Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

Fully automated analysis combining [18F]-FET-PET and multiparametric MRI including DSC perfusion and APTw imaging: a promising tool for objective evaluation of glioma progression.

PURPOSE: To evaluate diagnostic accuracy of fully automated analysis of multimodal imaging data using [18F]-FET-PET and MRI (including amide proton transfer-weighted (APTw) imaging and dynamic-susceptibility-contrast (DSC) perfusion) in differentiation of tumor progression from treatment-related changes in patients with glioma. MATERIAL AND METHODS: At suspected tumor progression, MRI and [18F]-FET-PET data as part of a retrospective analysis of an observational cohort of 66 patients/74 scans (51 glioblastoma and 23 lower-grade-glioma, 8 patients included at two different time points) were automatically segmented into necrosis, FLAIR-hyperintense, and contrast-enhancing areas using an ensemble of deep learning algorithms. In parallel, previous MR exam was processed in a similar way to subtract preexisting tumor areas and focus on progressive tumor only. Within these progressive areas, intensity statistics were automatically extracted from [18F]-FET-PET, APTw, and DSC-derived cerebral-blood-volume (CBV) maps and used to train a Random Forest classifier with threefold cross-validation. To evaluate contribution of the imaging modalities to the classifier's performance, impurity-based importance measures were collected. Classifier performance was compared with radiology reports and interdisciplinary tumor board assessments. RESULTS: In 57/74 cases (77%), tumor progression was confirmed histopathologically (39 cases) or via follow-up imaging (18 cases), while remaining 17 cases were diagnosed as treatment-related changes. The classification accuracy of the Random Forest classifier was 0.86, 95% CI 0.77-0.93 (sensitivity 0.91, 95% CI 0.81-0.97; specificity 0.71, 95% CI 0.44-0.9), significantly above the no-information rate of 0.77 (p = 0.03), and higher compared to an accuracy of 0.82 for MRI (95% CI 0.72-0.9), 0.81 for [18F]-FET-PET (95% CI 0.7-0.89), and 0.81 for expert consensus (95% CI 0.7-0.89), although these differences were not statistically significant (p > 0.1 for all comparisons, McNemar test). [18F]-FET-PET hot-spot volume was single-most important variable, with relevant contribution from all imaging modalities. CONCLUSION: Automated, joint image analysis of [18F]-FET-PET and advanced MR imaging techniques APTw and DSC perfusion is a promising tool for objective response assessment in gliomas.

[Importance of cellular tight junction complexes in the development of periprosthetic leakage after prosthetic voice rehabilitation]. / Bedeutung zellulärer Tight-junction-Komplexe bei der Entwicklung einer periprothetischen Leckage bei stimmprothetischer Versorgung.

BACKGROUND: The use of voice prostheses is currently the gold standard in voice rehabilitation after total laryngectomy. This method combines low complication rates and excellent rehabilitation results; however, approximately 30% of patients show periprosthetic leakage or severe fistula enlargement after laryngectomy and prosthetic voice restoration within the first 4 years. The development of this enlargement is controversially discussed in the literature but recently published studies have shown that high esophageal reflux plays a key role in this process, which leads to an inflammatory reaction and disturbs the intercellular tight junctions in the sense of an epithelial mesenchymal transition (EMT). MATERIAL AND METHODS: A total of 44 patients underwent 24 h pH monitoring, a sample biopsy from the region of the fistula and a subsequent biomolecular examination for intracellular junction proteins as well as a correlation between the severity of reflux and tracheoesophageal fistula problems before and after antireflux therapy with proton pump inhibitors (PPI). RESULTS: Immunohistochemical staining revealed decreases in membrane E-cadherin and ß-catenin and a significant increase in the cytoplasmic fraction, depending on the severity of inflammation in the fistula tissue. In patients with an improvement of clinical fistula problems under oral PPI treatment an increase of membrane E-cadherin could be shown, whereas patients with persisting fistula enlargement demonstrated a further decrease of E-cadherin. CONCLUSION: The data indicate a central role of EMT in the development of fistula enlargement after total laryngectomy. Patients with periprosthetic leakage showed a loss of membrane bound E-cadherin and ß-catenin with an up-regulation of vimentin expression. In patients with mild or no leakage problems EMT could be resolved by aggressive antireflux treatment, whereas patients without any effect of PPI treatment on the fistula showed no reversal of EMT. These data contribute to the understanding of treatment resistant fistula enlargement after total laryngectomy.

[Vacuum shoe system vs.forefoot offloading shoe for the management of metatarsal fractures. A prospective, randomized trial]. / Abrollende Vakuumstützorthese versus Vorfulssentlastungsschuh zur Behandlung von Metatarsalefrakturen. Eine prospektive, randomisierte Untersuchung.

BACKGROUND: Metatarsal fractures are managed using different types of forefoot offloading orthosis. Theaim of this prospective study was to evaluate the clinical and pedographic results of a vacuum shoe system in comparison to a forefoot unloading shoe. METHOD: 20 patients (14 women/6 men--age: 36.4 +/- 14.1 years) were prospectively included in the study. The patients were followed up at four different time points. Detailed clinical and radiological examinations were carried out, functional scores were measured and a pedographic assessment was performed. RESULTS: Between the study groups no differences were seen in functional scoring. A complete bony healing was achieved within the 3 months of followup in all patients. The heelstrike to heelstrike time was without significant differences in the pedographic analysis. Adequate forefoot unloading was achieved with both orthosis. The load sharing between fore-, mid- and hindfoot showed no significant differences in the pedographic analysis. Patients' satisfaction was rated with higher values for the vacuum shoe system, but without significance. CONCLUSION: Both shoe systems show an adequate unloading of the forefoot. Therefore both orthosis may be used for the treatment of metatarsal fractures.

PET lung ventilation/perfusion imaging using (68)Ga aerosol (Galligas) and (68)Ga-labeled macroaggregated albumin.

Pulmonary imaging using ventilation/perfusion (V/P) single-photon emission tomography (V/P scan) with Tc-99m-labeled radiotracers is a well-established diagnostic tool for clinically suspected pulmonary embolism (PE). Ga-68 aerosol (Galligas) and Ga-68-labeled macroaggregated albumin (MAA) are potential tracers for positron emission tomography (PET) lung V/P imaging and could display an advantage over conventional V/P scans in terms of sensitivity and specificity. After radiochemical and animal studies, the clinical applicability of Ga-68 aerosol (Galligas) and Ga-68-labeled MAA was investigated in an exploratory study in patients with clinical suspicion of PE. PET scans were acquired using a 16-slice Gemini TF positron emission tomography/computed tomography (PET/CT) scanner. The acquisition protocol included low-dose computed tomography (CT) for attenuation correction (AC). Dosimetry calculations and continuative phantom measurements were performed. Structural analyses showed no modification of the particles due to the labeling process. In addition, in vitro experiments showed stability of Ga-68 MAA in various media. As expected, Ga-68-labeled human serum albumin microspheres (HSAM) were completely retained in the lung of the animals. In clinical use, PET lung ventilation and perfusion imaging using Ga-68 aerosol (Galligas) and Ga-68-labeled MAA was successful in all cases. In one case a clinically suspected PE could be detected and verified. The administered activity of Ga-68 aerosol (Galligas) and Ga-68-labeled MAA may be reduced by more than 50%, resulting in comparable radiation exposure to conventional V/P scans. In conclusion, Ga-68 aerosol (Galligas) and Ga-68-labeled MAA are efficient substitutes for clinical use and could be an interesting alternative with high accuracy for lung V/P imaging with Tc-99m-labeled radiotracers, especially in times of Mo-99 shortages and increasing use and spread of PET/CT scanners and Ga-68 generators, respectively.

Large granular lymphocyte lymphoma with leukemic phase and suspicion of leptomeningeal lymphomatosis in a cat - a case report.

INTRODUCTION: In this case report we present a feline large granular lymphocyte (LGL) lymphoma, a rare morphologically distinct subtype of lymphoma, in a twelve-year-old female spayed domestic short hair cat, with high suspicion of leptomeningeal lymphomatosis due to magnetic resonance imaging findings and results of cerebral spinal fluid analyses. Diagnosis of LGL lymphoma was confirmed by means of blood cytology and polymerase chain reaction for antigen receptor rearrangements.

INTRODUCTION: Dans ce rapport de cas, nous présentons un Large Granular Lymphocyte (LGL) lymphome, un sous-type rare de lymphome, chez une chatte domestique à poil court stérilisée de douze ans, avec une forte suspicion de lymphomatose leptoméningée en raison des résultats de l'imagerie par résonance magnétique et de l'analyse du liquide céphalo-rachidien. Le diagnostic de LGL-lymphome a été confirmé par une cytologie sanguine et une réaction en chaîne de la polymérase pour les réarrangements des récepteurs d'antigènes.

Regulation of aggrecanases from the ADAMTS family and aggrecan neoepitope formation during in vitro chondrogenesis of human mesenchymal stem cells.

Aggrecanases from the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) family are important therapeutic targets due to their essential role in aggrecan depletion in arthritic diseases. Whether their function is also important for matrix rearrangements during chondrogenesis and thus, cartilage regeneration, is however so far unknown. The aim of this study was to analyse the expression and function of ADAMTS with aggrecanase activity during chondrogenic differentiation of human mesenchymal stem cells (MSCs). Chondrogenic differentiation was induced in bone marrow-derived MSC pellets and expression of COL2A1, aggrecan, ADAMTS1, 4, 5, 9, 16 and furin was followed by quantitative RT-PCR. Formation of the NITEGE (ADAMTS-cleaved) and DIPEN (MMP-cleaved) aggrecan neoepitopes was detected by immunohistochemistry. While the expression of ADAMTS4, 9, 16 and furin was up-regulated during chondrogenesis, ADAMTS1 and 5 were down-regulated. Despite this regulation of ADAMTS, no formation of NITEGE neoepitopes occurred in MSC pellets, indicating no ADAMTS-induced cleavage of aggrecan. In contrast, MMP-induced cleavage of aggrecan appeared at 14 d after induction of chondrogenesis. Submission of differentiated MSC pellets to IL1ß treatment for 3 d resulted in strong upregulation of ADAMTS1, 4 and 5, rapid proteoglycan depletion, and stimulation of ADAMTS-induced but not MMP-induced cleavage of aggrecan. Thus, there is no evidence for ADAMTS-induced aggrecan cleavage during chondrogenesis, but proteoglycan turnover is rapidly inducible under inflammatory signals. Therapeutic aggrecanase inhibition for treatment of arthritic disease may thus not impede regenerative self-healing pathways based on chondrogenesis of local progenitor cells in the joint.

Effect of lyophilized lactobacilli and 0.03 mg estriol (Gynoflor®) on vaginitis and vaginosis with disrupted vaginal microflora: a multicenter, randomized, single-blind, active-controlled pilot study.

OBJECTIVES: To evaluate the efficacy of lyophilized lactobacilli in combination with 0.03 mg estriol when compared to metronidazole in the treatment of bacterial vaginal infections. SETTING: Multicenter, randomized, single-blind, active-controlled pilot study in 3 independent gynecological practices in Belgium. METHODS: Forty-six, 18- to 50-year-old premenopausal women with a disrupted vaginal flora due to a bacterial vaginal infection (bacterial vaginosis, aerobic vaginitis) were included, provided that fresh phase-contrast microscopy of the vaginal fluid showed lactobacillary flora grade 2B or 3. Patients were given a blinded box with either 12 vaginal tablets of Gynoflor® (study medication) or 6 vaginal suppositories containing 500 mg metronidazole (control medication). Eight efficacy variables were studied to assess the status of the vaginal flora at entry, 3-7 days (control 1), 4-6 (control 2) weeks and 4 months after the end of therapy. RESULTS: At control 1, the combined variables equally improved in the lactobacilli group as in the metronidazole group. At control 2, the lactobacillus preparation showed slightly inferior results when compared to metronidazole. At 4 months, this analysis could not be performed due to low numbers, but analysis of recurrence rate and extra medication needed was not different between both groups. CONCLUSION: Lyophilized lactobacilli in combination with low-dose estriol are equivalent to metronidazole in the short-term treatment of bacterial vaginal infections, but have less effect after 1 month. Further studies are required to evaluate the long-term efficacy of lactobacilli when applied repeatedly.

[Anaplasma phagocytophilum infection in a cat in Switzerland]. / Anaplasma phagocytophilum Infektion bei einer Katze in der Schweiz.

The following case report describes the diagnosis and therapy of a cat with an Anaplasma phagocytophilum infection. The cat from the canton of St. Gallen was presented because of lethargy and lack of appetite. The clinical symptoms established were fever and minor exsiccosis. The diagnosis of granulocytic anaplasmosis was established through microscopic evidence of inclusion bodies in neutrophil granulocytes, the detection of pathogen DNA in the blood by PCR and positive IgM and IgG antibody titers by serological testing. Following this diagnosis the cat was treated for 20 days with doxycycline. As the body temperature normalised, the activity of the cat improved while normalisation of food intake was delayed. After therapy Anaplasma phagocytophilum DNA could not be detected by PCR and a complete remission of abnormal serum chemistry and hematological parameters could be shown.

Soil and water bioengineering: Practice and research needs for reconciling natural hazard control and ecological restoration.

Soil and water bioengineering is a technology that encourages scientists and practitioners to combine their knowledge and skills in the management of ecosystems with a common goal to maximize benefits to both man and the natural environment. It involves techniques that use plants as living building materials, for: (i) natural hazard control (e.g., soil erosion, torrential floods and landslides) and (ii) ecological restoration or nature-based re-introduction of species on degraded lands, river embankments, and disturbed environments. For a bioengineering project to be successful, engineers are required to highlight all the potential benefits and ecosystem services by documenting the technical, ecological, economic and social values. The novel approaches used by bioengineers raise questions for researchers and necessitate innovation from practitioners to design bioengineering concepts and techniques. Our objective in this paper, therefore, is to highlight the practice and research needs in soil and water bioengineering for reconciling natural hazard control and ecological restoration. Firstly, we review the definition and development of bioengineering technology, while stressing issues concerning the design, implementation, and monitoring of bioengineering actions. Secondly, we highlight the need to reconcile natural hazard control and ecological restoration by posing novel practice and research questions.

Characterization and N-terminal sequencing of a calcium binding protein from the calcareous concretion organic matrix of the terrestrial crustacean Orchestia cavimana.

We extracted proteins from the organic matrix of calcareous concretions, which represents the calcium storage form in a terrestrial crustacean. Electrophoretic analyses of water-soluble organic-matrix proteinaceous components revealed 11 polypeptides, 6 of which are probably glycosylated. Among the unglycosylated proteins, we characterized a 23 kDa polypeptide, with an isoelectric point of 5.5, which is able to bind calcium. Its N-terminal sequence is rich in acidic amino acids (essentially aspartic acid). All these characteristics suggest its involvement in the calcium precipitation process within the successive layers of the organic matrix.

Use of the avidin-biotin-peroxidase complex (ABC) method for the localization of rabbit cathepsin B in cells and tissues.

Visualization of rabbit cathepsin B was achieved utilizing monospecific sheep antibodies and the avidin-biotin-peroxidase complex (ABC) method. This technique was applied to stain 1) paraffin sections of the liver, 2) fixed fibroblasts from tissue culture, and 3) fixed mesenteries. Cathepsin B was found to be localized within cells of the lining of the liver sinusoids (most probably Kupffer cells), in perinuclear granules of cultured fibroblasts, and within histiocytes of the mesentery. The results demonstrate that the method permits precise and highly sensitive localization of cathepsin B within cells and tissues. Compared to fluorescent staining of cathepsin B, the ABC method has the advantage that routine paraffin sections can be stained, and that all the orthodox histological staining procedures can still be carried out.

Calcium pathway through a mineralizing epithelium in the crustacean Orchestia in pre-molt: ultrastructural cytochemistry and X-ray microanalysis.

During the pre-exuvial period of the terrestrial crustacean Orchestia, the calcium of the old cuticle is almost entirely reabsorbed and stored as calcareous concretions in the lumen of the midgut posterior caeca. The elaboration of these concretions is due to transport by the caecal epithelium. With ultrastructural cytochemistry controlled by X-ray microanalysis, it can be demonstrated that the main sites of ionized or ionizable calcium are the apical microvilli and an extracellular (lateral and basal) network of channels. Direct precipitating cytochemical methods, using potassium pyroantimonate or pyrophosphate, potassium oxalate or oxalic acid, sodium fluoride, sodium tungstate, and indirect substitution methods, using lead acetate or nitrate and cobalt nitrate were comparatively used. The results are interpreted in favour of the hypothesis of an extracellular transport pathway for calcium through the lateral smooth septate junctions, in conjunction with a more classical apical transport through the microvilli.

Changes in hormones, metabolites, and milk after treatment with sometribove (recombinant methionyl bST) in Deutsches Fleckvieh and German black and white cows.

Twelve second-lactation Deutsches Fleckvieh cows, (FV, a dual-purpose breed) and 12 German Black and White (BW, a dairy breed) were used to evaluate similarities and differences in the response to a prolonged-release formulation of sometribove (N-methionyl bovine somatotropin, bST). Cows were milked twice daily and fed a basic diet (70% corn silage, 30% alfalfa hay) ad libitum plus 1 kg of concentrate. Additionally, concentrates and supplements were offered at the rate of 1 kg for each 22 kg of milk produced above 12 kg/d. Six cows of each breed were treated s.c. with 500 mg of sometribove at 14-d intervals from wk 9 to 29 postpartum (pp). Blood was collected by jugular vein puncture once weekly from wk 7 to 33 pp and daily for 14 d after the first and last (11th) injection of bST. Somatotropin (ST), insulin-like growth factor I (IGF-I), insulin, thyroid hormones, nonesterified fatty acids (NEFA), liver enzymes, and blood metabolites were evaluated. During bST treatment, plasma ST increased significantly on d 7 in both breeds and then decreased on d 14 after injection. Plasma IGF-I was positively correlated with ST. Plasma NEFA were high on d 7 and decreased on d 14. In response to bST, the average milk yield increased for FV and BW cows by 5.1 kg/d (29.7%) and 5.0 kg/d (28%), respectively, and 4% fat-corrected milk (FCM) increased by 5.0 kg/d (28%) and 5.3 kg/d (19.9%), respectively. Milk content of fat, protein, lactose, number of somatic cells, and body weight were similar across treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

[Histological findings following preoperative catheter embolization in hypernephroid renal carcinoma (author's transl)]. / Histologische Ergebnisse nach präoperativer Katherembolisation beim hypernephroiden Nierenkarzinom.

The authors investigated the histological findings in various embolization materials and at various interval before operation in 11 hypernephroid renal carcinoma patients who had been subjected to a preoperative transfemoral catheter embolization of the renal artery. The embolization materials used were fibrin-thrombin, pieces of gelatine sponge, collagen and GAW-spirals. The periods at which nephrectomy was carried out ranged from immediately after the embolization to six weeks later. From the histological point of view, total necrosis of the tumour did not occur in any case; only in three cases could a subtotal necrosis be achieved and in all the other cases the tumour-free parenchyma showed greater damage as a result of more pronounced ischemic infarction than did the tumour. A complete and lasting elimination of a tumourous kidney cannot be achieved by embolization of the renal artery. The obvious reasons for this are the tendency towards recurrence of canalization and the formation of collateral circulation.

[Optic neuritis in children]. / Les névrites optiques chez l'enfant.

Study of 40 children who presented a first episode of idiopathic optic neuritis. A mean follow-up of more than 8 years revealed only 15% of multiple sclerosis. This frequency is much lower than in adults. The visual outcome is also better. Significant factors are: absence of papilloedema, unilaterality, recurrence, HLA B7 and DR2, oligoclonal cerebrospinal fluid, anomalies of the VEPs.

[Polycythemia caused by liver carcinoma in cattle and sheep]. / Polyglobulie infolge Leberkarzinom bei Rind und Schaf.

Polycythemia associated with hepatic carcinoma was diagnosed in a 10-year-old cow, an 8-month-old heifer and a 3-year-old sheep. The cow was referred to our clinic because of weight loss, reduced appetite, hematuria, marked reddening of the mucosa of the tear canal, oral cavity and vestibule and an increased hematocrit. Clinical examination also revealed injected scleral vessels. The erythrocyte count, the PCV, hemoglobin concentration and the activities of the hepatic enzymes were increased. Ultrasonographic examination revealed a very large liver with a focal echogenic lesion. Based on all findings, a diagnosis of polycythemia associated with a liver tumor, was made. The cow was slaughtered. Multifocal liver tumors were diagnosed histologically as hepatocellular carcinoma. The heifer and sheep had similar clinical and hematological findings. Hepatocellular carcinoma was diagnosed in the heifer and cholangiocellular carcinoma in the sheep. It was concluded that in all three patients, polycythemia was caused by hepatic carcinoma.