Characterizing the frequency of modifiable histological changes observed on surveillance biopsies in pediatric kidney allograft recipients.

BACKGROUND: Rejection is responsible for just under 50% of graft loss in the pediatric kidney transplant population. Early identification and treatment of allograft injury, specifically modifiable pathologies such as subclinical rejection (SCR), calcineurin inhibitor toxicity, and BK virus nephropathy, may improve allograft survival. Protocol surveillance biopsy (SB) currently offers the earliest opportunity for targeted interventions. METHODS: This is a single-center retrospective review of 215 kidney SBs obtained from 2008 to 2016 in 97 pediatric kidney transplant recipients. SBs were obtained at 6, 12, and 24 months post-transplantation. Frequency of abnormal histologic findings, estimated glomerular filtration rate at time of SB, and SB-related complications were recorded. Data were analyzed to investigate possible time trends and the presence of demographic or clinical associations with abnormal histologic findings. RESULTS: Potentially modifiable histologic findings were seen in 38.1% of all SBs. SCR was found with increasing frequency across all time points with an estimated 49% increase in the odds of a SCR finding per additional 6 months post-transplantation (aOR 1.49, 95% CI 1.06-2.09, p = 0.022). Among follow-up biopsies in patients who underwent treatment for SCR, 50% had no SCR and 18.8% showed histologic improvement. The complication rate associated with SB was 1.9% (4/215 SBs) and consisted of only minor complications. CONCLUSIONS: SBs are safe and offer the opportunity to identify and treat modifiable histologic changes in the pediatric kidney transplant population. The performance of SBs for up to 2 years after transplantation can have meaningful clinical impact.

Did death certificates and a death review process agree on lung cancer cause of death in the National Lung Screening Trial?

BACKGROUND/AIMS: Randomized controlled trials frequently use death review committees to assign a cause of death rather than relying on cause of death information from death certificates. The National Lung Screening Trial, a randomized controlled trial of lung cancer screening with low-dose computed tomography versus chest X-ray for heavy and/or long-term smokers ages 55-74 years at enrollment, used a committee blinded to arm assignment for a subset of deaths to determine whether cause of death was due to lung cancer. METHODS: Deaths were selected for review using a pre-determined computerized algorithm. The algorithm, which considered cancers diagnosed during the trial, causes and significant conditions listed on the death certificate, and the underlying cause of death derived from death certificate information by trained nosologists, selected deaths that were most likely to represent a death due to lung cancer (either directly or indirectly) and deaths that might have been erroneously assigned lung cancer as the cause of death. The algorithm also selected deaths that might be due to adverse events of diagnostic evaluation for lung cancer. Using the review cause of death as the gold standard and lung cancer cause of death as the outcome of interest (dichotomized as lung cancer versus not lung cancer), we calculated performance measures of the death certificate cause of death. We also recalculated the trial primary endpoint using the death certificate cause of death. RESULTS: In all, 1642 deaths were reviewed and assigned a cause of death (42% of the 3877 National Lung Screening Trial deaths). Sensitivity of death certificate cause of death was 91%; specificity, 97%; positive predictive value, 98%; and negative predictive value, 89%. About 40% of the deaths reclassified to lung cancer cause of death had a death certificate cause of death of a neoplasm other than lung. Using the death certificate cause of death, the lung cancer mortality reduction was 18% (95% confidence interval: 4.2-25.0), as compared with the published finding of 20% (95% confidence interval: 6.7-26.7). CONCLUSION: Death review may not be necessary for primary-outcome analyses in lung cancer screening trials. If deemed necessary, researchers should strive to streamline the death review process as much as possible.

Results of the two incidence screenings in the National Lung Screening Trial.

BACKGROUND: The National Lung Screening Trial was conducted to determine whether three annual screenings (rounds T0, T1, and T2) with low-dose helical computed tomography (CT), as compared with chest radiography, could reduce mortality from lung cancer. We present detailed findings from the first two incidence screenings (rounds T1 and T2). METHODS: We evaluated the rate of adherence of the participants to the screening protocol, the results of screening and downstream diagnostic tests, features of the lung-cancer cases, and first-line treatments, and we estimated the performance characteristics of both screening methods. RESULTS: At the T1 and T2 rounds, positive screening results were observed in 27.9% and 16.8% of participants in the low-dose CT group and in 6.2% and 5.0% of participants in the radiography group, respectively. In the low-dose CT group, the sensitivity was 94.4%, the specificity was 72.6%, the positive predictive value was 2.4%, and the negative predictive value was 99.9% at T1; at T2, the positive predictive value increased to 5.2%. In the radiography group, the sensitivity was 59.6%, the specificity was 94.1%, the positive predictive value was 4.4%, and the negative predictive value was 99.8% at T1; both the sensitivity and the positive predictive value increased at T2. Among lung cancers of known stage, 87 (47.5%) were stage IA and 57 (31.1%) were stage III or IV in the low-dose CT group at T1; in the radiography group, 31 (23.5%) were stage IA and 78 (59.1%) were stage III or IV at T1. These differences in stage distribution between groups persisted at T2. CONCLUSIONS: Low-dose CT was more sensitive in detecting early-stage lung cancers, but its measured positive predictive value was lower than that of radiography. As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advanced-stage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

The polyp prevention trial continued follow-up study: no effect of a low-fat, high-fiber, high-fruit, and -vegetable diet on adenoma recurrence eight years after randomization.

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), and low-fat (20% of total energy) diet on the recurrence of adenomatous polyps in the large bowel over a period of 4 years. Although intervention participants reported a significantly reduced intake of dietary fat, and increased fiber, fruit, and vegetable intakes, their risk of recurrent adenomas was not significantly different from that of the controls. Since the PPT intervention lasted only 4 years, it is possible that participants need to be followed for a longer period of time before treatment differences in adenoma recurrence emerge, particularly if diet affects early events in the neoplastic process. The PPT-Continued Follow-up Study (PPT-CFS) was a post-intervention observation of PPT participants for an additional 4 years from the completion of the trial. Of the 1,905 PPT participants, 1,192 consented to participate in the PPT-CFS and confirmed colonoscopy reports were obtained on 801 participants. The mean time between the main trial end point colonoscopy and the first colonoscopy in the PPT-CFS was 3.94 years (intervention group) and 3.87 years (control group). The baseline characteristics of 405 intervention participants and 396 control participants in the PPT-CFS were quite similar. Even though the intervention group participants increased their fat intake and decreased their intakes of fiber, fruits, and vegetables during the PPT-CFS, they did not go back to their prerandomization baseline diet (P < 0.001 from paired t tests) and intake for each of the three dietary goals was still significantly different from that in the controls during the PPT-CFS (P < 0.001 from t tests). As the CFS participants are a subset of the people in the PPT study, the nonparticipants might not be missing completely at random. Therefore, a multiple imputation method was used to adjust for potential selection bias. The relative risk (95% confidence intervals) of recurrent adenoma in the intervention group compared with the control group was 0.98 (0.88-1.09). There were no significant intervention-control group differences in the relative risk for recurrence of an advanced adenoma (1.06; 0.81-1.39) or multiple adenomas (0.92; 0.77-1.10). We also used a multiple imputation method to examine the cumulative recurrence of adenomas through the end of the PPT-CFS: the intervention-control relative risk (95% confidence intervals) for any adenoma recurrence was 1.04 (0.98-1.09). This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1745-52).

Does nonsteroidal anti-inflammatory drug use modify the effect of a low-fat, high-fiber diet on recurrence of colorectal adenomas?

The Polyp Prevention Trial was designed to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), low-fat (20% energy) diet on recurrence of adenomatous polyps. Participants > or =35 years of age, with histologically confirmed colorectal adenoma(s) removed in the prior 6 months, were randomized to the intervention or control group. Demographic, dietary, and clinical information, including use of nonsteroidal anti-inflammatory drugs (NSAID), was collected at baseline and four annual visits. Adenoma recurrence was found in 754 of 1,905 participants and was not significantly different between groups. NSAID use was associated with a significant reduction in recurrence [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.63-0.95]. In this analysis, NSAIDs modified the association between the intervention and recurrence at baseline (P = 0.02) and throughout the trial (P = 0.008). Among participants who did not use NSAIDs, the intervention was in the protective direction but did not achieve statistical significance (OR, 0.87; 95% CI, 0.69-1.09). The intervention was protective among males who did not use NSAIDs at baseline (OR, 0.71; 95% CI, 0.54-0.94), but not among NSAIDs users (OR, 1.09; 95% CI, 0.74-1.62). For females, corresponding OR estimates were 1.28 (95% CI, 0.86-1.90) and 2.30 (95% CI, 1.24-4.27), respectively. The protective association observed for NSAID use was stronger among control (OR, 0.63; 95% CI, 0.47-0.84) than for intervention group participants (OR, 0.97; 95% CI, 0.74-1.28). These results should be interpreted cautiously given that they may have arisen by chance in the course of examining multiple associations and Polyp Prevention Trial study participants were not randomly assigned to both dietary intervention and NSAID use. Nevertheless, our results suggest that adopting a low-fat, high-fiber diet rich in fruits and vegetables may lower the risk of colorectal adenoma recurrence among individuals who do not regularly use NSAIDs.

The association of calcium and vitamin D with risk of colorectal adenomas.

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial designed to determine the effects of a high-fiber, high-fruit and vegetable, low-fat diet on the recurrence of adenomatous polyps in the large bowel. Detailed dietary intake and supplement use data were collected at baseline and at each of 4 annual study visits. Adenoma recurrence was ascertained by complete colonoscopy at baseline and after 1 and 4 y. Recurrence was found in 754 of the 1905 trial participants. We evaluated the association between calcium and vitamin D intake and adenomatous polyp recurrence after adjusting for intervention group, age, gender, nonsteroidal anti-inflammatory drug use, total energy intake, and the interaction of gender and intervention group. Vitamin D models were also adjusted for the location of the clinic site. Dietary variables were adjusted for total energy intake via the residual method. There were no overall significant associations between adenoma recurrence and dietary calcium intake [odds ratio (OR) for the 5th compared with the lowest quintile = 0.91; 95% CI = 0.67-1.23; P-trend = 0.68], total calcium intake (OR = 0.86; 95% CI = 0.62-1.18; P-trend = 0.20), or dietary vitamin D intake (OR = 0.93; 95% CI = 0.69-1.25; P-trend = 0.43) averaged over follow-up. Total vitamin D intake was weakly inversely associated with adenoma recurrence (OR = 0.84; 95% CI = 0.62-1.13; P-trend = 0.03). Supplemental calcium and vitamin D use during follow-up also were inversely associated with adenoma recurrence (OR for any compared with no use = 0.82; 95% CI = 0.68-0.99; and OR = 0.82; 95% CI = 0.68-0.99; for calcium and vitamin D, respectively). Slightly stronger associations were noted for the prevention of multiple recurrences. Our analyses did not suggest a significant effect modification between total calcium and total vitamin D intake (P = 0.14) on risk for adenoma recurrence. This trial cohort provides some evidence that calcium and vitamin D may be inversely associated with adenoma recurrence.

Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer.

The Lung Screening Study (LSS) was a pilot study designed to assess the feasibility of conducting a large scale randomized controlled trial (RCT) of low radiation dose spiral computed tomography (LDCT) versus chest X-ray (CXR) for lung cancer screening. Baseline results of LSS have been previously reported. Here, we report on the findings at the year one screen and on the final results of the LSS study. A total of 1660 subjects were randomized to the LDCT arm and 1658 to the CXR arm. Compliance with screening declined from 96% at baseline to 86% at year one in the LDCT arm and declined from 93% at baseline to 80% at year one in the CXR arm. Positivity rates for the year one screen were 25.8% for LDCT and 8.7% for CXR. Cancer yield was significantly less at year one for LDCT, 0.57%, than at baseline, 1.9%; cancer yield for CXR increased from 0.45% at baseline to 0.68% at year one. Forty lung cancers in the LDCT arm and 20 in the CXR arm were diagnosed over the study period. Stage I cancers comprised 48% of cases in the LDCT arm and 40% in the CXR arm. A total of 16 stage III-IV cancers were observed in the LDCT arm versus nine in the CXR arm. The LSS has established the feasibility of a RCT comparing annual spiral CT to chest X-ray for lung cancer screening.

Carotenoids, vitamin A and risk of adenomatous polyp recurrence in the polyp prevention trial.

One trial reported beta-carotene supplementation was protective of adenomatous polyp recurrence in nonsmokers. We now examine the relation of serum and dietary carotenoids and vitamin A to adenomatous polyp recurrence in a subcohort of 834 participants in a low fat, high fiber, high fruit and vegetable dietary intervention, the Polyp Prevention Trial. Multivariate odds ratio (OR) and 95% confidence intervals (CI) of polyp recurrence were obtained using baseline or the average (first 3 years of the trial) carotenoid and vitamin A values after adjustment for covariates. Compared to the lowest quartile of baseline alpha-carotene concentrations, the OR of multiple polyp recurrence for the highest quartile was 0.55 (95% CI = 0.30-0.99) and the OR of right-sided recurrence was 0.60 (95% CI = 0.37-0.95). Baseline dietary intakes of alpha-carotene and vitamin A from food with/without supplements were inversely associated with any recurrence (p for linear trend = 0.03-alpha-carotene; p = 0.004 and p = 0.007 -intakes of vitamin A). Compared to the lowest quartile of averaged beta-carotene concentrations, the OR of multiple adenomas for the highest quartile was 0.40 (95% CI = 0.22-0.75) with an inverse trend (p = 0.02). The risk was inversely related to averaged: alpha-carotene concentrations and right-sided polyps; alpha-carotene intake and recurrence of any, multiple and right-sided polyps; beta-carotene intake and multiple adenoma recurrence; vitamin A from food (with supplements) and each adverse endpoint. Thus, alpha-carotene and vitamin A may protect against recurrence in nonsmokers and nondrinkers or be indicative of compliance or another healthy lifestyle factor that reduces risk.

Evaluation guidelines for adult and pediatric kidney transplant programs: the Missouri experience.

CONTEXT: Rigorous candidate evaluation is paramount for estimating risk and long-term success with transplantation. In addition, because of increasing waiting times, patients are seeking listing at multiple centers or transferring waiting time from one center to another. Variations in center evaluation criteria are becoming increasingly important to patients. OBJECTIVE: To describe the similarities and differences among the evaluation guidelines for adult and pediatric kidney transplant programs in Missouri. DESIGN: A descriptive design was used. SETTING AND PARTICIPANTS: Kidney transplant nurse coordinators from 7 adult and 4 pediatric kidney transplant programs from 10 centers in Missouri were invited to submit the kidney transplant candidate evaluation guidelines from their programs. RESULTS: Guidelines were submitted by nurse coordinators from all programs. Consults with the kidney transplant team members, including surgeon, nephrologist, social worker, and nurse coordinator, were included in all of the programs. For the adult programs, 67% (20/30) of the tests and laboratory values were agreed on by at least 70% of the program transplant team members. Similarly, for the pediatric programs, 62% (16/26) of the age-appropriate tests and laboratory values were agreed on by at least 75% of the program transplant team members. CONCLUSIONS: Within the Missouri programs, testing is consistent whether the center is large or small, adult or pediatric. Transplant teams should periodically review their kidney transplant recipient evaluation criteria for similarities to and differences from the current state-of-the-science and surrounding programs.