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.

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.

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.

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.

[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.

[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.

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.

Combined open and endovascular stent grafting of internal carotid artery fibromuscular dysplasia: long term results.

BACKGROUND: Symptomatic fibromuscular dysplasia (FMD) of the internal carotid artery (ICA) can present as thrombo-embolic ischemic events, spontaneous or post-traumatic dissection, aneurysmal degeneration or intracranial haemorrhage and needs definitive surgical treatment. PATIENTS AND METHODS: Six patients and nine ICA with FMD were revascularised using a carotid approach with minimal exposure of the common, external and internal carotid arteries for covered stent repair. All patients were female, the age ranged from 30 to 65 years (mean 44). RESULTS: One patient suffered from a perioperative transient neurological deficit. Duplex revealed a patent stent. The patient fully recovered after 5h, not showing any changes on repeat CT scans. One patient developed a recurrent laryngeal nerve palsy. The symptoms gradually resolved within 1 month. No perioperative strokes or deaths occurred. During a mean follow up of 48 months (range 13-63) no thromboembolic neurological events, graft occlusions or haemodynamically significant stenoses occurred. CONCLUSION: ICA FMD stent grafting is an alternative to open surgery or percutaneous endovascular intervention with excellent long-term results.

Increased rates of pulmonary metastases following sham laparotomy compared to CO2 pneumoperitoneum and the inhibition of metastases utilizing perioperative immunomodulation and a tumor vaccine.

BACKGROUND: Subcutaneous tumor growth and establishment is increased after laparotomy; significantly smaller increases have been noted after CO2pneumoperitoneum (CO2 pneumo). Less is known about the impact of surgery on the fate of blood borne tumor cells. The extent of surgical abdominal wall trauma also correlates with the extent of early postoperative immunosuppression and the inflammatory response. These changes may favor lung metastases (mets) formation. This study's hypotheses were: (a) a reduction in surgical trauma or (b) a perioperative (periop) tumor vaccine or nonspecific immune up-regulation would limit lung mets formation. An intravenous tumor cell injection lung met model was used to test these hypotheses. METHODS: Study 1 determined the incidence of lung mets after sham laparotomy (OP) and CO2 pneumo. Three groups were studied (n=25/group) : Anesthesia control (AC), CO2 pneumo, and OP. 1 x 105 TA3Haushka adenocarcinoma cells were inoculated via tail vein injection into all mice immediately after surgery. Study 2 determined the impact of perioperative immunomodulation on lung mets formation. Five groups were studied (n=20/group) : AC, OP, OP + Monophosphoryl Lipid A (MPLA), OP + lysed tumor cells (LTC), or OP + MPLA + LTC. The vaccine consisted of 5 x 105 lysed TA3Ha tumor cells (LTC) and was given 5 times preop and once postop to the vaccine groups. MPLA, the nontoxic moiety of lipopolysaccharide, was used both as a vaccine adjuvant in the OP + MPLA + LTC group and as a nonspecific perioperative immune up-regulator in the OP + MPLA group. Five periop injections of MPLA were given to the OP + MPLA group. All mice were given tail vein injections of tumor cells after surgery. Fourteen days after surgery all mice were sacrificed, the lungs transected en bloc, and India ink injected into the trachea. The lungs were placed in Fekete's solution to counterstain the tumor foci white. The number of surface lung metastases was determined by two blinded observers, separately. RESULTS: In Study 1, there were significantly more lung tumors in the OP group (median=31.5) than the AC group (median=9; p<0.05) or the CO2 Pneumo group (median=6.5; p<0.05). There were no significant differences in the number of metastases between the AC and the CO2 Pneumo groups or in the incidence of animals in each group with 1 or more lung mets. In Study 2 significantly fewer metastases were noted for the Op + LTC group (median=3; p<0.05) and the OP + LTC + MPLA group (median=0; p<0.05) when compared to the OP group (median=20). Although the OP + MPLA group mice had fewer metastases (median=4) than the OP group, this difference was not significant. Significantly fewer of the OP + LTC + MPLA group mice developed one or more lung tumors than in the OP, OP + MPLA, and the OP + LTC groups. CONCLUSIONS: Full sham laparotomy was associated with more postoperative lung metastases than CO2 pneumo or anesthesia alone in this murine model. Up-regulation of the immune system in the perioperative period with lysed tumor cells, alone or in combination with MPLA, resulted in significantly fewer postoperative lung metastases. MPLA alone resulted in a less marked reduction of lung metastases.

1-Aminomethylisoquinoline-4-carboxylates as novel dipeptidylpeptidase IV inhibitors.

Structure-activity relationship within a series of 1-aminoalkylisoquinoline-4-carboxylates as inhibitors of DPP-IV is described. A primary aminomethyl group is required to maintain biological activity. Substitution of the isoquinoline at the 6- and 8-positions with methoxy groups increases potency to 53 times that of the lead compound SDZ 029-576.

Secretion of MCP-1 and IL-6 by cytokine stimulated production of reactive oxygen species in endothelial cells.

Endothelial cells are known to produce reactive oxygen species by several mechanisms. Functional consequences of increased production of reactive oxygen species were investigated in vitro after stimulation with several proinflammatory cytokines. Time dependent increases in DCF-fluorescence as a measure of reactive oxygen load were quantified in single cells after incubation with TNF-alpha, IL-1 and IFN-gamma. The increased DCF-fluorescence was inhibited by cell permeant antioxidative substances Tiron and Tempol. NMMA, an inhibitor of nitric oxide synthase reduced endothelial DCF-fluorescence only marginally, indicating a minor participation of nitric oxide production in this detection system. Cytokine induced endothelial DCF-fluorescence increased in the presence of NADH, whereas coincubation with NADPH or xanthine was without effect. Flavoenzyme inhibitor diphenyliodonium abolished stimulated DCF-fluorescence. Cytokine induced release of MCP-1 and IL-6 by endothelial cells was completely inhibited in the presence of Tiron and Tempol, whereas NMMA was less effective. Collectively these data indicate that cytokine stimulated endothelial cells increase their reactive oxygen species production probably via NADH oxidase and this production may critically be involved in the secretion of MCP-1 and IL-6.

A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.