Molecular characterization of a large unselected cohort of metastatic colorectal cancers in relation to primary tumor location, rare metastatic sites and prognosis

Background: We have reported that BRAF V600E mutations and microsatellite instability-high (MSI-H) are more prevalent in a population-based cohort of metastatic colorectal cancer (mCRC) patients than has been reported from clinical trials or hospital-based patient groups. The aim was to explore if other mutations in mCRC differ in prevalence between these cohorts in relation to mismatch repair status and primary tumor location and if presence of bone or brain metastases is associated with any mutations. Material and methods: A population-based cohort of 798 mCRC patients from three regions in Scandinavia was used. Forty-four cancer related genes were investigated in a custom designed Ampliseq hotspot panel. Differences in survival were analyzed using the Kaplan–Meier estimator and the Cox regression analysis. Results: Determination of mutations was possible in 449/501 patients for 40/44 genes. Besides BRAF V600E, seen in 19% of the tumors, none of the other mutations appeared more prevalent than in trial cohorts. BRAF V600E and MSI-H, seen in 8%, were associated with poor prognosis as was right-sided primary tumor location (39%) when compared to left-sided and rectum together; however, in a multivariable regression, only the BRAF mutation retained its statistical significance. No other mutations were associated with poor prognosis. ERBB2 alterations were more common if bone metastases were present at diagnosis (17% vs. 4%, p = .011). No association was found for brain metastases. Fifty-two percent had an alteration that is treatable with an FDA-approved targeted therapy, chiefly by EGFR-inhibitor for RAS wild-type and a check-point inhibitor for MSI-H tumors. Conclusions: Right-sided tumor location, BRAF V600E mutations, but no other investigated mutation, and MSI-H are more commonly seen in an unselected cohort than is reported from clinical patient cohorts, likely because they indicate poor prognosis. Half of the patients have a tumor that is treatable with an already FDA-approved targeted drug for mCRC.publishedVersio

Worldwide Cutaneous Malignant Melanoma Incidences Analyzed by Sex, Age, and Skin Type Over Time (1955–2007): Is HPV Infection of Androgenic Hair Follicular Melanocytes a Risk Factor for Developing Melanoma Exclusively in People of European-Ancestry?

The cutaneous malignant melanoma (CMM) incidence has been increasing in an exponential manner in certain populations around the world for over 7 decades. To help illuminate the etiology, we performed worldwide temporal (1955–2007) CMM incidence analysis by sex, age (0–14, 15–29, 30–49, 50–69, 70–85+), and skin type on 6 continents using data from the International Agency for Research on Cancer. We observe an exponential increase in the CMM incidence over time and an increase of about 2 orders of magnitude between age groups 0–14 and 15–29 exclusively in European-ancestry populations around the world independent of skin type (I–III or III–IV). Other populations like the Chinese (III-IV) had much lower CMM incidences that either remained stable or temporally decreased but did not display a dramatic increase between the youngest age groups. The dramatic increase in the incidence between the youngest age groups found only in European-ancestry populations suggests one of the most important risk factors for CMM may be developing androgenic hair, the occurrence of which appears to correlate with the distribution of CMM over male and female body sites. Besides that potential new risk factor, the increasing CMM incidence with increasing age, known not to be from cumulative UV doses, may be associated with age-related changes to skin, i.e., thinning epidermis causing lower vitamin D3 levels, and hair, i.e., whitening from higher reactive oxygen species. The temporal exponential increasing CMM incidence in European-ancestry populations may be due to Human Papilloma Virus infection of follicular hair melanocytes, found in CMM biopsies

The Spectra of Large Toeplitz Band Matrices with a Randomly Perturbed Entry

This report is concerned with the union $sp_{\Omega}^{(j,k)}T_{n}(a)$ of all possible spectra that may emerge when perturbing a large $n \times n$ Toeplitz band matrix $T_{n}(a)$ in the $(j,k)$ site by a number randomly chosen from some set $\Omega$. The main results give descriptive bounds and, in several interesting situations, even provide complete identifications of the limit of $sp_{\Omega}^{(j,k)}T_{n}(a)$ as $n \to \infty$. Also discussed are the cases of small and large sets $\Omega$ as well as the "discontinuity of the infinite volume case", which means that in general $sp_{\Omega}^{(j,k)}T_{n}(a)$ does not converge to something close to $sp_{\Omega}^{(j,k)}T_{n}(a)$ as $n \to \infty$, where $T(a)$ is the corresponding infinite Toeplitz matrix. Illustrations are provided for tridiagonal Toeplitz matrices, a notable special case. \ud \ud The second author was supported by UK Enginering and Physical Sciences Research Council Grant GR/M1241

Worldwide Cutaneous Malignant Melanoma Incidences Analyzed by Sex, Age, and Skin Type Over Time (1955–2007): Is HPV Infection of Androgenic Hair Follicular Melanocytes a Risk Factor for Developing Melanoma Exclusively in People of European-Ancestry?

The cutaneous malignant melanoma (CMM) incidence has been increasing in an exponential manner in certain populations around the world for over 7 decades. To help illuminate the etiology, we performed worldwide temporal (1955–2007) CMM incidence analysis by sex, age (0–14, 15–29, 30–49, 50–69, 70–85+), and skin type on 6 continents using data from the International Agency for Research on Cancer. We observe an exponential increase in the CMM incidence over time and an increase of about 2 orders of magnitude between age groups 0–14 and 15–29 exclusively in European-ancestry populations around the world independent of skin type (I–III or III–IV). Other populations like the Chinese (III-IV) had much lower CMM incidences that either remained stable or temporally decreased but did not display a dramatic increase between the youngest age groups. The dramatic increase in the incidence between the youngest age groups found only in European-ancestry populations suggests one of the most important risk factors for CMM may be developing androgenic hair, the occurrence of which appears to correlate with the distribution of CMM over male and female body sites. Besides that potential new risk factor, the increasing CMM incidence with increasing age, known not to be from cumulative UV doses, may be associated with age-related changes to skin, i.e., thinning epidermis causing lower vitamin D3 levels, and hair, i.e., whitening from higher reactive oxygen species. The temporal exponential increasing CMM incidence in European-ancestry populations may be due to Human Papilloma Virus infection of follicular hair melanocytes, found in CMM biopsies

Recurrent Acute Pancreatitis Probably Induced by Rosuvastatin Therapy: A Case Report

Context. Approximately 1.4–2% of all cases of acute pancreatitis are drug related in general population. The literature on statin-induced pancreatitis consists primarily of anecdotal case reports. We report a case of possible rosuvastatin-induced pancreatitis. Case Report. A 67-year-old female presented with progressively worsening abdominal pain and vomiting for 7 days. Home medications included rosuvastatin and clonidine. CT scan of abdomen, with intravenous contrast, showed findings consistent with acute pancreatitis. She responded to conservative management. Rosuvastatin was resumed at the time of discharge from the hospital, and she presented two months later with recurrence of acute pancreatitis. Further workup ruled out all likely causes of acute pancreatitis. Rosuvastatin was stopped completely when she was discharged the second time, and she did not have any further episodes of acute pancreatitis. She was completely asymptomatic throughout the 18-month follow-up period. Conclusion. This paper reinforces the possible association of rosuvastatin, a novel statin, with acute pancreatitis, even though the exact underlying mechanism of statin-induced pancreatitis remains unknown

Stability and convergence of discretisations of initial value p.d.e.'s

This paper examines the stability and convergence of discretisations of initial value p.d.e.'s using spatial discretisation followed by time integration with an explicit one-step method. A Cauchy integral representation is used to bound the growth in the discrete solution. New results are obtained regarding sufficient conditions for both algebraic and strong stability. Sufficient conditions are also derived for convergence on a finite time interval

Parental Labor Market Success and Children's Education Attainment

This study examines the effects of parental labor market activities on children's education attainment. In contrast to the existing literature we consider parental experiences until the children graduate from school. In addition, the effects of the regional economic environment during teacher's decision about the secondary school track are analyzed. Using data drawn from the German Socio-Economic Panel an ordered probit estimator is used to model children's education attainment. With respect to parental labor market participation we find that father's full-time and mother's part-time employment have significant positive effects on children's education attainment. Furthermore, we obtain evidence that the regional GDP growth rate and the regional unemployment rate when children are 10 years old are significantly related to the education that these children ultimately achieve. Our interpretation is that regional economic conditions affect teachers'recommendations for the secondary school track, which are given during the last year of primary school. The results reveal the less successful parents are on the labor market, the lower the average education level of their children. A second important conclusion is that children who live in regions which experience a poor economic performance over a longer period are, on average, less educated than children who live in more affluent regions.education attainment, parental labor supply, macroeconomic uncertainty, family structure, intergenerational link

Sn whisker growth mitigation by using NiO sublayers

The potential of NiO sublayers for whisker growth mitigation has been examined. A thin NiO film was applied on a Cu-coated substrate before the deposition of a thicker Sn layer. The growth of Sn whiskers was then followed by optical and scanning electron microscopy and was compared with the whisker growth on a control sample without the NiO sublayer. No whiskers were observed on the sample with the NiO layer even after 12 months, whereas the control sample developed whiskers of size and density that is generally expected, based on the vast amount of published work on the topic. The mechanisms of whisker growth and whisker growth suppression are briefly discussed as well.Comment: 7 figure

Ticagrelor versus clopidogrel in patients with acute coronary syndromes and chronic obstructive pulmonary disease: An analysis from the platelet inhibition and patient outcomes (PLATO) trial

Background Patients with chronic obstructive pulmonary disease (COPD) experiencing acute coronary syndromes (ACS) are at high risk for clinical events. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor versus clopidogrel reduced the primary endpoint of death from vascular causes, myocardial infarction, or stroke after ACS, but increased the incidence of dyspnea, which may lead clinicians to withhold ticagrelor from COPD patients. Methods and Results In 18 624 patients with ACS randomized to treatment with ticagrelor or clopidogrel, history of COPD was recorded in 1085 (5.8%). At 1 year, the primary endpoint occurred in 17.7% of patients with COPD versus 10.4% in those without COPD (P<0.001). The 1‐year event rate for the primary endpoint in COPD patients treated with ticagrelor versus clopidogrel was 14.8% versus 20.6% (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.54 to 0.97), for death from any cause 8.4% versus 12.4% (HR=0.70; 95% CI: 0.47 to 1.04), and for PLATO‐defined major bleeding rates at 1 year 14.6% versus 16.6% (HR=0.85; 95% CI: 0.61 to 1.17). Dyspnea occurred more frequently with ticagrelor (26.1% vs. 16.3%; HR=1.71; 95% CI: 1.28 to 2.30). There was no differential increase in the relative risk of dyspnea compared to non‐COPD patients (HR=1.85). No COPD status‐by‐treatment interactions were found, showing consistency with the main trial results. Conclusions In this post‐hoc analysis, COPD patients experienced high rates of ischemic events. Ticagrelor versus clopidogrel reduced and substantially decreased the absolute risk of ischemic events (5.8%) in COPD patients, without increasing overall major bleeding events. The benefit‐risk profile supports the use of ticagrelor in patients with ACS and concomitant COPD. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872