To determine the effect of estrogen replacement therapy (ERT) on recurrence rate and survival in women who have undergone surgery for stage I or II endometrial cancer.
After surgery, eligible ...patients were allocated to therapy with ERT or placebo after undergoing hysterectomy with or without pelvic and aortic nodal sampling. Planned duration of hormonal versus placebo treatment was 3 years, with an additional 2 years of follow-up.
The median follow-up time for all 1,236 eligible and assessable patients was 35.7 months. Stage, grade, histologic subtype, and percentage of patients receiving adjuvant therapy were similarly distributed between the groups. The median age at diagnosis for the 618 patients randomly assigned to ERT was 57 years (range, 26 to 91 years). Two hundred fifty-one patients (41.1%) were compliant with ERT for the entire treatment period. Disease recurrence was experienced in 14 patients (2.3%). Eight patients (1.3%) developed a new malignancy. There were 26 deaths (4.2%), and five deaths (0.8%) were a result of endometrial cancer. The median age at diagnosis for the 618 patients in the placebo group was 57 years (range, 30 to 88 years). Twelve patients (1.9%) experienced disease recurrence. Ten patients (1.6%) developed a new malignancy. There were 9 deaths (3.1%) in the placebo group, and four deaths (0.6%) were a result of endometrial cancer.
Although this incomplete study cannot conclusively refute or support the safety of exogenous estrogen with regard to risk of endometrial recurrence, it is noteworthy that the absolute recurrence rate (2.1%) and the incidence of new malignancy were low.
HbA1c from ≥ 5.7% to < 6.5% (39-46 mmol/mol) indicates prediabetes according to American Diabetes Association guidelines, yet its identification of prediabetes specific for type 1 diabetes has not ...been assessed. A composite glucose and C-peptide measure, Index60, identifies individuals at high risk for type 1 diabetes.
We compared Index60 and HbA1c thresholds as markers for type 1 diabetes risk.
TrialNet Pathway to Prevention study participants with ≥ 2 autoantibodies (GADA, IAA, IA-2A, or ZnT8A) who had oral glucose tolerance tests and HbA1c measurements underwent 1) predictive time-dependent modeling of type 1 diabetes risk (n = 2776); and 2) baseline comparisons between high-risk mutually exclusive groups: Index60 ≥ 2.04 (n = 268) vs HbA1c ≥ 5.7% (n = 268). The Index60 ≥ 2.04 threshold was commensurate in ordinal ranking with the standard prediabetes threshold of HbA1c ≥ 5.7%.
In mutually exclusive groups, individuals exceeding Index60 ≥ 2.04 had a higher cumulative incidence of type 1 diabetes than those exceeding HbA1c ≥ 5.7% (P < 0.0001). Appreciably more individuals with Index60 ≥ 2.04 were at stage 2, and among those at stage 2, the cumulative incidence was higher for those with Index60 ≥ 2.04 (P = 0.02). Those with Index60 ≥ 2.04 were younger, with lower BMI, greater autoantibody number, and lower C-peptide than those with HbA1c ≥ 5.7% (P < 0.0001 for all comparisons).
Individuals with Index60 ≥ 2.04 are at greater risk for type 1 diabetes with features more characteristic of the disorder than those with HbA1c ≥ 5.7%. Index60 ≥ 2.04 is superior to the standard HbA1c ≥ 5.7% threshold for identifying prediabetes in autoantibody-positive individuals. These findings appear to justify using Index60 ≥ 2.04 as a prediabetes criterion in this population.
Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or ...prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.
We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.
A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.
Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.
Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, ...develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15-65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0-40) was an average of 3.15 for all participants (range 0-14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean=50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed episodic ataxia type 1 and episodic ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed episodic ataxia type 1 (21%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.
Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies ...show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.
We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18–45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L−1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed).
Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI −0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six 13% participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten 22% participants in the imatinib group and two 9% in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events.
A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required.
Juvenile Research Diabetes Foundation.
Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in ...recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy.
We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial.
Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants.
Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials.
Concurrent chemoradiotherapy is the standard of care for locally advanced cervix cancer; the optimal chemotherapy regimen is not yet defined. This trial was designed to compare the outcome of ...protracted venous infusion (PVI) fluorouracil (FU) with standard weekly cisplatin and concurrent radiation therapy (RT).
Patients with stage IIB, IIIB, and IVA cervical cancer with clinically negative aortic nodes were eligible. Pelvic RT dose was 45 Gy with a parametrial boost to involved sides of 5.4 to 9 Gy, and high- or low-dose rate intracavitary brachytherapy. Standard therapy was weekly cisplatin 40 mg/m2, and experimental therapy was PVI FU 225 mg/m2/d for 5 d/wk for six cycles during RT.
The study was closed prematurely when a planned interim futility analysis indicated that PVI FU/RT had a higher treatment failure rate (35% higher) and would, most likely, not result in an improvement in progression-free survival compared with weekly cisplatin/RT. The PVI FU/RT arm continues to show a higher risk of treatment failure (relative risk RR unadjusted, 1.29) and a higher mortality rate (RR unadjusted, 1.37). There was no difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at distant sites in the PVI FU arm.
In this study, PVI FU does not show improved outcome over weekly cisplatin. Future research should explore combinations of FU with cisplatin, new radiosensitizers, and active drugs combined with RT to reduce the high rate of pelvic and distant treatment failure still seen in advanced cervix cancer.
Introduction
This paper develops a methodology and defines a measure that can be used to separate subjects that received an experimental therapy into those that benefitted from those that did not in ...recent‐onset type 1 diabetes. Benefit means a slowing (or arresting) the decline in beta‐cell function over time. The measure can be applied to comparing treatment arms from a clinical trial or to response at the individual level.
Methods
An analysis of covariance model was fitted to the 12‐month area under the curve C‐peptide following a 2‐hour mixed meal tolerance test from 492 individuals enrolled on five TrialNet studies of recent‐onset type 1 diabetes. Significant predictors in the model were age and C‐peptide at study entry. The observed minus the model‐based expected C‐peptide value (quantitative response, QR) is defined to reflect the effect of the therapy.
Results
A comparison of the primary hypothesis test for each study included and a t test of the QR value by treatment group were comparable. The results were also confirmed for a new TrialNet study, independent of the set of studies used to derive the model. With our proposed analytical method and using QR as the end‐point, we conducted simulation studies, to estimate statistical power in detecting a biomarker that expresses differential treatment effect. The QR in its continuous form provided the greatest statistical power when compared to several ways of defining responder/non‐responder using various QR thresholds.
Conclusions
This paper illustrates the use of the QR, as a measure of the magnitude of treatment effect at the aggregate and subject‐level. We show that the QR distribution by treatment group provides a better sense of the treatment effect than simply giving the mean estimates. Using the QR in its continuous form is shown to have higher statistical power in comparison with dichotomized categorization.
This paper proposes a quantitative end‐point in the study of recent‐onset type 1 diabetes that measures the effect of a treatment on the stimulated C‐peptide of an individual patient and, in the aggregate, discriminate those who benefited (responders) from those who did not (non‐responders). The quantitative response measure can be used to evaluate promising biomarkers or other prognostic characteristics and is defined by the difference between the observed and expected C‐peptide levels.
We demonstrated that a 2-week course of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) delayed T1D progression by a median of 24 months in high risk relatives of patients with ...T1D (76 multiple islet autoantibody positive dysglycemic relatives; 912 day median follow-up). Over the study 72% of the placebo-treated and 43% of the teplizumab-treated participants were diagnosed with T1D. We hypothesized that teplizumab treatment would also result in a secondary outcome of improved C-peptide responses to oral glucose tolerance tests (OGTT) compared to placebo. The C-peptide, 1 hr insulin secretory rate (early ISR), and glucose area under the curve (AUC) means were calculated for each study timepoint. Results were modeled using ANCOVA, regressing on treatment group, age and the baseline value of the dependent variable. Teplizumab treatment was associated with a greater on-study C-peptide AUC (teplizumab vs. placebo adjusted means: 1.94 vs. 1.73 nmol/L; p=0.009). For both groups, C-peptide AUC mean slopes over a mean of 7.9 months preceding study entry were similar and significantly less than zero (declining; p=0.03). In the placebo group, this decline continued over the 6 months after study entry. By contrast, the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.003 relative to study entry). Insulin secretion during the 1st hr of the OGTT also declined in participants treated with placebo, but increased in those treated with teplizumab at 6 months (p=0.007). Increases in C-peptide AUC were correlated with increases in partially exhausted KLRG1+TIGIT+ CD8+ T cells (r=0.403; p=0.018). Although rates of diabetes were reduced in teplizumab-treated participants, OGTTs showed persistent dysglycemia.
In conclusion, we found declines in C-peptide responses to OGTTs in high risk individuals prior to study treatment that were abrogated in the 6 month period after immunomodulation with teplizumab.
Disclosure
E.K. Sims: None. B.N. Bundy: None. K.D. Stier: None. E. Serti: None. N. Lim: None. G.T. Nepom: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. K.C. Herold: Consultant; Self; Provention Bio, Inc.
Funding
National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
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