Capturing the Shear and Secondary Compression Waves: High-Frame-Rate Ultrasound Imaging in Saturated Foams.

We experimentally observe the shear and secondary compression waves inside soft porous water-saturated melamine foams by high-frame-rate ultrasound imaging. Both wave speeds are supported by the weak frame of the foam. The first and second compression waves show opposite polarity, as predicted by Biot theory. Our experiments have direct implications for medical imaging: melamine foams exhibit a similar microstructure as lung tissue. In the future, combined shear wave and slow compression wave imaging might provide new means of distinguishing malignant and healthy pulmonary tissue.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors).

BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biologic therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Although BCR-ABL tyrosine kinase inhibitors modestly increase the overall risk of infection, dasatinib has been associated with cytomegalovirus and hepatitis B virus reactivation. BRAF/MEK kinase inhibitors do not significantly affect infection susceptibility. The effect of Bruton tyrosine kinase inhibitors (ibrutinib) among patients with B-cell malignancies is difficult to distinguish from that of previous immunosuppression. However, cases of Pneumocystis jirovecii pneumonia (PCP), invasive fungal infection and progressive multifocal leukoencephalopathy have been occasionally reported. Because phosphatidylinositol-3-kinase inhibitors (idelalisib) may predispose to opportunistic infections, anti-Pneumocystis prophylaxis and prevention strategies for cytomegalovirus are recommended. No increased rates of infection have been observed with venetoclax (antiapoptotic protein Bcl-2 inhibitor). Therapy with Janus kinase inhibitors markedly increases the incidence of infection. Pretreatment screening for chronic hepatitis B virus and latent tuberculosis infection must be performed, and anti-Pneumocystis prophylaxis should be considered for patients with additional risk factors. Cancer patients receiving mTOR inhibitors face an increased incidence of overall infection, especially those with additional risk factors (prior therapies or delayed wound healing). IMPLICATIONS: Specific preventive approaches are warranted in view of the increased risk of infection associated with some of the reviewed agents.

Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis.

Fluoroquinolone (FQ) and fluconazole prophylaxis is recommended for patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). However, due to an uncertain scientific basis and the increasing emergence of resistant germs, this policy should be questioned. Therefore, FQ and fluconazole prophylaxis was omitted in alloHCT at our center. In this retrospective analysis, all consecutive patients (n = 63) who underwent first alloHCT at our institution from September 2010 to September 2013 were included. Patients neither received FQ nor fluconazole prophylaxis. Day 100 mortality, incidence of febrile neutropenia, bacterial infections, and invasive fungal diseases (IFD) were assessed. Sixteen patients who started conditioning under antimicrobial treatment/prophylaxis due to pre-existing neutropenia (3/16), IFD (12/16), or aortic valve replacement (1/16) were excluded from the analysis. Finally, 47 patients were transplanted without prophylaxis as intended. Day 100 mortality was 9 %. Febrile neutropenia occurred in 62 % (29/47); 17/47 patients (36 %) experienced a blood stream infection (BSI) with detection of Gram-positive bacteria in 14 patients, Gram-negative bacteria in five patients, and candida in one patient, respectively. Coagulase-negative staphylococci were the most frequently isolated Gram-positive bacteria; 12/21 isolated Gram-positive and 3/6 Gram-negative bacteria were FQ resistant. In 21 % (10/47) of the patients, IFD (1x proven, 1x probable, and 8x possible) were diagnosed. To conclude, all three criteria, day 100 mortality, the incidence of IFD, and BSI, are in the range of published data for patients transplanted with FQ and fluconazole prophylaxis. These data demonstrate that alloHCT is feasible without FQ and fluconazole prophylaxis.

Identification of invasive fungal diseases in immunocompromised patients by combining an Aspergillus specific PCR with a multifungal DNA-microarray from primary clinical samples.

The increasing incidence of invasive fungal diseases (IFD), most of all invasive aspergillosis (IA) in immunocompromised patients emphasises the need to improve the diagnostic tools for detection of fungal pathogens. We investigated the diagnostic performance of a multifungal DNA-microarray detecting 15 different fungi [Aspergillus, Candida, Fusarium, Mucor, Rhizopus, Scedosporium and Trichosporon species (spp.)] in addition to an Aspergillus specific polymerase chain reaction (PCR) assay. Biopsies, bronchoalveolar lavage and peripheral blood samples of 133 immunocompromised patients (pts) were investigated by a multifungal DNA-microarray as well as a nested Aspergillus specific PCR assay. Patients had proven (n = 18), probable (n = 29), possible (n = 48) and no IFD (n = 38) and were mostly under antifungal therapy at the time of sampling. The results were compared to culture, histopathology, imaging and serology, respectively. For the non-Aspergillus IFD the microarray analysis yielded in all samples a sensitivity of 64% and a specificity of 80%. Best results for the detection of all IFD were achieved by combining DNA-microarray and Aspergillus specific PCR in biopsy samples (sensitivity 79%; specificity 71%). The molecular assays in combination identify genomic DNA of fungal pathogens and may improve identification of causative pathogens of IFD and help overcoming the diagnostic uncertainty of culture and/or histopathology findings, even during antifungal therapy.

Persistence with opioid treatment in Germany in patients suffering from chronic non-malignant or cancer pain.

BACKGROUND: The aim of the present study was to assess factors influencing opioid persistence in a large patient cohort of 32,158 patients receiving opioid treatment for either chronic non-malignant or cancer pain. METHODS: Data from 32,158 patients with first-time prescription of an opioid in the timeframe from January 2009 until December 2013 treated in 115 orthopedic, 104 neurological and 1129 general practitioner practices were retrospectively analyzed (Disease Analyzer database Germany). A Cox proportional hazards regression model was used to estimate the relationship between non-persistence and the demographic and clinical variables described previously for a maximum follow-up period of 1 year. RESULTS: After 1 year of follow-up, 69% of patients treated with opioids had stopped medication intake (refill gap of 90 days). There was a significantly increased risk of treatment discontinuation for younger patients (<40 years HR: 1.45; 41-50 years HR: 1.37; 51-60 years HR: 1.23; 61-70 years HR: 1.22) as compared with patients aged >70. Cancer pain was associated with a significantly lower risk of therapy discontinuation (HR: 0.69), whereas persistence was considerably less probable for diagnoses such as various kinds of back pain (HR: 1.26), osteoarthritis (HR: 1.14) and spondylarthritis (HR: 1.09). Chronic comorbidities such as diabetes, hypertension, heart insufficiency, and dementia were associated with a decreased risk of treatment discontinuation. CONCLUSION: Our study showed that persistence with opioid treatment is associated with cancer pain, chronic comorbidities and depression, while younger age and chronic non-malignant pain (especially due to back pain) increase the possibility of opioid discontinuation. It will be the task of future studies to assess reasons for opioid discontinuation in more detail, which is an important step towards improving patient care and health outcomes.

Assessment of Aspergillus-specific PCR as a screening method for invasive aspergillosis in paediatric cancer patients and allogeneic haematopoietic stem cell recipients with suspected infections.

Invasive aspergillosis (IA) remains difficult to diagnose in immunocompromised patients, because diagnostic EORTC/MSG criteria are often not met. As biomarkers might elucidate the pathogen, we analysed the performance of an Aspergillus PCR assay in blood for diagnosis of IA in immunocompromised paediatric patients with suspected infections. Ninety-five haemato-oncological paediatric patients were included over a period of 3 years, the underlying diseases consisting of acute leukaemia, solid tumours, non-malignant immunocompromising disorders and haematopoietic stem cell transplantation recipients. We retrospectively analysed 253 consecutive episodes of suspected infections. Thirty-eight patients had possible IA, none of the patients fulfilled EORTC/MSG criteria of probable/proven IA. PCR positivity was observed in 97/967 analyses. Sensitivity, specificity, positive and negative predictive value of the PCR per episode were 34%, 78%, 31% and 81% using possible IA as endpoint. Taken together, an undirected blood screening by Aspergillus-specific PCR is of little diagnostic value in a heterogenous paediatric patient cohort. Harnessing PCR for diagnosis of IA should thus be focused on blood analyses of more homogenous high-risk patients and/or analyses of bronchoalveolar lavage, tissue or cerebrospinal fluid specimens.

Aspergillus PCR-based investigation of fresh tissue and effusion samples in patients with suspected invasive Aspergillosis enhances diagnostic capabilities.

Although it is a severe complication in immunocompromised patients, diagnosing invasive fungal disease (IFD), especially invasive aspergillosis (IA), remains difficult. In certain clinical scenarios, examining tissue samples for identification of the infectious organism becomes important. As culture-based methods rarely yield results, the performance of an Aspergillus-specific nested PCR in fresh tissue or pleural effusion samples was evaluated. Fresh tissue (n = 59) and effusion (n = 47) specimens from 79 immunocompromised patients were subjected to an Aspergillus-specific PCR assay. Twenty-six patients had proven (n = 20) or probable (n = 6) IFD, according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria, while the remaining patients were classified as having either possible IFD (n = 30) or no IFD (n = 23). IA was identified as the underlying IFD in 21/26 proven/probable cases. PCR positivity was observed for 18/21 proven/probable and 6 possible IA cases; cases classified as no IA did not show positive signals. Patients with proven IFD (n = 5) with cultures positive for non-Aspergillus molds also had negative Aspergillus PCR results. Aspergillus PCR performance analysis yielded sensitivity and specificity values of 86% (95% confidence interval [CI], 65% to 95%) and 100% (95% CI, 86% to 100%), respectively, thus leading to a diagnostic odds ratio of >200. In this analysis, good diagnostic performance of the PCR assay for detection of IA was observed for tissue samples, while effusion samples showed lower sensitivity rates. PCR testing represents a complementary tool; a positive PCR result strengthens the likelihood of IA, whereas IA seems unlikely in cases with negative results but findings could indicate non-Aspergillus IFD. Thus, PCR testing of these specimens enhances the diagnostic capabilities.

Low-dose liposomal amphotericin B in the prevention of invasive fungal infections in patients with prolonged neutropenia: results from a randomized, single-center trial.

BACKGROUND: We performed a prospective, randomized, open-label trial to evaluate the efficacy of low-dose liposomal amphotericin B (L-AmB) to reduce the incidence of invasive fungal infections (IFI) in patients with hematological malignancies and prolonged neutropenia (>10 days) following intensive chemotherapy. PATIENTS AND METHODS: In 219 neutropenic episodes (NE) of 132 patients randomization was performed. Patients received either 50 mg L-AmB every other day (arm A) or no systemic antifungal prophylaxis (arm B). RESULTS: In the first NE of each patient the incidence of proven or probable IFI (primary end point) was five of 75 patients (6.7%) in arm A and 20 of 57 patients (35%) in arm B (P=0.001). Invasive aspergillosis occurred less frequently in patients receiving L-AmB-prophylaxis (P=0.0057), whereas the reduction of invasive candidiasis did not reach statistical significance (P=0.0655). In all NE the incidence of IFI was five of 110 NE (4.6%) in arm A versus 22 of 109 NE (20.2%) in arm B (P<0.01). Adverse events, possibly related to L-AmB, were observed in five NE (4.6%) and L-AmB was discontinued in three NE (2.8%). No grade 3 or 4 toxicities were observed. CONCLUSIONS: Antifungal prophylaxis with low-dose L-AmB proved to be feasible and effective in our trial.

Quantitative real-time RT-PCR detects elevated Wilms tumor gene (WT1) expression in autologous blood stem cell preparations (PBSCs) from acute myeloid leukemia (AML) patients indicating contamination with leukemic blasts.

High-dose chemotherapy with subsequent autologous stem cell transplantation is believed to be of therapeutic benefit in patients with acute myeloid leukemia (AML), especially when no allogeneic bone marrow donor is available. One of the main risks is contamination of the stem cell preparations with leukemic blasts, which may account for a higher relapse rate compared to allogeneic bone marrow transplantation. Since overexpression of WT1 is common in leukemic blasts, we investigated, whether PBSCs from AML patients express WT1 at a higher level as compared to patients with solid cancers. PBSCs of seven patients with AML and of five patients with solid cancers were investigated for WT1 expression. Total WT1 copy count was determined in a standardized quantitative real time RT-PCR. WT1 expression was found in all AML PBSCs with an average copy number of 49.99 +/- 61.09. In solid cancers WT1 expression was statistically significantly lower with a copy number of 3.51 +/- 1.92. In AML patients with sustained complete remission we found a nearly significantly lower WT1 expression than in patients who relapsed within the first year after stem cell transplantation. Our data show a higher WT1 expression in PBSCs of AML patients compared to patients with solid cancers. This finding might indicate a contamination with leukemic blasts. Quantification of WT1 in PBSCs might therefore be useful to estimate the risk of relapse after autologous stem cell transplantation in AML patients.