Conservative versus Surgical Management of Fifth Metatarsal Diaphyseal Fractures: A Retrospective Review.

BACKGROUND: Historically, distal fifth metatarsal diaphyseal fractures have been treated with conservative management, with only limited research evaluating surgical treatment of these fractures. This study was performed to compare surgical versus conservative treatment of distal fifth metatarsal diaphyseal fractures in athletes and nonathletes. METHODS: A retrospective review of 53 patients with surgical or conservative treatment of isolated fifth metatarsal diaphyseal fractures was performed. Data recorded included age, sex, tobacco use, diagnosis of diabetes mellitus, time to clinical union, time to radiographic union, athletic versus nonathletic status, time to return to full activity, surgical fixation method, and complications. RESULTS: Patients treated surgically had a mean clinical union time of 8.2 weeks, radiographic union time of 13.5 weeks, and return to activity time of 12.9 weeks. Patients treated conservatively had a mean clinical union time of 16.3 weeks, radiographic union time of 25.2 weeks, and return to activity time of 20.7 weeks. Delayed unions and nonunions occurred in 27.0% of patients (10 of 37) treated conservatively and in none in the surgical group. CONCLUSIONS: Surgical treatment significantly decreased time to radiographic union, clinical union, and return to activity by an average of 8 weeks compared with conservative treatment. We suggest that surgical treatment of distal fifth metatarsal fractures is a viable option that may significantly decrease the patient's time to clinical union, radiographic union, and return to activity.

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3ß) a key regulator of glycolysis. Pharmacological inhibition of GSK3ß results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3ß inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

Evolution of cranial shape in a continental-scale evolutionary radiation of Australian lizards.

A defining character of adaptive radiations is the evolution of a diversity of morphological forms that are associated with the use of different habitats, following the invasion of vacant niches. Island adaptive radiations have been thoroughly investigated but continental scale radiations are more poorly understood. Here, we use 52 species of Australian agamid lizards and their Asian relatives as a model group, and employ three-dimensional geometric morphometrics to characterize cranial morphology and investigate whether variation in cranial shape reflects patterns expected from the ecological process of adaptive radiation. Phylogenetic affinity, evolutionary allometry, and ecological life habit all play major roles in the evolution of cranial shape in the sampled lizards. We find a significant association between cranial shapes and life habit. Our results are in line with the expectations of an adaptive radiation, and this is the first time detailed geometric morphometric analyses have been used to understand the selective forces that drove an adaptive radiation at a continental scale.

Comparison of Hallux Rigidus Surgical Treatment Outcomes Between Active Duty and Non-Active Duty Populations A Retrospective Review.

BACKGROUND: Our aim in this study was to compare the long-term outcomes of three different surgical procedures for the treatment of hallux rigidus (ie, cheilectomy, decompressive osteotomy, and arthrodesis) between active duty military and non-active duty patients. METHODS: A retrospective review of 80 patients (95 feet) undergoing surgical treatment for hallux rigidus was performed. Telephone survey was used to obtain postoperative outcome measures and subjective satisfaction. Additional data recorded and analyzed included age, sex, status of patient (active duty or non-active duty), grade of hallux rigidus, surgical procedure performed, date of surgery, time to return to full activity, ability to return to full duty, and follow-up time postoperatively. RESULTS: The decompressive osteotomy group had the highest return-to-duty rate, satisfaction rate, and Maryland Foot Scores of all three surgical groups, although these differences were not statistically significant. Active duty and non-active duty patients did not have statistically significant differences in outcomes measures (ie, time to return to full activity, ability to return to full duty, satisfaction, or postoperative Maryland Foot Score) in any of the three surgical groups. CONCLUSIONS: Decompressive osteotomy, cheilectomy, and first metatarsophalangeal joint arthrodesis are all reliable and effective procedures for treatment of hallux rigidus in both active duty military and non-active duty patients. Active duty military personal have a high rate of returning to their prior military activities after surgical treatment of hallux rigidus.

Hypermutation In Pancreatic Cancer.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Genomic analyses identify molecular subtypes of pancreatic cancer.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-ß, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Symptomatic Bipartite Medial Cuneiform: Report of Five Cases and Review of the Literature.

UNLABELLED: Bipartition of the medial cuneiform is a well-described but rarely seen anatomic variant. The majority of literature focuses on anatomic description and incidents based on studies of archeological collections. Symptomatic cases can be overlooked or misdiagnosed initially given the vague complaint of pain either chronic in nature or following an acute injury that could result in a myriad of foot conditions. Treatment ranges from orthotics, immobilization, injection therapy, and surgery. Presented here is a series of 5 cases treated successfully with conservative and surgical measures. LEVELS OF EVIDENCE: Therapeutic, Level IV.

HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

NMR relaxometry and diffusometry in characterizing structural, interfacial and colloidal properties of heavy oils and oil sands.

We present a discussion of the use of NMR in the characterization of heavy oils and oil sands and their interactions with water and solid surfaces. The phenomena probed by the NMR techniques take place over different length scales, ranging from molecular, through colloidal to macroscopic. During the course of the last 15 years, NMR applications have grown from their initial use in studying conventional oils in rocks to the characterization of more viscous oils in unconsolidated porous media. In particular, (1)H NMR relaxometry and diffusometry are considered with a view to the identification of oil and water in oilfield fluids and their environment. After some theoretical considerations, various topics of current significance to petroleum recovery and production are discussed, including oil viscosity (with new experimental viscosity correlations added), oil sands characterization, heavy oil emulsions, and the identification of solvent effects on oil components and asphaltene solution behaviour and interactions. We show that, increasingly, NMR is becoming an invaluable and versatile characterization tool in petroleum science, in both laboratory and field.

Callus Distraction Versus Single-Stage Lengthening With Bone Graft for Treatment of Brachymetatarsia: A Systematic Review.

Brachymetatarsia deformity is a cosmetically displeasing anomaly that can become physically symptomatic. The surgical techniques most commonly used to repair the anomaly include single-stage lengthening with a bone graft, callus distraction, or a combination of bone grafting and callus distraction. A systematic review of the published data was performed to compare the outcomes of these 3 surgical procedures. A total of 61 studies reporting the use of callus distraction or single-stage lengthening, or both, for the treatment of brachymetatarsia were included in the present review. The incidence of major postoperative complications after callus distraction, single-stage lengthening, and the combination procedure was 49 (12.62%), 13 (3.72%), and 3 (33.33%), respectively. The number of minor complications with callus distraction, single-stage lengthening, and the combination procedure was 152 (39.18%), 55 (15.76%), and 1 (11.11%); the mean percentage of the original length achieved was 37.36%, 25.98% and 36.00%; and the mean length achieved was 17.5, 13.2, and 14.0 mm, respectively. The healing index (mo/cm) and healing time was 2.31 and 16.04 weeks, 1.90 and 9.35 weeks, and 3.93 and 14.62 weeks for callus distraction, single-stage lengthening, and the combination procedure, respectively. Our findings indicate that the callus distraction technique is associated with greater length gained but results in greater complication rates and requires almost twice the time to heal. Single-stage lengthening with a bone graft was associated with fewer complications and faster healing times than callus distraction but with lesser gains in length. From the information reported in the studies we reviewed, the prevalence of bilateral brachymetatarsia was 44.52%, and the female/male ratio was 13.7:1. Both of these findings seem to contradict the usual data given (72% for bilateral brachymetatarsia and a female/male ratio of 25:1).

Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial.

PURPOSE: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. EXPERIMENTAL DESIGN: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 amplification; KRAS wild-type; and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). RESULTS: Tumor biopsy and archived tumor samples were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 amplification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. CONCLUSIONS: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options.

Retained viable plant material in the calcaneus: a case report of a 22-year-old soldier with atypical heel pain.

Foreign bodies can be difficult to diagnose and should be considered in the differential diagnosis of unexplained pain, even in the absence of recalled trauma. We present the case of a 22-year-old male with a painful left heel. The patient did not recall a specific traumatic incident, and there were no clinical signs of trauma or infection. Plain films of the foot were nonrevealing, but magnetic resonance imaging revealed a sinus tract and left calcaneal defect. A biopsy of the calcaneal defect revealed viable woody material embedded and partially integrated with the surrounding bone. Postoperatively the patient's pain completely resolved. This case illustrates the importance of radiopathologic pursuit of an etiology of unexplained foot pain in an otherwise healthy person.

Whole genomes redefine the mutational landscape of pancreatic cancer.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

New material of Beelzebufo, a hyperossified frog (Amphibia: Anura) from the late cretaceous of Madagascar.

The extant anuran fauna of Madagascar is exceptionally rich and almost completely endemic. In recent years, many new species have been described and understanding of the history and relationships of this fauna has been greatly advanced by molecular studies, but very little is known of the fossil history of frogs on the island. Beelzebufo ampinga, the first named pre-Holocene frog from Madagascar, was described in 2008 on the basis of numerous disarticulated cranial and postcranial elements from the Upper Cretaceous (Maastrichtian) Maevarano Formation of Madagascar. These specimens documented the presence of a hyperossified taxon that differed strikingly from extant Malagasy frogs in its large size and heavy coarse cranial exostosis. Here we describe and analyse new, articulated, and more complete material of the skull, vertebral column, and hind limb, as well as additional isolated elements discovered since 2008. µCT scans allow a detailed understanding of both internal and external morphology and permit a more accurate reconstruction. The new material shows Beelzebufo to have been even more bizarre than originally interpreted, with large posterolateral skull flanges and sculptured vertebral spine tables. The apparent absence of a tympanic membrane, the strong cranial exostosis, and vertebral morphology suggest it may have burrowed during seasonally arid conditions, which have been interpreted for the Maevarano Formation from independent sedimentological and taphonomic evidence. New phylogenetic analyses, incorporating both morphological and molecular data, continue to place Beelzebufo with hyloid rather than ranoid frogs. Within Hyloidea, Beelzebufo still groups with the South American Ceratophryidae thus continuing to pose difficulties with both biogeographic interpretations and prior molecular divergence dates.

Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling.

The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-ß, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.

Histomolecular phenotypes and outcome in adenocarcinoma of the ampulla of vater.

PURPOSE: Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. PATIENTS AND METHODS: We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. RESULTS: Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P < .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P < .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. CONCLUSION: Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.

MicroRNA in aqueous humor from patients with cataract.

MicroRNAs (miRNAs) are small non-coding RNA molecules with regulatory function and marked tissue specificity that can modulate multiple gene targets. They have been detected in body fluids and are associated with various physiologic and pathologic processes. We analyzed aqueous humor (AH) from human subjects undergoing cataract surgery to establish the presence and relative quantities of known miRNAs. AH was collected from patients without known ocular diseases other than cataract and a normal systemic history. Quantitative real-time PCR in an array platform was used to detect known miRNAs present in the AH. Among the 264 miRNAs tested, 110 were present in the AH. The top 5 abundant miRNAs identified were miR-202, miR-193b, miR-135a, miR-365, and miR-376a. The presence of miRNAs in AH suggests that they may have functional roles in regulating target genes in tissues lining the anterior chamber. Further analysis of the AH miRNA population may identify potential gene targets and provide insights regarding their roles in AH regulation, glaucoma and anterior segment disease processes.