Reversible Pulmonary Hypertension due to Combined Fistula between the Left Anterior Descending Artery (LAD) and Pulmonary Artery and Severe Stenosis of the LAD.

Coronary artery fistulas are usually diagnosed accidentally without the presence of any symptoms. On the other hand, the combination of fistula between the left anterior descending artery (LAD) and pulmonary artery (PA) and severe stenosis of the LAD, as in this case report, is a potential life-threatening condition. A 72-year-old patient was treated surgically after being diagnosed with fistula between the LAD and PA, severe stenosis of the LAD, and severe pulmonary hypertension. In following paragraphs, the case of this man and significant issues regarding the development and management of coronary artery fistulas are analyzed.

Epidemiology and diagnosis of pulmonary embolism in lung cancer patients: is there a role for age adjusted D-dimers cutoff?

Our knowledge about the incidence of pulmonary embolism (PE) and the performance of age adjusted D-dimers (Dd) cutoff amongst patients with lung cancer (LC) and suspected PE, remains limited. We retrospectively analyzed all clinically suspected patients who underwent computed tomography pulmonary angiography (CTPA) in a tertiary hospital during a 19 month period. Cancer diagnosis was established using ICD10 code. Eligible for Dd analysis were those tested up to 24 h prior to the scan. We analyzed 2549 patients (54.6% males, median age 68.8 years, IQR 57-78), 15.8% had active LC and 5.4% other cancers (oC), while 70% were scanned in the Emergency Department (ED) and the rest during hospitalization. Overall incidence of PE was 16%. LC, but not oC, increased significantly the risk for PE (OR 1.58, 95% CI 1.21-2.06). LC patients were less likely to have bilateral (aOR 0.16, 95% CI 0.07-0.4) or central PE (aOR 0.2, 95% CI 0.09-0.48). Amongst those diagnosed with PE in the ED, LC increased all-cause inhospital mortality (aOR 6.7, 95% CI 2.64-16.95). When age adjusted instead of conventional Dd cutoff was used for ruling out PE in the ED, specificity for LC patients increased (10.16% vs 3.91%) without false negative tests (negative likelihood ratio-NLR = 0). A higher cutoff of 1.13 mg/l raised specificity to 28.9%, with only one case missed (sensitivity: 97.4%, NLR: 0.09, 95% CI 0.01-0.64). LC increases the risk for PE and adversely affects prognosis. Age adjusted and probably an even higher, "LC adjusted" Dd cutoff, could increase the specificity of the test without compromising its sensitivity.

Serum-free light chains adjusted for renal function are a potential biomarker for post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management.

Molecular alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients.

The contribution of molecular alterations in bone marrow mesenchymal stromal cells (BM-MSC) to the pathogenesis of acute myeloid leukemia (AML) is poorly understood. Thus we assessed genome-wide genetic, transcriptional and epigenetic alterations in BM-MSC derived from AML patients (AML BM-MSC). Whole-exome sequencing (WES) of AML BM-MSC samples from 21 patients revealed a non-specific pattern of genetic alterations in the stromal compartment. The only mutation present in AML BM-MSC at serial time points of diagnosis, complete remission and relapse was a mutation in the PLEC gene encoding for cytoskeleton key player Plectin in one AML patient. Healthy donor controls did not carry genetic alterations as determined by WES. Transcriptional profiling using RNA sequencing revealed deregulation of proteoglycans and adhesion molecules as well as cytokines in AML BM-MSC. Moreover, KEGG pathway enrichment analysis unravelled deregulated metabolic pathways and endocytosis in both transcriptional and DNA methylation signatures in AML BM-MSC. Taken together, we report molecular alterations in AML BM-MSC suggesting global changes in the AML BM microenvironment. Extended investigations of these altered niche components may contribute to the design of niche-directed therapies in AML.

[Space-occupying lesion in the maxillary sinus]. / Eine Raumforderung im Sinus maxillaris.

During the preoperative diagnostics of an 80-year-old male patient prior to a planned endarterectomy, an unclear space-occupying lesion was detected in the right nasopharyngeal cavity. It proved to be a dense soft tissue space-occupying lesion of the right maxillary sinus. The histological investigations revealed a partially necrotically decomposed malignant tumor below normal respiratory mucosa free from dysplasia. This case demonstrates the difficulties in differential diagnostics, particularly involving (aberrant) expression of cytokeratin.

A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance.

In April 2013 our group published a review on predictive molecular pathology in this journal. Although only 2 years have passed many new facts and stimulating developments have happened in diagnostic molecular pathology rendering it worthwhile to present an up-date on this topic. A major technical improvement is certainly given by the introduction of next-generation sequencing (NGS; amplicon, whole exome, whole genome) and its application to formalin-fixed paraffin-embedded (FFPE) tissue in routine diagnostics. Based on this 'revolution' the analyses of numerous genetic alterations in parallel has become a routine approach opening the chance to characterize patients' malignant tumors much more deeply without increasing turn-around time and costs. In the near future this will open new strategies to apply 'off-label' targeted therapies, e.g. for rare tumors, otherwise resistant tumors etc. The clinically relevant genetic aberrations described in this review include mutation analyses of RAS (KRAS and NRAS), BRAF and PI3K in colorectal cancer, KIT or PDGFR alpha as well as BRAF, NRAS and KIT in malignant melanoma. Moreover, we present several recent advances in the molecular characterization of malignant lymphoma. Beside the well-known mutations in NSCLC (EGFR, ALK) a number of chromosomal aberrations (KRAS, ROS1, MET) have become relevant. Only very recently has the clinical need for analysis of BRCA1/2 come up and proven as a true challenge for routine diagnostics because of the genes' special structure and hot-spot-free mutational distribution. The genetic alterations are discussed in connection with their increasingly important role in companion diagnostics to apply targeted drugs as efficient as possible. As another aspect of the increasing number of druggable mutations, we discuss the challenges personalized therapies pose for the design of clinical studies to prove optimal efficacy particularly with respect to combination therapies of multiple targeted drugs and conventional chemotherapy. Such combinations would lead to an extremely high complexity that would hardly be manageable by applying conventional study designs for approval, e.g. by the FDA or EMA. Up-coming challenges such as the application of methylation assays and proteomic analyses on FFPE tissue will also be discussed briefly to open the door towards the ultimate goal of reading a patients' tissue as 'deeply' as possible. Although it is yet to be shown, which levels of biological information are most informative for predictive pathology, an integrated molecular characterization of tumors will likely offer the most comprehensive view for individualized therapy approaches. To optimize cancer treatment we need to understand tumor biology in much more detail on morphological, genetic, proteomic as well as epigenetic grounds. Finally, the complex challenges on the level of drug design, molecular diagnostics, and clinical trials make necessary a close collaboration among academic institutions, regulatory authorities and pharmaceutical companies.

International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

A comprehensive analysis of the cellular and EBV-specific microRNAome in primary CNS PTLD identifies different patterns among EBV-associated tumors.

Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.

Predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance.

The increasing importance of targeting drugs in the treatment of several tumor entities (breast, colon, lung, malignant melanoma (MM), lymphoma, and so on) and the necessity of a companion diagnostic (human epidermal growth factor receptor 2, Kirsten rat sarcoma viral oncogene, epidermal growth factor receptor (EGFR), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and so on) is leading to new challenges for surgical pathology. As all the biomarkers to be specifically detected are tissue based, a precise and reliable diagnostic is absolutely crucial. To meet this challenge, surgical pathology has adapted a number of molecular methods (semi-quantitative immunohistochemistry, fluorescence in situ hybridization), PCR and its multiple variants, (pyro/Sanger) sequencing, next-generation sequencing, DNA-arrays, methylation analyses, and so on) to be applicable for formalin-fixed paraffin-embedded (FFPE) tissue. To read a patients' tissue as 'deeply' as possible and to obtain information on morphological, genetic, proteomic as well as epigenetic background is the actual task of pathologists and molecular biologists in order to provide the clinicians with information relevant for individualized medicine. The intensified cooperation of clinicians and pathologists will provide the basis of improved clinical drug selection as well as guide development of new cancer gene therapies and molecularly targeted drugs by research units and the pharmaceutical industry. This review will give some information on (1) biomarker detection methods adapted to FFPE tissue, (2) the potency of predictive pathology in tumor detection and treatment and (3) the implications of pathology on the development of new drugs in molecularly targeted and gene therapies.

[Epstein-Barr virus-associated lymphoproliferations and lymphomas]. / Epstein-Barr-Virus-assoziierte Lymphoproliferationen und Lymphome.

Epstein-Barr virus (EBV) is a lymphotropic herpesvirus infecting > 95 % of the worldwide population. In case of an immunodeficiency of various causes, the virus may lead to the development of a wide spectrum of lymphoproliferations and lymphomas. This encompasses mononucleosis-like lymphoproliferations, hyperplasias of various B-cell subsets as well as aggressive non-Hodgkin lymphomas and classical Hodgkin lymphoma. These lesions occur frequently extranodal and present with a polymorphous histology with angioinvasion and necrosis. Clinical data combined with the immunohistological detection of CD30 expression in the activated infected cells and the demonstration of EBV-encoded proteins and RNA transcripts are helpful for achieving precise classification of these lesions.

Oral eosinophilic ulcer, an Epstein-Barr virus-associated CD30+ lymphoproliferation?

Eosinophilic ulcer of the oral mucosa is a benign lesion of unclear pathogenesis mostly affecting the tongue. It has been suggested to represent a reactive pattern to several stimuli. We report on a 12-year-old boy who presented with a painless infiltrating ulcer on the gingiva of the lower jaw, which was covered by necrotic yellowish slough. There were no pathologic features of the jawbones or regional lymph nodes. Histopathological, immunohistochemical and gene rearrangement studies were in agreement with eosinophilic ulcer with predominant oligoclonal CD3+ and CD30+ T lymphocytes expressing the Epstein-Barr virus membrane protein. The ulcer resolved within 4 weeks and follow-up for 3 years revealed no evidence of recurrence. Epstein-Barr virus may have played a role in triggering this reactive lymphoproliferative disorder.

High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas.

Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including classical Hodgkin lymphoma (cHL) cells, relative to normal B cells. Inhibition of MAML-protein activity by a dominant negative form of MAML or by small hairpin RNAs targeting MAML2 in cHL cells resulted in downregulation of the NOTCH target genes HES7 and HEY1, which we identified as overexpressed in cHL cells, and in reduced proliferation. Furthermore, a NOTCH gene-expression signature in cHL cells confirmed their cell-autonomous NOTCH activity. Finally, in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro. These data strongly suggest direct targeting of the NTC as treatment strategy for NOTCH-dependent malignancies.

Spondylolysis: a review and reappraisal.

The aim of this review was to provide of the current knowledge in pathophysiology, diagnosis and management of spondylolysis based on the authors' experience and the pertinent medical literature. Spondylolysis represents a weakness or stress fracture in one of the bony bridges that connect the upper with the lower facet joints of the vertebra. It is the most common cause of low back pain in young athletes. One-half of all paediatric and adolescent back pain in athletic patients is related to various disturbances in the posterior elements including spondylolysis. The most common clinical presentation of spondylolysis is low back pain. This is aggravated by activity and is frequently accompanied by minimal or no physical findings. A pars stress fracture or early spondylolysis are common and a misdiagnosis is often made. Plain radiography with posteroanterior (P-A), lateral and oblique views have proved very useful in the initial diagnostics of low back pain, but imaging studies such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans are more sensitive in the establishment of the diagnosis. Several treatment options are available. Surgical treatment is indicated only for symptomatic cases when conservative methods fail. The fact that early and multiple imaging studies may have a role in the diagnosis of pars lesions and the selection of the optimal treatment approaches is also highlighted.

Decreasing trends of ultrasonographic prevalence of cystic echinococcosis in a rural Greek area.

Greece is considered as one of the endemic European countries for cystic echinococcosis (CE). We evaluated the prevalence trends of CE in the rural area of Trikala, Central Greece, through ultrasound records for the period 2001-2008. Of the 47,045 total number of abdominal ultrasound tests performed in the period 2001-2008, a total of 153 individuals had abdominal CE. Despite this generally high figure, significantly lower prevalence rates were noted during the second half of the study period. The implementation of a national campaign for CE control, started in 1984, has led to decreasing annual detection rates of CE in Central Greece.

Primary atypical teratoid/rhabdoid tumor of the spine in an infant.

Atypical teratoid/rhabdoid tumor of the spine is a rare pediatric neoplasm with poor prognosis. We report a case of an atypical teratoid/rhabdoid tumor of the cervical spine in a 2-months-old infant. The patient presented with rapidly progressing tetraparesis and respiratory failure. Magnetic resonance imaging of the spinal cord revealed an intradural, extramedullary mass occupying the spinal canal on the right at the level of C1-C5. Tumor cells were immunohistochemically positive for epithelial membrane antigen, vimentin, cytokeratins, S-100 protein, and CD57/Leu-7 antigen. Despite chemotherapy, the infant presented with progressive neurological deterioration and died 6 months after initial diagnosis. We review the literature on spinal malignant rhabdoid tumor and discuss the pathology, treatment, and outcome of these rare neoplasms.

Valorization of lignite combustion residues and ferroalumina in the production of aggregates.

The present research study investigates the synergy of industrial solid by-products from lignite combustion (fly ash and bottom ash) and aluminum production (ferroalumina) in the production of lightweight aggregates (LWA). The process consists of two stages, pelletization and sintering. Bottom ash (BA) is used as the principal raw material in mixtures while ferroalumina (FAL) is added in lower percentages (5-30 wt%). BA carbon content is used as the fuel of sintering process in high temperatures, around 1250 degrees C, and gas generation is responsible for porous structure formation. Physical properties such as porosity, water absorption and bulk density, of sintering products are measured. Increase of FAL percentage in sintering mixtures results in decrease of porosity from 61% to 35% and of water absorption from 61% to 21% and in increase of bulk density from 1.02 g/cm(3) to 1.80 g/cm(3) of the produced aggregates. Aggregates produced by FAL addition up to 20 wt% are characterized as LWA. Aggregates formed are used in the production of concrete specimens. Compressive strength of concrete increases by increasing FAL addition in aggregates from 5 wt% to 15 wt% (highest strength value), while decrease by increasing FAL addition from 20 wt% to 30 wt%. FAL addition in lignite ashes sintering mixtures (up to 15 wt%) is considered as an important parameter for enhancing aggregates strength.

Treatment of PTLD with rituximab and CHOP reduces the risk of renal graft impairment after reduction of immunosuppression.

We addressed the effect of post-transplant lymphoproliferative disorder (PTLD) treatment with rituximab monotherapy or CHOP-based chemotherapy (+/- rituximab) after upfront immunosuppression reduction (IR) on renal graft function in a longitudinal analysis of 58 renal transplant recipients with PTLD and 610 renal transplant controls. Changes in the estimated glomerular filtration rate over time were calculated from a total of 6933 creatinine measurements over a period of >1 year using a linear mixed model with random and fixed effects. Renal graft function significantly improved with treatment of PTLD, especially in the chemotherapy subgroup. Patients treated with IR+chemotherapy +/- rituximab had a noninferior graft function compared with untreated controls suggesting that the negative impact of IR on the renal graft function can be fully compensated by the immunosuppressive effect of CHOP. The immunosuppressive effect of single agent rituximab may partially compensate the negative impact of IR on the graft function. Thus, it is possible to reduce immunosuppression when using chemotherapy to treat PTLD.

Methicillin resistant staphylococcus aureus thoracic spondylitis late after cervical spine surgery.

BACKGROUND: Spondylodiscitis is a known and serious complication of spinal surgery. A rare case of a late and remote thoracis spondrylitis due to methicillin resistant staphylococcus aureus following cervical surgery is presented. CASE REPORT: A 50 year-old-male was treated for cervical degenerative disease via a combined anterior and posterior cervical approach (discectomy with fusion and laminectomy). Three years later a cervical epidural abscess was formed which was treated successfully conservatively. After 18 months he developed spondylitis of the second thoracic vertebra. The patient was further treated surgically via a dorsolateral extracavitary thoracic approach. Laboratory analysis revealed Methicillin Resistant Staphylococcus Aureus (MRSA) spondylitis sensitive to linezolid. Inflammation markers declined and clinical symptoms ameliorated. At 12-month follow-up the patient did not show any evidence of recurrence of the infection. CONCLUSIONS: A high rate of suspicion must be maintained in patients presenting with signs of spinal infection and neurological impairment even many years after the initial operation. Optimal investigation and outcome require close clinical monitoring and a well coordinated multidisciplinary approach.