Metastasis directed treatment of brain metastases from colorectal cancer - a Danish population-based cohort study.

Background: Brain metastases (BMs) are an uncommon presentation of metastatic colorectal cancer (mCRC) with reported incidence of about 2-4%. Today, there is an increased awareness towards a metastasis directed treatment approach with either surgical resection, stereotactic radiotherapy (SRT) or both. We examined patient characteristics and survival for patients treated with a localized modality for BM from CRC in a nationwide population-based study.Methods: A registry-based cohort study of all patients with a resected primary colorectal cancer and localized treatment of BM during 2000-2013. We computed descriptive statistics and analysed overall survival by the Kaplan-Meier method and Cox regression.Results: A total of 38131 patients had surgery for a primary CRC and 235 patients were recorded with a metastasis directed treatment for BM, comprising resection alone (n = 158), SRT alone (n = 51) and combined resection and SRT (n = 26). Rectal primary tumor (48.9% vs. 36.2%, p < .001) and lung metastasectomy (11.9 vs 2.8%, p < .001) were more frequent in the BM group. The median survival of patients receiving localized treatment for BM was 9.6 months (95% confidence interval (CI) 7.2-10.8). The 1- and 5-year overall survival were 41.7% (95% CI 35-48%) and 11.2% (95% CI 6.9-16.3%). In multivariate analysis, nodal stage was associated with increased mortality with a hazard ratio of 1.63 (95% CI 1.07-2.60, p = .03) for N2 stage with reference to N0.Conclusion: We report a median overall survival of 9.6 months for patients receiving localized treatment for BM from CRC. Lung metastases and rectal primary tumor are more common in the population treated for BM.

Methodological development and biological observations of cell free DNA with a simple direct fluorescent assay in colorectal cancer.

BACKGROUND: Cell free DNA (cfDNA) has shown promising utility as prognostic biomarker for patients with colorectal cancer (CRC), with an ongoing need to optimize and validate the laboratory methodology. Here, we report our optimization and validation of a direct fluorescent assay and display the potential utility in patients with colorectal cancer. METHODS: Plasma cfDNA was analyzed by a direct fluorescent assay (DFA) and compared to quantification by droplet digital PCR (ddPCR). For clinical validation, baseline blood samples were available for a total of 273 patients from six different Nordic trials, covering patients with locally advanced rectal cancer (n = 176, cohorts A + B), liver limited metastatic CRC (n = 75C + D) and wide spread metastatic CRC (n = 22 E + F). RESULTS: Validating the DFA analysis with ddPCR revealed a strong correlation with an R2 of 0.81. For the clinical cohorts, the levels of cfDNA were: 0.8 ng/uL (95%CI 0.75-0.83) (A + B), 0.93 ng/uL (95%CI 0.86-1.02) (C + D) and 1.2 ng/uL (95%CI 0.85-1.47) (E + F), respectively (p < 0.01). All cohorts of colorectal cancer had higher levels of cell free DNA than healthy individuals (n = 94) (p < 0.01). CONCLUSION: Analysis of cell free DNA by a direct fluorescent assay could be an attractive laboratory option for a rapid inexpensive quantification of cell free DNA.

Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer.

Background: Treatment of patients with locally advanced rectal cancer (LARC) is based on a combination of chemo-radiotherapy (CRT) and surgery. The rate of distant recurrences remains over 25%. Circulating cell-free DNA (cfDNA) in plasma is a mixture of normal and cancer-specific DNA segments and is a promising biomarker in patients with colorectal cancer. The aim of our study was to investigate plasma cfDNA as a prognostic marker for outcome in patients with LARC treated with neoadjuvant CRT and surgery. Patients and methods: In total, 123 patients with LARC were included in 2 biomarker studies. Patients were treated with neoadjuvant CRT before TME surgery. Fifty-two (42%) of the patients received induction chemotherapy with capecitabine + oxaliplatin. Total cfDNA was measured by direct fluorescent assay in EDTA plasma samples obtained at baseline, after induction chemotherapy, and after CRT. Serial samples 5 years after surgery were collected in 51 patients (41%). Results: Median follow-up was 55 months. Distant or local recurrence was seen in 30.9% of the patients. Patients with baseline cfDNA levels above the 75th quartile had a higher risk of local or distant recurrence and shorter time to recurrence compared with patients with plasma cfDNA below the 75th percentile (HR = 2.48, 95% CI: 1.3-4.8, P = 0.007). The same applied to disease-free survival (DFS) (HR = 2.43, 95% CI: 1.27-4.7, P = 0.015). In multivariate analysis, a high cfDNA level was significantly associated with time to progression and DFS. During follow-up, the association remained significant regardless of time point for sample analysis. Conclusion: We have demonstrated an association between a high baseline plasma level of cfDNA and increased risk of recurrence, shorter time to recurrence, and shorter DFS in patients with LARC. Consequently, cfDNA could potentially improve pre- and post-treatment risk assessment and facilitate individualized therapy for patients with LARC.

Streptococcus pneumoniae: proteomics of surface proteins for vaccine development.

Two formulations of pneumococcal vaccines are currently available to prevent invasive disease in adults and children. However, these vaccines will not protect against the majority of Streptococcus pneumoniae serotypes. The use of highly conserved cell-wall-associated proteins in vaccines may circumvent this problem. A proteomics approach was used to identify 270 S. pneumoniae cell-wall-associated proteins, which were then screened in a process that included in-silico, in-vitro and in-vivo validation criteria. Five potential candidates for inclusion in a vaccine were selected, expressed in Escherichia coli, and purified for use in immunisation experiments. These proteins were detected in at least 40 different serotypes of S. pneumoniae, and were expressed in S. pneumoniae isolates causing infection. Two of the five candidate proteins, the putative lipoate protein ligase (Lpl) and the ClpP protease, resulted in a reduced CFU titre and a trend towards reduced mortality in an animal sepsis model for investigating new S. pneumoniae protein vaccines.

Novel surface polypeptides of Campylobacter jejuni as traveller's diarrhoea vaccine candidates discovered by proteomics.

Campylobacter jejuni is one of the most common causes of traveller's diarrhoea and food poisoning, therefore development of a vaccine is important. Using biochemical fractionation and mass spectrometry analysis, we identified more than 110 surface polypeptides. Eight C. jejuni identified surface proteins were expressed in Escherichia coli and purified. Mice were immunized with different doses of these purified proteins and challenged orally with C. jejuni strains ML1 and ML53. The degree of protection of mice was tested by intestinal colonization. At least two groups of mice vaccinated with purified proteins clear the infection faster than control mice. Here, we present the use of a proteomics based approach for the identification of novel protein based C. jejuni vaccines for the first time.

Procalcitonin as a marker of postoperative complications.

OBJECTIVE: Procalcitonin (PCT) is a 116 amino acid peptide that functions as a pro-hormone for calcitonin in the C cells of the thyroid gland. Large quantities of intact PCT are present in the blood of patients with sepsis, particularly when organ dysfunction occurs. PCT has been proposed as an early marker of postoperative complications. The aim of this study was to examine the diagnostic accuracy of PCT as a marker of postoperative complications by systematically reviewing the existing literature. MATERIAL AND METHODS: The databases PubMed, Embase and the Cochrane Library were searched to find studies on the diagnostic accuracy of PCT in the postoperative phase. Primary studies were retrieved using specific inclusion and exclusion criteria. RESULTS: A total of nine studies were included. These studies were heterogeneous regarding the spectrum of patients, complications, design and methodological quality according to QUADAS (quality assessment of studies of diagnostic accuracy). This could explain the marked variation in diagnostic accuracy. Considering all types of complications the sensitivity ranged from 37% to 100% and the specificity from 70% to 100%. On examining the infectious complications separately, it was found that the sensitivity ranged from 70% to 86% and the specificity from 45% to 98%. CONCLUSIONS: Owing to a pronounced heterogeneity among the existing studies, the diagnostic accuracy of PCT as a marker for postoperative complications is not yet sufficiently clarified.

Efficacy of 3 commonly used hearing aid circuits: A crossover trial. NIDCD/VA Hearing Aid Clinical Trial Group.

CONTEXT: Numerous studies have demonstrated that hearing aids provide significant benefit for a wide range of sensorineural hearing loss, but no carefully controlled, multicenter clinical trials comparing hearing aid efficacy have been conducted. OBJECTIVE: To compare the benefits provided to patients with sensorineural hearing loss by 3 commonly used hearing aid circuits. DESIGN: Double-blind, 3-period, 3-treatment crossover trial conducted from May 1996 to February 1998. SETTING: Eight audiology laboratories at Department of Veterans Affairs medical centers across the United States. PATIENTS: A sample of 360 patients with bilateral sensorineural hearing loss (mean age, 67.2 years; 57% male; 78.6% white). INTERVENTION: Patients were randomly assigned to 1 of 6 sequences of linear peak clipper (PC), compression limiter (CL), and wide dynamic range compressor (WDRC) hearing aid circuits. All patients wore each of the 3 hearing aids, which were installed in identical casements, for 3 months. MAIN OUTCOME MEASURES: Results of tests of speech recognition, sound quality, and subjective hearing aid benefit, administered at baseline and after each 3-month intervention with and without a hearing aid. At the end of the experiment, patients ranked the 3 hearing aid circuits. RESULTS: Each circuit markedly improved speech recognition, with greater improvement observed for soft and conversationally loud speech (all 52-dB and 62-dB conditions, P

Metabolic response to air temperature and wind in day-old mallards and a standard operative temperature scale.

Most duckling mortality occurs during the week following hatching and is often associated with cold, windy, wet weather and scattering of the brood. We estimated the thermoregulatory demands imposed by cold, windy weather on isolated 1-d-old mallard (Anas platyrhynchos) ducklings resting in cover. We measured O2 consumption and evaporative water loss at air temperatures from 5 degrees to 25 degrees C and wind speeds of 0.1, 0.2, 0.5, and 1.0 m/s. Metabolic heat production increased as wind increased or temperature decreased but was less sensitive to wind than that of either adult passerines or small mammals. Evaporative heat loss ranged from 5% to 17% of heat production. Evaporative heat loss and the ratio of evaporative heat loss to metabolic heat production was significantly lower in rest phase. These data were used to define a standard operative temperature (Tes) scale for night or heavy overcast conditions. An increase of wind speed from 0.1 to 1 m/s decreased Tes by 3 degrees -5 degrees C.

Frequency of common cystic fibrosis gene mutations in chronic bronchitis patients.

It has been suggested that the delta F508 deletion, the most common mutation in the cystic fibrosis (CF) gene, might be linked to chronic bronchial hypersecretion. We investigated whether such an association could be found in chronic bronchitis, since chronic bronchial hypersecretion is an important and specific element of chronic bronchitis. We screened 100 patients hospitalized for chronic bronchitis with six of the most frequently occurring CF gene mutations: delta F508, R553X, G542X, G551D, N1303K, and 621-1G-->T. Only one patient affected by chronic bronchitis and diffuse bronchiectasis was heterozygous for the deletion delta F508; no other mutations were found. This is not significantly different from the expected frequency of CF carriers in northern Europe, which is 1 in 25. Thus, no association between the most commonly occurring cystic fibrosis genes and chronic bronchitis is likely to exist and routine screening of patients without further signs of cystic fibrosis would seem to be of no benefit in northern Europe.

Common CFTR mutations are not likely to predispose to chronic bronchitis in northern Germany.

The frequency of six common mutations in the cystic fibrosis transmembrane conductance regulator gene was studied in 100 patients hospitalized with chronic bronchitis. Only one patient with chronic bronchitis and diffuse bronchiectasis was heterozygous for the common delta F508 mutation. R553X, G542X, G551D, N1303K and 621 + 1G-->T were not detected. This result is not significantly different from the frequency of cystic fibrosis carriers in Northern Europe. Predisposition of heterozygotes for chronic bronchitis is therefore unlikely.