Management of meningeal solitary fibrous tumors/hemangiopericytoma; surgery alone or surgery plus postoperative radiotherapy?

INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.

Personalising sarcoma care using quantitative multimodality imaging for response assessment.

Over the last decades, technological developments in the field of radiology have resulted in a widespread use of imaging for personalising medicine in oncology, including patients with a sarcoma. New scanner hardware, imaging protocols, image reconstruction algorithms, radiotracers, and contrast media, enabled the assessment of the physical and biological properties of tumours associated with response to treatment. In this context, medical imaging has the potential to select sarcoma patients who do not benefit from (neo-)adjuvant treatment and facilitate treatment adaptation. Due to the biological heterogeneity in sarcomas, the challenge at hand is to acquire a practicable set of imaging features for specific sarcoma subtypes, allowing response assessment. This review provides a comprehensive overview of available clinical data on imaging-based response monitoring in sarcoma patients and future research directions. Eventually, it is expected that imaging-based response monitoring will help to achieve successful modification of (neo)adjuvant treatments and improve clinical care for these patients.

X-ray phase contrast imaging of spherical capsules.

We demonstrate that a laser-based synchrotron X-ray source can be used to image and characterize in a single laser shot spherical capsules similar to ICF targets. Thus, we establish this source potential for real-time ultrafast imaging of the ICF laser driver interaction with the target. To produce the X-ray beam we used a 160 TW high power laser system with 3.2 J and 20 fs incident on a supersonic gas jet target at 2.5 Hz repetition rate. We produced 2.7 × 109 photons/0.1% BW/sr/shot at 10 keV with a critical energy Ec = 15.1 keV. In our experimental conditions the spatial resolution was 4.3 µm in the object plane. We show that it is feasible to image the capsule structure and experimentally retrieve the phase information.

Individual risk evaluation for local recurrence and distant metastasis in Ewing sarcoma: A multistate model: A multistate model for Ewing sarcoma.

BACKGROUND: We investigated the effects of surgical margins, histological response, and radiotherapy on local recurrence (LR), distant metastasis (DM), and survival in Ewing sarcoma. PROCEDURE: Disease evolution was retrospectively studied in 982 patients with Ewing sarcoma undergoing surgery after chemotherapy using a multistate model with initial state surgery, intermediate states LR, pulmonary metastasis (DMpulm), other DM ± LR (DMother), and final state death. Effect of risk factors was estimated using Cox proportional hazard models. RESULTS: The median follow-up was 7.6 years (95% CI, 7.2-8.0). Risk factors for LR are pelvic location, HR 2.04 (1.10-3.80), marginal/intralesional resection, HR 2.28 (1.25-4.16), and radiotherapy, HR 0.52 (0.28-0.95); for DMpulm the risk factors are <90% necrosis, HR 2.13 (1.13-4.00), and previous pulmonary metastasis, HR 4.90 (2.28-8.52); for DMother are 90% to 99% necrosis, HR 1.56 (1.09-2.23), <90% necrosis, HR 2.66 (1.87-3.79), previous bone/other metastasis, HR 3.08 (2.03-4.70); and risk factors for death without LR/DM are pulmonary metastasis, HR 8.08 (4.01-16.29), bone/other metastasis, HR 10.23 (4.90-21.36), and <90% necrosis, HR 6.35 (3.18-12.69). Early LR (0-24 months) negatively influences survival, HR 3.79 (1.34-10.76). Once DMpulm/DMother arise only previous bone/other metastasis remain prognostic for death, HR 1.74 (1.10-2.75). CONCLUSION: Disease extent and histological response are risk factors for progression to DM or death. Tumor site and surgical margins are risk factors for LR. If disease progression occurs, previous risk factors lose their relevance. In case of isolated LR, time to recurrence is important for decision-making. Radiotherapy seems protective for LR especially in pelvic/axial. Low percentages of LR in extremity tumors and associated toxicity question the need for radiotherapy in extremity Ewing sarcoma.

Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation.

Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course.

Microbiology neutralization of zearalenone using Lactococcus lactis and Bifidobacterium sp.

The aim of the study was to neutralize zearalenone by lactic acid bacteria (LAB) such as Lactococcus lactis and Bifidobacterium sp. and investigate the mechanism of zearalenone (ZEA) binding. Neutralization of ZEA by LAB was confirmed by identification of binding kinetics and spectroscopic studies such as Fourier transform infrared spectroscopy (FT-IR) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The obtained results showed that the kinetic process of zearalenone binding to L. lactis is not homogeneous but is expressed with an initial rapid stage with about 90% of ZEA biosorption and with a much slower second step. In case of Bifidobacterium sp., the neutralization process is homogeneous; the main stage can be described with about 88% of ZEA biosorption. MALDI-TOF-MS measurements and FTIR analysis confirmed the uptake of zearalenone molecules by bacterial species. Moreover, the assessment of dead and live lactic acid bacteria cells after zearalenone treatment was performed using fluorescence microscopy. Graphical abstract Microbiology neutralization of zearalenone using Lactococcus lactis and Bifidobacterium sp. was confirmed by identification of binding kinetics and spectroscopic studies such as FT-IR spectroscopy and MALDI-TOF-MS spectrometry. The mechanism of ZEA binding was also investigated.

The impact of chronic hepatitis C infection on cholesterol metabolism in PBMCs is associated with microRNA-146a expression.

Chronic hepatitis C (CHC) infection is known to induce important changes in host cholesterol metabolism. MicroRNAs (miRNAs) regulate the expression of many genes and, in consequence, control various processes, including human metabolism and response to viral infection. Recently, the alteration of the immune-associated miR-146a, which is abundantly present in peripheral blood mononuclear cells (PBMCs), was found in some viral infections. The study aimed to analyse the influence of hepatitis C virus (HCV) infection on miR-146a expression in PBMCs in vivo and in vitro, as well as to assess the possible impact of miR-146a alteration on the intracellular cholesterol level in PBMCs. Blood samples collected from 42 healthy donors and 72 CHC patients were the source of materials. HCV RNA, intracellular cholesterol level and miR-146a expression were determined in PBMCs, as well as HCV genotype and interferon (IFN)α concentration in sera. The influence of miR-146a inhibition on cholesterol expression in PBMCs was analysed in vitro after transient cell transfections with mirVana™ anti-miR-146a Inhibitor. Our data demonstrated an alteration of miR-146a and intracellular cholesterol expression in PBMCs and of IFNα concentration in sera of genotype 1, HCV-infected patients compared to the healthy donors. Also, in cultured PBMCs, miR-146a expression and intracellular cholesterol level were significantly decreased in CHC patients compared to the healthy donors. In vitro blockage of miR-146a expression in PBMCs of CHC patients greatly impaired intracellular cholesterol expression. In these conditions, miR-146a expression was positively correlated with the intracellular cholesterol level. These results suggest that genotype 1 HCV infection may alter miR-146a expression in PBMCs and, consequently, contribute to the observed dysregulation of cholesterol synthesis.

Interactions between smoking, increased serum levels of anti-CCP antibodies, rheumatoid factors, and erosive joint disease in patients with early, untreated rheumatoid arthritis.

OBJECTIVES: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset. METHOD: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity. RESULTS: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6-9.3], IgM-RF (OR 4.9, 95% CI 1.9-12), and IgA-RF (OR 2.8, 95% CI 1.2-6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes. CONCLUSIONS: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.

Chronic fatigue in Hodgkin lymphoma survivors and associations with anxiety, depression and comorbidity.

BACKGROUND: Fatigue is a frequent and persistent problem among Hodgkin lymphoma (HL) survivors. We investigated the prevalence of clinically relevant fatigue in HL survivors and the relation between fatigue and anxiety and depression. METHODS: Fatigue was measured through the generic European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and Fatigue Assessment Scale (FAS). Anxiety and depression were measured with the Hospital Anxiety and Depression Scale. Questionnaires were mailed to 267 HL survivors. Results were compared with a Dutch age-matched normative population. RESULTS: Response rate was 68% (median age 46 years, mean time since diagnosis 4.6 years). Prevalence of fatigue was significantly higher among HL survivors than in the norm population (FAS 41% vs 23%, QLQ-C30 43% vs 28%), as were fatigue levels. There was a significant association between fatigue, anxiety and depression. Of the HL survivors with high symptom levels of depression, 97% also reported fatigue. In multivariate analysis, depression was strongly associated with high levels of fatigue and, to a lesser extent, anxiety and comorbidity. CONCLUSIONS: Prevalence rates of fatigue are significantly higher in HL survivors than in the general population and differences are clinically relevant. Depression and anxiety were strongly associated with high levels of fatigue. Reducing fatigue levels by treatment of depression and anxiety should be further explored.

Screening for coronary artery disease after mediastinal irradiation in Hodgkin lymphoma survivors: phase II study of indication and acceptance†.

BACKGROUND: Cardiovascular diseases are the most common nonmalignant cause of death in Hodgkin lymphoma (HL) survivors, especially after mediastinal irradiation. We investigated the role of computed tomographic coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, and related CTA findings to exercise testing and subsequent interventions. PATIENTS AND METHODS: Patients were eligible for this phase II study if at least 10 years disease-free and treated with mediastinal radiotherapy. Screening consisted of electrocardiogram, exercise testing and CTA. Primary end point was significant CAD (stenosis >50%) on CTA. CTA screening was considered to be indicated for testing in a larger population if ≥6 of 50 CTA scanned patients (12%) would need revascularization. Screening was evaluated with a questionnaire before and after screening. RESULTS: Fifty-two patients were included, and 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. There were 45 evaluable scans. Significant CAD on CTA was found in 20% (N = 9), significantly increased compared with the 7% expected abnormalities (P = 0.01, 95% confidence interval 8.3% to 31.7%). In 11% (N = 5), significant stenosis was confirmed at coronary angiography, and revascularization was carried out. Additionally, two patients were treated with optimal medical therapy. Ninety percent of patients were content with screening, regardless whether the CTA showed abnormalities. CONCLUSIONS: Prevalence of significant CAD among HL survivors is high, while asymptomatic even in the presence of life-threatening CAD. This might justify screening by CTA in asymptomatic HL survivors who had mediastinal radiotherapy, but needs to be evaluated in a larger cohort. The trial protocol was approved by the Ethics Committee of the LUMC and registered with ClinicalTrials.gov, NCT01271127.

Incidence and centralization of chordoma in the Netherlands: A nationwide study between 1991 and 2020.

INTRODUCTION: Chordomas are rare malignant bone tumors arising in the axial skeleton, with an incidence of 0.3-0.88 per million inhabitants. We studied the annual incidence rate and centralization of treatment for chordoma in the Netherlands. METHODS: We retrieved pathology excerpts from the PALGA nationwide Dutch Pathology Registry between 1991 and 2019 for patients with a chordoma to calculate incidence rates. From pathology reports we extracted patient age at diagnosis, sex, year of diagnosis, localization of primary tumor, histologic chordoma subtype (conventional including chondroid, poorly differentiated or dedifferentiated), center of diagnosis (bone tumor referral center (BTC) or other hospital), and partial identification of the BTCs. RESULTS: A total of 420 individual chordoma patients were identified in the given time period. The incidence of chordoma increased from 0.593 per million inhabitants between 1991-1995 to 1.111 from 2015-2019 (P = 0.001). Median age at diagnosis was 63 years (range 1-95), 252 patients (60%) were male. The proportion of samples analyzed in a BTC either primarily or secondary, as a consultation, revision or referral, increased significantly from 29.3% to 84.4% (P < 0.001). Most primary and secondary samples were analyzed at the Leiden University Medical Center (LUMC, 54.4% and 57% respectively). CONCLUSIONS: This study shows an increase in the standardized incidence of pathology proven chordoma in the Netherlands. We observed an increase in samples being analysed in the specialized BTCs as well, which is in line with current guidelines and will hopefully lead to more accurate diagnoses and optimal treatment plans for chordoma patients in specialized treatment centers.

Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors.

BACKGROUND: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.

Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development.

BACKGROUND: The RASopathies are a class of human genetic syndromes caused by germline mutations in genes that encode protein components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Costello syndrome (CS) is a RASopathy caused by mutations in the HRAS gene, a key regulator of signal transduction. OBJECTIVE: To quantify the specific cutaneous phenotype observed in 46 individuals with Costello syndrome with confirmed HRAS mutations. METHODS: This was a cross-sectional study. Dermatological surveys were designed by the authors and were completed by parents of mutation-positive individuals with CS at the Costello Syndrome Family Network (CSFN) conferences in 2007 and 2009. Dermatological examinations were performed by the authors at the CSFN conferences. RESULTS: Cutaneous papillomas were reported in 33 of the 46 (72%) participants, with age of onset ranging from infancy to 22years. Individuals with CS are more likely than patients with cardiofaciocutaneous syndrome (CFC) to present with cutaneous papillomas (72% vs. 5%, P<0·001) and palmoplantar keratoderma (76% vs. 36%, P<0·001). Individuals with CS are less likely than individuals with CFC to present with sparse or absent eyebrows (9% vs. 90%, P<0·001) or keratosis pilaris (33% vs. 80%, P=0·001). This study also identified that loose, redundant skin on the hands and feet, 'stippled' dermatoglyphs (pachydermatoglyphia) on the fingertips (eight of 26, 31%) and acanthosis nigricans (17 of 46, 37%) are frequent features of CS. CONCLUSIONS: While there is significant phenotypic overlap among syndromes of the Ras/MAPK pathway, individuals with CS are more likely than individuals with CFC syndrome to present with cutaneous papillomas, palmoplantar keratoderma and full eyebrows, and are less likely to present with ulerythema ophryogenes, keratosis pilaris or multiple naevi. The dermatological features of CS, a Ras dysregulation syndrome, share many features with cutaneous paraneoplastic syndromes. This may provide further insight into the role of Ras signalling in cutaneous paraneoplastic syndromes.

Evaluation of novel genetic algorithm generated schemes for positron emission tomography (PET)/magnetic resonance imaging (MRI) image fusion.

The use and benefits of a multimodality approach in the context of breast cancer imaging are discussed. Fusion techniques that allow multiple images to be viewed simultaneously are discussed. Many of these fusion techniques rely on the use of color tables. A genetic algorithm that generates color tables that have desired properties such as satisfying the order principle, the rows, and columns principle, have perceivable uniformity and have maximum contrast is introduced. The generated 2D color tables can be used for displaying fused datasets. The advantage the proposed method has over other techniques is the ability to consider a much larger set of possible color tables, ensuring that the best one is found. We asked radiologists to perform a set of tasks reading fused PET/MRI breast images obtained using eight different fusion techniques. This preliminary study clearly demonstrates the need and benefit of a joint display by estimating the inaccuracies incurred when using a side-by-side display. The study suggests that the color tables generated by the genetic algorithm are good choices for fusing MR and PET images. It is interesting to note that popular techniques such as the Fire/Gray and techniques based on the HSV color space, which are prevalent in the literature and clinical practice, appear to give poorer performance.

[An immediate removable complete denture for the transition from a natural to a prosthetic occlusal system]. / Een immediate volledige gebitsprothese voor de overgang van een natuurlijk naar een prothetisch occlusiesysteem.

During the process of losing teeth, the fabrication of an immediate removable complete denture usually plays an important role. The path from a natural to a prosthetic occlusal system separates itself into a phased and a non-phased treatment. Various patient-related factors are of importance in the decision-making process for a phased or a non-phased treatment, such as the patient's time available, the medical indication, the complexity of the natural occlusal system, and the motivation for treatment. A positive result can be more confidently predicted in the case of a phased treatment than a non-phased treatment. Placement of an immediate removable complete denture requires immediate aftercare. Particularly in the case of non-phased treatment, the fabrication of a new complete removable denture will be required within 1 year.

LEDs Make It Resilient: Effects on Plant Growth and Defense.

Light spectral composition influences plant growth and metabolism, and has important consequences for interactions with plant-feeding arthropods and their natural enemies. In greenhouse horticulture, light spectral composition can be precisely manipulated by light-emitting diodes (LEDs), and LEDs are already used to optimize crop production and quality. However, because light quality also modulates plant secondary metabolism and defense, it is important to understand the underlying mechanisms in the context of the growth-defense trade-off. We review the effects of the spectral composition of supplemental light currently used, or potentially used, in greenhouse horticulture on the mechanisms underlying plant growth and defense. This information is important for exploring opportunities to optimize crop performance and pest management, and thus for developing resilient crop-production systems.

Determinants of late HIV diagnosis among different transmission groups in Finland from 1985 to 2005.

OBJECTIVES: To study determinants of late HIV diagnosis in a low-HIV-prevalence (<0.1%) country where HIV spread among men who have sex with men (MSM) and heterosexuals in the 1980s, and among injecting drug users (IDUs) in the late 1990s. METHODS: Newly diagnosed HIV cases referred to the Helsinki University Central Hospital between 1985 and 2005 were reviewed to identify determinants of late HIV diagnosis, defined as diagnosis when the first CD4 count was <200 cells/microL, or when AIDS occurred within 3 months of HIV diagnosis. Determinants of late diagnosis were analysed using multivariate logistic regression. RESULTS: Among 934 HIV cases, 211 (23%) were diagnosed late. In the first 4-year interval of each sub-epidemic (1985-1989 for MSM and heterosexuals, 1998-2001 for IDUs), rates of late HIV diagnosis were 13%, 18% and 6%, respectively, but increased thereafter to 29%, 27% and 37%. Late diagnosis was associated with non-Finnish ethnicity, older age, male gender, lack of earlier HIV testing, diagnosis at health care settings and later stage of the sub-epidemic. CONCLUSIONS: The lower rate of late diagnosis in the first 4-year interval of each HIV sub-epidemic suggests that the early stages of the HIV epidemic in Finland were detected early. This factor may have contributed to the low prevalence of HIV infection in Finland. The stage and age of the epidemic should be taken into account when interpreting the data on late HIV diagnosis, especially in cross-country comparisons.

Ex vivo correction of selenoprotein N deficiency in rigid spine muscular dystrophy caused by a mutation in the selenocysteine codon.

Premature termination of translation due to nonsense mutations is a frequent cause of inherited diseases. Therefore, many efforts were invested in the development of strategies or compounds to selectively suppress this default. Selenoproteins are interesting candidates considering the idiosyncrasy of the amino acid selenocysteine (Sec) insertion mechanism. Here, we focused our studies on SEPN1, a selenoprotein gene whose mutations entail genetic disorders resulting in different forms of muscular diseases. Selective correction of a nonsense mutation at the Sec codon (UGA to UAA) was undertaken with a corrector tRNA(Sec) that was engineered to harbor a compensatory mutation in the anticodon. We demonstrated that its expression restored synthesis of a full-length selenoprotein N both in HeLa cells and in skin fibroblasts from a patient carrying the mutated Sec codon. Readthrough of the UAA codon was effectively dependent on the Sec insertion machinery, therefore being highly selective for this gene and unlikely to generate off-target effects. In addition, we observed that expression of the corrector tRNA(Sec) stabilized the mutated SEPN1 transcript that was otherwise more subject to degradation. In conclusion, our data provide interesting evidence that premature termination of translation due to nonsense mutations is amenable to correction, in the context of the specialized selenoprotein synthesis mechanism.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.