Publications

OBJECTIVES: The aim of this study was to evaluate how often the European Medicines Agency (EMA) has authorized drugs based on nonrandomized studies and whether there is an association between treatment effects and EMA preference for further testing in randomized clinical trials (RCTs).

STUDY DESIGN AND SETTING: We reviewed all initial marketing authorizations in the EMA database on human medicines between 1995 and 2015 and included authorizations granted without randomized data. We extracted data on treatment effects and EMA preference for further testing in RCTs.

RESULTS: Of 723 drugs, 51 were authorized based on nonrandomized data. These 51 drugs were licensed for 71 indications. In the 51 drug-indication pairs with no preference for further RCT testing, effect estimates were large [odds ratio (OR): 12.0 (95% confidence interval {CI}: 8.1-17.9)] compared to effect estimates in the 20 drug-indication pairs for which future RCTs were preferred [OR: 4.3 (95% CI 2.8-6.6)], with a significant difference between effects (P = 0.0005).

CONCLUSION: Nonrandomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on nonrandomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.

RATIONALE, AIMS, AND OBJECTIVES: Decision curve analysis (DCA) is a widely used method for evaluating diagnostic tests and predictive models. It was developed based on expected utility theory (EUT) and has been reformulated using expected regret theory (ERG). Under certain circumstances, these 2 formulations yield different results. Here we describe these situations and explain the variation.

METHODS: We compare the derivations of the EUT- and ERG-based formulations of DCA for a typical medical decision problem: "treat none," "treat all," or "use model" to guide treatment. We illustrate the differences between the 2 formulations when applied to the following clinical question: at which probability of death we should refer a terminally ill patient to hospice?

RESULTS: Both DCA formulations yielded identical but mirrored results when treatment effects are ignored; they generated significantly different results otherwise. Treatment effect has a significant effect on the results derived by EUT DCA and less so on ERG DCA. The elicitation of specific values for disutilities affected the results even more significantly in the context of EUT DCA, whereas no such elicitation was required within the ERG framework.

CONCLUSION: EUT and ERG DCA generate different results when treatment effects are taken into account. The magnitude of the difference depends on the effect of treatment and the disutilities associated with disease and treatment effects. This is important to realize as the current practice guidelines are uniformly based on EUT; the same recommendations can significantly differ if they are derived based on ERG framework.

Prognostic biomarkers in allogeneic hematopoietic cell transplantation (allo-HCT) are needed to improve risk assessment and help guide therapeutic and surveillance strategies to mitigate the risk of death from the procedure. We previously identified hypoalbuminemia at day +90 post-transplantation as an independent predictor of increased nonrelapse mortality (NRM) and inferior overall survival (OS) in patients with acute myelogenous leukemia and myelodysplastic syndrome who were treated with an allo-HCT. Here, we aim to confirm the prognostic significance of day +90 hypoalbuminemia in 783 patients, median age 52 years (range, 18 to 76), who received an allo-HCT for various hematologic malignancies and bone marrow failure syndromes. Multivariate analysis for NRM demonstrated a negative effect of low serum albumin levels (<3.0 versus 3.0 to 3.5 versus >3.5 g/dL) at day +90 post-transplantation (hazard ratios, 8.03 [95% CI, 3.59 to 17.97] versus 2.84 [95% CI, 1.59 to 5.08] versus reference; P < .0001). This was also the case for OS (hazard ratios, 6.86 [95% CI, 4.24 to 11.10] versus 1.52 [95% CI, 1.05 to 2.20] versus reference; P < .0001). Patients with hypoalbuminemia at day +90 post-transplantation are more likely to die from causes other than relapse, particularly infections. This large study confirms the ability of day +90 serum hypoalbuminemia to predict worse NRM and inferior OS. Presence of hypoalbuminemia at day +90 should drive a more rigorous real-time surveillance strategy considering the anticipated high-risk of NRM and poor survival in these patients. Future studies should consider incorporating day +90 serum albumin levels in prognostic models of NRM and OS.

Statins are widely prescribed, yet statin muscle pain limits their use, leading to increased cardiovascular risk. No validated therapy for statin muscle pain exists. The goal of the study was to assess whether metformin was associated with reduced muscle pain. A secondary analysis of data from the ACCORD trial was performed. An ACCORD sub-study assessed patients for muscle cramps and leg/calve pain while walking, typical non-severe statin muscle pain symptoms. We compared muscle pain between patients using a statin (n = 445) or both a statin and metformin (n = 869) at baseline. Overall patient characteristics were balanced between groups. Unadjusted analysis showed fewer reports of muscle cramps (35%) and leg/calve pain while walking (40%) with statins and metformin compared to statin only (muscle cramps, 42%; leg/calve pain while walking, 47%). Multivariable regression demonstrated a 22% odds reduction for muscle cramps (P = 0.049) and a 29% odds reduction for leg/calve pain while walking (P = 0.01). Metformin appears to reduce the risk of non-severe statin muscle pain and additional research is needed to confirm the findings and assess metformin's impact on statin adherence and related cardiovascular outcomes.

Hypoalbuminaemia has been previously described to predict worse non-relapse mortality (NRM) and inferior overall survival (OS) in allogeneic haematopoietic cell transplant (allo-HCT) recipients. Here, we evaluate the role of hypoalbuminaemia (<35 g/l) at time of onset of acute graft-versus-host disease (aGVHD) when incorporated into the refined aGVHD score. The study population consisted of 522 patients, median age 53 (18-75) years, who underwent an allo-HCT mostly for haematological malignancies. Standard risk (SR) aGVHD comprised 467 patients (89%) and the number of high risk (HR) cases was 55 (11%). Median follow-up for all surviving patients was 26 (3-55) months. Two-year OS was significantly better in patients with SR aGVHD with a serum albumin ≥35 g/l compared to SR with albumin <35 g/l [70% (95% CI = 64-76%) vs. 49% (95% CI = 42-56%), P < 0·0001]. Also, patients with SR aGVHD and a serum albumin level of ≥35 g/l had a significantly lower NRM at 1-year post-transplantation [6% (95% CI = 3-10%) vs. 25% (95% CI = 20-32%), P < 0·0001]. After our findings are validated in a large cohort of patients, we propose that hypoalbuminaemia should be incorporated into the refined aGVHD risk score to further its ability to predict outcomes within this group.

Background Cardiac autonomic neuropathy is thought to cause adverse cardiovascular effects in diabetes mellitus. Pulmonary vein ganglia ( PVG ), which have been implicated in normal and abnormal heart rhythm regulation, have not been fully investigated in type 1 diabetes mellitus (T1D). We examined the functional and anatomical effects of T1D on PVG and studied the details of T1D-induced remodeling on the PVG structure and function. Methods and Results We used a mouse model of T1D (Akita mouse), immunofluorescence, isolated Langendorff-perfused hearts, and mathematical simulations to explore the effects of T1D on PVG . Whole-mount atrial immunofluorescence of choline acetyltransferase and tyrosine hydroxylase labeling showed that sympathetic and parasympathetic somas of the PVG neurons were significantly hypotrophied in T1D hearts versus wild type. Stimulation of PVG in isolated Langendorff-perfused hearts caused more pronounced P-P interval prolongation in wild type compared with Akita hearts. Propranolol resulted in a comparable P-P prolongation in both phenotypes, and atropine led to more pronounced P-P interval shortening in wild type compared with Akita hearts. Numerical modeling using network simulations revealed that a decrease in the sympathetic and parasympathetic activities of PVG in T1D could explain the experimental results. Conclusions T1D leads to PVG remodeling with hypotrophy of sympathetic and parasympathetic cell bodies and a concomitant decrease in the PVG sympathetic and parasympathetic activities.

BACKGROUND: Next-generation sequencing has identified somatic mutations that are prognostic of cancer.

PATIENTS AND METHODS: We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen.

RESULTS: The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival.

CONCLUSION: This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.

BACKGROUND: A 48-hour wireless capsule results often vary from the first to second day. Previous investigations comparing discrepant acid reflux readings have yielded variable results. In this study we investigated differences in data obtained on day 1 versus day 2, and the effect of time of capsule placement on discrepancies.

METHODS: We performed a retrospective cohort study. Patients undergoing a 48-hour wireless capsule study between January 2012 through November 2013 were eligible for inclusion. We collected reflux data for each patient and calculated the proportion of patients in four groups based on abnormal DeMeester score groups (+/+, -/+, +/-, -/-). We placed patients into morning placement or afternoon placement categories and calculated the proportions of patients with various DeMeester score discrepancies.

KEY RESULTS: This study evaluated 229 patients. The mean day 1 DeMeester score was 28.38 and the mean day 2 DeMeester score was 23.24 (P<0.0001). The mean day 1 DeMeester score in the morning group was 24.9 and 31.7 in the afternoon group (P<0.05). The mean total DeMeester score in the morning placement group was 23.1 and 30.6 in the afternoon group (P<0.05). Twenty-five percent of afternoon patients had a +day 1/-day 2 DeMeester discordance, whereas only 12% of morning placement patients had this discordance (P=0.26).

CONCLUSIONS: Afternoon capsule placement is associated with a significantly increased amount of acid reflux on day 1. Approximately 10% of 48-hour esophageal wireless monitoring studies may falsely overestimate reflux when the capsule is placed in the afternoon. Capsule placement should ideally be performed in the morning.

The tissue expansion process is done after mastectomies to increase the submuscular space in preparation for the placement of permanent breast implant. The process is often believed to be painful by patients who are often intimidated by the prospect of mechanically stretching out their skin and muscle. This study aims to quantify the pain experienced by patients and determine the different pain management techniques used. We used a case series approach, in which patients who were undergoing serial tissue expansion process were asked to rate their pain and anxiety on a scale from 1 to 10, using a questionnaire and the visual analog scale. Pain was rated during and after the expansion procedure, and patients were also surveyed to find the most commonly used and most effective pain management technique. Patients typically reported very little pain during and after the procedure, with an average of 0.4 to 2.5 pain experienced out of 10. The pain did not last, on average, longer than 1 day. Furthermore, the most widely used and most helpful pain medication was ibuprofen. During the tissue expansion procedure, the mean anxiety level was 0.64 (1.3). The findings show that tissue expansion process is a relatively low pain procedure and is not a contraindication for undergoing breast reconstruction. Ibuprofen, a mild treatment with few side effects, was efficacious in pain relief though most patients required no pain relief.

BACKGROUND: Increasing number of patients with preexisting breast implants desire breast conservation therapy for breast cancer. There is paucity of comparative data on tumor margins and re-excisions in these patients. High re-excision rates up to 25% have been reported in breast conservation therapy patients; efforts to obtain cosmesis and avoid implant rupture might increase this further. We analyzed tumor margins, re-excision rates, and recurrence in previously augmented versus non-augmented patients undergoing lumpectomy for breast cancer. We preserved preexisting implants if feasible with oncologic clearance and cosmesis.

METHODS: Institutional review board-approved retrospective analysis was performed on patients undergoing lumpectomy with history of prior breast augmentation (N = 52) and consecutively selected non-augmented patients (N = 51). Based on tumor distance to inked margin, we grouped margins as negative (≥2 mm), close (<2 mm), and positive. Patients were followed up clinically and with imaging in the outpatient clinic, and recurrences were documented.

RESULTS: Patients in the non-augmented group were significantly more likely to have larger tumors (T2 and above; P = 0.05) compared with the augmented group. Although more patients in the augmented group had positive margins, this was not statistically significant (6 vs 3, P = 0.86). No difference was noted between re-excision rates among the augmented versus non-augmented groups (21.1% vs 19.6%, respectively; odds ratio, 0.91; 95% confidence interval, 0.35-2.37; P = 0.85); these remained unchanged even when adjusting for tumor stage (P = .75) and margins (P = 0.73). Although more patients in the augmented group recurred (4 vs 0), this was not statistically significant (P = 0.1).

CONCLUSIONS: Our results indicate that, from the oncological standpoint, patients with prior augmentation can undergo lumpectomy with equivalent tumor margins and re-excision rates. To the best of our knowledge, this is the first reported comparative study between these 2 groups.