SAKK57/16 Nab-paclitaxel and Gemcitabine in Soft Tissue Sarcoma (NAPAGE): a phase I/II trial.

BACKGROUND: To determine whether the combination of nab-paclitaxel with gemcitabine has activity in patients with pretreated soft tissue sarcoma (STS). PATIENTS AND METHODS: NAPAGE is a phase Ib/II clinical trial investigating the combination of nab-paclitaxel (nab-pc) with gemcitabine employing two cohorts. One of a dose-de-escalation phase and one of expansion. In phase I, nab-pc was given at 150 mg/m2 in combination with gemcitabine 1000 mg/m2 every two weeks, until disease progression or unacceptable toxicity. This dose was recommended for phase II (RP2D), as there was no dose limiting toxicity (DLT) or discontinuations due to adverse events (AEs). The primary endpoint of the phase II was progression-free rate (PFR) at 3 months (H0: 20%, H1:40%). The secondary endpoints included progression free survival (PFS), overall survival (OS), AEs, objective response and patient-reported outcomes (PRO). Efficacy analysis was by intention to treat. RESULTS: The 3-month PFR was 56.4% (95% confidence interval CI: 39.6-72.2%). The 3-month and 6-month PFS were 58.4% (95% CI: 41.3-72.1%) and 44.6% (95% CI: 28.4-59.5%), respectively. Median PFS was 5.3 months (95% CI: 1.4-8.2) and median OS was 12.8 months (95% CI: 10.5-39.2). The most common treatment-related grade ≥ 3 AE were neutropenia (18%), followed by anemia (2.6%), hypertension (2.6%) and alanine aminotransferase increase (2.6%). Grade 1 and grade 2 peripheral sensory neuropathy (PNP) occurred in 15.4% and 20.5%, respectively. No grade 3-4 PNP was reported. CONCLUSIONS: Combining nab-pc and gemcitabine is safe. Promising activity is observed in pretreated STS patients with manageable toxicity. This regimen should be considered for further exploration.

Optical analysis of glutamate spread in the neuropil.

Fast synaptic communication uses diffusible transmitters whose spread is limited by uptake mechanisms. However, on the submicron-scale, the distance between two synapses, the extent of glutamate spread has so far remained difficult to measure. Here, we show that quantal glutamate release from individual hippocampal synapses activates extracellular iGluSnFr molecules at a distance of >1.5 µm. 2P-glutamate uncaging near spines further showed that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-Rs and N-methyl-D-aspartate (NMDA)-Rs respond to distant uncaging spots at approximately 800 and 2000 nm, respectively, when releasing the amount of glutamate contained in approximately five synaptic vesicles. The uncaging-induced remote activation of AMPA-Rs was facilitated by blocking glutamate transporters but only modestly decreased by elevating the recording temperature. When mimicking release from neighboring synapses by three simultaneous uncaging spots in the microenvironment of a spine, AMPA-R-mediated responses increased supra-additively. Interfering with extracellular glutamate diffusion through a glutamate scavenger system weakly reduced field synaptic responses but not the quantal amplitude. Together, our data suggest that the neuropil is more permissive to short-range spread of transmitter than suggested by theory, that multivesicular release could regularly coactivate nearest neighbor synapses and that on this scale glutamate buffering by transporters primarily limits the spread of transmitter and allows for cooperative glutamate signaling in extracellular microdomains.

Can toxin warfare against fungal parasitism influence short-term Dolichospermum bloom dynamics? - A field observation.

Cyanobacterial blooms often consist of numerous co-existing cyanobacterial species, with predominant taxa dynamically varying intra-annually. Parasitism by fungi (chytrids) has come into focus as an important factor driving short-term bloom dynamics. Using microscopic analysis, Illumina sequencing and cyanobacterial toxin analyses, we monitored the seasonal succession of Dolichospermum blooms in a reservoir along with environmental parameters. We identified two consecutive Dolichospermum blooms that were characterized by a straight and a coiled morphotype, separated by a complete bloom collapse. Phylotyping provided evidence for three putative Dolichospermum amplicon sequence variants (ASVs); i.e. Dolichospermum1 & 2 in the first bloom (straight filaments) and Dolichospermum3 in the second bloom (coiled filaments). Morphotype succession as well as total filament concentration did not correlate with any of the measured environmental parameters. Fungal parasitism by the chytrid Rhizosiphon crassum occurred in straight Dolichospermum filaments only. Coiled filaments showed no infection despite ambient presence of chytrids, deduced from fungal ASVs, throughout the entire observation period. Toxin concentrations (microcystins (MCs) and anabaenopeptins) correlated significantly with the abundance of the straight Dolichospermum morphotype. Enhanced cyanotoxin biosynthesis in the straight Dolichospermum morphotype, interpreted as a defensive reaction to fungal parasitism, appeared to come at the expense of lowered competitiveness with the co-occurring coiled morphotype. Our findings support the hypothesis that selective parasitism by chytrids is an important factor driving short-term morphotype and toxin dynamics within cyanobacterial blooms.

[Prognostic and predictive methylation biomarkers in HNSCC : Epigenomic diagnostics for head and neck squamous cell carcinoma (HNSCC)]. / Prognostische und prädiktive Methylierungsbiomarker für HNSCC : Epigenomische Diagnostika für Plattenepithelkarzinome des Kopf- und Halsbereichs (HNSCC).

BACKGROUND: Prognostic and predictive biomarkers for personalized treatment management in head and neck squamous cell carcinoma (HNSCC) are of great clinical interest. OBJECTIVE: DNA methylation is an epigenetic process involved in gene regulation and could be a source of potential prognostic and predictive biomarkers. METHODS: This study comprises literature research in PubMed and own studies. RESULTS: Gene methylation, e.g. of PITX2, is a strong, human papillomavirus (HPV)-independent prognostic biomarker. SHOX2 and SEPT9 methylation in circulating cell-free DNA within blood plasma correlates with tumor stage and prognosis. Methylation of diverse immune checkpoints, e.g., PD­1, PD-L1, and CTLA4, is also prognostic and correlates with gene expression. CONCLUSION: DNA methylation is a source of efficient prognostic blood plasma- and tissue-based biomarkers. However, prior to clinical implementation, studies must prove that biomarker-guided treatment selection can lead to better outcomes or reduced toxicity. The applicability of DNA methylation as a predictive biomarker for targeted drug-based cancer therapy seems promising, although further validation is needed.

Gadolinium DTPA Enhancement Characteristics of the Rat Sciatic Nerve after Crush Injury at 4.7T.

BACKGROUND AND PURPOSE: Traumatic peripheral nerve injury is common and results in loss of function and/or neuropathic pain. MR neurography is a well-established technique for evaluating peripheral nerve anatomy and pathology. However, the Gd-DTPA enhancement characteristics of acutely injured peripheral nerves have not been fully examined. This study was performed to determine whether acutely crushed rat sciatic nerves demonstrate Gd-DTPA enhancement and, if so, to evaluate whether enhancement is affected by crush severity. MATERIALS AND METHODS: In 26 rats, the sciatic nerve was crushed with either surgical forceps (6- to 20-N compressive force) or a microvascular/microaneurysm clip (0.1-0.6 N). Animals were longitudinally imaged at 4.7T for up to 30 days after injury. T1WI, T2WI, and T1WI with Gd-DTPA were performed. RESULTS: Forceps crush injury caused robust enhancement between days 3 and 21, while clip crush injury resulted in minimal-to-no enhancement. Enhancement after forceps injury peaked at 7 days and was seen a few millimeters proximal to, in the region of, and several centimeters distal to the site of crush injury. Enhancement after forceps injury was statistically significant compared with clip injury between days 3 and 7 (P < .04). CONCLUSIONS: Gd-DTPA enhancement of peripheral nerves may only occur above a certain crush-severity threshold. This phenomenon may explain the intermittent observation of Gd-DTPA enhancement of peripheral nerves after traumatic injury. The observation of enhancement may be useful in judging the severity of injury after nerve trauma.

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract.

BACKGROUND: Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC. METHODS: Relative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival. RESULTS: SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865-0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873). CONCLUSIONS: SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.

Dynamic posterior stabilization for degenerative lumbar spine disease: a large consecutive case series with long-term follow-up by additional postal survey.

INTRODUCTION: Dynamic stabilization of the degenerated spine was invented to overcome the negative side effects of fusion surgery like adjacent segment degeneration. Amongst various different implants DSS(®) is a pedicle-based dynamic device for stabilizing the spine and preserving motion. Nearly no clinical data of the implant have been reported so far. The current analysis presents results from a single spine surgeon who has been using DSS(®) for the past 5 years and recorded all treatment and outcome data in the international Spine Tango registry. MATERIALS/METHODS: From the prospectively documented overall patient pool 436 cases treated with DSS(®) could be identified. The analysis was enhanced with a mailing of COMI patient questionnaires for generating longer-term follow-ups up to 4 years. RESULTS: 387 patients (189 male, 198 female; mean age 67.3 years) with degenerative lumbar spinal disease including degenerative spondylolisthesis (6.1 %) could be evaluated. The type of degeneration was mainly spinal stenosis (89.9 %). After a mean follow-up of 1.94 years, the COMI score and NRS back and leg pain improved significantly and to a clinically relevant extent. The postoperative trend analysis could not determine a relevant deterioration of these outcomes until 4 years postoperative. 10 patients were revised (2.6 %) and the implant was removed; in most cases, a fusion was performed. Another 5 cases (1.3 %) had an extension of the dynamic stabilization system to the adjacent level. 84.2 % of patients rated that the surgery had helped a lot or had helped. DISCUSSION: The results of this large consecutive series with a follow-up up to 4 years could demonstrate a good and stable clinical outcome after posterior dynamic stabilization with DSS(®). For degenerative diseases of the lumbar spine, this treatment seems to be a valid alternative to fusion surgery.

PIAS1 is a determinant of poor survival and acts as a positive feedback regulator of AR signaling through enhanced AR stabilization in prostate cancer.

Novel drugs like Abiraterone or Enzalutamide, which target androgen receptor (AR) signaling to improve androgen deprivation therapy (ADT), have been developed during the past years. However, the application of these drugs is limited because of occurrence of inherent or acquired therapy resistances during the treatment. Thus, identification of new molecular targets is urgently required to improve current therapeutic prostate cancer (PCa) treatment strategies. PIAS1 (protein inhibitor of activated STAT1 (signal transducer and activator of transcription-1)) is known to be an important cell cycle regulator and PIAS1-mediated SUMOylation is essential for DNA repair. In this context, elevated PIAS1 expression has already been associated with cancer initiation. Thus, in the present study, we addressed the question of whether PIAS1 targeting can be used as a basis for an improved PCa therapy in combination with anti-androgens. We show that PIAS1 significantly correlates with AR expression in PCa tissue and in cell lines and demonstrate that high PIAS1 levels predict shorter relapse-free survival. Our patient data are complemented by mechanistic and functional in vitro experiments that identify PIAS1 as an androgen-responsive gene and a crucial factor for AR signaling via prevention of AR degradation. Furthermore, PIAS1 knockdown is sufficient to decrease cell proliferation as well as cell viability. Strikingly, Abiraterone or Enzalutamide treatment in combination with PIAS1 depletion is even more effective than single-drug treatment in multiple PCa cell models, rendering PIAS1 as a promising target protein for a combined treatment approach to improve future PCa therapies.

[Primary liver tumours in childhood]. / Primäre Lebertumoren im Kindesalter.

The reported prevalence of focal liver lesions in adult patients and children is different. The article discusses pediatric liver tumors under the criteria of histopathology and contrast enhanced ultrasound (CEUS) features. Aim of this article is also to support the already established Pediatric Registry of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) to collect data on safety and applications of ultrasound contrast agents in children (www.efsumb.org).

Geometry of mass.

We study the effect of mass on geometric descriptions of gauge field theories. In an approach in which the massless theory resembles general relativity, the introduction of the mass entails non-zero torsion and the generalization to Einstein-Cartan-Sciama-Kibble theories. The relationships to pure torsion formulations (teleparallel gravity) and to higher gauge theories are also discussed.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).

BACKGROUND: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS: In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS: The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS: Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00544700.

Anatoxin-a producing Tychonema (Cyanobacteria) in European waterbodies.

In order to identify the cyanobacterial species responsible of anatoxin-a (ATX) production in Lake Garda (Northern Italy), an intensive isolation and culturing of filamentous cyanobacteria were established since 2014 from environmental samples. In this work, we report a detailed account of the strategy adopted, which led to the discovery of a new unexpected producer of ATX, Tychonema bourrellyi. So far, this species is the first documented example of cultured Oscillatoriales able to produce ATX isolated from pelagic freshwater ecosystems. The isolated filaments were identified adopting a polyphasic approach, which included microscopic species identification, genetic characterisation and phylogenetic analyses based on 16S rRNA genes. The taxonomic identification was further confirmed by the high (>99%) rbcLX sequence similarities of the T. bourrellyi strains of Lake Garda with those deposited in DNA sequence databases. More than half of the isolates were shown to produce a significant amount of ATX, with cell quota ranging between 0.1 and 2.6 µg mm(-3), and 0.01 and 0.35 pg cell(-1). The toxic isolates were tested positive for anaC of the anatoxin-a synthetase (ana) gene cluster. These findings were confirmed with the discovery of one ATX producing T. bourrellyi strain isolated in Norway. This strain and a further non-ATX producing Norwegian Tychonema bornetii strain tested positive for the presence of the anaF gene of the ana gene cluster. Conversely, none of the Italian and Norwegian Tychonema strains were positive for microcystins (MCs), which was also confirmed by the absence of mcyE PCR products in all the samples analysed. This work suggests that the only reliable strategy to identify cyanotoxins producers should be based on the isolation of strains and their identification with a polyphasic approach associated to a concurrent metabolomic profiling.

Contrast enhanced ultrasound in pediatric patients: a real challenge.

Ultrasound (US) imaging in the paediatric population has been a routine technique for decades, in part because of the advantages it offers over other imaging modalities. Off-label use (and its funding) is of the utmost importance in paediatrics because many drugs have not been evaluated in randomised trials in children. As a consequence such drugs are not specifically approved for use in children. This is also true for the contrast agents used in CEUS. The off-label use of CEUS in paediatric patients illustrates the need to deal with unresolved legal issues while at the same time balancing this with the need for high diagnostic performance in daily clinical routine. In addition to approved indications with a focus on the liver and Doppler enhancement, CEUS is safe and effective for the examination of many organs, as recently highlighted by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). This article provides a summary of the available literature describing the utility of CEUS in paediatric patients. Furthermore, we suggest the establishment of a registry to collect data on safety and applications of ultrasound contrast agents in children. A paediatric registry has recently been introduced by EFSUMB (www.efsumb.org).

Measurement of shear wave velocity using acoustic radiation force impulse imaging is not hampered by previous use of ultrasound contrast agents.

PURPOSE: To assess the inter-observer reproducibility of acoustic radiation force impulse imaging (ARFI) between 2 skilled physicians and to evaluate if ultrasound contrast agents (UCA) affect the measurement of shear wave velocity (SWV) using ARFI. PATIENTS AND METHODS: 53 patients (29 males, 24 females, 59 ± 15 [22-84] years) who underwent contrast enhanced ultrasound (CEUS) examination were included. ARFI was performed on liver segment V by physicians A and B before CEUS, and by physician A within 4-6 minutes and 7-10 minutes after contrast injection. In a subgroup of 31 patients (15 males, 16 females, 57 ± 18 [22-84] years), ARFI was also performed on focal liver lesions (FLL) by physician A before CEUS, and within 4-6 minutes and 7-10 minutes after contrast injection. RESULTS: The SWV values obtained by physician A and B before CEUS yielded an intra-class correlation coefficient value of 0.913 (95% CI, 0.849-0.950). No significant differences were shown between the SWV values of liver segment V in all 53 patients and of FLL in the subgroup of 31 patients obtained before CEUS and that of within 4-6 minutes and 7-10 minutes after contrast injection (all P > 0.05). CONCLUSION: ARFI showed excellent inter-observer reproducibility between 2 skilled physicians. UCA did not affect the measurement of SWV in both liver parenchyma and FLL, at least when performed 4 minutes after the contrast injection. ARFI may become an additional tool in the differential diagnosis of FLL.

Conventional ultrasound for lymph node evaluation, update 2013.

Conventional ultrasound is regarded as the first method of choice to evaluate lymph node disease due to its high resolution. The combination of various features obtained from the patients history including age, acute or chronic onset, symptoms, and a knowledge of underlying systemic diseases as well as imaging criteria, most importantly B-mode (gray-scale) and colour Doppler imaging (CDI) are the basis for the differential diagnosis of lymphadenopathy. New ultrasound techniques such as elastography and contrast-enhanced ultrasound may provide further information. In addition, ultrasound evaluation of lymph nodes is an essential adjunct to the clinical investigation in staging of malignant neoplasia and lymphoma. In this paper the current literature is reviewed regarding conventional B-mode and Doppler ultrasound for the evaluation of lymphadenopathy. The ultrasound criteria for the differential diagnosis of enlarged and structurally altered lymph nodes are summarized and also limitations are described.

Artifacts and pitfalls in contrast-enhanced ultrasound of the liver.

Ultrasound technology is always connected to possible artefacts. Since introduction of ultrasound technology the knowledge of those artefacts is eminent to avoid misinterpretations. It is important to know that with the introduction of new ultrasound technology the possibility of artefacts are rising.Whereas artefacts initially were limited to B-mode sonography, every technological step (colour Doppler sonography, contrast enhanced sonography) comes with a range of new artefacts. This article is written to explain the technological basics of ultrasound artefacts and provide the reader with examples in daily practice and how to avoid them.

Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression.

Mitochondrial dysfunction might have a central role in the pathophysiology of depression. Phenotypically, depression is characterized by lack of energy, concentration problems and fatigue. These symptoms might be partially explained by reduced availability of adenosine triphosphate (ATP) as a consequence of impaired mitochondrial functioning. This study investigated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), an established model to investigate the pathophysiology of depression. Mitochondrial respiration was assessed in intact PBMCs in 22 individuals with a diagnosis of major depression (MD) compared with 22 healthy age-matched controls using high-resolution respirometry. Individuals with MD showed significantly impaired mitochondrial functioning: routine and uncoupled respiration as well as spare respiratory capacity, coupling efficiency and ATP turnover-related respiration were significantly lower in the MD compared with the control group. Furthermore, mitochondrial respiration was significantly negatively correlated with the severity of depressive symptoms, in particular, with loss of energy, difficulties concentrating and fatigue. The results suggest that mitochondrial dysfunction contributes to the biomolecular pathophysiology of depressive symptoms. The decreased immune capability observed in MD leading to a higher risk of comorbidities could be attributable to impaired energy supply due to mitochondrial dysfunction. Thus mitochondrial respiration in PBMCs and its functional consequences might be an interesting target for new therapeutical approaches in the treatment of MD and immune-related comorbidities.