Publications

Although colorectal cancer (CRC) is a common cause of cancer-related death, it is fortunately amenable to screening with faecal tests for occult blood and endoscopic tests. Despite the evidence for the efficacy of guaiac-based faecal occult blood tests (gFOBT), they have not been popular with primary care providers in many jurisdictions, in part because of poor sensitivity for advanced colorectal neoplasms (advanced adenomas and CRC). In order to address this issue, high sensitivity gFOBT have been recommended, however, these tests are limited by a reduction in specificity compared with the traditional gFOBT. Where colonoscopy is available, some providers have opted to recommend screening colonoscopy to their patients instead of faecal testing, as they believe it to be a better test. Newer methods for detecting occult human blood in faeces have been developed. These tests, called faecal immunochemical tests (FIT), are immunoassays specific for human haemoglobin. FIT hold considerable promise over the traditional guaiac methods including improved analytical and clinical sensitivity for CRC, better detection of advanced adenomas, and greater screenee participation. In addition, the quantitative FIT are more flexible than gFOBT as a numerical result is reported, allowing customisation of the positivity threshold. When compared with endoscopy, FIT are less sensitive for the detection of advanced colorectal neoplasms when only one time testing is applied to a screening population; however, this is offset by improved participation in a programme of annual or biennial screens and a better safety profile. This review will describe how gFOBT and FIT work and will present the evidence that supports the use of FIT over gFOBT, including the cost-effectiveness of FIT relative to gFOBT. Finally, specific issues related to FIT implementation will be discussed, particularly with respect to organised CRC screening programmes.

BACKGROUND

Tenofovir disoproxil fumarate (TDF) may cause acute kidney injury and proximal tubular dysfunction. However, no detailed studies document urinary phosphate wasting as a marker of TDF-induced tubulopathy.

METHODS

Records of HIV-infected patients with presumed TDF toxicity were reviewed. We describe the characteristics and clinical course of 15 patients who had documented elevated (>20%) fractional excretion of phosphate (FEphos).

RESULTS

Patients were predominantly Caucasian and male (73 and 80%, respectively), with a mean age of 56 years (range 38-76). Of the 15 patients, 11 had a estimated glomerular filtration rate (eGFR) of >90 mL/min/1.73(2) at time of TDF initiation. The mean duration of TDF therapy prior to diagnosis of TDF toxicity was 64 months. Mean FEphos was 34% (range 20-62). The mean eGFR at TDF initiation was 104 mL/min/1.73 m(2) [standard deviation (SD) 17.0] with a gradual decline to 69 mL/min/1.73 m(2) (SD 19.0) by the time of TDF discontinuation. Of 10 patients with repeated FEphos after TDF discontinuation, 9 had improvement of their FEphos. Of these individuals, 6 had normalization of their FEphos. Estimated GFR improved in 12 patients after discontinuation of TDF, though importantly, none returned to their baseline eGFR.

CONCLUSIONS

Urinary phosphate wasting is a sensitive marker for TDF-induced proximal tubulopathy and is associated with unrecognized and permanent renal function decline. Tubular dysfunction can develop after years of TDF therapy in those with normal kidney function at the time of drug initiation. This suggests that continuing vigilance be maintained in all those on TDF.

A minimal clinically important difference (MCID) is an important concept used to determine whether a medical intervention improves perceived outcomes in patients. Prior to the introduction of the concept in 1989, studies focused primarily on statistical significance. As most recent clinical trials in systemic lupus erythematosus (SLE) have failed to show significant effects, determining a clinically relevant threshold for outcome scores (that is, the MCID) of existing instruments may be critical for conducting and interpreting meaningful clinical trials as well as for facilitating the establishment of treatment recommendations for patients. To that effect, methods to determine the MCID can be divided into two well-defined categories: distribution-based and anchor-based approaches. Distribution-based approaches are based on statistical characteristics of the obtained samples. There are various methods within the distribution-based approach, including the standard error of measurement, the standard deviation, the effect size, the minimal detectable change, the reliable change index, and the standardized response mean. Anchor-based approaches compare the change in a patient-reported outcome to a second, external measure of change (that is, one that is more clearly understood, such as a global assessment), which serves as the anchor. Finally, the Delphi technique can be applied as an adjunct to defining a clinically important difference. Despite an abundance of methods reported in the literature, little work in MCID estimation has been done in the context of SLE. As the MCID can help determine the effect of a given therapy on a patient and add meaning to statistical inferences made in clinical research, we believe there ought to be renewed focus on this area. Here, we provide an update on the use of MCIDs in clinical research, review some of the work done in this area in SLE, and propose an agenda for future research.

BACKGROUND

Current approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk.

METHODS

Based on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk. We identified corresponding assays to develop the Hazard Identification Approach for Breast Carcinogens (HIA-BC), a method for detecting chemicals that may raise breast cancer risk. Finally, we conducted a literature-based pilot test of the HIA-BC.

RESULTS

The HIA-BC identifies assays capable of detecting alterations to biological processes relevant to breast cancer, including cellular and molecular events, tissue changes, and factors that alter susceptibility. In the pilot test of the HIA-BC, chemicals associated with breast cancer all demonstrated genotoxic or endocrine activity, but not necessarily both. Significant data gaps persist.

CONCLUSIONS

This approach could inform the development of toxicity testing that targets mechanisms relevant to breast cancer, providing a basis for identifying safer chemicals. The study identified important end points not currently evaluated by federal testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor β activity. This approach could be extended to identify the biological processes and screening methods relevant for other common diseases.