Very-high-risk localized prostate cancer: definition and outcomes.

BACKGROUND: Outcomes in men with National Comprehensive Cancer Network (NCCN) high-risk prostate cancer (PCa) can vary substantially-some will have excellent cancer-specific survival, whereas others will experience early metastasis even after aggressive local treatments. Current nomograms, which yield continuous risk probabilities, do not separate high-risk PCa into distinct sub-strata. Here, we derive a binary definition of very-high-risk (VHR) localized PCa to aid in risk stratification at diagnosis and selection of therapy. METHODS: We queried the Johns Hopkins radical prostatectomy database to identify 753 men with NCCN high-risk localized PCa (Gleason sum 8-10, PSA >20 ng ml(-1), or clinical stage ≥T3). Twenty-eight alternate permutations of adverse grade, stage and cancer volume were compared by their hazard ratios for metastasis and cancer-specific mortality. VHR criteria with top-ranking hazard ratios were further evaluated by multivariable analyses and inclusion of a clinically meaningful proportion of the high-risk cohort. RESULTS: The VHR cohort was best defined by primary pattern 5 present on biopsy, or ≥5 cores with Gleason sum 8-10, or multiple NCCN high-risk features. These criteria encompassed 15.1% of the NCCN high-risk cohort. Compared with other high-risk men, VHR men were at significantly higher risk for metastasis (hazard ratio 2.75) and cancer-specific mortality (hazard ratio 3.44) (P<0.001 for both). Among high-risk men, VHR men also had significantly worse 10-year metastasis-free survival (37% vs 78%) and cancer-specific survival (62% vs 90%). CONCLUSIONS: Men who meet VHR criteria form a subgroup within the current NCCN high-risk classification who have particularly poor oncological outcomes. Use of these characteristics to distinguish VHR localized PCa may help in counseling and selection optimal candidates for multimodal treatments or clinical trials.

Learning chronobiology by improving Wikipedia.

Although chronobiology is of growing interest to scientists, physicians, and the general public, access to recent discoveries and historical perspectives is limited. Wikipedia is an online, user-written encyclopedia that could enhance public access to current understanding in chronobiology. However, Wikipedia is lacking important information and is not universally trusted. Here, 46 students in a university course edited Wikipedia to enhance public access to important discoveries in chronobiology. Students worked for an average of 9 h each to evaluate the primary literature and available Wikipedia information, nominated sites for editing, and, after voting, edited the 15 Wikipedia pages they determined to be highest priorities. This assignment (http://www.nslc.wustl.edu/courses/Bio4030/wikipedia_project.html) was easy to implement, required relatively short time commitments from the professor and students, and had measurable impacts on Wikipedia and the students. Students created 3 new Wikipedia sites, edited 12 additional sites, and cited 347 peer-reviewed articles. The targeted sites all became top hits in online search engines. Because their writing was and will be read by a worldwide audience, students found the experience rewarding. Students reported significantly increased comfort with reading, critiquing, and summarizing primary literature and benefited from seeing their work edited by other scientists and editors of Wikipedia. We conclude that, in a short project, students can assist in making chronobiology widely accessible and learn from the editorial process.

The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment.

Although age-related macular degeneration (AMD) is not a classic inflammatory disease like uveitis, inflammation has been found to have an important role in disease pathogenesis and progression. Innate immunity and autoimmune components, such as complement factors, chemokines, cytokines, macrophages, and ocular microglia, are believed to be heavily involved in AMD development. Targeting these specific inflammatory molecules has recently been explored in an attempt to better understand and treat AMD. Although antivascular endothelial growth factor therapy is the first line of defence against neovascular AMD, anti-inflammatory agents such as corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressive agents (eg, methotrexate and rapamycin), and biologics (eg, infliximab, daclizumab, and complement inhibitors) may provide an adjunct or alternative mechanism to suppress the inflammatory processes driving AMD progression. Further investigation is required to evaluate the long-term safety and efficacy of these drugs for both neovascular and non-neovascular AMD.

Glenohumeral mechanics: a study of articular geometry, contact, and kinematics.

Stereophotogrammetry was used to investigate the functional relations between the articular surface geometry, contact patterns, and kinematics of the glenohumeral joint. Nine normal shoulder specimens were elevated in the scapular plane by using simulated muscle forces in neutral rotation (NR) and starting rotation (SR). Motion was quantified by analyzing the translations of the geometric centers of the humeral head cartilage and bone surfaces relative to the glenoid surface. In both NR and SR, the ranges of translations of the center of the humeral head cartilage surface were greatest in the inferior-superior direction (NR 2.0 +/- 0.7 mm, SR 2.9 +/- 1.2 mm). Results of this study also show that joints with less congruence of the articular surfaces exhibit larger translations, and elevation in SR yields greater translations than in NR. Kinematic analyses with the humeral head bone surface data yielded larger values of translation than analyses that used the cartilage surface data, suggesting that similar overestimations may occur in radiographic motion studies. Results of this study demonstrate that small translations of the humeral head center occurred in both SR and NR. The proximity of the origin of the helical axes to the geometric center of the humeral head articular surface confirmed that glenohumeral elevation is mainly rotation about this geometric center with small translations.

Effects of repetitive subfailure strains on the mechanical behavior of the inferior glenohumeral ligament.

The mechanical response of the inferior glenohumeral ligament to varying subfailure cyclic strains was studied in 33 fresh frozen human cadaver shoulders. The specimens were tested as bone-ligament-bone preparations representing the 3 regions of the inferior glenohumeral ligament (superior band and anterior and posterior axillary pouches) through use of uniaxial tensile cycles. After mechanical preconditioning, each specimen was subjected to 7 test segments, consisting of a baseline strain level L1 (400 cycles) alternating with either 1 (group A, 10 shoulders), 10 (group B, 13 shoulders), or 100 (group C, 10 shoulders) cycles at increasing levels (L2, L3, L4) of subfailure strain. Cycling to higher levels of subfailure strain (L2, L3, L4) produced dramatic declines in the peak load response of the inferior glenohumeral ligament for all specimens. The group of ligaments subjected to 100 cycles of higher subfailure strains demonstrated a significantly greater decrease in load response than the other 2 groups. Ligament elongation occurred with cyclic testing at subfailure strains for all 3 groups, averaging 4.6% +/- 2.0% for group A, 6.5% +/- 2.6% for group B, and 7.1% +/- 3.2% for group C. Recovery of length after an additional time of nearly 1 hour was minimal. The results from this study demonstrate that repetitive loading of the inferior glenohumeral ligament induces laxity in the ligament, as manifested in the peak load response and measured elongations. The mechanical response of the ligament is affected by both the magnitude of the cyclic strain and the frequency of loading at the higher strain levels. The residual length increase was observed in all of the specimens and appeared to be largely unrecoverable. This length increase may result from accumulated microdamage within the ligament substance, caused by the repetitively applied subfailure strains. The clinical relevance of the study is that this mechanism may contribute to the development of acquired glenohumeral instability, which is commonly seen in the shoulders of young athletes who participate in repetitive overhead sports activities.

Anterior and posterior musculotendinous anatomy of the supraspinatus.

The objective of this study was to quantitatively describe the supraspinatus musculotendinous architecture. After supraspinatus muscles were harvested from 25 embalmed shoulders, each muscle was divided into an anterior and posterior muscle belly on the basis of muscle fiber insertion. Pennation angles and musculotendinous dimensions were measured, and the physiologic cross-sectional area was calculated for each muscle belly. The physiologic cross-sectional areas of the anterior and posterior bellies were calculated to be 140 +/- 43 mm2 and 62 +/- 25 mm2, respectively, whereas their tendon cross-sectional areas were 26.4 +/- 11.3 mm2 and 31.2 +/- 10.1 mm2, respectively. The average anterior-to-posterior ratios for the muscle physiologic cross-sectional area and the tendon cross-sectional area were 2.45 +/- 0.82 and 0.87 +/- 0.30, respectively. Thus, a larger anterior muscle pulls through a smaller tendon area. These data suggest that physiologically, anterior tendon stress is significantly greater than posterior tendon stress and that rotator cuff tendon repairs should incorporate the anterior tendon whenever possible, inasmuch as it functions as the primary contractile unit.