ATM mutations in patients with hereditary pancreatic cancer

Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. SIGNIFICANCE: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.     

The prognostic inhomogeneity in pT3 rectal carcinomas

To obtain data on locoregional recurrence and survival rates in prognostically inhomogeneous pT3 rectal carcinomas we analyzed the data on 853 patients of the Erlangen Registry for Colo-Rectal Carcinomas (ERCRC) and 600 patients of the Study Group for Colo-Rectal Carcinoma (SGCRC), stage I-III, treated by radical surgery alone. The category pT3 was subdivided according to the histological measurement of the maximal tumor invasion beyond the outer border of the muscularis propria: pT3a (up to 5 mm) and pT3b (more than 5 mm). In the ERCRC locoregional recurrence rates were 10.4% (95% confidence interval 6.0-14.6) for pT3a and 26.3% (20.6-31.6) for pT3b (P<0.0001). The cancer-related 5-year survival rates were 85.4% (80.6-90.5) for pT3a and 54.1% (48.5-60.5) for pT3b (P<0.0001). Lymph node negative pT3a and pT2 patients showed very similar 5-year survival rates (91.2% vs. 93.6%, respectively) as well as lymph node positive pT3a and pT2 patients (77.8% vs. 82.8%, respectively). In the SGCRC patients similar but statistically marginal differences between pT3a and pT3b tumors were observed. An extended pT classification (pT1, pT2, pT3a, pT3b, pT4) thus allows an improved prediction of outcome in rectal carcinoma patients. The subdivision of pT3 enables the identification of stage II patients (pT3a pNO) who might not benefit from adjuvant treatment.     

Axial parkinsonian symptoms can be improved: the role of levodopa and bilateral subthalamic stimulation

OBJECTIVE: To assess the effects of high frequency stimulation of the subthalamic nucleus (STN) on axial symptoms occurring in advanced stages of Parkinson's disease (PD). METHODS: The efficacy of STN stimulation on total motor disability score (unified Parkinson's disease rating scale (UPDRS) part III) were evaluated in 10 patients with severe Parkinson's disease. The subscores were then studied separately for limb akinesia, rigidity, and tremor, which are known to respond to levodopa, and axial signs, including speech, neck rigidity, rising from a chair, posture, gait, and postural stability, which are known to respond less well to levodopa. Patients were clinically assessed in the "off" and "on" drug condition during a levodopa challenge test performed before surgical implantation of stimulation electrodes and repeated 6 months after surgery under continuous STN stimulation. A complementary score for axial symptoms from the "activities of daily living" (ADL)-that is, speech, swallowing, turning in bed, falling, walking, and freezing-was obtained from each patient's questionnaire (UPDRS, part II). RESULTS: Improvements in total motor disability score (62%), limb signs (62%), and axial signs (72%) obtained with STN stimulation were statistically comparable with those obtained with levodopa during the preoperative challenge (68%, 69%, and 59%, respectively). When levodopa and STN stimulation were combined there was a further improvement in total motor disability (80%) compared with preoperative levodopa administration. This consisted largely of an additional improvement in axial signs (84%) mainly for posture and postural stability, no further improvement in levodopa responsive signs being found. Axial symptoms from the ADL showed similar additional improvement when levodopa and STN stimulation were combined. CONCLUSION: These findings suggest that bilateral STN stimulation improves most axial features of Parkinson's disease and that a synergistic effect can be obtained when stimulation is used in conjunction with levodopa treatment.     

Short-term functional and clinical outcomes after ACL reconstruction with hamstrings autograft: transtibial versus anteromedial portal technique

Purpose

Several studies have suggested that drilling the femoral tunnel through an anteromedial arthroscopic portal during anterior cruciate ligament reconstruction allows more anatomic placement of the graft. However, no studies have investigated whether the anteromedial approach results in better outcomes compared to the traditional transtibial drilling approach when a hamstring autograft is used. The purpose of the present study is to investigate short-term functional and clinical outcome differences between male patients recovering from anterior cruciate ligament reconstruction with a hamstring autograft using the transtibial femoral tunnel drilling approach versus the anteromedial approach.

Methods

Lysholm score, functional test and isokinetic data were collected at 3 and 6 months after surgery in 51 male patients who received a standardized rehabilitation in a large outpatient facility. Multivariate and univariate analyses of variance were used to assess group, time and interaction effects.

Results

All outcomes except isokinetic knee flexion at 180°/s improved from 3 to 6 months for both groups (p ≤ 0.05). The anteromedial approach group had better Lysholm scores at 3 months (p ≤ 0.05) and better performance in the timed lateral movement functional tests at 3 and 6 months (p ≤ 0.05). No other comparisons were significant (n.s).

Conclusions

Both groups had comparable outcomes on most measures. The differences in the Lysholm score and lateral movement functional tests may suggest a quicker return of function and performance for the anteromedial approach group. Clinicians should take into consideration the surgical technique as they progress patients recovering from ACL reconstruction through the different phases of the rehabilitation protocol.

Level of evidence

Therapeutic study, Level II.     

Mechanisms of virus-induced asthma exacerbations: state-of-the-art. A GA2LEN and InterAirways document

Viral infections of the respiratory tract are the most common precipitants of acute asthma exacerbations. Exacerbations are only poorly responsive to current asthma therapies and new approaches to therapy are needed. Viruses, most frequently human rhinoviruses (RV), infect the airway epithelium, generate local and systemic immune responses, as well as neural responses, inducing inflammation and airway hyperresponsiveness. Using in vitro and in vivo experimental models the role of various proinflammatory or anti-inflammatory mediators, antiviral responses and molecular pathways that lead from infection to symptoms has been partly unravelled. In particular, mechanisms of susceptibility to viral infection have been identified and the bronchial epithelium appeared to be a key player. Nevertheless, additional understanding of the integration between the diverse elements of the antiviral response, especially in the context of allergic airway inflammation, as well as the interactions between viral infections and other stimuli that affect airway inflammation and responsiveness may lead to novel strategies in treating and/or preventing asthma exacerbations. This review presents the current knowledge and highlights areas in need of further research.     

EAACI Food Allergy and Anaphylaxis Guidelines: diagnosis and management of food allergy

Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence‐based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non‐life‐threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.