Mutational evolution after chemotherapy-progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis

Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected from mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA from pretreatment and progressive disease (PD) samples were sequenced with a next-generation sequencing panel targeting 106 genes. A total of 712 samples from 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first-line, 85 second-line and 133 later-line [≥third-line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples from later-line had more baseline mutations (P = .002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40-3.69) compared to first-line. RAS/BRAF wild-type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22-2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens.     

Primary anaplastic large cell lymphoma in the dura of the brain: case report and prediction of a favorable prognosis

Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma composed of CD30-positive lymphoid cells. ALCL arising in the dura matter of the brain is even more infrequent, in which only one case has been reported worldwide so far. We report a case of a 30-year-old immunocompetent male with a dura-based mass, radiographically consistent with meningioma. However, the excised mass via a left parieto-occipital craniotomy was composed of large, pleomorphic lymphoid cells to be immunopositive for CD3, CD30, anaplastic lymphoma kinase protein-1 (ALK-1) and epithelial membrane antigen (EMA), and immunonegative for CD20, CD15 and CD68. Multiple ALK gene fusion signals in the ALK locus were detected by fluorescence in situ hybridization (FISH) analysis. The patient was treated with CHOP chemotherapy and intrathecal methotrexate along with brain radiation therapy, which resulted in a complete remission. In an analysis of 25 previously reported primary CNS ALCLs, ALK-1 positivity was shown to be prevalent in younger age, as ALCL occurs outside the brain. Patient less than 23 years, ALK-1 positivity and unifocal tumor may be associated with a better prognosis. However, sex, dural or leptomeningeal involvement, immune status, and tumor necrosis do not appear to have any influence on survival.     

Do knowledge infrastructure facilities support Evidence-Based Practice in occupational health? An exploratory study across countries among occupational physicians enrolled on Evidence-Based Medicine courses

Background  

Evidence-Based Medicine (EBM) is an important method used by occupational physicians (OPs) to deliver high quality health care. The presence and quality of a knowledge infrastructure is thought to influence the practice of EBM in occupational health care. This study explores the facilities in the knowledge infrastructure being used by OPs in different countries, and their perceived importance for EBM practice.     

Utilization of acute and long-term care in the last year of life: comparison with survivors in a population-based study

Background  

It is well-known that the use of care services is most intensive in the last phase of life. However, so far only a few determinants of end-of-life care utilization are known. The aims of this study were to describe the utilization of acute and long-term care among older adults in their last year of life as compared to those not in their last year of life, and to examine which of a broad range of determinants can account for observed differences in care utilization.     

Low and moderate-fat plant sterol fortified soymilk in modulation of plasma lipids and cholesterol kinetics in subjects with normal to high cholesterol concentrations: report on two randomized crossover studies

Background  

Although consumption of various plant sterol (PS)-enriched beverages is effective in lowering plasma cholesterol, the lipid-lowering potential of PS in a soymilk format has not been investigated thoroughly. Therefore, to evaluate the efficacy of PS-enriched soy beverages on plasma lipids and cholesterol kinetics, we conducted two separate 28 d dietary controlled cross-over studies. In study 1, the cholesterol-lowering efficacy of a low-fat (2 g/serving) PS enriched soy beverage was examined in 33 normal cholesterolemic subjects in comparison with 1% dairy milk. In study 2, we investigated the efficacy of a moderate-fat (3.5 g/serving) PS-enriched soy beverage on plasma cholesterol concentrations and cholesterol kinetic responses in 23 hypercholesterolemic subjects compared with 1% dairy milk. Both the low and moderate-fat PS-enriched soymilk varieties provided 1.95 g PS/d. Endpoint plasma variables were analyzed by repeated-measures ANOVA using baseline values as covariates for plasma lipid measurements.     

Minimizing Disparities in Surgical Care: A Research Focus for the Future

The wide array of questions and opportunities for surgical health services research offers important prospects for inquiry into surgical disparities. In this essay we discuss research that directly or indirectly addresses disparities in surgery, highlighting the strengths and the future directions such research efforts intimate as potential foci of collective attention. We then consider possible research approaches—including community-based participatory models—for confronting disparity and the potential role of research in quality improvement to help achieve the ultimate aim, an optimal level of health care for all.     

Silymarin inhibits melanin synthesis in melanocyte cells

Objectives The aim was to search for inhibitors of melanogenesis from natural resources. Methods The inhibitory effect of silymarin on melanogenesis in a spontaneously immortalized mouse melanocyte cell line, Mel‐Ab, was studied. Key findings Silymarin significantly prevented melanin production in a dose‐dependent manner with an IC50 value (concentration producing 50% maximal inhibition) of 28.2 μg/ml, without effects on cell viability. Also, silymarin inhibited l ‐DOPA oxidation activity of tyrosinase, the rate‐limiting melanogenic enzyme, in cell based‐systems but it did not directly affect cell‐free tyrosinase activity. Furthermore, Western blot analysis indicated that silymarin decreased the expression of tyrosinase protein. Conclusions This study suggests that the depigmenting effect of silymarin might be attributable to inhibition of tyrosinase expression and that silymarin may be useful as a natural skin‐lightening agent.