease. New models of chronic disease care include team-based paradigms that focus on continuous and patient-centred care. In such models the roles of providers and patients must change. In this article we focus on new roles for consultant physicians, as well as barriers and incentives to these roles.

Decline in haemoglobin A1c values in diabetic patients receiving interferon-alpha and ribavirin for chronic hepatitis C.

Haemoglobin A1c (A1c) levels are lower during haemolysis because of the shorter exposure of haemoglobin (Hb) to plasma glucose. Ribavirin (RBV) used in combination with interferon-alpha (IFN) for chronic hepatitis C causes reversible haemolytic anaemia. This study examined the extent to which RBV treatment influences A1c levels in diabetic patients. A retrospective analysis identified 32 diabetic patients who underwent hepatitis C treatment with IFN and RBV. Each subject had at least three measures of A1c, Hb and glucose: before, during and after therapy. A1c values decreased from a mean pretreatment level of 7.2% to an on-treatment A1c level of 5.2% [mean paired difference -2.01%; 95% confidence interval (CI) -1.59% to -2.43%; P < 0.001]. During therapy, mean Hb levels decreased from 15.1 g/dL at baseline to a nadir of 11.7 g/dL (P < 0.001) with a rise in lactose dehydrogenase levels and reticulocyte counts, and unchanged mean corpuscular volume values confirming haemolysis. At the same time, glucose levels declined by a mean of 38.4 mg/dL (95% CI 13.4-63.5 mg/dL; P = 0.002) as did body weights by a mean of 3.15 kg (P < 0.001). According to published glucose-A1c correlation tables, this decline of glucose concentration by 38.4 mg/dL correlates to a decline in A1c level of 1.08%. In conclusion, reductions of A1c levels by a mean of 2.01% during hepatitis C therapy with IFN + RBV are due to a combination of decreased glucose levels (1.08%) and RBV-induced haemolysis (0.93%). A1c levels should not be measured during hepatitis C treatment with IFN + RBV because they do not adequately reflect glycaemic control.

Cautionary tales in the interpretation of systematic reviews of therapy trials.

This is the second in a series of articles emphasizing the cautions in the interpretation of health-care studies. Systematic reviews are presented as comprehensive, unbiased summaries of evidence and are often referred to by clinicians, guideline developers and health policy-makers. Their strengths and limitations, and how their results can be subject to bias and misinterpretation, are discussed.