Improved survival for adenocarcinoma of the ampulla of Vater: fifty-five consecutive resections

HYPOTHESIS: After resection of an adenocarcinoma of the ampulla of Vater, certain clinical and pathologic characteristics influence long-term survival. DESIGN: Retrospective case series. SETTING: Major academic medical and pancreatic surgical center. PATIENTS: Fifty-five consecutive patients who underwent Whipple resection for ampullary adenocarcinoma from 1988 through 2001. INTERVENTIONS: Pylorus-preserving Whipple resection in 32 patients and standard Whipple resection in 23 patients. MAIN OUTCOME MEASURES: Postoperative survival. A multivariate Cox proportional hazards model was used to determine the effects of various factors on long-term survival after resection. RESULTS: There were no operative deaths, and all patients left the hospital. After a mean follow-up of 46.9 months, the overall 5-year Kaplan-Meier survival estimate was 67.7%. The median survival of the entire group has not yet been reached. Five-year postoperative survival estimates for node-negative (n = 32) and node-positive patients (n = 23) were 76.5% and 53.4%, respectively (P =.26). Patients whose tumors demonstrated perineural invasion (n = 12) had a 5-year survival estimate of 29.2% vs 78.8% for those whose did not (P<.001). On multivariate analysis, the absence of perineural invasion (P<.001) was an independent predictor of significantly improved postoperative survival. CONCLUSIONS: Compared with previous reports from our own and other centers, this series demonstrates improved postoperative survival by 10% to 20% in patients undergoing Whipple resection for adenocarcinoma of the ampulla of Vater. The reasons for this improved outcome are unclear, and the effect of adjuvant treatment cannot be determined from this analysis. The major factor associated with prolonged survival was the absence of perineural invasion in the resected tumor specimen.     

Enzymatic diagnostic test for Muscle-Eye-Brain type congenital muscular dystrophy using commercially available reagents

OBJECTIVES: Mutations disrupting the interaction of extra-cellular ligands and alpha-dystroglycan are responsible for an etiologically heterogeneous group of autosomal recessive congenital muscular dystrophies (CMD) that can have associated brain and eye abnormalities. The objective is to develop a diagnostic test for one of these CMDs, Muscle-Eye-Brain disease (MEB), due to mutations in the gene encoding Protein O-Mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). DESIGN AND METHODS: POMGnT1 enzyme activity was determined in extracts of muscle biopsies from four MEB patients and various controls using commercially available reagents. RESULTS: All four MEB muscle samples showed a highly significant decrease in POMGnT1 activity relative to controls. CONCLUSIONS: The assay of POMGnT1 activity in MEB muscle provides a rapid and relatively simple diagnostic test for this disease. CMDs associated with brain malformations such as MEB, WWS and FCMD are heterogenous in clinical presentation and on radiologic examination, suggesting that POMGnT1 assays of muscle biopsies should be used as a screening procedure for MEB in all CMD patients associated with brain malformations.     

The potentiation of human C1-inhibitor by dextran sulphate is transient in vivo: studies in a rat model

C1-inhibitor (C1-Inh) is an important regulator of inflammatory reactions because it is a potent inhibitor of the contact and complement system. C1-Inh application in inflammatory disease is, however, restricted because of the high doses required. The glycosaminoglycan-like molecule dextran sulphate (DXS) enhances C1-Inh function in vitro. Hence, we investigated whether co-administration with dextran sulphate reduces the amount of C1-Inh required, through enhancement in vivo. C1-Inh potentiation was measured in a newly developed C1s-inactivation assay that is based on activation of C4 by purified C1s. Activated C4 in rat plasma was quantified with a newly developed ELISA. Human C1-Inh (2.5 microM) inhibited C1s in rat plasma 55-fold faster in the presence of dextran sulphate (15 kDa, 5 microM). To study the stability of the complex in vivo, rats were given a mixture of C1-Inh (10 mg/kg) and dextran sulphate (3 mg/kg). C1-Inh activity during 5 h was analyzed ex vivo with the C1s inactivation assay. The noncovalent C1-Inh-dextran sulphate complex resulted in a transient enhancement of the inhibitory capacity of C1-Inh, lasting for 60-90 min. Dextran sulphate did not affect plasma clearance of C1-Inh. We conclude that the enhanced inhibitory capacity of C1-Inh complexed to dextran sulphate is transient in vivo. Hence, co-administration of these compounds seems a feasible approach to achieve short-term inhibition of complement in vivo.     

A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document

The European Union (EU) Council Recommendation on rare diseases urged the member states to implement national and EU collaborative actions to improve the health care of rare disease patients. Following this recommendation, the European Commission launched a tender on newborn screening (NBS) to report on current practices of laboratory testing, form a network of experts and provide guidance on how to further implement NBS screening in a responsible way, the latter of which was provided in an Expert Opinion document. After consultation of experts from EU member states, (potential) candidate member states and European Free Trade Association countries, in a consensus meeting in June 2011, 70 expert opinions were finalized. They included the need to develop case definitions for all disorders screened for to facilitate assessment and international outcome studies. Decision whether a screening program should be performed can be based on screening criteria updated from the traditional Wilson and Jungner (1968) criteria, relating to disease, treatment, test and cost. The interest of the child should be central in the assessment of pros and cons. A European NBS body should assess evidence on (new) screening candidate disorders. For rare conditions, best level evidence should be used. The health system should ensure treatment to cases diagnosed by screening, controlled and revised by follow-up outcome studies. Screening methodology should aim to avoid unintended findings, such as mild forms and carrier status information, as much as possible. Activities to improve NBS in Europe, such as training and scientific evaluation, could benefit from collaboration at EU level and beyond.The European Union (EU) Council Recommendation¹ on Rare Diseases (9 June 2009)² identified rare diseases (ie, a life-threatening or chronically debilitating condition affecting not more than five in 10 000 persons in the community) as a public health concern and highlighted the need for public health actions, promoting the development of research on rare disorders and the improvement of the health care of rare disease patients. Following this recommendation, the European Commission launched a tender on neonatal screening (=newborn screening, NBS) in July 2009 (http://ec.europa.eu/eahc/health/tenders_H09C2.html) in order to (1) report on the practices of neonatal screening for rare disorders implemented in all the member states, including number of centers, estimate the number of infants screened and the number of disorders included in the NBS, as well as reasons for the selection of these disorders, (2) to identify types of medical management and follow-up implemented in the member states, (3) to establish a network of experts analyzing the information and formulating a final opinion containing recommendations on best practices, and recommending a core panel of NBS conditions that could be included in all MS practices, and (4) to develop a decision-making matrix that could be used by member states'' programs to systematically expand (or contract) screening mandates.The focus of the tender activities was on NBS by using laboratory testing techniques (blood spot screening). All reports are available on the internet (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64).To get some insight into the current practices (points 1 and 2 above), an online survey was compiled and filled out by EU member states, (potential) member states and European Free Trade Association countries – in total 40 countries. Apart from the final report, available on the internet, the current practices are summarized in two journal articles: the first publication addresses the steps in screening programmes from blood spot to screening result³ and the second publication addresses the steps from screening laboratory results to treatment, follow-up and quality assurance.⁴As a third part of the activity and work methodology requested by the tender specifications, a European Union Network of Experts on Newborn Screening (EUNENBS) had to be constituted. Criteria for the inclusion of experts in EUNENBS (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64) include that all member states'' authorities should be represented in the network. Each countries'' competent authorities were invited to identify their experts to represent the country at the workshops in 2010 and 2011. Further experts represent European professional and scientific organizations involved in NBS, the representative of the US Secretary''s Advisory Committee on Heritable Disorders in Newborns and Children, additional fields of expertise (eg, ethics) and patient organizations. The list of EUNENBS members is available as Appendix 1 of the Expert Opinion document (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64). Most EUNENBS members have a background in health policy making, health technology assessment (HTA) and/or coordinating screening programs, many are involved in the service delivery of NBS in pediatrics, laboratory medicine and genetics. The task of EUNENBS was to supervise the work of the tender and participate in the revision of the tender deliverables, including the Expert Opinion document. The EUNENBS members have provided informally their input and advice without implying any obligation or commitment of their national authorities or organizations. Working documents were prepared reviewing most relevant scientific literature on the development of NBS policy and submitted to EUNENBS to stimulate the discussion during its meeting held on 6–7 December 2010, where the future of NBS was discussed in a workshop. Conclusions were integrated in a draft of the Expert Opinion document that was circulated by e-mail on 9 March 2011 to the membership of EUNENBS and to European Union Committee of Experts on Rare Diseases members from the Candidate and European Economic Area/European Free Trade Association countries inviting comments. This consultation ended on 6 April 2011. The preparation of the second draft, integrating the suggestions received, took place until 6 May 2011. Before the consensus meeting on 20 and 21 June 2011 in Luxembourg, the document was circulated for a second consultation, which took place from 11 to 27 May 2011, and amended considering the comments received. The Expert Opinion document was endorsed by the Boards of the International Society for Neonatal Screening and the European Society of Human Genetics in August and October 2011.Experiences from other countries have served as useful sources, although their applicability may need to be checked against information from EU countries and agreement needs to be sought with EUNENBS. This article presents the 70 Expert Opinions, resulting from the debate among the EUNENBS members with respect to the elements that are part of a system to evaluate the quality and ethical aspects of neonatal screening in the light of available literature, as well as the proposal for a decision matrix. We furthermore provide a brief discussion.     

Perineural invasion and associated pain in pancreatic cancer

Perineural invasion (PNI) is a prominent characteristic of pancreatic cancer. PNI is a process whereby cancer cells invade the surrounding nerves, thus providing an alternative route for metastatic spread and pain generation. PNI is thought to be an indicator of aggressive tumour behaviour and has been shown to correlate with poor prognosis of patients with pancreatic cancer. Recent studies demonstrated that some signalling molecules and pathways that are involved in PNI are also involved in pain generation. Targeting these signalling pathways has shown some promise in alleviating pain and reducing PNI, which could potentially improve treatment outcomes for patients with pancreatic cancer.     

Pulmonary fibrosis induced by γ-herpesvirus in aged mice is associated with increased fibroblast responsiveness to transforming growth factor-β

Young (4 month) and aged (15-18 months) mice were given intranasal saline or γ--herpesvirus-68 infection. After 21 days, aged, but not young mice, showed significant increases in collagen content and fibrosis. There were no differences in viral clearance or inflammatory cells (including fibrocytes) between infected aged and young mice. Enzyme-linked immunosorbent assays showed increased transforming growth factor-β in whole lung homogenates of infected aged mice compared with young mice. When fibroblasts from aged and young mice were infected in vitro, aged, but not young, fibroblasts upregulate alpha-smooth muscle actin and collagen I protein. Infection with virus in vivo also demonstrates increased alpha-smooth muscle actin and collagen I protein and collagen I, collagen III, and fibronectin messenger RNA in aged fibroblasts. Furthermore, evaluation revealed that aged fibroblasts at baseline have increased transforming growth factor-β receptor 1 and 2 levels compared with young fibroblasts and are resistant to apoptosis. Increased responsiveness to transforming growth factor-β was verified by increased collagen III and fibronectin messenger RNA after treatment in vitro with transforming growth factor-β.     

The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans

Mice with a null deletion mutation in the gamma interferon (IFN-gamma) receptor gene were used to study the role of IFN-gamma responsiveness during experimental pulmonary cryptococcosis. Cryptococcus neoformans was inoculated intratracheally into mice lacking the IFN-gamma receptor gene (IFN-gammaR-/-) and into control mice (IFN-gammaR+/+). The numbers of CFU in lung, spleen, and brain were determined to assess clearance; cytokines produced by lung leukocytes were measured, and survival curves were generated. In the present study, we demonstrate the following points. (i) IFN-gammaR-/- mice are markedly more susceptible to C. neoformans infection than IFN-gammaR+/+ mice. (ii) In the absence of IFN-gamma signaling, pulmonary CFU continue to increase over the course of infection, and the infection disseminates to the brain. (iii) In the absence of IFN-gamma receptor, recruitment of inflammatory cells in response to pulmonary cryptococcal infection is not impaired. (iv) At week 5 postinfection, IFN-gammaR-/- mice have recruited greater numbers of leukocytes into their lungs, with neutrophils, eosinophils, and lymphocytes accounting for this cellular increase. (v) IFN-gamma signaling is required for the development of a T1 over a T2 immune response in the lung following cryptococcal infection. These results indicate that in the absence of IFN- gamma responsiveness, even though the recruitment of pulmonary inflammatory cells is not impaired and the secretion of IFN-gamma is not affected, IFN-gammaR-/- mice do not have the ability to resolve the cryptococcal infection. In conclusion, our data suggest that proper functional IFN-gamma signaling, possibly through a mechanism which inhibits the potentially disease-promoting T2 response, is required for mice to confine the cryptococcal infection.