Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish section of the ERSPC

Background:

We derived estimates of overdiagnosis by polygenic risk groups and examined whether polygenic risk-stratified screening for prostate cancer reduces overdiagnosis.

Methods:

We calculated the polygenic risk score based on genotypes of 66 known prostate cancer loci for 4967 men from the Finnish section of the European Randomised Study of Screening for Prostate Cancer. We stratified the 72 072 men in the trial into those with polygenic risk below and above the median. Using a maximum likelihood method based on interval cancers, we estimated the mean sojourn time (MST) and episode sensitivity. For each polygenic risk group, we estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers.

Results:

Of the prostate cancers, 74% occurred among men with polygenic risk above population median. The sensitivity was 0.55 (95% confidence interval (CI) 0.45–0.65) and MST 6.3 (95% CI 4.2–8.3) years. The overall overdiagnosis was 42% (95% CI 37–52) of the screen-detected cancers, with 58% (95% CI 54–65) in men with the lower and 37% (95% CI 31–47) in those with higher polygenic risk.

Conclusion:

Targeting screening to men at higher polygenic risk could reduce the proportion of cancers overdiagnosed.     

Antimicrobial peptides: a potential role in ocular therapy

Bacterial pathogens are often involved in contact lens‐related adverse responses. This study aimed to find antimicrobial peptides and proteins that effectively eradicate or inhibit ocular bacteria. The antimicrobials were screened against Gram‐ negative and Gram‐positive bacteria originating from ocular sources. The viability of these ocular bacteria was measured after exposure to the peptides and proteins. Two conditions were used to grow bacteria, low nutrient phosphate‐buffered saline and high nutrient tryptone soya broth. Samples were taken at different times up to 48 h. In low nutrient conditions, protamine was found to be the most effective against all strains. Melittin was very effective against all strains except Serratia and one Pseudomonas isolate which were partially affected. In high nutrient condition, only melittin was effective in killing Staphylococcus aureus. Protamine and the combination of protamine and melittin had the greatest effect in eradicating the bacteria tested in low nutrient condition. Protamine alone and its combination with melittin may have potential therapeutic agents for ocular infections in an era of emerging antibiotic resistance.     

Occupational stress in migraine is weekend headache a myth or reality?

To determine whether or not the frequency of migraine attacks increased at weekends in employed patients and if so, whether or not this was related to the type of migraine, 35 female patients prospectively recorded the presence or absence of migraine attacks daily over a six-week period. They were also asked to estimate the frequency with which emotional factors predisposed to their migraine attacks and to provide details of their occupation. A diagnosis of common (migraine without aura) or classical migraine (migraine with aura) was made according to both the criteria of the Ad Hoc Committee on the Classification of Headache and those of the International Headache Society. Eleven percent and 6% of patients, respectively, felt that emotional factors "usually" or "always" predisposed to migraine attacks. There was no significant increase in the frequency of migraine attacks at weekends in either the total group or in the employed patients. Similarly, the type of migraine made no difference to the results. There was therefore no evidence for a delayed onset of migraine at weekends related to the weekday stress of employment.     

Tear film,contact lenses and tear biomarkers

This article summarises research undertaken since 1993 in the Willcox laboratory at the University of New South Wales, Sydney on the tear film, its interactions with contact lenses, and the use of tears as a source of biomarkers for ocular and non‐ocular diseases. The proteome, lipidome and glycome of tears all contribute to important aspects of the tear film, including its structure, its ability to defend the ocular surface against microbes and to help heal ocular surface injuries. The tear film interacts with contact lenses in vivo and interactions between tears and lenses can affect the biocompatibility of lenses, and may be important in mediating discomfort responses during lens wear. Suggestions are made for follow‐up research.     

PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer

Introduction  

The aim of this study was to develop and validate a prognostication model to predict overall and breast cancer specific survival for women treated for early breast cancer in the UK.     

Neoadjuvant chemoradiotherapy and multivisceral resection for primary locally advanced adherent colon cancer: A single institution experience

Background

Although there is an extensive body of literature on the role of neoadjuvant chemoradiotherapy (CRT) in the management of rectal cancer, its role in primary locally advanced adherent colon cancer (LAACC) is unclear.

Objective

To analyzed the outcomes of neoadjuvant CRT and multivisceral resection in the management of LAACC patietns.

Methods

We retrospectively reviewed our institutional Colorectal Carcinoma Database for 33 patients with potentially resectable, non-metastatic primary LAACC who received neoadjuvant CRT followed by multivisceral resection. CRT consisted of external beam radiation (45–50 Gy in 25 daily fractions) and concurrent 5-FU infusion (225 mg/m²/day).

Results

There were 21 males and 12 females. Median age was 64 (31–83) and median follow-up was 36 months. All patients had microscopically clear resection margins (R0). Complete pathologic response was documented in 1 patient (3%) and 66% had ypT4b disease. Post-operative complications were observed in 36% of patients with no 30-day mortality. The 3-year overall survival and 3-year disease-free survival were 85.9% and 73.7% respectively. Two patients developed a local recurrence.

Conclusions

Neoadjuvant CRT and en-bloc multivisceral resection may result in high rates of R0 resection and excellent local control with acceptable morbidity and mortality in selected patients with LAACC.     

<Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations in a population-based study of male breast cancer

Background

The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear.

Methods

We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk.

Results

Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives.

Conclusion

These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found.

     

Cat-301 immunoreactivity in the lateral geniculate nucleus and visual cortex of the strabismic amblyopic cat

Purpose: It was investigated whether alterations in neuronal structure and function occasioned by strabismic amblyopia also may be reflected in alterations in the expression on Y type neurons of a Cat-301 antibody sensitive antigen in the lateral geniculate nucleus (LGN) and cortex of our cat model of strabismic amblyopia. Methods/Results: The percentage of positively labelled cells was reduced in LGN laminae that received input from the deviated eye in strabismic amblyopic cats compared with normal cats. In the strabismic cortex, the density of immunopositive neurons was significantly reduced compared with normal, the effect being most pronounced in layer IV Conclusions: Despite previous physiological recordings indicating a decrease in X-cell associated acuity in strabismic amblyopia, the present findings imply that the changes in the early visual experience occasioned by strabismus also produce specific molecular changes in theY neuronal class.