[Allergenic and chemical pollutants of indoor environments and asthma: Characterization, assessment and eviction]. / Polluants allergéniques et chimiques de l'environnement intérieur et asthme : caractérisation, évaluation et éviction.

The environment of an asthmatic patient can contain numerous sources of pollutants that degrade the quality of indoor air and have major repercussions on the occurrence and control of asthma. Assessment and improvement of the quality of indoor air should be assigned a major role in pneumology and allergology consultations. Characterization of an asthmatic's environment entails a search for biological pollutants with mite allergens, mildew, and allergens resulting from the proximity of pets. It is important to evaluate the chemical pollution represented by exposure to volatile organic compounds, which are increasingly present in our lodgings. Active or second-hand smoking must in all circumstances be sought out and quantified. Assessment of the environment is mediated by several methods, of which the application depends not only on the pollutant sought out, but also on enzyme-linked immunosorbent assay (ELISA), which has an essential role in quantification of biological pollutants. Attempts at expulsion of the different indoor environment pollutants is mediated by indoor environment advisors, whose efforts are aimed at obtaining reliable evaluation and control of indoor air. Implemented as a form of tertiary prevention, their methods are conducive to improved asthma control, in adults as well as children.

Thromboelastography utilization for dabigatran reversal in a patient with acute kidney injury.

PURPOSE: This case report describes utilization of thromboelastography (TEG) in the setting of an acute major bleed in a patient on dabigatran who had concomitant acute kidney injury. SUMMARY: An 80-year-old female presented to the emergency department after a fall with complaints of pain in her knee, shoulder, and hip. Her medical history was significant for coronary artery disease, for which she took clopidogrel 75 mg daily, and atrial fibrillation, for which she took dabigatran 150 mg twice daily. The physical exam was remarkable for pain within the shoulder, hip, and knee, which had swelling and ecchymosis that extended into the right thigh. Given the possibility of compartment syndrome with multiple possible etiologies of coagulopathy, TEG and computed tomography angiography (CTa) of the right lower extremity were performed. The initial TEG showed prolonged R time and activated clotting time, indicating clotting factor dysfunction with no additional coagulopathy noted, including antiplatelet effects. On the basis of the TEG and CTa findings, it was decided to reverse dabigatran with 5 grams of idarucizumab. Approximately 1 hour after administration of idarucizumab, the patient was taken to interventional radiology where a limited angiogram of the right lower extremity showed no active extravasation. Because of the patient's renal dysfunction and the possibility of rebound hypercoaguability, repeat TEG tests were ordered at 4 and 8 hours after the initial reversal to ensure clearance of idarucizumab-dabigatran complexes. The repeat TEG values showed complete reversal of the initial coagulopathy noted. During the admission, the patient required no blood transfusions or surgical interventions and all her initial laboratory results improved. CONCLUSION: Serial TEG testing was successful at managing multiple coagulopathies in a patient at risk for trauma-induced compartment syndrome.

The "Burkitt-like" immunophenotype and genotype is rarely encountered in diffuse large B cell lymphoma and high-grade B cell lymphoma, NOS.

Burkitt lymphoma (BL) is a B cell lymphoma composed of monomorphic medium-sized blastic cells with basophilic cytoplasm and a high proliferation index. BL has a characteristic immunophenotype of CD10 and BCL6 positive and BCL2 negative and harbours MYC gene rearrangements (MYCR) in >90% of the cases. Owing to its highly aggressive nature, intensified chemotherapy regimens are usually administered, requiring an exact diagnosis. Since the diagnosis usually warrants an integration of morphologic, immunophenotypic and genetic findings and because there is a morphologic overlap with the new WHO category of high-grade B cell lymphoma, not otherwise specified (HGBL, NOS) and some cases of diffuse large B cell lymphoma (DLBCL), we wanted to test the distinctiveness of the CD10+, BCL6+, BCL2- and MYCR positive immunopheno-genotype in a large cohort of >1000 DLBCL and HGBL. Only 9/982 DLBCL classified by an expert panel of haematopathologists (0.9%) displayed a single MYCR and were CD10+, BCL6+ and BCL2-. In a similar fashion, only one out of 32 HGBL, NOS (3%) displayed the "Burkitt-like" genetic/immunophenotypic constitution. The samples of non-BL showing the BL-typic immunopheno-genotype, interestingly, harboured higher copy number variations (CNV) by OncoScan analysis (mean 7.3 CNVs/sample; range: 2-13 vs. 2.4; range 0-6) and were also distinct from pleomorphic BL cases regarding their mutational spectrum by NGS analysis. This implies that the characteristic immunophenotype of BL, in concert with a single MYCR, is uncommon in these aggressive lymphomas, and that this constellation favours BL.

[Possibilities of application of cardio-ankle vascular index in patients with cerebrovascular diseases]. / Vozmozhnosti primeneniya serdechno-lodyzhechnogo sosudistogo indeksa u bol'nykh s tserebrovaskulyarnymi zabolevaniyami.

This publication focuses on the feasibility of using the cardio-ankle vascular index (CAVI) in patients with cerebrovascular diseases. The authors consider the pathological conditions and risk factors of stroke associated with increased arterial stiffness, methods for its assessment, the advantages of using CAVI, the experience of using CAVI in patients with cardiovascular diseases, in particular, in neurological patients. The complexity of the application of CAVI in the Russian population, promising directions for determining the index in neurology as well as the importance of CAVI borderline indicators are shown. It is emphasized that stroke patients should be screened with a mandatory study of CAVI.

Randomized multicenter trial on percutaneous versus open access in endovascular aneurysm repair (PiERO).

BACKGROUND: In endovascular valve and aortic repair, vascular access through a percutaneous approach has become the competing technique to an open surgical approach. The effect on postoperative complications and surgical site infections (SSIs) has been investigated, but randomized evidence is lacking. The objective was to investigate whether percutaneous access of the common femoral artery (CFA) with a percutaneous closure device would decrease the number of SSIs compared with open surgical access of the CFA in endovascular aneurysm repair (EVAR). METHODS: Patients with an abdominal aortic aneurysm suitable for EVAR were randomized to open or percutaneous access of the main device (MD) through the CFA. Through the contralateral side, access was obtained with the other technique than the one for which the MD was randomized. The primary outcome was number of SSIs. Secondary outcomes were wound complications, visual analog scale for pain scores, and standardized wound assessment scores during follow-up. Preoperative screening culture and groin biopsy specimens were obtained from all patients. RESULTS: Both groups contained 137 groins. SSI rate was 1.5% in the open group vs 0% in the percutaneous group. For MDs only, SSI rate was 3.1% (odds ratio, 3.3; 95% confidence interval, 0.31-347; P = .34). Wound complications were comparable in both groups. Neither nasal nor groin Staphylococcus aureus carriage had a significant effect on SSIs, Southampton Wound Assessment score, or visual analog scale score. Adjusted pain score was 0.69 lower, in favor of percutaneous access. Wound assessment was better after 2 weeks (odds ratio, 3.57; 95% confidence interval, 1.02-12.44; P = .046), also in favor of percutaneous access. CONCLUSIONS: Percutaneous access of the CFA does not reduce the number of SSIs. It does, however, reduce pain and improve wound healing with less inflammation 1 day and 2 weeks after EVAR, respectively.

[The relationship of pathological ankle-brachial index and cognitive decline in patients after ischemic stroke]. / Sviaz' lodyzhechno-plechevogo indeksa i kognitivnykh narushenii u bol'nykh, perenesshikh ishemicheskii insul't.

AIM: To identify associations between cognitive impairment and values of ankle-brachial index (ABI) in patients after ischemic stroke at discharge from the hospital and over one-year follow-up. MATERIAL AND METHODS: The study included 375 patients with normal (n=192) and elevated (n=153) ABI who underwent ischemic stroke (IS). Neurological examination was performed using NIHSS, the Rankin scale, Barthel index, Rivermead Mobility Index at discharge from the hospital and over one-year follow-up. RESULTS AND CONCLUSION: Patients with elevated ABI had marked cognitive impairment and more severe neurological deficit compared to patients with normal ABI. Evaluation of ABI can help in predicting the development of post-stroke cognitive impairment in patients with IS.

Council of Europe Black Sea Area Project: International Cooperation for the Development of Activities Related to Donation and Transplantation of Organs in the Region.

BACKGROUND: In 2011, the European Directorate for the Quality of Medicines & Healthcare of the Council of Europe launched a 3-year collaborative project to address the organ shortage and improve access to transplant health services in Council of Europe member states in the Black Sea area (Armenia, Azerbaijan, Bulgaria, Georgia, Moldova, Romania, Turkey, Ukraine, and the Russian Federation) through the development of safe and ethical donation and transplantation programs. OBJECTIVE: Support the development of donation and transplantation programs through close interstate cooperation between national health organizations and relevant stakeholders. METHODOLOGY: Several work packages (WP) were established: WP1, project coordination (European Directorate for the Quality of Medicines & Healthcare); WP2, development and implementation of an effective legislative and financial framework (Czech Republic and France); WP3, establishment of National Transplant Authorities (Italy and Portugal); and WP4, clinical practices (DTI Foundation). Data collection, surveys, and expert visits allowed for the collection of first-hand information from each participant country at national, regional, and hospital levels. RESULTS: Data analysis showed the positive impact of the project represented by a tendency to increase the total donation rates (per million people) in the participant countries (2011 vs 2013): Azerbaijan, +7.3; Armenia, -0.7; Georgia, +3.3; Bulgaria, +0.9; Moldova, +2.5; Ukraine:, +0.8; Romania, +2.3; and Turkey, +2.7. CONCLUSIONS: Increases in total donation rates are the result of a number of initiatives in the Black Sea area, including the stepwise implementation of legislative, organizational and institutional country-specific recommendations tailored by the CoE, efforts of the respective Ministries of Health in each country and synergism with other European projects in the region. These countries should invest further in implementing the recommendations that emerged from this project to improve their organ donation and transplantation programs and progress toward self-sufficiency.

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

BACKGROUND: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. PATIENTS AND METHODS: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. RESULTS: Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, -34.6%; 1400 mg, -41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response. CONCLUSIONS: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT01046266 (ClinicalTrials.gov).

[Stenosis of the carotid artery in women with ischemic stroke and markers of inflammation]. / Stenozy karotidnykh arterii u zhenshchin s ishemicheskim insul'tom i markery vospaleniia.

AIM: To assess the relationship between the severity of stenosis of the carotid arteries, the level of female sex hormones and markers of subclinical inflammation in women with ischemic stroke (IS). MATERIAL AND METHODS: Two hundred and eleven women (mean age 68.9±9.23 years) were examined. A history of cardiovascular disease, previous cardiovascular events, type and subtype of stroke were recorded. Neurological status was assessed using neurological scales. Atherosclerosis was diagnosed by color duplex scanning of brachiocephalic arteries and laboratory testing (estradiol, markers of subclinical inflammation). RESULTS: Carotid artery stenosis of ≥50% was found in 13.3% of patients, less severe stenosis in 36.0%. Stenosis of ≥50% was positively correlated with the level of IL-18, TNF-alpha, and negatively correlated with the level of IL-6, IL-4, and MMSE score. In dynamics, there was a decrease in the level of TNF-alpha in all groups of patients, and an increase in the IL-4 level in women with carotid artery stenosis of ≥50%. CONCLUSION: Study of the influence of markers of subclinical inflammation on the atherosclerosis progression and recurrent disorders of cerebral circulation in women with IS should be continued.

[Clinical significance of the cardio-ankle vascular index in patients with stroke]. / Klinicheskoe znachenie otsenki serdechno-lodyzhechnogo sosudistogo indeksa u bol'nykh s ostrym narusheniem mozgovogo krovoobrashcheniya.

AIM: To study the clinical significance of the cardio-ankle vascular index (CAVI) in patients with stroke. MATERIAL AND METHODS: The study included 374 post-stroke patients. The state of peripheral arteries was assessed using CAVI and the ankle-shoulder index (ASI). RESULTS AND CONCLUSION: The pathological CAVI (>9.0) was identified in 45.4% patients, the reduced ASI (<0.9) in 19.8% patients. Stressful factors of daily life, hypodynamia, lack of work, low education were characteristic of the patients with pathological CAVI and ASI compared to those with normal CAVI. The frequency of diabetes mellitus, clinical signs of peripheral atherosclerosis, chronic heart failure and atrial fibrillation was higher in these patients as well. Ischemic stroke was more frequent in patients with peripheral atherosclerosis and higher vascular wall rigidity. Assessments of CAVI and ASI are necessary in patients with ischemic stroke to identify those with higher vascular wall rigidity and peripheral atherosclerosis and to undertake targeted preventive measures.

Simvastatin-doped pre-mixed calcium phosphate cement inhibits osteoclast differentiation and resorption.

Simvastatin, a cholesterol lowering drug, has been shown to have positive effects on fracture healing and bone regeneration based on its dual effect; bone anabolic and anti-resorptive. In this study the focus has been on the anti-resorptive effect of the drug and its impact on the degradation of acidic calcium phosphate cement. The drug was added to the pre-mixed acidic cement in three different doses (0.1, 0.25 and 0.5 mg/g cement) and the release was measured. Furthermore the effect of the loaded cements on osteoclast differentiation and resorption was evaluated by TRAP activity, number of multinucleated cells, gene expression and calcium ion concentration in vitro using murine bone marrow macrophages. The simvastatin did not affect the cell proliferation while it clearly inhibited osteoclastic differentiation at all three doses as shown by TRAP staining, TRAP activity and gene expression. Consistent with these results, simvastatin also impaired resorption of cements by osteoclasts as indicated by reduced calcium ion concentrations. In conclusion, our findings suggest that simvastatin-doped pre-mixed acidic calcium phosphate cement inhibits the osteoclastic mediated resorption of the cement thus slowing down the degradation rate. In addition with simvastatin's bone anabolic effect it makes the cement-drug combination a promising bone graft material, especially useful for sites with compromised bone formation.

Comparison of a quasi-dynamic and a static extraction method for the cytotoxic evaluation of acrylic bone cements.

In this study, two different extraction approaches were compared in order to evaluate the cytotoxicity of 7 different acrylic bone cements, mainly developed for spinal applications, to osteoblastic cells. Firstly, a static extraction was carried out continuously over 24h, a method widely used in literature. Secondly, a quasi-dynamic extraction method that allowed the investigation of time-dependent cytotoxic effects of curing acrylic bone cements to cells was introduced. In both cases the extraction of the cements was started at a very early stage of the polymerization process to simulate the conditions during clinical application. Data obtained by the quasi-dynamic extraction method suggest that the cytotoxicity of the setting materials mainly originates from the release of toxic components during the first hour of the polymerization reaction. It was also shown that a static extraction over 24h generally represents this initial stage of the curing process. Furthermore, compared to the static extraction, time-dependent cytotoxicity profiles could be detected using the quasi-dynamic extraction method. Specifically, a modification of commercial OsteopalV with castor oil as a plasticizer as well as a customized cement formulation showed clear differences in cytotoxic behavior compared to the other materials during the setting process. In addition, it was observed that unreacted monomer released from the castor oil modified cement was not the main component affecting the toxicity of the material extracts. The quasi-dynamic extraction method is a useful tool to get deeper insight into the cytotoxic potential of curing acrylic bone cements under relevant biological conditions, allowing systematic optimization of materials under development.

Double-lumen tubes and auto-PEEP during one-lung ventilation.

BACKGROUND: Double-lumen tubes (DLT) are routinely used to enable one-lung-ventilation (OLV) during thoracic anaesthesia. The flow-dependent resistance of the DLT's bronchial limb may be high as a result of its narrow inner diameter and length, and thus potentially contribute to an unintended increase in positive end-expiratory pressure (auto-PEEP). We therefore studied the impact of adult sized DLTs on the dynamic auto-PEEP during OLV. METHODS: In this prospective clinical study, dynamic auto-PEEP was determined in 72 patients undergoing thoracic surgery, with right- and left-sided DLTs of various sizes. During OLV, air trapping was provoked by increasing inspiration to expiration ratio from 1:2 to 2:1 (five steps). Based on measured flow rate, airway pressure (Paw) and bronchial pressure (Pbronch), the pressure gradient across the DLT (ΔPDLT) and the total auto-PEEP in the respiratory system (i.e. the lungs, the DLT and the ventilator circuit) were determined. Subsequently the DLT's share in total auto-PEEP was calculated. RESULTS: ΔPDLT was 2.3 (0.7) cm H2O over the entire breathing cycle. At the shortest expiratory time the mean total auto-PEEP was 2.9 (1.5) cm H2O (range 0-5.9 cm H2O). The DLT caused 27 to 31% of the total auto-PEEP. Size and side of the DLT's bronchial limb did not impact auto-PEEP significantly. CONCLUSIONS: Although the DLT contributes to the overall auto-PEEP, its contribution is small and independent of size and side of the DLT's bronchial limb. The choice of DLT does not influence the risk of auto-PEEP during OLV to a clinically relevant extent. CLINICAL TRIAL REGISTRATION: DRKS00005648.

Adapting ethical guidelines for adolescent health research to street-connected children and youth in low- and middle-income countries: a case study from western Kenya.

BACKGROUND: Street-connected children and youth (SCCY) in low- and middle-income countries (LMIC) have multiple vulnerabilities in relation to participation in research. These require additional considerations that are responsive to their needs and the social, cultural, and economic context, while upholding core ethical principles of respect for persons, beneficence, and justice. The objective of this paper is to describe processes and outcomes of adapting ethical guidelines for SCCY's specific vulnerabilities in LMIC. METHODS: As part of three interrelated research projects in western Kenya, we created procedures to address SCCY's vulnerabilities related to research participation within the local context. These consisted of identifying ethical considerations and solutions in relation to community engagement, equitable recruitment, informed consent, vulnerability to coercion, and responsibility to report. RESULTS: Substantial community engagement provided input on SCCY's participation in research, recruitment, and consent processes. We designed an assent process to support SCCY to make an informed decision regarding their participation in the research that respected their autonomy and their right to dissent, while safeguarding them in situations where their capacity to make an informed decision was diminished. To address issues related to coercion and access to care, we worked to reduce the unequal power dynamic through street outreach, and provided access to care regardless of research participation. CONCLUSIONS: Although a vulnerable population, the specific vulnerabilities of SCCY can to some extent be managed using innovative procedures. Engaging SCCY in ethical research is a matter of justice and will assist in reducing inequities and advancing their health and human dignity.

Resorption of monetite calcium phosphate cement by mouse bone marrow derived osteoclasts.

Recently the interest for monetite based biomaterials as bone grafts has increased; since in vivo studies have demonstrated that they are degradable, osteoconductive and improve bone healing. So far osteoclastic resorption of monetite has received little attention. The current study focuses on the osteoclastic resorption of monetite cement using primary mouse bone marrow macrophages, which have the potential to differentiate into resorbing osteoclasts when treated with receptor activator NF-κB ligand (RANKL). The osteoclast viability and differentiation were analysed on monetite cement and compared to cortical bovine bone discs. After seven days live/dead stain results showed no significant difference in viability between the two materials. However, the differentiation was significantly higher on the bone discs, as shown by tartrate resistant acid phosphatase (TRAP) activity and Cathepsin K gene expression. Moreover monetite samples with differentiated osteoclasts had a 1.4 fold elevated calcium ion concentration in their culture media compared to monetite samples with undifferentiated cells. This indicates active resorption of monetite in the presence of osteoclasts. In conclusion, this study suggests that osteoclasts have a crucial role in the resorption of monetite based biomaterials. It also provides a useful model for studying in vitro resorption of acidic calcium phosphate cements by primary murine cells.

Zebrafish: A possible tool to evaluate bioactive ions.

Zebrafish is a well-established model organism with a skeletal structure that highly resembles mammalian bone. Yet its use in the research field of biomaterials has been limited. One area that could benefit from this model system is the evaluation of ionic dissolution products from different materials. As a proof of concept we have evaluated the effect of silicate ions on the zebrafish larvae and compared it to a well-known osteoblastic cell line, MC3T3-E1 subclone 14. We have shown that sodium metasilicate (125 µM and 625 µM) induces more mineralisation in a dose-dependent manner in zebrafish larvae, 9 days post fertilisation as compared to the non-treated group. Moreover the same trends were seen when adding sodium metasilicate to MC3T3-E1 cultures, with more mineralisation and higher ALP levels with higher doses of silicate (25, 125 and 625 µM). These results indicate the feasibility of zebrafish larvae for ionic dissolution studies. The zebrafish model is superior to isolated cell cultures in the aspect that it includes the whole bone remodelling system, with osteoblasts, osteoclasts and osteocytes. Zebrafish could thus provide a powerful in vivo tool and be a bridge between cell culture systems and mammalian models.

Peripheral chemoreceptors tune inspiratory drive via tonic expiratory neuron hubs in the medullary ventral respiratory column network.

Models of brain stem ventral respiratory column (VRC) circuits typically emphasize populations of neurons, each active during a particular phase of the respiratory cycle. We have proposed that "tonic" pericolumnar expiratory (t-E) neurons tune breathing during baroreceptor-evoked reductions and central chemoreceptor-evoked enhancements of inspiratory (I) drive. The aims of this study were to further characterize the coordinated activity of t-E neurons and test the hypothesis that peripheral chemoreceptors also modulate drive via inhibition of t-E neurons and disinhibition of their inspiratory neuron targets. Spike trains of 828 VRC neurons were acquired by multielectrode arrays along with phrenic nerve signals from 22 decerebrate, vagotomized, neuromuscularly blocked, artificially ventilated adult cats. Forty-eight of 191 t-E neurons fired synchronously with another t-E neuron as indicated by cross-correlogram central peaks; 32 of the 39 synchronous pairs were elements of groups with mutual pairwise correlations. Gravitational clustering identified fluctuations in t-E neuron synchrony. A network model supported the prediction that inhibitory populations with spike synchrony reduce target neuron firing probabilities, resulting in offset or central correlogram troughs. In five animals, stimulation of carotid chemoreceptors evoked changes in the firing rates of 179 of 240 neurons. Thirty-two neuron pairs had correlogram troughs consistent with convergent and divergent t-E inhibition of I cells and disinhibitory enhancement of drive. Four of 10 t-E neurons that responded to sequential stimulation of peripheral and central chemoreceptors triggered 25 cross-correlograms with offset features. The results support the hypothesis that multiple afferent systems dynamically tune inspiratory drive in part via coordinated t-E neurons.

Diffuse large B-cell lymphomas of immunoblastic type are a major reservoir for MYC-IGH translocations.

The immunoblastic variant of diffuse large B-cell lymphoma (IB-DLBCL) has recently been recognized as an aggressive lymphoma type with inferior prognosis as compared with other DLBCL variants. At the same time, the presence of MYC rearrangements in DLBCL has been shown to indicate shorter survival in R-CHOP-treated patients. In this study, we investigated the occurrence of MYC gene rearrangements in IB-DLBCL versus non-IB-DLBCL in a large series. Using fluorescence in situ hybridization with an MYC break-apart and MYC-IGH fusion probe, we found that 13/39 evaluable IB-DLBCLs (33%) harbor translocations involving MYC, in contrast with only 5/68 (7%) in the non-IB-DLBCL group (P<0.01). The immunoglobulin heavy chain gene (IGH) was the translocation partner in all rearrangements (100%) involving MYC in IB-DLBCL, which is in contrast to what has been reported for DLBCL in the literature (50% to 70%). Moreover, MYC rearrangements occurred as the sole translocation in the majority of cases (77%), whereas across all DLBCLs the majority of MYC-rearranged cases carry additional rearrangements of either BCL2 and/or BCL6 genes (between 58% and 83% of cases). Finally, MYC-rearranged IB-DLBCLs were CD10 positive in 62% (8/13), whereas this was an uncommon feature in MYC germline IB-DLBCLs (15%). In conclusion, IB-DLBCLs are genetically characterized by frequent MYC-IGH translocations that often occur without additional BCL2 and/or BCL6 translocations. The activation of MYC, therefore, may be an important pathogenetic feature in IB-DLBCL.

Fluorescence in situ analysis of soft tissue tumor associated genetic alterations in formalin-fixed paraffin-embedded tissue.

No prospective studies are available to date evaluating the combined analysis of chromosomal alterations via interphase FISH in different soft tissue sarcoma (STS) subtypes. We tested 64 consecutive sarcoma specimens with FISH probes to detect aberrations specific for a given STS subtype. We first determined the translocation frequency in the specific STS subtypes in 48 tumors, with the primary pathological diagnosis as the gold standard. Subsequently, to evaluate sensitivity and specificity, all FISH probes were hybridized to 16 STS of hitherto unknown diagnosis. DDIT3 translocations occurred in 8/10 (80%) of myxoid liposarcomas. FOXO1 translocations were noted in 4/4 (100%) of alveolar but in none of 7 embryonal rhabdomyosarcomas. All 15 (100%) Ewing sarcomas/PNET and 4 clear cell sarcomas (4/4) harbored EWSR1 translocations. SS18 rearrangements were demonstrated in 8/9 (89%) synovial sarcomas. MDM2 amplification was noted in 7/8 (88%) atypical lipomatous tumors/well-differentiated and 3/3 (100%) dedifferentiated liposarcomas, respectively, but not in four pleomorphic liposarcomas. Sensitivities and specificities ranged from 80% to 100% and from 93% to 100%, respectively, with the highest values observed for FOXO1 (100% each). We conclude, therefore, that is possible to accurately predict the STS subtype using a panel of different subtype-specific FISH probes, thereby greatly facilitating the differential diagnosis of these tumors.