Citations

Purpose With improved patient care, better diagnosis, and more treatment options after tumor recurrence, outcomes after fluorouracil (FU) -based treatment are expected to have improved over time in early-stage colon cancer. Data from 18,449 patients enrolled onto 21 phase III trials conducted from 1978 to 2002 were evaluated for potential differences in time to recurrence (TTR), time from recurrence to death (TRD), and overall survival (OS) with regard to FU-based adjuvant regimens. Methods Trials were predefined as old versus newer era using initial accrual before or after 1995. Outcomes were compared between patients enrolled onto old- or newer-era trials, stratified by stage. Results Within the first 3 years, recurrence rates were lower in newer- versus old-era trials for patients with stage II disease, with no differences among those with stage III disease. Both TRD and OS were significantly longer in newer-era trials overall and within each stage. The lymph node (LN) ratio (ie, number of positive nodes divided by total nodes harvested) in those with stage III disease declined over time. TTR improved slightly, with larger number of LNs examined in both stages. Conclusion Improved TRD in newer trials supports the premise that more aggressive intervention (oxaliplatin- and irinotecan-based chemotherapy and/or surgery for recurrent disease) improves OS for patients previously treated in the adjuvant setting. Lower recurrence rates with identical treatments in those with stage II disease enrolled onto newer-era trials reflect stage migration over time, calling into question historical data related to the benefit of FU-based adjuvant therapy in such patients.

ABSTRACTVan der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1–2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype–phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA‐binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van de Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van de Woude syndrome. © 2013 Wiley Periodicals, Inc.

In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and tumor necrosis factor α (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor κB and its target genes involved in regulating survival, proliferation, and degradation of extracellular matrix. In particular, we identify matrix metalloproteinases (MMPs) as targets that drive ADM and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy.

ABSTRACTBackgroundVariants within the leucine‐rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine‐rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late‐onset sporadic disorders like Parkinson's disease.MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine‐rich repeat kinase 2 gene across 23 different sites in 15 countries.ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K‐R1398H‐K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.ConclusionsEstablishing individual patient‐based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society

The efficacy and safety of plerixafor + G‐CSF in enhancing hematopoietic stem cell mobilization and collection has been demonstrated in two phase III studies involving patients with NHL or MM. In these pivotal studies, plerixafor + G‐CSF significantly increased the proportion of patients achieving target stem cell yields, compared to placebo + G‐CSF. In this analysis, we compare the efficacy and safety of plerixafor + G‐CSF versus placebo + G‐CSF in patients enrolled in the two phase III studies, stratified by age: ≥60 years of age and <60 years of age. The proportion of older patients who achieved target stem cell yields was significantly higher in the plerixafor group than in placebo group (NHL: 50.9 vs. 25.4%, P < 0.001; MM: 69.6 vs. 23.7%, P < 0.001). In this older cohort, the median times to neutrophil and to platelet engraftment following autologous stem cell transplant were comparable between the plerixafor and placebo groups. Similar efficacy findings were observed in the younger age group. The most common adverse events (all grades) reported among older patients in the plerixafor group included diarrhea (41.3%), nausea (38.9%), fatigue (30.2%), and injection‐site reaction (29.4%). The frequency of adverse events was similar between the older and the younger age groups. Taken together, our subanalysis demonstrate that plerixafor + G‐CSF can be safely and effectively used in adult patients of all ages, including those ≥60 years, to support optimal stem cell mobilization for autologous stem cell transplantation. Am. J. Hematol. 88:1017–1023, 2013. © 2013 Wiley Periodicals, Inc.

We searched MEDLINE, CINAHL, and Cochrane Library database for articles published between January 1990 and December 2012. The update of this clinical practice guideline is based on 237 clinical trials, 54 reviews, and 23 meta-analyses on blood gas analysis (BGA) and hemoximetry. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation scoring system. BGA and hemoximetry are recommended for evaluating a patient's ventilatory, acid-base, and/or oxygenation status. BGA and hemoximetry are suggested for evaluating a patient's response to therapeutic interventions. BGA and hemoximetry are recommended for monitoring severity and progression of documented cardiopulmonary disease processes. Hemoximetry is recommended to determine the impact of dyshemoglobins on oxygenation. Capillary BGA is not recommended to determine oxygenation status. Central venous BGA and hemoximetry are suggested to determine oxygen consumption in the setting of early goal-directed therapies. For the assessment of oxygenation, a peripheral venous P O 2 is not recommended as a substitute for an arterial blood measurement (P aO 2 ). It is not recommended to use venous P CO 2 and pH as a substitute for arterial blood measurement of P aCO 2 and pH. It is suggested that hemoximetry is used in the detection and evaluation of shunts during diagnostic cardiac catheterization.

Purpose This study sought to characterize transformation incidence and outcome for patients with follicular lymphoma (FL) in a prospective observational series begun after diffusion of rituximab use. Patients and Methods Patients with newly diagnosed FL were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2009. Patients were actively followed for re-treatment, clinical or pathologic transformation, and death. Risk of transformation was analyzed via time to transformation by using death as a competing risk. Results In all, there were 631 patients with newly diagnosed grade 1 to 3a FL who had a median age at enrollment of 60 years. At a median follow-up of 60 months (range, 11 to 110 months), 79 patients had died, and 60 patients developed transformed lymphoma, of which 51 were biopsy proven. The overall transformation rate at 5 years was 10.7%, with an estimated rate of 2% per year. Increased lactate dehydrogenase was associated with increased risk of transformation. Transformation rate at 5 years was highest in patients who were initially observed and lowest in patients who initially received rituximab monotherapy (14.4% v 3.2%; P = .021). Median overall survival following transformation was 50 months and was superior in patients with transformation greater than 18 months after FL diagnosis compared with patients with earlier transformation (5-year overall survival, 66% v 22%; P < .001). Conclusion Follicular transformation rates in the immunochemotherapy era are similar to risk of death without transformation and may be lower than reported in older series. Post-transformation prognosis is substantially better than described in older series. Initial management strategies may influence the risk of transformation.

There has been an overall decline in the United States incidence of Primary CNS Lymphoma (PCNSL) from 1998 to 2008. This study's intent was to characterize the cohorts contributing to it. First, calculated the PCNSL incidence rates from nine Surveillance, Epidemiology, and End Results (SEER) registries for time period 1973 to 2008. Second, examined the time trends overall and by age and gender. Third, used 1992–2008 SEER data from the same registries to obtain overall trends for diffuse large B‐cell lymphoma (DLBCL). Last, rates were age‐adjusted to the 2000 US standard population and reported per 100,000 person‐years. Rates continued to increase in women at all ages and men aged 65 and older. In men aged 20–39 and 40–64 years incidence rates peaked in 1995 and then declined dramatically, stabilizing after 1998. The trends in the incidence of PCNSL over this time frame were significantly different from DLBCL for ages 20–39 (P < 0.001) and 40–64 (P < 0.001) years but were not different for the 65 years and older age group (P = 0.99). The overall PCNSL incidence rate declined since 1995 and was driven primarily by the changing incidence in young and middle‐aged men. The rate has continued to increase in men aged 65 years and older and in women. The trends in incidence in the younger age groups over this time period did not parallel those observed for DLBCL. Am. J. Hematol. 88:997–1000, 2013. © 2013 Wiley Periodicals, Inc.