Nevin Manimala

Contemp Clin Trials. 2021 Apr 3:106378. doi: 10.1016/j.cct.2021.106378. Online ahead of print.

ABSTRACT

Efficient identification of the optimal dose and dosing scheme is one of the most critical and challenging tasks in early-phase oncology trials. The results are far-reaching because advancing a sub-optimal dose to late-stage development may not only jeopardize patients’ safety or fail to deliver desired efficacy, but also be costly to sponsors as refined doses must be evaluated further before seeking regulatory approval. A good dose-escalation design is anticipated to yield high accuracy of selecting the correct dose while using fewer patients and keeping the trial duration short. Recently, treating a single patient at each lower dose level until certain events are triggered to switch to larger cohorts has gained much popularity. We name this approach “Single Patient Acceleration” (SPA), which is essentially a variant of the Accelerated Titration Design (ATD) by Simon et al. [25]. Although literature on novel dose-escalation methods is abundant in the past decade, there is a surprisingly lack of research on evaluating the ATD/SPA framework. In this article, we conduct comprehensive simulations to evaluate the performance of dose-escalation designs with or without SPA, and show that SPA improves design efficiency with similar or better accuracy to those without the “single patient” component under certain circumstances (e.g., slow initial enrollment, or the true maximum tolerated dose is at higher candidate dose levels). Potential safety concerns as a cost of efficiency improvement are also investigated in a quantitative manner to illustrate a comprehensive benefit-risk profile of SPA. Practical considerations and recommendations in using SPA are also discussed.

PMID:33823296 | DOI:10.1016/j.cct.2021.106378

Contemp Clin Trials. 2021 Apr 3:106392. doi: 10.1016/j.cct.2021.106392. Online ahead of print.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) screening (CRCS) facilitates early detection and lowers CRC mortality.

OBJECTIVES: To increase CRCS in a randomized trial of stepped interventions. Step 1 compared three modes of delivery of theory-informed minimal cue interventions. Step 2 was designed to more intensively engage those not completing CRCS after Step 1.

METHODS: Recruitment packets (60,332) were mailed to a random sample of individuals with a record of U.S. military service during the Vietnam-era. Respondents not up-to-date with CRCS were randomized to one of four Step 1 groups: automated telephone, telephone, letter, or survey-only control. Those not completing screening after Step 1 were randomized to one of three Step 2 groups: automated motivational interviewing (MI) call, counselor-delivered MI call, or Step 2 control. Intention-to-treat (ITT) analyses assessed CRCS on follow-up surveys mailed after each step.

RESULTS: After Step 1 (n = 1784), CRCS was higher in the letter, telephone, and automated telephone groups (by 1%, 5%, 7%) than in survey-only controls (43%), although differences were not statistically significant. After Step 2 (n = 516), there were nonsignificant increases in CRCS in the two intervention groups compared with the controls. CRCS following any combination of stepped interventions overall was 7% higher (P = 0.024) than in survey-only controls (55.6%).

CONCLUSIONS: In a nationwide study of veterans, CRCS after each of two stepped interventions of varying modes of delivery did not differ significantly from that in controls. However, combined overall, the sequence of stepped interventions significantly increased CRCS.

PMID:33823295 | DOI:10.1016/j.cct.2021.106392

Ann Vasc Surg. 2021 Apr 3:S0890-5096(21)00241-7. doi: 10.1016/j.avsg.2021.01.118. Online ahead of print.

ABSTRACT

INTRODUCTION: Persistent type II endoleaks (ELIIp) occur in 8% to 23% of patients submitted to endovascular aneurysm repair (EVAR) and may lead to aneurysm progression and rupture. Intraoperative embolization of the abdominal aortic aneurysm (AAA) sac is effective to prevent their occurrence, however a method to achieve complete sac thrombosis has not been standardized yet. Aim of our study was to identify factors associated with prevention of ELIIp after intraoperative embolization, in order to optimize technical details.

METHODS: Patients at high risk for ELIIp, who underwent EVAR with AAA – sac coil embolization were prospectively collected into a dedicated database from January 2012 to March 2015. The endoluminal residual sac volume (ERV), not occupied by the endograft [ERV= AAA total volume (TV) – (AAA-thrombus volume (THV) + endograft volume (EgV)] was calculated on preoperative computed tomography and the concentration of coils implanted (CCoil= n coils implanted/ERV) for each patient was evaluated. AAA volumetric evaluation was conducted by dedicated vessels analysis software (3Mensio). ELIIp presence was evaluated by contrast-enhanced ultrasound at 6 and 12-month. Patients with ELIIp at 12 months (Group 1) were clustered and compared to patients without ELIIp (Group 2), in order to evaluate the incidence of ELIIp in patients undergone to preventive AAA-sac embolization, and identify the predictors of ELIIp prevention. Morphological potential risk factors for ELIIp such as TV, THV, VR% and EgV were also considered in all patients. Statistical correlation was assessed by Fisher Exact Test.

RESULTS: Among 326 patients undergone to standard EVAR, 61 (19% – M: 96.7%, median age: 72 (IQR: 8) years, median AAA diameter: 57(IQR: 7) mm) were considered at high risk for ELIIp and were submitted to coil embolization. The median AAA total volume (TV) and median ERV were 156 (IQR: 59) cc and 46 (IQR: 26) cc, respectively. The median number and concentration of coils (IMWCE-38-16-45 Cook M-Ray) positioned in AAA-sac were 5 (IQR: 1) coils and 0.17 coil/cm³ (range 0.02-1.20). Among this high-risk population, the incidence of ELIIp was 29.5% and 23% at 6 and 12-month, respectively. Fourteen patients (23%) were clustered in Group1 and 47 (77%) in Group 2. Both groups were homogeneous for clinical characteristics and preoperative morphological risk factors. There were no differences in the preoperative median TV, AAA-thrombus volume (THV), %VR, EgV and number of implanted coils between Group1 and Group2. Patients in Group1 had a significantly higher ERV [59 (IQR: 13) cm³ vs 42 (IQR: 27) cm³, P = .002] and lower CCoil [0.09 (IQR: 0.03) vs 0.18 (IQR: 0.21), P = .006] than patients of Group2. ELIIp was significantly related to the presence of ERV > 49 cm³ (86 % vs 42 %, Group1 and Group2 respectively, P = .006) and CCoil < 0.17coil/ cm³ (100% vs 68%, Group1 e Group2 respectively, P = .014).

CONCLUSION: According with our results, Coil concentration and endoluminal residual volume can affect the efficacy of the AAA – sac embolization in the prevention of ELIIp, moreover CCoil ≥ 0.17coil/ cm³ maight be considered to determine the tailored number of coils.

PMID:33823259 | DOI:10.1016/j.avsg.2021.01.118

J Pediatr Endocrinol Metab. 2021 Apr 7. doi: 10.1515/jpem-2021-0051. Online ahead of print.

ABSTRACT

OBJECTIVES: It is unclear whether body weight status (underweight/normal weight/overweight/obese) is associated with allergic disease. Our objective was to investigate the relationship between body weight status (body mass index; BMI) and atopic allergic disease in prepubertal children, and to compare children with atopic allergic diseases with non atopic healthy children.

METHODS: A prospective cross sectional study of 707 prepubertal children aged 3-10 years was performed; the participants were 278 atopic children with physician-diagnosed allergic disease (allergic rhinitis and asthma) (serum total IgE level >100 kU/l and eosinophilia >4%, or positivity to at least one allergen in skin test) and 429 non atopic healthy age- and sex-matched controls. Data were collected between December 2019 and November 2020 at the Pediatric General and Pediatric Allergy Outpatient Clinics of Bezmialem Vakıf University Hospital.

RESULTS: Underweight was observed in 11.6% of all participants (10.8% of atopic children, 12.2% of healthy controls), and obesity in 14.9% of all participants (18.0% of atopic children, 12.8% of controls). Obese (OR 1.71; 95% CI: 1.08-2.71, p=0.021), and overweight status (OR 1.62; 95% CI: 1.06-2.50, p=0.026) were associated with an increased risk of atopic allergic disease compared to normal weight in pre-pubertal children. This association did not differ by gender. There was no relationship between underweight status and atopic allergic disease (OR 1.03; 95% CI: 0.63-1.68, p=0.894).

CONCLUSIONS: Overweight and obesity were associated with an increased risk of atopic allergic disease compared to normal weight among middle-income and high-income pre pubertal children living in Istanbul.

PMID:33823105 | DOI:10.1515/jpem-2021-0051

J Pediatr Endocrinol Metab. 2021 Apr 7. doi: 10.1515/jpem-2020-0714. Online ahead of print.

ABSTRACT

OBJECTIVES: Childhood obesity is a public health concern worldwide, with rates continuing to rise, despite preventive measures. Lifestyle modification remains the mainstay in the treatment of patients with excessive weight, but unfortunately, this is not always successful. Options for medical management of obesity in the paediatric population are limited.

METHODS: Seven adolescents (all girls, mean age 14.9 years) with a body mass index (BMI) above 98th percentile and serious complications secondary to obesity were offered an intense weight management programme. The participants were reviewed by a multidisciplinary team every two weeks for advice and support, and treated with daily subcutaneous injections of liraglutide (dose range 1.2-3.0 mg). Scores for anxiety and depression were evaluated using the Revised Child Anxiety and Depression Scale.

RESULTS: The results showed a significant weight loss over the three months with an average reduction of 5.4 kg (4.2%; 95% CI 1.93-8.78; p=0.0087). The mean drop in BMI was 2.1 kg/m², which is statistically significant (95% CI 0.973-3.199; p=0.0037). Resolution of complications (raised intracranial pressure and steatohepatitis) was noted following weight loss. Anxiety and depressive symptoms improved over the three-month intervention course, especially features of separation anxiety disorder. Liraglutide was well tolerated by all patients.

CONCLUSIONS: Liraglutide medication, alongside a dedicated multidisciplinary team guided lifestyle therapy, is effective and safe in the treatment for excessive weight in adolescents, leading to the reversal of the complications related to obesity and improvement in the psychological symptoms.

PMID:33823101 | DOI:10.1515/jpem-2020-0714

J Pediatr Endocrinol Metab. 2021 Apr 7. doi: 10.1515/jpem-2020-0600. Online ahead of print.

ABSTRACT

OBJECTIVES: We validated a continuous cardiometabolic risk (CMR) measure among adolescents.

METHODS: Five metabolic syndrome (MetS) components including waist circumference, triglycerides, high-density lipoprotein cholesterol, fasting blood glucose, and mean arterial pressure were assessed in a national cohort of U.S. adolescents (n=560; 16.5 ± 0.5 y/o at baseline) in 10th grade (2010, Wave 1 (W1)), and follow-up assessments four (W4) and seven (W7) years later. Separately by wave, linear regressions were fitted to each MetS component controlling for age, sex, and race/ethnicity, and yielded standardized residuals (Z-scores). Wave-specific component Z-scores were summed to obtain composite CMR Z-scores. Four- and seven-year CMR change (CMR-diff W1-W4 and W1-W7). and average CMR risk (CMR-avg; (W1 + W4)/2 and (W1 + W7)/2) were calculated using the CMR Z-scores. W7 MetS was determined using adult criteria. Student’s t-test and receiver operating characteristic (ROC) curve were conducted.

RESULTS: Participants meeting the adult criteria for MetS at W7 (74 of 416, 17.8%) had statistically significant (p<0.01) higher values for W1 CMR Z-scores (0.92 vs. -0.21), W4 CMR Z-scores (1.69 vs. -0.28), W7 CMR Z-scores (2.21 vs. -0.55), W1-W4 CMR-avg (1.53 vs. -0.27), W1-W7 CMR-diff (1.29 vs. -0.21), and W1-W7 CMR-avg (1.46 vs. -0.48) than those not meeting MetS criteria. Most results were similar for males and females in the sex-stratified analyses. The areas under the ROC curve were 0.61, 0.71, and 0.75 for W1, W4 and W7 Z-scores.

CONCLUSIONS: Findings support the validity of the continuous CMR Z-scores calculated using linear regression in evaluating and monitoring CMR profiles from adolescence to early adulthood.

PMID:33823099 | DOI:10.1515/jpem-2020-0600

Int J Biostat. 2021 Apr 6. doi: 10.1515/ijb-2020-0151. Online ahead of print.

ABSTRACT

In regression models, predictor variables with inherent ordering, such ECOG performance status or novel biomarker expression levels, are commonly seen in medical settings. Statistically, it may be difficult to determine the functional form of an ordinal predictor variable. Often, such a variable is dichotomized based on whether it is above or below a certain cutoff. Other methods conveniently treat the ordinal predictor as a continuous variable and assume a linear relationship with the outcome. However, arbitrarily choosing a method may lead to inaccurate inference and treatment. In this paper, we propose a Bayesian mixture model to consider both dichotomous and linear forms for the variable. This allows for simultaneous assessment of the appropriate form of the predictor in regression models by considering the presence of a changepoint through the lens of a threshold detection problem. This method is applicable to continuous, binary, and survival outcomes, and it is easily amenable to penalized regression. We evaluated the proposed method using simulation studies and apply it to two real datasets. We provide JAGS code for easy implementation.

PMID:33823087 | DOI:10.1515/ijb-2020-0151

Cancer. 2021 Apr 6. doi: 10.1002/cncr.33543. Online ahead of print.

ABSTRACT

BACKGROUND: Although both PSA nadir (PSAn) and testosterone levels at PSA failure are known prognostic factors in men undergoing radiation therapy (RT) and androgen deprivation therapy (ADT) for unfavorable-risk prostate cancer (PC), it is unclear whether their prognostic significance is independent or overlapping.

METHODS: Seventy-five men treated with RT with or without 6 months of ADT for unfavorable-risk nonmetastatic PC enrolled in 2 prospective clinical trials between 1986 and 2001 formed the study cohort. Competing risks and Cox multivariable regression were used to assess whether low versus normal serum testosterone at the time of PSA failure and higher PSAn after initial therapy were independently associated with the risk of PC-specific (PCSM) and all-cause mortality (ACM) adjusting for PC prognostic factors.

RESULTS: After a median follow-up of 15.34 years (interquartile range, 6.66-16.88 years), there were 53 deaths (73.3%): 30 (56.6%) were from PC. Low testosterone at PSA failure was significantly associated with an increased risk of PCSM (adjusted HR [AHR], 7.77; 95% CI, 1.14-52.99; P = .04) and ACM (AHR, 3.01; 95% CI, 1.01-8.96; P = .05), as was higher PSAn (PCSM AHR, 1.03; 95% CI, 1.01-1.05; P < .01; ACM AHR, 1.04; 95% CI, 1.02-1.07; P < .01), although the prognostic significance of PSAn was only noted in men with a normal testosterone at PSA failure.

CONCLUSIONS: Low testosterone level at PSA failure in high-risk patients with PC treated with RT is associated with increased PCSM and ACM risk. In men with normal testosterone levels at the time of PSA failure, an elevated PSAn was associated with worse PCSM and ACM risk.

LAY SUMMARY: This study investigates whether the prostate-specific antigen (PSA) nadir and normal versus low testosterone at the time of PSA failure provide mutually exclusive or overlapping prognostic information following treatment with radiation and androgen deprivation therapy for unfavorable-risk patients with prostate cancer using data from 2 prospective clinical trials. It was found that both provided prognostic information; however, higher PSA nadir was only found to be of prognostic significance in men with normal testosterone levels at PSA failure.

PMID:33823065 | DOI:10.1002/cncr.33543

Cancer. 2021 Apr 6. doi: 10.1002/cncr.33536. Online ahead of print.

ABSTRACT

BACKGROUND: The potential role of occupational exposures in the development of nasopharyngeal carcinoma (NPC) remains unclear, particularly in high-incidence areas.

METHODS: The authors conducted a population-based case-control study, consisting of 2514 incident NPC cases and 2586 randomly selected population controls, in southern China from 2010 to 2014. Occupational history and other covariates were self-reported using a questionnaire. Multivariate logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of NPC associated with occupational exposures. Restricted cubic splines were used to evaluate potentially nonlinear duration-response relations.

RESULTS: Individuals who had exposure to occupational dusts (OR, 1.45; 95% CI, 1.26-1.68), chemical vapors (OR, 1.37; 95% CI, 1.17-1.61), exhausts/smokes (OR, 1.42; 95% CI, 1.25-1.60), or acids/alkalis (OR, 1.56; 95% CI, 1.30-1.89) in the workplace had an increased NPC risk compared with those who were unexposed. Risk estimates for all 4 categories of occupational exposures appeared to linearly increase with increasing duration. Within these categories, occupational exposure to 14 subtypes of agents conferred significantly higher risks of NPC, with ORs ranging from 1.30 to 2.29, including dust from metals, textiles, cement, or coal; vapor from formaldehyde, organic solvents, or dyes; exhaust or smoke from diesel, firewood, asphalt/tar, vehicles, or welding; and sulfuric acid, hydrochloric acid, nitric acid, and concentrated alkali/ammonia.

CONCLUSIONS: Occupational exposures to dusts, chemical vapors, exhausts/smokes, or acids/alkalis are associated with an excess risk of NPC. If the current results are causal, then the amelioration of workplace conditions might alleviate the burden of NPC in endemic areas.

LAY SUMMARY: The role of occupational exposures in the development of nasopharyngeal carcinoma (NPC) remains unclear, particularly in high-incidence areas. The authors conducted a population-based study with 2514 incident NPC cases and 2586 population controls in southern China and observed that occupational exposures were associated with an increased risk of NPC. Duration-response trends were observed with increasing duration of exposure. These findings provide new evidence supporting an etiologic role of occupational exposures for NPC in a high-incidence region.

PMID:33823062 | DOI:10.1002/cncr.33536

Transl Behav Med. 2021 Apr 5:ibab004. doi: 10.1093/tbm/ibab004. Online ahead of print.

ABSTRACT

Few studies have examined the relative effectiveness of reinforcing versus aversive consequences at changing behavior in real-world environments. Real-time sensing devices makes it easier to investigate such questions, offering the potential to improve both intervention outcomes and theory. This research aims to describe the development of a real-time, operant theory-based secondhand smoke (SHS) intervention and compare the efficacy of aversive versus aversive plus reinforcement contingency systems. Indoor air particle monitors were placed in the households of 253 smokers for approximately three months. Participants were assigned to a measurement-only control group (N = 129) or one of the following groups: 1.) aversive only (AO, N = 71), with aversive audio/visual consequences triggered by the detection of elevated air particle measurements, or 2.) aversive plus reinforcement (AP, N = 53), with reinforcing consequences contingent on the absence of SHS added to the AO intervention. Residualized change ANCOVA analysis compared particle concentrations over time and across groups. Post-hoc pairwise comparisons were also performed. After controlling for Baseline, Post-Baseline daily particle counts (F = 6.42, p = 0.002), % of time >15,000 counts (F = 7.72, p < 0.001), and daily particle events (F = 4.04, p = 0.02) significantly differed by study group. Nearly all control versus AO/AP pair-wise comparisons were statistically significant. No significant differences were found for AO versus AP groups. The aversive feedback system reduced SHS, but adding reinforcing consequences did not further improve outcomes. The complexity of real-world environments requires the nuances of these two contingency systems continue to be explored, with this study demonstrating that real-time sensing technology can serve as a platform for such research.

PMID:33823045 | DOI:10.1093/tbm/ibab004