What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications.

Degenerative disorders of the intervertebral discs (IVDs) are generally characterized by enhanced matrix degradation, angiogenesis, innervation, and increased expression of catabolic cytokines. In this study, we investigated the effects of inflammatory cytokines, IL-1␤, and TNF-␣, on the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in human IVD degeneration. IL-1␤ and TNF-␣ stimulated the gene expression of VEGF, NGF, and BDNF in nucleus pulposus (NP) cells isolated from patient tissues. Immunohistochemical results demonstrated a positive correlation between IL-1␤ and VEGF/NGF/BDNF expression in human IVD tissues. RNA expression analysis of patient tissues also identified positive correlations between VEGF and platelet endothelial cell adhesion molecule-1 (PECAM-1) and between NGF/BDNF and protein gene product 9.5 (PGP9.5). Our findings suggest that IL-1␤ is generated during IVD degeneration, which stimulates the expression of VEGF, NGF, and BDNF, resulting in angiogenesis and innervation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J. Orthop. Res. 29: 265-269, 2011 Keywords: interleukin-1␤; vascular endothelial growth factor (VEGF); angiogenesis; innervation; intervertebral disc (IVD) Degenerative changes in intervertebral discs (IVDs) include increased expression of catabolic cytokines, decreased synthesis of normal IVD matrix and enhanced matrix degradation, and disc cell senescence and apoptosis.1-5 IVD degeneration results in the loss of hydrophilic matrix molecules leading to spinal instability and is the main cause of disc-related diseases, such as disc herniation and spinal stenosis. Normal lumbar IVD is avascular and aneural except for the outer third of the annulus fibrosus (AF). However, previous studies have described the ingrowth of nerves into the AF and nucleus pulposus (NP) of degenerated IVD 6,7 and these nerves were usually accompanied by microvascular blood vessels.8 Though, the mechanisms underlying nerve ingrowth and neovascularization are largely unknown.Neurotrophins play a role in the survival, growth, differentiation, and function of neurons.9 The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been detected in human IVD degeneration and have been implicated in the promotion of nerve ingrowth and generation of discogenic pain. 8,10,11 A histologic study examining degenerative IVD tissues from rats demonstrated that the major population of disc-innervating dorsal root ganglion neurons was the NGF-dependent neurons.

Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers, such as PD-L1 immunohistochemistry, tumor mutation burden, or tumor-infiltrating lymphocytes.

Background Computer navigation and robotic assistance technologies are used to improve the accuracy of component positioning in total knee arthroplasty (TKA), with the goal of improving function and optimizing implant longevity. The purpose of this study was to analyze trends in the use of technology-assisted TKA, identify factors associated with the use of these technologies, and describe potential drivers of cost. Methods The Nationwide Inpatient Sample database was used to identify patients who underwent TKA using conventional instrumentation, computer navigation, and robot-assisted techniques between 2005 and 2014. Variables analyzed include patient demographics, hospital and payer types, and hospital charges. Descriptive statistics were used to describe trends. Univariate and multivariate analyses were performed to identify differences between conventional and technology-assisted groups. Results Our analysis identified 6,060,901 patients who underwent TKA from 2005 to 2014, of which 273,922 (4.5%) used computer navigation and 24,084 (0.4%) used robotic assistance. The proportion of technology-assisted TKAs steadily increased over the study period, from 1.2% in 2005 to 7.0% in 2014. Computer navigation increased in use from 1.2% in 2005 to 6.3% in 2014. Computer navigation was more likely to be used in the Western United States, whereas robot-assisted TKAs were more likely to be performed in the Northeast. Increased hospital charges were associated with the use of technology assistance ($53,740.1 vs $47,639.2). Conclusions The use of computer navigation and robot-assisted TKA steadily increased over the study period, accounting for 7.0% of TKAs performed in the United States in 2014. Marked regional differences in the use of these technologies were identified. The use of these technologies was associated with increased hospital charges.

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A significant correlation was detected between the deregulation of specific types of miRNAs, such as miR-519a, miR-153 and miR-485-5p, and clinical variables as well as histological subtypes in ovarian cancers. Hence, these miRNAs may perform functions as diagnostic or prognostic biomarkers.

PurposeAngiogenesis plays an important role in the growth, progression, and metastasis of tumors. Vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival in several cancers. We investigated the present case-control study to determine whether there is an association between the VEGF 936C > T polymorphism and stomach cancer.Patients and MethodsThe association of functional single nucleotide polymorphisms (SNPs) of the VEGF gene with stomach cancer development was evaluated in a case-control study of 154 Korean stomach cancer patients. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.ResultsOur results revealed significant association of T allele-bearing genotypes with increased risk for stomach cancer development. Genotype frequencies of the VEGF 936C > T polymorphisms were significantly different between patient and control groups (CT, AOR: 2.007, 95% CI: 1.277 - 3.156, TT, AOR: 4.790, 95% CI: 1.174 - 19.539, CT + TT, AOR: 2.147, 95% CI: 1.382 - 3.337). When stratified by gender and age, genotype frequencies were significantly different for stomach cancer in women and in patients younger than 55 years (in women, CT, OR: 3.049, 95% CI: 1.568 - 5.930, CT+TT, OR: 3.132, 95% CI: 1.638 - 5.990; in < 55 years, CT, OR: 3.306, 95% CI: 1.413 - 7.732, CT + TT, OR: 3.967, 95% CI: 1.729 - 9.104). In addition, this association partially remained in cases with intestinal and diffuse-type stomach cancer.ConclusionOur present study suggests that the VEGF 936C > T polymorphism is a susceptibility factor for stomach cancer, at least in Korean.

Background The purpose of this study is to assess the epidemiology, population-specific treatment trends, and complications of distal radius fractures in the United States. Methods The PearlDiver database (Humana [2007–2014], Medicare [2005–2014]) was used to access US inpatient and outpatient data for all patients who had undergone operative and nonoperative treatment for a distal radius fracture in the United States. Epidemiologic analysis was performed followed by age-based stratification, to assess prevalence, treatment trends, and rates of complications. Results A total of 1,124,060 distal radius treatment claims were captured. The incidence of distal radius fractures follows a bimodal distribution with distinct peaks in the pediatric and elderly population. Fractures in the pediatric population occurred predominately in males, whereas fractures in the elderly population occurred more frequently in females. The most commonly used modality of treatment was nonoperative; however, the use of internal fixation increased significantly during the study period, from 8.75 to 20.02%, with a corresponding decrease in percutaneous fixation. The overall complication rate was 8.3%, with mechanical symptoms most frequently reported. Conclusions The last decade has seen a significant increase in the use of internal fixation as treatment modality for distal radius fractures. The impetus for this change is likely multifactorial and partly related to recent innovations including volar locking plates and an increasingly active elderly population. The implicated financial cost must be weighed against the productivity cost of maintaining independent living to determine the true burden to the healthcare system.