Multimodal therapy improves survival in patients with CNS metastasis from uterine cancer: a retrospective analysis and literature review

OBJECTIVE: Brain metastasis from uterine cancer is a rare event. Consequently, the optimal management strategy is not defined. We reviewed our institution's experience with brain metastasis from endometrial cancer along with the extant medical literature to develop management recommendations. METHODS: Twenty patients with CNS metastasis were identified. Information regarding symptoms, treatment, and survival was collected. The Kaplan-Meier method was used to compare survival data. RESULTS: The incidence of CNS metastasis was 0.97%. Median patient age at initial diagnosis of endometrial cancer was 62.0 years and 64.0 years at diagnosis of brain metastasis. Most patients initially presented with advanced FIGO stage: 9 stage IVB, 4 stage IIIC, 4 stage IIIA, 2 stage IB, and 1 stage IA. The median interval from diagnosis of endometrial cancer to diagnosis of brain metastasis was 11.5 months (range 0.6-73.6). Median survival after diagnosis of brain metastasis was 2.0 months (range 0.1-39.2). Improved survival was seen in patients treated with multimodal therapy compared to patients who only received whole brain radiotherapy (WBRT) (p=0.0001) or compared to patients who received no treatment (p=0.009). No difference in survival was seen between patients treated with WBRT versus no therapy. The survival advantage associated with multimodal therapy was also supported by case reports and case series in the literature. CONCLUSIONS: Based upon the data presented along with the medical literature, multimodal therapy appears to improve the survival of patients with CNS metastasis from uterine cancer.     

Parent presence during complex invasive procedures and cardiopulmonary resuscitation: a systematic review of the literature

We conducted a systematic review of the literature on parent presence during complex invasive pediatric procedures and/or resuscitation. We identified 15 studies that met our inclusion criteria. All studies were summarized chronologically according to level of evidence. The studies all demonstrated that parents prefer to have the choice about whether they remain at their child's side during complex invasive procedures and resuscitation, but they also revealed that apprehensions and controversy abound among clinicians regarding this practice. Despite the endorsements of the American Academy of Pediatrics and the Society of Critical Care Medicine and the recommendations of the American Heart Association, few pediatric institutions have drafted guidelines, conducted clinical education, or committed sufficient staff resources to fully support this practice. We present this review not only to illustrate the various perspectives of parents/guardians, clinicians, and pediatric patients themselves that have been reported to date but also to encourage more research so that the practice can be performed safely and benefit parents, their children, and clinicians alike.     

Construction and immunological characterization of a novel nontoxic protective pneumolysin mutant for use in future pneumococcal vaccines

Pneumolysin, the pore-forming toxin produced by Streptococcus pneumoniae, may have an application as an immunogenic carrier protein in future pneumococcal conjugate vaccines. Most of the 90 S. pneumoniae serotypes identified produce pneumolysin; therefore, this protein may confer non-serotype-specific protection against pneumococcal infections such as pneumonia, meningitis, and otitis media. However, as pneumolysin is highly toxic, a nontoxic form of pneumolysin would be a more desirable starting point in terms of vaccine production. Previous pneumolysin mutants have reduced activity but retain residual toxicity. We have found a single amino acid deletion that blocks pore formation, resulting in a form of pneumolysin that is unable to form large oligomeric ring structures. This mutant is nontoxic at concentrations greater than 1,000 times that of the native toxin. We have demonstrated that this mutant is as immunogenic as native pneumolysin without the associated effects such as production of the inflammatory mediators interleukin-6 and cytokine-induced neutrophil chemoattractant KC, damage to lung integrity, and hypothermia in mice. Vaccination with this mutant protects mice from challenge with S. pneumoniae. Incorporation of this mutant pneumolysin into current pneumococcal vaccines may increase their efficacy.     

Moderators of peer contagion: a longitudinal examination of depression socialization between adolescents and their best friends.

This longitudinal study examined peer contagion of depressive symptoms over an 18-month interval within a sample of 100 11th-grade adolescents. Three types of peer contagion moderators were examined, including characteristics of adolescents (social anxiety, global self-worth), friends (level of friends' peer-perceived popularity), and the relationship between them (friendship quality). Measures were collected using adolescents' and their friends' reports of depressive symptoms, adolescents' reports of social anxiety, global self-worth, friendship quality, and a sociometric assessment of peer-perceived popularity. Results indicated that among girls higher levels of social anxiety were associated with adolescents' greater susceptibility to peer contagion. Among boys, higher levels of friends' peer perceived popularity and lower levels of positive friendship quality each were associated with greater susceptibility to depressive symptom contagion.     

Phagocytosis of Borrelia burgdorferi and Treponema pallidum potentiates innate immune activation and induces gamma interferon production

We examined the interactions of live and lysed spirochetes with innate immune cells. THP-1 monocytoid cells were activated to comparable extents by live Borrelia burgdorferi and by B. burgdorferi and Treponema pallidum lysates but were poorly activated by live T. pallidum. Because THP-1 cells poorly internalized live spirochetes, we turned to an ex vivo peripheral blood mononuclear cell system that would more closely reflect spirochete-mononuclear phagocyte interactions that occur during actual infection. In this system, B. burgdorferi induced significantly greater monocyte activation and inflammatory cytokine production than did borrelial lysates or T. pallidum, and only B. burgdorferi elicited gamma interferon (IFN-gamma) from NK cells. B. burgdorferi was phagocytosed avidly by monocytes, while T. pallidum was not, suggesting that the enhanced response to live B. burgdorferi was due to phagocytosis of the organism. When cytochalasin D was used to block phagocytosis of live B. burgdorferi, cytokine production decreased to levels comparable to those induced by B. burgdorferi lysates, while the IFN-gamma response was abrogated altogether. In the presence of human syphilitic serum, T. pallidum was efficiently internalized and initiated responses resembling those observed with live B. burgdorferi, including the production of IFN-gamma by NK cells. Depletion of monocytes revealed that they were the primary source of inflammatory cytokines, while dendritic cells (DCs) directed IFN-gamma production from innate lymphocytes. Thus, phagocytosis of live spirochetes initiates cell activation programs in monocytes and DCs that differ qualitatively and quantitatively from those induced at the cell surface by lipoprotein-enriched lysates. The greater stimulatory capacity of B. burgdorferi versus T. pallidum appears to be explained by the successful recognition and phagocytosis of B. burgdorferi by host cells and the ability of T. pallidum to avoid detection and uptake by virtue of its denuded outer membrane rather than by differences in surface lipoprotein expression.     

A comparison of human umbilical cord matrix stem cells and temporomandibular joint condylar chondrocytes for tissue engineering temporomandibular joint condylar cartilage

The temporomandibular joint (TMJ) presents many problems in modern musculoskeletal medicine. Patients who suffer from TMJ disorders often experience a major loss in quality of life due to the debilitating effects that TMJ disorders can have on everyday activities. Cartilage tissue engineering can lead to replacement tissues that could be used to treat TMJ disorders. In this study, a spinner flask was used for a period of 6 days to seed polyglycolic acid (PGA) scaffolds with either TMJ condylar chondrocytes or mesenchymal-like stem cells derived from human umbilical cord matrix (HUCM). Samples were then statically cultured for 4 weeks either in growth medium containing chondrogenic factors or in control medium. Immunohistochemical staining of HUCM constructs after 4 weeks revealed a strong presence of collagen I and minute amounts of collagen II, whereas TMJ constructs revealed little collagen I and no collagen II. The HUCM constructs were shown to contain more GAGs than the TMJ constructs quantitatively at week 0 and histologically at week 4. Moreover, the cellularity of HUCM constructs was 55% higher at week 0 and nearly twice as high after 4 weeks, despite being seeded at the same density. The increased level of biosynthesis and higher cellularity of HUCM constructs clearly demonstrates that the HUCM stem cells outperformed the TMJ condylar cartilage cells under the prescribed conditions. HUCM stem cells may therefore be an attractive alternative to condylar cartilage cells for TMJ tissue engineering applications. Further, given the availability and ease of obtaining HUCM stem cells, these findings may have far-reaching implications, leading to novel developments in both craniofacial and orthopaedic tissue replacement therapies.     

Diminishing Efficacy of Combination Therapy, Response-Heterogeneity, and Treatment Intolerance Limit the Attainability of Tight Risk Factor Control in Patients with Diabetes

Objective. To evaluate the attainability of tight risk factor control targets for three diabetes risk factors and to assess the degree of polypharmacy required. Data Sources/Study Setting. National Health and Nutrition Examination Survey‐III. Study Design. We simulated a strategy of “treating to targets,” exposing subjects to a battery of treatments until low‐density lipoprotein (LDL)‐cholesterol (100 mg/dL), hemoglobin A1c (7 percent), and blood pressure (130/80 mm Hg) targets were achieved or until all treatments had been exhausted. Regimens included five statins of increasing potency, four A1c‐lowering therapies, and eight steps of antihypertensive therapy. Data Collection/Extraction Methods. We selected parameter estimates from placebo‐controlled trials and meta‐analyses. Principal Findings. Under ideal efficacy conditions, 77, 64, and 58 percent of subjects achieved the LDL, A1c, and blood pressure targets, respectively. Successful control depended highly on a subject's baseline number of treatments. Using the least favorable assumptions of treatment tolerance, success rates were 11–17 percentage points lower. Approximately 57 percent of subjects required five or more medication classes. Conclusions. A significant proportion of people with diabetes will fail to achieve targets despite using high doses of multiple, conventional treatments. These findings raise concerns about the feasibility and polypharmacy burden needed for tight risk factor control, and the use of measures of tight control to assess the quality of care for diabetes.     

Choosing early pregnancy termination methods in Urban Mozambique

Little is known about who chooses medication abortion with misoprostol and why. Women seeking early abortion in 5 public hospitals in Maputo, Mozambique were recruited in 2005 and 2006 to explore decision-making strategies, method preferences and experiences with misoprostol and vacuum aspiration for early abortion. Client screenings (n = 1799), structured clinical surveys (n = 837), in-depth exit interviews (n = 70), and nurse focus groups (n = 2) were conducted. Triangulation of qualitative and quantative data revealed seemingly contradictory findings. Choice of method reflected women’s heightened concerns about privacy, pain, quality of home support, HIV infection risk, sexuality, and safety of research participation. Urban Mozambican women are highly motivated to find early pregnancy termination techniques that they deem socially and clinically low-risk. Although 42% found vaginal misoprostol self-administration challenging and 25% delayed care for over a week to amass funds for user fees, almost all (96%) reported adequate preparation and comfort with home management. Women reported satisfaction with all methods and quality of care, even if the initial method failed or pain management or postabortion contraception were not offered. A more nuanced understanding of what women value most can yield service delivery models that are responsive and effective in reducing maternal death and disability from unsafe abortion.