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The energetic costs of duplicating chromatin are large and therefore likely depend on nutrient sensing checkpoints and metabolic inputs. By studying chromatin modifiers regulated by epithelial growth factor, we identified histone acetyltransferase 1 (HAT1) as an induced gene that enhances proliferation through coordinating histone production, acetylation, and glucose metabolism. In addition to its canonical role as a cytoplasmic histone H4 acetyltransferase, we isolated a HAT1-containing complex bound specifically at promoters of H4 genes. HAT1-dependent transcription of H4 genes required an acetate-sensitive promoter element. HAT1 expression was critical for S-phase progression and maintenance of H3 lysine 9 acetylation at proliferation-associated genes, including histone genes. Therefore, these data describe a feedforward circuit whereby HAT1 captures acetyl groups on nascent histones and drives H4 production by chromatin binding to support chromatin replication and acetylation. These findings have important implications for human disease, since high HAT1 levels associate with poor outcomes across multiple cancer types.

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OBJECTIVES: Perineural invasion (PNI) has not yet gained universal acceptance as an independent predictor of adverse outcomes for prostate cancer treated with external beam radiotherapy (EBRT). We analyzed the prognostic influence of PNI for a large institutional cohort of prostate cancer patients who underwent EBRT with and without androgen deprivation therapy (ADT). MATERIAL AND METHODS: We, retrospectively, reviewed prostate cancer patients treated with EBRT from 1993 to 2007 at our institution. The primary endpoint was biochemical failure-free survival (BFFS), with secondary endpoints of metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Univariate and multivariable Cox proportional hazards models were constructed for all survival endpoints. Hazard ratios for PNI were analyzed for the entire cohort and for subsets defined by NCCN risk level. Additionally, Kaplan-Meier survival curves were generated for all survival endpoints after stratification by PNI status, with significant differences computed using the log-rank test. RESULTS: Of 888 men included for analysis, PNI was present on biopsy specimens in 187 (21.1%). PNI was associated with clinical stage, pretreatment PSA level, biopsy Gleason score, and use of ADT (all P<0.01). Men with PNI experienced significantly inferior 10-year BFFS (40.0% vs. 57.8%, P = 0.002), 10-year MFS (79.7% vs. 89.0%, P = 0.001), and 10-year PCSS (90.9% vs. 95.9%, P = 0.009), but not 10-year OS (67.5% vs. 77.5%, P = 0.07). On multivariate analysis, PNI was independently associated with inferior BFFS (P<0.001), but not MFS, PCSS, or OS. In subset analysis, PNI was associated with inferior BFFS (P = 0.04) for high-risk patients and with both inferior BFFS (P = 0.01) and PCSS (P = 0.05) for low-risk patients. Biochemical failure occurred in 33% of low-risk men with PNI who did not receive ADT compared to 8% for low-risk men with PNI treated with ADT (P = 0.01). CONCLUSION: PNI was an independently significant predictor of adverse survival outcomes in this large institutional cohort, particularly for patients with NCCN low-risk disease. PNI should be carefully considered along with other standard prognostic factors when treating these patients with EBRT. Supplementing EBRT with ADT may be beneficial for select low-risk patients with PNI though independent validation with prospective studies is recommended.

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AbstractThe published version of this article unfortunately contained an error. Author "E. Mark Mahone" has been published incorrectly by capturing "Mark Mahone" as family name when it should only be "Mahone". Given in this article is the corrected name.

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PURPOSE/OBJECTIVE(S): Cranial radiation therapy (CRT) may disrupt the corpus callosum (CC), which plays an important role in basic motor and cognitive functions. The aim of this prospective longitudinal study was to assess changes in CC mid-sagittal areas, CC volumes, and performance on neuropsychological (NP) tests related to the CC in children following CRT. MATERIALS/METHODS: Twelve pediatric patients were treated with CRT for primary brain malignancies. Thirteen age-matched healthy volunteers served as controls. Brain MRIs and NP assessment emphasizing motor dexterity, processing speed, visuomotor integration, and working memory (visual and verbal) were performed at baseline and at 6, 15, and 27 months following completion of CRT. Linear mixed effects (LME) analyses were used to evaluate patient NP performance and changes in regional CC volumes (genu, anterior body, mid-body, posterior body, and splenium) and mid-sagittal areas over time and with radiation doses, correcting for age at CRT start. RESULTS: The mean age at CRT was 9.41 (range 1.2-15.7) years. The median prescription dose was 54 (range 18-59.4) Gy. LME analysis revealed a significant decrease in overall CC volumes over time (p < 0.00001), with no overall effect of radiation dose. Analysis of individual CC regions demonstrated a significant decrease in all regional volumes over time (p < 0.00001) in patients, with no effect of radiation dose. Only in the splenium was there a trend toward a dose-dependent effect (p = 0.093). Patients had significantly reduced NP performance across visits-most notably in motor dexterity and visual working memory (both p < 0.0001). CONCLUSIONS: These prospective data demonstrate a significant decrease in CC regional volumes after CRT, with associated decline in neurocognitive function, most notably in manual dexterity, attention, and working memory. Further prospective study of larger cohorts of patients is needed to establish the relationship between CRT dose, neuroanatomical, and functional changes in the CC.

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PURPOSE: Existing definitions of high-risk prostate cancer consist of men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of National Comprehensive Cancer Network (NCCN) high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multiple NCCN high-risk factors, primary Gleason pattern 5 disease and/or ≥5 biopsy cores with Gleason sums of 8 to 10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients. METHODS AND MATERIALS: All men consecutively treated with definitive radiation by a single provider from 1993 to 2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 patients (34%) with VHR disease. Multivariate-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariate-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men. RESULTS: Men with VHR disease compared to other NCCN high-risk men experienced a higher 10-year incidence of BF (54.0% vs 35.4%, respectively, P<.001), DM (34.9% vs 13.4%, respectively, P<.001), PCSM (18.5% vs 5.9%, respectively, P<.001), and OM (36.4% vs 27.0%, respectively, P=.04). VHR men with a detectable prostate-specific antigen (PSA) concentration at the end of radiation (EOR) remained at high risk of 10-year PCSM compared to VHR men with an undetectable EOR PSA (31.0% vs 13.7%, respectively, P=.05). CONCLUSIONS: NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be explored further, as should novel agents.

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Pancreatic ductal adenocarcinoma is a highly lethal cancer that is rarely curable at the time of presentation. Unfortunately, most patients are diagnosed with either metastatic or locally advanced disease, which is not amenable to surgery owing to the high likelihood of incomplete resection. Given the generally poor prognosis with propensity for metastatic failure greater than that for local failure, treatment options are variable, and include chemotherapy, radiotherapy, targeted therapies, and combinations thereof. This review summarizes the current evidence for definitive management of locally advanced pancreatic adenocarcinoma, as well as the role of palliative therapies. Future directions, including the development of predictive biomarkers and novel systemic agents, are also discussed.

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PURPOSE: People with tetraplegia face substantial physical and financial hardships. Although upper extremity reconstruction has been advocated for people with tetraplegia, these procedures are markedly underused in the United States. Population-based preference evaluation of upper extremity reconstruction is important to quantify the value of these reconstructive procedures. This study sought to establish the preferences for 3 health states: tetraplegia, tetraplegia with corrected pinch function, and tetraplegia with corrected elbow extension function. METHODS: A computer-based, time trade-off survey was administered to a cohort of 81 able-bodied second-year medical students who served as a surrogate for the general public. This survey instrument has undergone pilot testing and has established face validity to evaluate the 3 health states of interest. Utilities were calculated based on an estimated 20 years of remaining life. RESULTS: The mean utility for the tetraplegic health state was low. On average, respondents gave up 10.8 +/- 5.0 out of a hypothetical 20 years for perfect health, for a utility of tetraplegia equal to 0.46. For recovery of pinch function, respondents gave up an average of 6.5 +/- 4.3 years, with a corresponding health utility of 0.68. For recovery of elbow extension function, respondents gave up an average of 7.6 +/- 4.5 years, with a corresponding health utility of 0.74. CONCLUSIONS: This study established the preferences for 2 upper extremity surgical interventions: tetraplegia with pinch and tetraplegia with elbow extension. The findings from this study place a high value on upper-limb reconstructive procedures with tetraplegia.

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BACKGROUND: Arthritis of the proximal interphalangeal joint is a debilitating condition commonly treated with arthroplasty. The pyrolytic carbon (pyrocarbon) implant has been developed for proximal interphalangeal joint arthroplasty in these patients. This prospective outcomes study evaluated the outcomes and complications of the pyrocarbon implant for the proximal interphalangeal joint. METHODS: Consecutive candidates for proximal interphalangeal joint arthroplasty with pyrocarbon implants were evaluated prospectively. Functional measurements and the Michigan Hand Outcomes Questionnaire were administered preoperatively and at 3, 6, and 12 months postoperatively. Preoperative means and 12-month postoperative means for all functional measures were compared using paired t tests and nonparametric Wilcoxon signed rank sum test, and effect size was reported for the Michigan Hand Outcomes Questionnaire. RESULTS: Fourteen patients treated with 21 implants were enrolled in the study. At the 12-month follow-up period, mean active arc of motion was 38 degrees, decreasing slightly from the preoperative value. Mean grip strength improved from 11.3 kg to 15.1 kg, although the difference was not statistically significant. Mean key pinch values improved significantly from 6.6 kg preoperatively to 9.2 kg at the 12-month follow-up (p = 0.03). Jebsen-Taylor test scores showed improvement, although not significantly. Changes in all Michigan Hand Outcomes Questionnaire domains showed a large effect size. Three patients experienced squeaking of the implant and three patients experienced dislocation of the pyrocarbon joint. CONCLUSION: The pyrocarbon implant for proximal interphalangeal joint arthroplasty shows encouraging results, primarily in patient satisfaction and pain relief, but is associated with complications related to implant dislocations, which required prolonged treatment with external fixators.

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Poland's syndrome is a rare congenital disorder that is characterized by hypoplasia of the pectoralis muscles and ipsilateral webbing of the fingers. The name of this condition pays homage to Dr. Alfred Poland of Guy's Hospital, who in 1841 described a case of these two deformities during the autopsy of a 27-year-old convict. An exploration of the historical series reveals a clear progression of knowledge about this syndrome, accumulated by scientists across Europe and America. As such, the name "Poland's syndrome" stands as a point of contention to those who oppose the injudicious use of eponyms in medicine. An analysis of the relevant literature reveals a stepwise understanding of what has come to be known as Poland's syndrome.

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SUMMARY: The use of evidence has become a force in American medicine to improve the quality of health care. Funding decisions from payers will demand studies with high-level evidence to support many of the costly interventions in medicine. Plastic surgery is certainly not immune to this national tidal wave to revamp the health care system by embracing evidence-based medicine in our practices. In scientific contributions of plastic surgery research, application of evidence-based principles should enhance the care of all patients by relying on science rather than opinions. In this article, the genesis of evidence-based medicine is discussed to guide plastic surgery in this new revolution in American medicine.

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Hand gestures play a crucial role in religious art. An examination of Judeo-Christian art finds an ecclesiastical language that is concealed in metaphors and expressed by unique hand gestures. Many of these hand signs convey messages that are not familiar to most people admiring these paintings. Investigating the history and classifying some of the predominant hand signs found in Judeo-Christian art might serve to stimulate discussion concerning the many nuances of symbolic art. This presentation examines the meaning behind 8 common hand signs in Judeo-Christian art.

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