Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms.

Peripheral T-cell lymphomas (PTCLs), especially angioimmunoblastic and follicular TCLs, have a dismal prognosis because of the lack of efficient therapies, and patients' symptoms are often dominated by an inflammatory phenotype, including fever, night sweats, weight loss, and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on T-cell follicular helper-type PTCL (TFH-PTCL) disease progression and symptoms. We showed that ITK-SYK-driven murine PTCLs and primary human TFH-PTCL xenografts both induced inflammation in mice, including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving interferon gamma (CD4+ malignant T cells) and interleukin 6 (IL-6; activated granulocytes), ultimately inducing broad JAK activation (JAK1/2/3 and TYK2) in both cell types. Inflammatory granulocyte depletion via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox), or IL-6 deletion within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration, and enhanced mouse survival. Furthermore, unselective JAK inhibitors (ruxolitinib) inhibited both TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions, and an intact JAK/STAT signaling pathway for TFH-PTCL development and also support broad JAK inhibition as an effective treatment strategy in early disease stages.

Guideline Concordance of Treatment and Outcomes Among Adult Non-Hodgkin Lymphoma Patients in Sub-Saharan Africa: A Multinational, Population-Based Cohort.

BACKGROUND: Although non-Hodgkin lymphoma (NHL) is the 6th most common malignancy in Sub-Saharan Africa (SSA), little is known about its management and outcome. Herein, we examined treatment patterns and survival among NHL patients. METHODS: We obtained a random sample of adult patients diagnosed between 2011 and 2015 from 11 population-based cancer registries in 10 SSA countries. Descriptive statistics for lymphoma-directed therapy (LDT) and degree of concordance with National Comprehensive Cancer Network (NCCN) guidelines were calculated, and survival rates were estimated. FINDINGS: Of 516 patients included in the study, sub-classification was available for 42.1% (121 high-grade and 64 low-grade B-cell lymphoma, 15 T-cell lymphoma and 17 otherwise sub-classified NHL), whilst the remaining 57.9% were unclassified. Any LDT was identified for 195 of all patients (37.8%). NCCN guideline-recommended treatment was initiated in 21 patients. This corresponds to 4.1% of all 516 patients, and to 11.7% of 180 patients with sub-classified B-cell lymphoma and NCCN guidelines available. Deviations from guideline-recommended treatment were initiated in another 49 (9.5% of 516, 27.2% of 180). By registry, the proportion of all patients receiving guideline-concordant LDT ranged from 30.8% in Namibia to 0% in Maputo and Bamako. Concordance with treatment recommendations was not assessable in 75.1% of patients (records not traced (43.2%), traced but no sub-classification identified (27.8%), traced but no guidelines available (4.1%)). By registry, diagnostic work-up was in part importantly limited, thus impeding guideline evaluation significantly. Overall 1-year survival was 61.2% (95%CI 55.3%-67.1%). Poor ECOG performance status, advanced stage, less than 5 cycles and absence of chemo (immuno-) therapy were associated with unfavorable survival, while HIV status, age, and gender did not impact survival. In diffuse large B-cell lymphoma, initiation of guideline-concordant treatment was associated with favorable survival. INTERPRETATION: This study shows that a majority of NHL patients in SSA are untreated or undertreated, resulting in unfavorable survival. Investments in enhanced diagnostic services, provision of chemo(immuno-)therapy and supportive care will likely improve outcomes in the region.

Induction of pulmonary HLA-G expression by SARS-CoV-2 infection.

The non-classical human leukocyte antigen (HLA)-G exerts immune-suppressive properties modulating both NK and T cell responses. While it is physiologically expressed at the maternal-fetal interface and in immune-privileged organs, HLA-G expression is found in tumors and in virus-infected cells. So far, there exists little information about the role of HLA-G and its interplay with immune cells in biopsies, surgical specimen or autopsy tissues of lung, kidney and/or heart muscle from SARS-CoV-2-infected patients compared to control tissues. Heterogeneous, but higher HLA-G protein expression levels were detected in lung alveolar epithelial cells of SARS-CoV-2-infected patients compared to lung epithelial cells from influenza-infected patients, but not in other organs or lung epithelia from non-viral-infected patients, which was not accompanied by high levels of SARS-CoV-2 nucleocapsid antigen and spike protein, but inversely correlated to the HLA-G-specific miRNA expression. High HLA-G expression levels not only in SARS-CoV-2-, but also in influenza-infected lung tissues were associated with a high frequency of tissue-infiltrating immune cells, but low numbers of CD8+ cells and an altered expression of hyperactivation and exhaustion markers in the lung epithelia combined with changes in the spatial distribution of macrophages and T cells. Thus, our data provide evidence for an involvement of HLA-G and HLA-G-specific miRNAs in immune escape and as suitable therapeutic targets for the treatment of SARS-CoV-2 infections.

Vie Scope® versus videolaryngoscopy in expected difficult airways: a randomized controlled trial.

PURPOSE: The management of patients with an anticipated difficult airway remains challenging. We evaluated laryngeal visualization with the recently introduced Vie Scope® as a straight blade laryngoscope consisting of an illuminated tube necessitating bougie-facilitated intubation vs Macintosh videolaryngoscopy. METHODS: We conducted a prospective randomized controlled noninferiority trial. Patients undergoing elective ear, nose, and throat or oral and maxillofacial surgery with an anticipated difficult airway were randomized 1:1 to receive tracheal intubation with the Vie Scope or Macintosh videolaryngoscope (C-MAC®). The primary outcome measure was laryngeal visualization by the percentage of glottis opening (POGO) scale. Secondary outcome measures were the time to successful intubation (TTI) and first-attempt and overall success rates. RESULTS: We included two sets of 29 patients in our analysis. For visualization, the Vie Scope was noninferior to videolaryngoscopy (VL) with mean (standard deviation [SD]) POGO scores of 71 (31)% vs 64 (30)% in the VL group [difference in means, 7 (8)%; 95% confidence interval, -9 to 23; P = 0.38]. Mean (SD) TTI was 125 (129) sec in the Vie Scope and 51 (36) sec in the VL group (difference in means, 75 sec; 95% confidence interval, 25 to 124; P = 0.005). The first-attempt and overall success rates were 22/29 (76%) and 27/29 (93%) in both groups. Two patients per group were switched to a different device. Four accidental esophageal intubations occurred in the Vie Scope group, these were presumably due to bougie misplacement. CONCLUSION: Visualization with the Vie Scope was noninferior to VL in patients with an anticipated difficult airway, but TTI was longer in the Vie Scope group. STUDY REGISTRATION: ClinicalTrials.gov (NCT05044416); registered 5 September 2021.

RéSUMé: OBJECTIF: La prise en charge des patients dont les voies aériennes sont anticipées comme étant difficiles demeure un défi. Nous avons évalué la visualisation laryngée obtenue avec le nouveau Vie Scope®, un laryngoscope à lame droite constitué d'un tube éclairé nécessitant une intubation facilitée par bougie, par rapport à celle obtenue avec un vidéolaryngoscope Macintosh. MéTHODE: Nous avons réalisé une étude randomisée contrôlée prospective de non-infériorité. Les patient·es bénéficiant d'une chirurgie non urgente des oreilles, du nez et de la gorge ou une chirurgie buccale et maxillo-faciale présentant des voies aériennes anticipées comme difficiles ont été randomisé·es à un ratio 1:1 à recevoir une intubation trachéale avec un laryngoscope Vie Scope ou un vidéolaryngoscope Macintosh (C-MAC®). Le critère d'évaluation principal était la visualisation laryngée selon l'échelle de pourcentage d'ouverture de la glotte (POGO). Les critères d'évaluation secondaires étaient le délai avant une intubation réussie et les taux de réussite de la première tentative et globaux. RéSULTATS: Nous avons inclus deux groupes de 29 patient·es dans notre analyse. En matière de visualisation, le Vie Scope n'était pas inférieur à la vidéolaryngoscopie (VL), avec des scores POGO moyens (écart type [ET]) de 71 (31) % vs 64 (30) % dans le groupe VL [différence dans les moyennes, 7 (8) %; intervalle de confiance à 95 %, ­9 à 23; P = 0,38]. Le délai moyen (ET) avant une intubation réussie était de 125 (129) sec avec le Vie Scope et de 51 (36) secondes dans le groupe VL (différence dans les moyennes, 75 sec; intervalle de confiance à 95 %, 25 à 124; P = 0,005). Les taux de réussite de la première tentative et de réussite globale étaient de 22/29 (76 %) et 27/29 (93 %) dans les deux groupes. Un dispositif différent a dû être utilisé chez deux patient·es par groupe. Quatre intubations œsophagiennes accidentelles sont survenues dans le groupe Vie Scope; celles-ci étaient probablement dues à un mauvais placement de la bougie. CONCLUSION: La visualisation obtenue avec le Vie Scope n'était pas inférieure à la vidéolaryngoscopie chez les patient·es dont les voies aériennes étaient anticipées comme difficiles, mais le délai avant une intubation réussie était plus long dans le groupe Vie Scope. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05044416); registered 5 September 2021.

Intrinsic subtypes in Ethiopian breast cancer patient.

PURPOSE: The recent development of multi-gene assays for gene expression profiling has contributed significantly to the understanding of the clinically and biologically heterogeneous breast cancer (BC) disease. PAM50 is one of these assays used to stratify BC patients and individualize treatment. The present study was conducted to characterize PAM50-based intrinsic subtypes among Ethiopian BC patients. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tissues were collected from 334 BC patients who attended five different Ethiopian health facilities. All samples were assessed using the PAM50 algorithm for intrinsic subtyping. RESULTS: The tumor samples were classified into PAM50 intrinsic subtypes as follows: 104 samples (31.1%) were luminal A, 91 samples (27.2%) were luminal B, 62 samples (18.6%) were HER2-enriched and 77 samples (23.1%) were basal-like. The intrinsic subtypes were found to be associated with clinical and histopathological parameters such as steroid hormone receptor status, HER2 status, Ki-67 proliferation index and tumor differentiation, but not with age, tumor size or histological type. An immunohistochemistry-based classification of tumors (IHC groups) was found to correlate with intrinsic subtypes. CONCLUSION: The distribution of the intrinsic subtypes confirms previous immunohistochemistry-based studies from Ethiopia showing potentially endocrine-sensitive tumors in more than half of the patients. Health workers in primary or secondary level health care facilities can be trained to offer endocrine therapy to improve breast cancer care. Additionally, the findings indicate that PAM50-based classification offers a robust method for the molecular classification of tumors in the Ethiopian context.

PIK3CA-mutations in breast cancer.

PURPOSE: Phosphatidylinositide-3-kinase (PI3K) regulates proliferation and apoptosis; somatic PIK3CA-mutations may activate these processes. Aim of this study was to determine the prevalence of PIK3CA-mutations in a cohort of early stage breast cancer patients and the association to the course of disease. PATIENTS AND METHODS: From an unselected cohort of 1270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT01592825) 1123 tumours were tested for the three PIK3CA hotspot-mutations H1047R, E545K, and E542K by qPCR. Primary objectives were the prevalence of somatic PIK3CA-mutations and their association to tumour characteristics. Secondary objective was the association of PIK3CA-mutations to recurrence-free interval (RFI) and overall survival. RESULTS: PIK3CA-mutation rate was 26.7% (300 of 1123). PIK3CA-mutations were significantly more frequent in steroid hormone-receptor (SHR)-positive HER2-negative (31.4%), and G1 and G2 tumours (32.8%). Overall, we did not observe a significant association of PIK3CA-mutations to RFI. In SHR-positive BCs with PIK3CA-mutations, a strong trend for impaired  RFI was observed (adjusted HR 1.64, 95% CI 0.958-2.807), whilst in SHR-negative BCs PIK3CA-mutations were insignificantly associated with improved RFI (adjusted HR 0.49; 95% CI 0.152-1.597). Of note, we observed a significantly detrimental prognostic impact of PIK3CA-mutations on RFI in SHR-positive, HER2-negative BCs if only aromatase inhibitors were administered as adjuvant therapy (adjusted HR 4.44, 95% CI 1.385-13.920), whilst no impact was observed in tamoxifen treated patients. CONCLUSION: This cohort study speficies the overall mutation rate of PIK3CA in early breast cancer. The impact of PIK3CA-mutations on RFI and OS was heterogeneous. Our results suggest that estrogen deprivation failes to be active in case of PIK3CA-mutation.

IGF2BP1 is the first positive marker for anaplastic thyroid carcinoma diagnosis.

Anaplastic thyroid carcinomas (ATC) are rare, but represent the most lethal malignancy of the thyroid. Selective molecular markers and drivers distinguishing ATC from other thyroid carcinomas of follicular origin remain largely unknown, limiting advances in diagnosis and treatment. In a retrospective study, we analyzed gene expression in 36 ATC, 18 poorly differentiated, 132 papillary, and 55 follicular thyroid carcinoma, as well as 124 paired and unpaired normal thyroid tissues in three independent cohorts by RNA-sequencing and immunohistochemistry. RNA-sequencing data in the test cohort suggested selective ATC protein biomarkers. Evaluation of these revealed that ATCs are characterized by the de novo expression of various testis antigens, including melanoma-associated antigen A3 (MAGEA3), but most importantly the oncofetal IGF2 mRNA binding protein 1 (IGF2BP1). Shallow whole genome sequencing essentially excluded that IGF2BP1 upregulation results from gene copy number alterations. Immunohistochemical analyses in all three tumor cohorts confirmed the selective de novo expression of IGF2BP1 protein in ATC. In sum, 75% (27/36) of all tested ATC and 0.5% (1/204) of poorly and well-differentiated thyroid carcinoma tissue samples were positive for IGF2BP1 protein. This indicates that IGF2BP1 protein expression identifies ATC with a diagnostic odds ratio of 612 (95% CI: 74.6-5021). In addition, we found that MAGEA3 is exclusively, although less consistently upregulated in ATC, presenting with an odds ratio of 411 (95% CI: 23.8-7098.7). Importantly, we provide confirmatory evidence that IGF2BP1 and MAGEA3 expression distinguishes ATC from poorly differentiated thyroid carcinoma. IGF2BP1 furthermore identified ATC foci within low-grade follicular thyroid carcinoma. In conclusion, IGF2BP1 represents the most promising single-gene marker available for ATC, followed by MAGEA3, improving on current techniques. Robust markers are essential to help distinguish this high-grade malignancy from other thyroid carcinomas, to guide surgical decision making, therapy and post-resection/therapy monitoring strategies.

Presence of Parvovirus B19 but Not Herpesvirus Genome in Acute Skin Rash after Allogeneic Stem Cell Transplantation Correlates with Outcome.

INTRODUCTION: Skin rash is a first symptom of acute graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (ASCT) but can also be caused by viruses. The relevance of virus DNA analyses in skin rash for diagnosis and clinical outcome is unknown. OBJECTIVES: To record the frequencies of detection of herpes and parvovirus B19 (ParvoB19) DNA in skin rash within 100 days after ASCT and to analyze their relevance for diagnosis, clinical course, and non-relapse mortality (NRM). METHODS: We retrospectively identified 55 patients with virus DNA analysis for CMV, EBV, HHV6, HHV8, HSV, VZV, or ParvoB19. We assessed the rate of virus DNA detection and studied associations with histological diagnosis, virus DNA from concomitantly analyzed blood, clinical presentation, exanthema treatment, and NRM. RESULTS: CMV, EBV, HHV6, HHV8, HSV, VZV and ParvoB19 DNA were detected in 12.5, 11.8, 10, 0, 0, 2.9, and 26.7% of exanthemas. Histopathological diagnosis was not associated with virus polymerase chain reaction (PCR) results. Detection of CMV, EBV, or HHV6 DNA but not ParvoB19 in skin and blood was associated with PCR results (p = 0.016; p < 0.001; p = 0.067; p = n.a.). Detection of CMV, EBV, HHV6, or ParvoB19 DNA in the skin was not significantly associated with patient, ASCT, or GvHD characteristics. Detection of ParvoB19 but not herpes virus DNA was associated with less immunosuppressive treatment (p = 0.015) and lower NRM (p = 0.041). In multivariate analyses, detection of ParvoB19 was associated with a lower NRM. CONCLUSIONS: Detection of ParvoB19 DNA in exanthema after ASCT might be associated with lower NRM.

Evaluation of antihyperalgesic and analgesic effects of 35% nitrous oxide when combined with remifentanil: A randomised phase 1 trial in volunteers.

BACKGROUND: Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE: To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN: Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING: University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS: Twenty-one healthy male volunteers. INTERVENTIONS: Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES: Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS: Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ±â€Š9.25 and 24.4 ±â€Š7.3 cm2, respectively) compared with remifentanil (51.0 ±â€Š17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS: Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand. TRIAL REGISTRATION: EudraCT-No.: 2011-000966-37.

Breast cancer pathology services in sub-Saharan Africa: a survey within population-based cancer registries.

BACKGROUND: Pathologists face major challenges in breast cancer diagnostics in sub-Saharan Africa (SSA). The major problems identified as impairing the quality of pathology reports are shortcomings of equipment, organization and insufficiently qualified personnel. In addition, in the context of breast cancer, immunohistochemistry (IHC) needs to be available for the evaluation of biomarkers. In the study presented, we aim to describe the current state of breast cancer pathology in order to highlight the unmet needs. METHODS: We obtained information on breast cancer pathology services within population-based cancer registries in SSA. A survey of 20 participating pathology centres was carried out. These centres represent large, rather well-equipped pathologies. The data obtained were related to the known population and breast cancer incidence of the registry areas. RESULTS: The responding pathologists served populations of between 30,000 and 1.8 million and the centres surveyed dealt with 10-386 breast cancer cases per year. Time to fixation and formalin fixation time varied from overnight to more than 72 h. Only five centres processed core needle biopsies as a daily routine. Technical problems were common, with 14 centres reporting temporary power outages and 18 centres claiming to own faulty equipment with no access to technical support. Only half of the centres carried out IHC in their own laboratory. For three centres, IHC was only accessible outside of the country and one centre could not obtain any IHC results. A tumour board was established in 13 centres. CONCLUSIONS: We conclude that breast cancer pathology services ensuring state-of-the-art therapy are only available in a small fraction of centres in SSA. To overcome these limitations, many of the centres require larger numbers of experienced pathologists and technical staff. Furthermore, equipment maintenance, standardization of processing guidelines and establishment of an IHC service are needed to comply with international standards of breast cancer pathology.

Expression, Regulation and Function of microRNA as Important Players in the Transition of MDS to Secondary AML and Their Cross Talk to RNA-Binding Proteins.

Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the spectrum of cytogenetic alterations and oncogenic mutations, the extent of a predisposing defective osteohematopoietic niche, and the irregularity of the tumor microenvironment is highly diverse. However, the exact underlying pathophysiological mechanisms resulting in hematopoietic failure in patients with MDS and sAML remain elusive. There is recent evidence that the post-transcriptional control of gene expression mediated by microRNAs (miRNAs), long noncoding RNAs, and/or RNA-binding proteins (RBPs) are key components in the pathogenic events of both diseases. In addition, an interplay between RBPs and miRNAs has been postulated in MDS and sAML. Although a plethora of miRNAs is aberrantly expressed in MDS and sAML, their expression pattern significantly depends on the cell type and on the molecular make-up of the sample, including chromosomal alterations and single nucleotide polymorphisms, which also reflects their role in disease progression and prediction. Decreased expression levels of miRNAs or RBPs preventing the maturation or inhibiting translation of genes involved in pathogenesis of both diseases were found. Therefore, this review will summarize the current knowledge regarding the heterogeneity of expression, function, and clinical relevance of miRNAs, its link to molecular abnormalities in MDS and sAML with specific focus on the interplay with RBPs, and the current treatment options. This information might improve the use of miRNAs and/or RBPs as prognostic markers and therapeutic targets for both malignancies.

Chronic active Epstein-Barr virus infection of T-cell type, systemic form in an African migrant: case report and review of the literature on diagnostics standards and therapeutic options.

BACKGROUND: Chronic active Epstein-Barr virus (EBV) infection (CAEBV) of the T-/NK-cell type, systemic form is a rare and potentially life-threatening illness caused by persistent EBV infection. The highest incidence is found in children and adolescents with increased frequency among Asians and Native Americans, while the disease is uncommon in Western countries. Typically patients present with unspecific symptoms, like fever, lymphadenopathy, hepatosplenomegaly and liver dysfunction. Due to fatal complications including hemophagocytic syndrome, coagulopathy, multiple organ failure and development of EBV-positive lymphoproliferative disease (LPD) or lymphoma early diagnosis is critical for successful treatment. However, in consequence of the lack of experience due to the low incidence in Europe, a broad spectrum of clinical manifestations and a particularly unexpected group of patients, diagnosis can be challenging. Inhere we describe the clinicopathological findings of an African adult with CAEBV associated LPD with a brief review of the literature. CASE PRESENTATION: A 42-year-old African man with fever, enlargement of the spleen and a suspected epileptic seizure was referred to our hospital. Diagnostic testing repeatedly revealed a massive EBV-DNA load in peripheral blood. Whole-body PET-CT-scan presented a strong uptake at multiple bone marrow sites, the thyroid and the adrenal glands. Histopathological analysis of bone marrow and thyroid gland revealed a highly proliferating, atypical and predominantly intravascular cytotoxic T-cell population with intracellular EBV-encoded RNA. Clonality analysis revealed the presence of polyclonal T-cell-receptor. Based on these findings a CAEBV of the T-/NK-cell type, systemic form was diagnosed. Subsequent therapy including three cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone resulted in decreased EBV load, clinical improvement and ongoing complete remission. CONCLUSION: Adult-onset CAEBV of T/NK-cell type usually comprises a poor prognosis and is extremely rare in Western countries. Therefore, our case highlights the need for a clinical awareness of this disease in patients with systemic illness and for a comprehensive multidisciplinary diagnostic approach to facilitate diagnosis. Treatment options include antiviral drugs, immunosuppressive agents and systemic chemotherapy with or without allogeneic stem cell transplantation. Given the limited data these options need to be decided upon in each patient individually considering severity of the disease, comorbidities and response.

Comparison of coronary artery calcification, carotid intima-media thickness and ankle-brachial index for predicting 10-year incident cardiovascular events in the general population.

AIMS: To compare the predictive value of coronary artery calcification (CAC), carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) in a primary prevention cohort depending on risk factor profile to determine which of the three markers improves cardiovascular (CV) risk discrimination best in which risk group. METHODS AND RESULTS: We quantified CAC, CIMT, and ABI in 3108 subjects (mean age 59.2 ± 7.7, 47.1% male) without prevalent CV diseases from the population-based Heinz Nixdorf Recall study. Associations with incident major CV events (coronary event, stroke, CV death; n = 223) were assessed during a follow-up period of 10.3 ± 2.8 years with Cox proportional regressions in the total cohort and stratified by Framingham risk score (FRS) groups. Discrimination ability was evaluated with Harrell's C. All three markers were associated with CV events (hazard ratio [95% confidence interval (CI)]: CAC: 1.31 (1.23-1.39) per 1-unit increase in log(CAC + 1) vs. CIMT: 1.27 (1.13-1.43) per 1 SD vs. ABI: 1.30 (1.14-1.49) per 1 SD, in FRS adjusted models). Considering reclassification, CAC lead to highest reclassification in the total cohort, while also for CIMT and ABI significant improvement in net-reclassification was observed [NRI (95% CI): CAC: 0.55 (0.42-0.69); CIMT: 0.32 (0.19-0.45); ABI: 0.19 (0.10-0.28)]. CONCLUSION: Coronary artery calcification provides the best discrimination of risk compared with CIMT and ABI, particularly in the intermediate risk group, whereas CIMT may be an alternative measure for reassurance in the low risk group.

Left ventricle size quantification using non-contrast-enhanced cardiac computed tomography--association with cardiovascular risk factors and coronary artery calcium score in the general population: The Heinz Nixdorf Recall Study.

BACKGROUND: Increased left ventricular (LV) size is associated with cardiovascular mortality and morbidity. Once non-contrast cardiac computed tomography (CT) is performed for other purposes, information of LV size is readily available. PURPOSE: To determine the association of gated CT-derived LV size with cardiovascular risk factors and coronary artery calcification (CAC) and to describe age- and gender-specific normative values in a general population cohort. MATERIAL AND METHODS: LV area was quantified from non-contrast-enhanced CT in axial, end-diastolic images at a mid-ventricular slice in participants of the population-based Heinz Nixdorf Recall Study, free of known cardiovascular disease. LV index (LVI) was calculated by the quotient of LV area and body surface area (BSA). Crude and adjusted regression analyses were used to determine the association of LVI with risk factors and CAC. RESULTS: Overall, 3926 subjects (age 59 ± 8 years, 53% women) were included in this analysis. From quantification in end-diastolic phase, men had larger LV index (2232 ± 296 mm(2)/m(2) vs. 2088 ± 251 mm(2)/m(2), both P < 0.0001). LVI was strongly correlated systolic blood pressure (men, PE [95% CI]: 22.8 [15.5-30.2] mm(2)/10 mmHg; women, 23.4 [18.1-28.6]), and antihypertensive medication (men, 45.2 [14.7-75.8] mm(2); women: 46.5 [22.7-70.2], all P < 0.005). Cholesterol levels were associated with LVI in univariate analysis, however, correlations were low (R(2) ≤ 0.04). In multivariable regression, blood pressure, antihypertensive medication and cholesterol levels, remained associated with LVI (P < 0.05). LVI was linked with CAC in unadjusted (men, increase of CAC + 1 by 13.0% [1.4-25.8] with increased LVI by 1 standard deviation of LVI, P = 0.03; women, 20.7% [10.0-32.3], P < 0.0001) and risk factor adjusted models (men, 14.6% [3.7-26.6], P = 0.007); women, 17.4% [7.8-27.8], P = 0.0002). CONCLUSION: Non-contrast cardiac CT derived LV index is associated with body size and hypertension. LVI is weakly linked with CAC-score. Further studies need to evaluate whether assessment of LV dimensions from cardiac CT helps identifying subjects with increased cardiovascular risk.

Progression of coronary artery calcification seems to be inevitable, but predictable - results of the Heinz Nixdorf Recall (HNR) study.

AIM: Coronary artery calcification (CAC), as a sign of atherosclerosis, can be detected and progression quantified using computed tomography (CT). We develop a tool for predicting CAC progression. METHODS AND RESULTS: In 3481 participants (45-74 years, 53.1% women) CAC percentiles at baseline (CACb) and after five years (CAC5y) were evaluated, demonstrating progression along gender-specific percentiles, which showed exponentially shaped age-dependence. Using quantile regression on the log-scale (log(CACb+1)) we developed a tool to individually predict CAC5y, and compared to observed CAC5y. The difference between observed and predicted CAC5y (log-scale, mean±SD) was 0.08±1.11 and 0.06±1.29 in men and women. Agreement reached a kappa-value of 0.746 (95% confidence interval: 0.732-0.760) and concordance correlation (log-scale) of 0.886 (0.879-0.893). Explained variance of observed by predicted log(CAC5y+1) was 80.1% and 72.0% in men and women, and 81.0 and 73.6% including baseline risk factors. Evaluating the tool in 1940 individuals with CACb>0 and CACb<400 at baseline, of whom 242 (12.5%) developed CAC5y>400, yielded a sensitivity of 59.5%, specificity 96.1%, (+) and (-) predictive values of 68.3% and 94.3%. A pre-defined acceptance range around predicted CAC5y contained 68.1% of observed CAC5y; only 20% were expected by chance. Age, blood pressure, lipid-lowering medication, diabetes, and smoking contributed to progression above the acceptance range in men and, excepting age, in women. CONCLUSION: CAC nearly inevitably progresses with limited influence of cardiovascular risk factors. This allowed the development of a mathematical tool for prediction of individual CAC progression, enabling anticipation of the age when CAC thresholds of high risk are reached.

Coronary artery calcification, intima-media thickness, and ankle-brachial index are complementary stroke predictors.

BACKGROUND AND PURPOSE: Coronary artery calcification (CAC), a marker of coronary atherosclerosis, predicts stroke in addition to established risk factors. Whether CAC's predictive value can be improved by peripheral atherosclerosis markers, namely carotid intima-media thickness (CIMT) and ankle-brachial index (ABI), was unknown. METHODS: A total of 3289 participants of the population-based Heinz Nixdorf Recall study (45-75 years; 48.8% men) without previous stroke or coronary heart disease were evaluated for incident stroke for 9.0±1.9 years. CAC, CIMT, and ABI were examined as stroke predictors. RESULTS: Eighty-four strokes occurred during follow-up. In multivariable Cox proportional hazard regressions, CAC (hazard ratio, 1.45 [95% confidence interval, 1.11-1.88] per SD increase in ln(CAC+1); SD, 2.40), CIMT (1.34 [1.08-1.66] per SD increase; SD, 0.127 mm), and ABI (1.55 [1.32-1.82] per SD decrease; SD, 0.148) were associated with stroke in addition to established risk factors. When combined with each other, ln(CAC+1)'s hazard ratio remained similar when CIMT (1.41 [1.09-1.83]) was inserted into the multivariable model, but slightly decreased when ABI (1.31 [1.01-1.72]) or CIMT and ABI (1.29 [0.99-1.68]) were included. Although CAC alone did not significantly elevate the area under the curve in Harrell's c-statistics (by 0.009; P=0.379) in addition to established risk factors, the combination of CAC and ABI increased area under the curve (by 0.029; P=0.047), as did ABI (by 0.025; P=0.038) but not CIMT (by 0.002; P=0.795) alone. The combination of CAC and ABI also resulted in significant category-free net reclassification and integrated discrimination improvement. CONCLUSIONS: CAC, CIMT, and ABI provide complementary information about stroke risk. ABI, which is distinctive in a small subpopulation, had the highest and CIMT, which is distributed across a larger range of values, had the lowest predictive value.

Left atrial size quantification using non-contrast-enhanced cardiac computed tomography - association with cardiovascular risk factors and gender-specific distribution in the general population: the Heinz Nixdorf Recall study.

BACKGROUND: Left atrial (LA) size is associated with cardiovascular mortality and morbidity. Once cardiac computed tomography (CT) is performed, information on LA size is readily available without additional contrast media or radiation exposure. PURPOSE: To determine the association of CT-derived LA area and body surface area-adjusted (BSA) LA index with cardiovascular risk factors and describe age- and gender-specific normative values in a general population cohort. MATERIAL AND METHODS: This study included 3945 participants (mean age, 59 ± 8 years; 53% women) from the community-based Heinz Nixdorf Recall Study. LA area in an axial image at the level of the mitral valve was quantified from non-contrast-enhanced electron-beam CT by manual delineations of the boundaries of the LA with exclusion of subjects with prevalent cardiovascular disease. Definition of normative values was performed in subjects without predictors of LA enlargement. RESULTS: LA quantification was feasible in all subjects. Men had larger LA size (1856 mm(2) vs. 1677 mm(2), P < 0.0001), while after adjustment for BSA, this effect was inverted (910 mm(2)/m(2) vs. 933 mm(2)/m(2) for men and women, P < 0.0001). Determinants of body size were major predictors of LA size (body mass index [BMI]: R(2) = 0.195, BSA: R(2 )= 0.216, both P < 0.0001). Blood pressure was associated with LA size (parameter-estimate [95% confidence interval] = 51.0 (4.9-57.1) mm(2)/10 mmHg for systolic, 31.4 (25.4-37.4) mm(2)/5 mmHg for diastolic blood pressure, 214.6 (186.9-242.3) mm(2) for antihypertensive medication, P < 0.0001 for all). Cholesterol levels, lipid-lowering therapy, and diabetes were associated with LA in univariable analysis, however, correlations were low (r(2 )≤ 0.026). Current smoking was associated with reduced LA size (-115.9 [-149.0 - -82.8] mm(2), P < 0.0001). In multivariable regression, BMI, blood pressure, antihypertensive medication, and smoking remained associated with LA size (P < 0.005). CONCLUSION: Non-contrast-enhanced cardiac CT enables LA quantification with body size, hypertension, and smoking status being predictors of LA size.