The Frequency of Germline BRCA and Non-BRCA HR-Gene-Variants in a Cohort of Pancreatic Cancer Patients.

Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.

[Acute coronary syndrome without ST-elevation (NSTE-ACS)]. / Akutes Koronarsyndrom ohne ST-Hebung (NSTE-ACS).

The timing of an invasive diagnosis and treatment strategy in patients with an acute coronary syndrome without ST-elevation (NSTE-ACS) depends on the patient's risk profile. In addition to the clinical symptoms, ST/T alterations in the resting ECG as well as an increase and kinetics of troponin are of crucial importance in this setting. For the majority of patients the highly sensitive troponin enables a rapid rule in or rule out strategy of a non-ST-segment elevation myocardial infarction (NSTEMI) with a 0/3 h algorithm. An even faster 0/1 h algorithm is increasingly being used; however, troponin only helps to identify patients with NSTEMI. Troponin-negative patients can still suffer from unstable angina pectoris. A dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASS) and an ADP receptor antagonist should be initiated in the acute phase and continued for 12 months, irrespective of the initial treatment strategy, e.g. percutaneous coronary intervention (PCI), bypass surgery or conservative treatment. In patients with a high bleeding risk a duration of 6 months only may be considered, whereas in patients with a high risk of ischemia the DAPT might be prolonged for up to 36 months.

Metastatic mediastinal mature teratoma with malignant transformation in a young man with an adenocarcinoma in a Klinefelter's syndrome: Case report and review of the literature.

Malignant transformation of mediastinal mature teratoma is extremely rare and worsens the prognosis of the disease. Transformation can appear synchronously to or several years after the initial diagnosis. Clinical and radiological signs can orientate the clinician but the definitive diagnosis is obtained thanks to histology. An 11 year-old boy presented with a mediastinal mature teratoma and bone and pulmonary metastases. He received six cycles of chemotherapy combining etoposide, ifosfamide, cisplatin, followed by resection of a 16×14×9cm mediastinal mass. Karyotype analysis revealed the presence of an additional sex chromosome X (47 XXY) pathognomonic of Klinefelter's syndrome. Ten years later, sciatalgia revealed malignant transformation of a pre-existing sacral bone metastasis into gastrointestinal adenocarcinoma. The patient received four cycles of chemotherapy combining oxaliplatin, 5-fluorouracil and cetuximab. This treatment was followed by a complete resection of the sacral metastasis and completed with adjuvant irradiation of 54Gy in 30 daily fractions. Twelve months after the diagnosis of relapse, the patient remained alive without disease. To our knowledge, this is the first case of adenocarcinoma developed in bone metastases of a mediastinal mature teratoma in a boy with a Klinefelter's syndrome. We propose a review of the literature and an analysis of 20 others published cases of mediastinal teratoma with malignant transformation into adenocarcinoma.

Distinguishing globally-driven changes from regional- and local-scale impacts: The case for long-term and broad-scale studies of recovery from pollution.

Marine ecosystems are subject to anthropogenic change at global, regional and local scales. Global drivers interact with regional- and local-scale impacts of both a chronic and acute nature. Natural fluctuations and those driven by climate change need to be understood to diagnose local- and regional-scale impacts, and to inform assessments of recovery. Three case studies are used to illustrate the need for long-term studies: (i) separation of the influence of fishing pressure from climate change on bottom fish in the English Channel; (ii) recovery of rocky shore assemblages from the Torrey Canyon oil spill in the southwest of England; (iii) interaction of climate change and chronic Tributyltin pollution affecting recovery of rocky shore populations following the Torrey Canyon oil spill. We emphasize that "baselines" or "reference states" are better viewed as envelopes that are dependent on the time window of observation. Recommendations are made for adaptive management in a rapidly changing world.

Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini.

Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment.

Characterization of an α-l-fucosidase from the periodontal pathogen Tannerella forsythia.

The periodontal pathogen Tannerella forsythia expresses several glycosidases which are linked to specific growth requirements and are involved in the invasion of host tissues. α-l-Fucosyl residues are exposed on various host glycoconjugates and, thus, the α-l-fucosidases predicted in the T. forsythia ATCC 43037 genome could potentially serve roles in host-pathogen interactions. We describe the molecular cloning and characterization of the putative fucosidase TfFuc1 (encoded by the bfo_2737 = Tffuc1 gene), previously reported to be present in an outer membrane preparation. In terms of sequence, this 51-kDa protein is a member of the glycosyl hydrolase family GH29. Using an artificial substrate, p-nitrophenyl-α-fucose (KM 670 µM), the enzyme was determined to have a pH optimum of 9.0 and to be competitively inhibited by fucose and deoxyfuconojirimycin. TfFuc1 was shown here to be a unique α(1,2)-fucosidase that also possesses α(1,6) specificity on small unbranched substrates. It is active on mucin after sialidase-catalyzed removal of terminal sialic acid residues and also removes fucose from blood group H. Following knock-out of the Tffuc1 gene and analyzing biofilm formation and cell invasion/adhesion of the mutant in comparison to the wild-type, it is most likely that the enzyme does not act extracellularly. Biochemically interesting as the first fucosidase in T. forsythia to be characterized, the biological role of TfFuc1 may well be in the metabolism of short oligosaccharides in the periplasm, thereby indirectly contributing to the virulence of this organism. TfFuc1 is the first glycosyl hydrolase in the GH29 family reported to be a specific α(1,2)-fucosidase.

Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy.

Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.

Invasive Propionibacterium acnes infections in a non-selective patient cohort: clinical manifestations, management and outcome.

An increasing number of reports suggest that Propionibacterium acnes can cause serious invasive infections. Currently, only limited data exist regarding the spectrum of invasive P. acnes infections. We conducted a non-selective cohort study at a tertiary hospital in the UK over a 9-year-period (2003-2012) investigating clinical manifestations, risk factors, management, and outcome of invasive P. acnes infections. Forty-nine cases were identified; the majority were neurosurgical infections and orthopaedic infections (n = 28 and n = 15 respectively). Only 2 cases had no predisposing factors; all neurosurgical and 93.3 % of orthopaedic cases had a history of previous surgery and/or trauma. Foreign material was in situ at the infection site in 59.3 % and 80.0 % of neurosurgical and orthopaedic cases respectively. All neurosurgical and orthopaedic cases required one or more surgical interventions to treat P. acnes infection, with or without concomitant antibiotic therapy; the duration of antibiotic therapy was significantly longer in the group of orthopaedic cases (median 53 vs 19 days; p = 0.0025). All tested P. acnes isolates were susceptible to penicillin, ampicillin and chloramphenicol; only 1 was clindamycin-resistant. Neurosurgical and orthopaedic infections account for the majority of invasive P. acnes infections. Most cases have predisposing factors, including previous surgery and/or trauma; spontaneous infections are rare. Foreign material is commonly present at the site of infection, indicating that the pathogenesis of invasive P. acnes infections likely involves biofilm formation. Since invasive P. acnes infections are associated with considerable morbidity, further studies are needed to establish effective prevention and optimal treatment strategies.

The early response to a novel coronavirus in the Middle East.

The detection of a novel coronavirus in patients from the Arabian Peninsula in late 2012 raised serious concerns of a possible international outbreak. Ministries of health of the three affected countries invited missions from the World Health Organization to participate in a review of data and capacity to detect and respond to further cases. Recommendations were made for investigations to answer critical questions about human-to-human transmission and the geographic extent of the virus. Additional recommendations were made to improve surveillance capacity by acquiring the capacity to test for the virus and enhance syndromic surveillance. Available evidence continues to suggest an unknown animal reservoir for the virus with sporadic zoonotic transmission the primary epidemiological pattern of transmission. Human-to-human transmission, while it can occur, does not appear to be sustained in the community.

[Malignant focal liver lesions]. / Maligne fokale Leberläsionen.

Focal liver lesions are a very common occurrence. The detection and differentiation of such lesions is particularly important for the management of oncology patients and is a core task for radiology. The early and conclusive detection of malignant liver processes in a cost-efficient manner and with a low radiation dose for the patient requires systematic and skillful use of the various radiological methods. This review explains the application of current radiological methods for the detection and differentiation of malignant liver lesions and the typical appearance of the most commonly found liver malignancies.

Multiplex real-time PCR and blood culture for identification of bloodstream pathogens in patients with suspected sepsis.

Severe sepsis is increasingly a cause of death. Rapid and correct initial antimicrobial treatment reduces mortality. The aetiological agent(s) cannot always be found in blood cultures (BCs). A novel multiplex PCR test (SeptiFast (alpha version)) that allows identification of 20 bacterial and fungal species directly from blood was used, comparatively with BC, in a multicentre trial of patients with suspected bacterial or fungal sepsis. Five hundred and fifty-eight paired samples from 359 patients were evaluated. The rate of positivity was 17% for BC and 26% for SeptiFast. Ninety-six microorganisms were isolated with BC, and 186 microorganisms were identified with SeptiFast; 231 microorganisms were found by combining the two tests. Of the 96 isolates identified with BC, 22 isolates were considered to be contaminants. Of the remaining 74 non-contaminant BC isolates available for comparison with SeptiFast, 50 were identified as a species identical to the species identified with SeptiFast in the paired sample. Of the remaining 24 BC isolates for which the species, identified in the BC, could not be detected in the paired SeptiFast sample, 18 BC isolates were identified as a species included in the SeptiFast master list, and six BC isolates were identified as a species not included in the SeptiFast master list. With SeptiFast, 186 microorganisms were identified, 12 of which were considered to be contaminants. Of the 174 clinically relevant microorganisms identified with SeptiFast, 50 (29%) were detected by BC. More than half of the remaining microorganisms identified with SeptiFast (but not isolated after BC) were also found in routine cultures of other relevant samples taken from the patients. Future clinical studies should assess whether the use of SeptiFast is of significant advantage in the detection of bloodstream pathogens.

Prevalence of Dientamoeba fragilis among patients consulting complementary medicine practitioners in the British Isles.

A high prevalence of Dientamoeba fragilis is reported in faecal samples collected from patients attending complementary medicine practitioners in the British Isles. Specimens were collected directly after passing into sodium acetate-acetic acid-formalin (SAF). During two observation periods in 2002-04 and 2005-07, a D fragilis prevalence of 14.6% (n = 543) and 16.9% (n = 421), respectively, was recorded. These results confirm a surprisingly high prevalence of D fragilis among a selected population. Clinical information was only available for half of the patients with D fragilis; 50% of requests with clinical information reported gastrointestinal symptoms. For further work on its pathogenic role and prevalence among patients with gastrointestinal symptoms, immediate collection in SAF should be considered the optimal sampling modality for UK based laboratories.

[Experience with the s-GAP flap for autologous breast reconstruction]. / Der Stellenwert der s-GAP-Lappenplastik in der Brustrekonstruktion - Ein Erfahrungsbericht.

In breast reconstruction with autologous tissue the DIEP flap has become the gold standard in recent years. The superior gluteal artery perforator (s-GAP) flap is an alternative harvested from the buttock. We present our experience with the s-GAP flap and discuss its role in breast reconstruction. All s-GAP flaps performed for breast reconstruction in the Department of Plastic and Hand Surgery, Behandlungszentrum Vogtareuth from June 2002 until February 2007 were retrospectively analysed. Out of 59 flaps 4 flaps failed, the success rate was 94 %. Partial or fat necrosis occurred in 2 cases. The s-GAP flap served as a safe reconstructive alternative to the DIEP flap. Advantages of the s-GAP flap are reliable perforators, the safe vascular supply and the firm fat structure which facilitates the breast reconstruction. The donor site morbidity is minimal, the gluteal muscles stay intact and the scar is easy to hide in the underwear. Disadvantages are a demanding preparation with a prolonged operating time compared to the DIEP flap. The s-GAP flap is a reliable and safe option for autologeous breast reconstruction. It is the method of choice for staged bilateral breast reconstruction or if the DIEP flap is not available, particularly in the thin patient.

[Free axillary flaps: a versatile area for harvesting of plicable flaps with a nearly undetectable scar]. / Freie, mikrovaskuläre axilläre Lappenplastiken - vielseitig verwendbar, gut formbar und narbenarmer Hebedefekt.

BACKGROUND: This article is about 7 cases of free axillary flaps based on the lateral thoracic vessels. PATIENTS AND METHODS: Preoperative ultrasound markings were performed. Indications were defects which needed very smooth and plicable flaps for coverage with a short and well detectable scar. RESULTS: Flap loss was not noticed, dissection was demanding due to the very small venous drainage of the flaps and took all over 6.5 hours. A comparison with standard flaps of the subscapular vascular system is given. CONCLUSIONS: The authors recommend the free axillary flap based on the lateral thoracic vessels as a versatile flap for special indications.

Otitis media and a neck lump--current diagnostic challenges for Paragonimus-like trematode infections.

A 29 year-old Nigerian studying in the UK presented with a neck lump and otitis media. Paragonimus-like trematode eggs were found in the neck lump aspirate. Morphologically these eggs resembled Paragonimus uterobilateralis or Achillurbainia congolensis. We favoured the diagnosis of achillurbainiasis over extrapulmonary paragonimiasis on the basis of clinical features and because we could not amplify DNA sequences using PCR primers specific for Paragonimus species. We discuss current diagnostic challenges for this rare parasitic infection.

Dysbiosis and pouchitis.

BACKGROUND AND METHODS: The exact aetiology of pouchitis is unknown, but an association with dysbiosis has been suggested. This is a retrospective review of 17 studies published between 1985 and 2005, identified by a search of the Medline, Pubmed and Embase databases. RESULTS: The methodology of the studies varied widely. Many were performed at a time when the distinction between a healthy and an inflamed pouch was vague; misclassification of patients makes the analysis of data difficult and conclusions uncertain. CONCLUSION: The evidence that dysbiosis is a cause of pouchitis is poor. Nevertheless, available data allow the construction of an algorithm to aid management and suggest a structured approach for future research.

Videocapsule endoscopy is useful for the diagnosis of intestinal lymphangiectasia.

We study two authentic cases of protein-losing enteropathy, the diagnosis of which was facilitated using Given M2A videocapsule endoscopy. The first case corresponded to a primary intestinal lymphangiectasia confirmed by jejunum biopsies and the second one to a protein-losing enteropathy with lymphatic abnormalities secondary to a chronic constrictive pericarditis. In the first case, the mucosa of jejunum presented with a diffuse oedematous aspect, whitish villi, white curved lines probably related to submucosal dilated lymphatics and lacteal juice. In the second case, capsule endoscopy showed oedematous aspect of jejunum mucosa associated with white curved lines similar to those observed in the first case. Videocapsule endoscopy is useful in cases of protein-losing enteropathy to identify presence of intestinal lymphangiectasia and to specify their localisation after ruling out other disorders liable to induce protein-losing gastrointestinal syndrome.

Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population.

AIMS/HYPOTHESIS: Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance. METHODS: A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women). RESULTS: A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: -43% to -30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: -20% to -10%; p<0.0001) and NEFA by 40% (95% CI: -51% to -27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to -24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (-35%; p<0.0001) and plasma glucose concentration (-0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups. CONCLUSIONS/INTERPRETATION: Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.