CASP8 D302H and meningioma risk: an analysis of five case-control series

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.     

Decrease in mast cells in oral squamous cell carcinoma: possible failure in the migration of these cells

It is becoming accepted that multiple cell types in stromal microenvironment are involved in tumorigenesis. In this setting, mast cells (MC) display a diversity of roles that may contribute to the defense against tumors or tumor progression. Thus, the aim of this study was to evaluate density and migration of MCs in OSCC (oral squamous cell carcinoma) and pre-malignant oral hyperkeratosis (leukoplakia) as well as their relationship with clinical and microscopic parameters. The tryptase and c-kit expression was analyzed in 38 cases of OSCC, 26 cases of leukoplakia, and 12 cases of clinically healthy oral mucosa (control) by means of immunohistochemistry. The tryptase(+) cell numbers were decreased in OSCC (P=0.0003) and leukoplakia (P=0.03) compared with control. Similar numbers of tryptase(+) cells were observed in leukoplakia and OSCC (P=0.31). The density of c-kit(+) MCs was also significantly lower in OSCC and leukoplakia in relation to control resulting in a reduced c-kit(+)/tryptase(+) relationship in OSCC (19%) in comparison with leukoplakia (59%) and control (63%). No correlation was observed between MC populations with clinical and microscopic characteristics of OSCC. Our findings suggest that the decrease in MC numbers in pre-malignant and malignant oral lesions may be related to the migration failure of these cells, possibly reflecting an important modification in the microenvironment during tumor initiation and progression.     

Effects of ritanserin on sleep disturbances of dysthymic patients

Ritanserin, a selective and potent serotonin-2 antagonist, is effective in the treatment of a variety of syndromes related to anxiety and depression, including dysthymic disorder. In animals and healthy volunteers, ritanserin specifically increases slow-wave sleep and the hypothesis arises that this effect on sleep may contribute to its therapeutic properties. Therefore, we studied the effects of ritanserin on sleep in a group of dysthymic patients (DSM-III). Polygraphic recording as well as subjective evaluations of the quality of sleep were performed before and at the end of a 4-week period of double-blind medication with either ritanserin (10 mg o.d. in the morning) or placebo. At baseline, patients showed at fragmented and superficial sleep, with low amounts of slow wave sleep. Ritanserin significantly increased Slow Wave Sleep and changed the frequency and distribution of some stage transitions during the night. No other sleep parameters were modified by ritanserin treatment.     

In vivo confocal microscopy: increased conjunctival or episcleral leukocyte adhesion in patients who wear contact lenses with lower oxygen permeability (Dk) values

PURPOSE: Contact lens wear is known to threaten the health of the ocular surface. In vivo confocal microscopy (IVCM) to visualize leukocyte rolling and extravasation in inflammation was recently described. We tested the hypothesis that contact lens wear is associated with measurable inflammation in superficial vessels. METHODS: Leukocyte rolling and sticking (hallmarks of the inflammatory process) were recorded by IVCM. IVCM was performed on conjunctival or episcleral blood vessels bilaterally on 55 contact lens wearers (15 male, 40 female) and 22 non-contact lens wearers (8 male, 14 female). Data were analyzed in 2 ways. Considering each vessel as an independent variable resulted in 132 analyzable vessel segments (13 daily disposable contact lenses, 67 traditional contact lenses, 14 rigid gas-permeable lenses, and 38 controls). Considering each subject as an independent variable resulted in analyzable data for 47 subjects (5 daily disposable contact lens wearers, 22 traditional contact lens wearers, 5 rigid contact lens wearers, and 15 control patients). Free-flowing, sticking, and rolling cells were counted in the vessels. Multiple parameters including mean flow velocity, shear rate, rolling cells/mm/min, and sticking cells/mm were calculated. RESULTS: We found no significant difference in leukocyte adhesion between control patients and patients wearing daily disposable, traditional disposable, or rigid gas-permeable lenses in both types of statistical analyses. However, the data regarding vessel segments as an independent variable show that there were more rolling cells in patients who wore contact lenses with oxygen permeability values (Dk) less than 10 as compared to those who wore contact lenses with oxygen permeability values greater than 16 (P < 0.01) or compared to controls (P < 0.01). CONCLUSION: IVCM is a novel, powerful technique to recognize a critical but subclinical component of inflammation. Although our data indicate that contact lens wear does not markedly increase rolling and sticking of leukocytes in conjunctival or episcleral vessels, there may be subclinical inflammation in association with lenses with the lowest oxygen permeability.     

A class comparison method with filtering-enhanced variable selection for high-dimensional data sets

High-throughput molecular analysis technologies can produce thousands of measurements for each of the assayed samples. A common scientific question is to identify the variables whose distributions differ between some pre-specified classes (i.e. are differentially expressed). The statistical cost of examining thousands of variables is related to the risk of identifying many variables that truly are not differentially expressed, and many different multiple testing strategies have been used for the analysis of high-dimensional data sets to control the number of these false positives. An approach that is often used in practice to reduce the multiple comparisons problem is to lessen the number of comparisons being performed by filtering out variables that are considered non-informative 'before' the analysis. However, deciding which and how many variables should be filtered out can be highly arbitrary, and different filtering strategies can result in different variables being identified as differentially expressed. We propose the filtering-enhanced variable selection (FEVS) method, a new multiple testing strategy for identifying differentially expressed variables. This method identifies differentially expressed variables by combining the results obtained using a variety of filtering methods, instead of using a pre-specified filtering method or trying to identify an optimal filtering of the variables prior to class comparison analysis. We prove that the FEVS method probabilistically controls the number of false discoveries, and we show with a set of simulations and an example from the literature that FEVS can be useful for gaining sensitivity for the detection of truly differentially expressed variables.     

The genetics of FAP and FAP-like syndromes

The presence of multiple adenomatous polyps in the large bowel confers a high lifetime risk of colorectal cancer. Although many cases of classical familial adenomatous polyposis (> 100 polyps) can be accounted for by mutations in the adenomatous polyposis coli (APC) gene, a large group of patients remains with multiple (5–100) adenomas and in whom there is no detectable APC mutation. Recently two new genetic variants have been found to be associated with multiple colorectal adenomas and cancer, MYH/MUTYH on chromosome 1p and the HMPS/CRAC1 locus on chromosome 15q13–q14. New information also continues to emerge regarding the less common hamartomatous polyposis conditions, Peutz–Jeghers syndrome and Juvenile Polyposis syndrome. In approximately half to two thirds of these families, germline genetic variants can now be uncovered. In this review we draw together some of the most recent information pertinent to the molecular pathogenesis of colorectal polyposis.     

Epilepsy in the end-of-life phase in patients with high-grade gliomas

Epilepsy is common in patients with brain tumors. Patients presenting seizures as the first sign of a malignant glioma are at increased risk of recurrent seizures despite treatment with antiepileptic drugs. However, little is known about the incidence of epilepsy in the last stage of disease and in the end–of-life phase of brain tumor patients. We retrospectively analyzed the incidence of seizures in the last months of life in a series of patients affected by high-grade gliomas who were assisted at home during the whole course of the disease until death. A total of 157 patients were available for analysis. Of these patients, 58 (36.9 %) presented seizures in the last month before death. The risk of seizures in the end-of-life phase is higher in patients presenting previous history of epilepsy, particularly in patients with late-onset epilepsy. Out of the 58 patients presenting seizures in the last month of life, 86.2 % had previously had seizures and 13.8 % were seizure free. Most patients may encounter swallowing difficulties in taking anticonvulsants orally due to dysphagia and disturbances of consciousness, thus anticonvulsant treatment needs to be modified in advance. Loss of seizure control in the end-of-life phase may influence the quality of life of patients and their caregivers.     

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL–Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia

BackgroundAcute myeloid leukemia (AML) accounts for approximately 20% of pediatric leukemia cases; 30% of these patients experience relapse. The antileukemia properties of natural killer (NK) cells and their safety profile have been reported in AML therapy. We proposed a phase 2, open, prospective, multicenter, nonrandomized clinical trial for the adoptive infusion of haploidentical K562-mb15-41BBL–activated and expanded NK (NKAE) cells as a consolidation strategy for children with favorable and intermediate risk AML in first complete remission after chemotherapy (NCT02763475).Patients and MethodsBefore the NKAE cell infusion, patients underwent a lymphodepleting regimen. After the NKAE cell infusion, patients were administered low doses (1 × 10⁶/IU/m²) of subcutaneous interleukin-2. The primary study endpoint was AML relapse-free survival. We needed to include 35 patients to demonstrate a 50% reduction in relapses.ResultsSeven patients (median age, 7.4 years; range, 0.78-15.98 years) were administered 13 infusions of NKAE cells, with a median of 36.44 × 10⁶ cells/kg (range, 6.92 × 10⁶ to 193.2 × 10⁶ cells/kg). We observed chimerism in 4 patients (median chimerism, 0.065%; range, 0.05-0.27%). After a median follow-up of 33 months, the disease of 6 patients (85.7%) remained in complete remission. The 3-year overall survival was 83.3% (95% confidence interval, 68.1-98.5), and the cumulative 3-year relapse rate was 28.6% (95% confidence interval, 11.5-45.7). The study was terminated early because of low patient recruitment.ConclusionThis study emphasizes the difficulties in recruiting patients for cell therapy trials, though NKAE cell infusion is safe and feasible. However, we cannot draw any conclusions regarding efficacy because of the small number of included patients and insufficient biological markers.