Ιατρικά Άρθρα Αλέξανδρος Γ. Σφακιανάκης: 02/10/17

Παρασκευή 10 Φεβρουαρίου 2017

Imaging and cell count in cleared intact cochlea in the Mongolian gerbil using laser scanning confocal microscopy

Publication date: Available online 9 February 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): M. Risoud, J. Sircoglou, G. Dedieu, M. Tardivel, C. Vincent, N.-X. Bonne
ObjectivesTo draw up a clearing protocol for Mongolian gerbil cochlea, and to assess the feasibility of quantifying and analyzing 3D cell architecture in the transparent cochleae.Materials and methodsFreshly dissected inner ears were prepared on a 13-day protocol: fixation, microdissection, post-fixation, decalcification, pretreatment (signal enhancement, permeabilization and blocking), fluorescent labeling (indirect immunolabeling and direct labeling), dehydration, clearing in Spalteholz solution (MSBB: methyl salicylate and benzyl benzoate) and mounting. Image acquisition used laser scanning confocal microscopy. ImageJ software was used to measure the length of the organ of Corti thus available for analysis and to count inner and outer hair cells.ResultsFour cochleas underwent imaging. 3D reconstruction enabled organ of Corti length to be measured, at a mean 1269±346μm. Mean inner and outer hair-cell count per organ of Corti length was 142±44 and 400±122, respectively.ConclusionCochlear clearing by MSBB was feasible in Mongolian gerbils and provided high-resolution immunofluorescence-labeled inner-ear images. To our knowledge, this was the first application of the technique in this species. Cell count could thus be performed along the organ of Corti length without traumatic dissection.

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Injectable chondroplasty: Enzymatic reshaping of cartilage grafts

Publication date: Available online 10 February 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): J.R. Gandy, A. Foulad, K.K. Chao, B.J.F. Wong
Objective/hypothesisTo develop an injection-based enzymatic technique that selectively softens cartilage tissue for reshaping cartilaginous structures in the head and neck.Materials and methodsTwo groups were formed using fresh rabbit ears: (1) whole rabbit ear group; (2) composite graft group (2.5mm×3.0cm specimens sectioned from the central region of the pinna). Subperichondrial injections using three enzymes (hyaluronidase, pronase, and collagenase II) in sequence were performed for the experimental specimens from both groups. In the control specimens, phosphate buffered saline was injected in a similar fashion. The whole ear specimens were then photographed while held upright in the anatomical vertical position to evaluate for buckling, which corresponds to the integrity of the cartilage. In addition, backlight photography was performed for all specimens to further evaluate the effect of the enzymes, such that increased light intensity represents increased cartilage digestion.ResultsThe application of the digestive enzymes resulted in marked reduction of cartilage tissue matrix resiliency, while preserving overlying skin layers. Enzymatically treated whole pinnae buckled at the site where enzymes were delivered. Backlit images revealed increased local light intensity at the regions of digestion. There was no obvious destruction of the overlying skin upon visual inspection.ConclusionsThis study demonstrates the feasibility of injectable chondroplasty as a potential alternative method to conventional surgery for auricular cartilage reshaping. Sequential injection of hyaluronidase, pronase, and collagenase II into the subperichondrial space can be performed to digest and soften cartilage structure with minimal involvement of surrounding tissue. Future studies will need to include chondrocyte viability testing and optimization of delivery techniques.

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Advances in understanding tumour evolution through single-cell sequencing

Publication date: Available online 11 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Jack Kuipers, Katharina Jahn, Niko Beerenwinkel
The mutational heterogeneity observed within tumours poses additional challenges to the development of effective cancer treatments. A thorough understanding of a tumour’s subclonal composition and its mutational history is essential to open up the design of treatments tailored to individual patients. Comparative studies on a large number of tumours permit the identification of mutational patterns which may refine forecasts of cancer progression, response to treatment and metastatic potential.The composition of tumours is shaped by evolutionary processes. Recent advances in next-generation sequencing offer the possibility to analyse the evolutionary history and accompanying heterogeneity of tumours at an unprecedented resolution, by sequencing single cells. New computational challenges arise when moving from bulk to single-cell sequencing data, leading to the development of novel modelling frameworks.In this review, we present the state of the art methods for understanding the phylogeny encoded in bulk or single-cell sequencing data, and highlight future directions for developing more comprehensive and informative pictures of tumour evolution.

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Calendar

Publication date: 28 February 2017
Source:Journal of Controlled Release, Volume 248

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Publication date: 28 February 2017
Source:Journal of Controlled Release, Volume 248

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Editorial Board

Publication date: 28 February 2017
Source:Journal of Controlled Release, Volume 248

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Prevention of nanoparticle aggregation during freeze-drying

Publication date: 28 February 2017
Source:Journal of Controlled Release, Volume 248
Author(s): Kinam Park

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Belladonna

Belladonna: An herbaceous plant bearing the scientific name Atropa belladonna or Atropa bella-donna, also known as deadly nightshade. The leaves and berries of the plant are highly toxic and can lead to hallucinations and delirium when ingested. Eating just a few berries from the plant can be fatal in children. The belladonna plant has a long history of use by humans for medicines, cosmetics, and poisons. It is native to Europe, Western Asia, and North Africa but has been naturalized in parts of North America.

Atropine is one of the active substances found in belladonna, an agent that is also used in medicine for its effects on the involuntary nervous system (anticholinergic properties). Other active ingredients in belladonna that have similar properties are hyoscyamine and scopolamine. Belladonna was used in the past as a cosmetic by women, because of its anticholinergic actions in producing dilation of the pupils of the eye. Belladonna has been used as a sedative and cold remedy, among other medical applications, but oral consumption of any belladonna product is highly unsafe and should be strictly avoided.

Symptoms of overdose can include:

blurred vision,
dilated pupils,
rapid heart rate,
headache,
dry mouth,
confusion,
hallucinations, and
seizures.

The name belladonna is derived from the Italian words for "beautiful (bella) woman (donna)."

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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A retrospective analysis of catheter-based sources in intravascular brachytherapy

Publication date: Available online 10 February 2017
Source:Brachytherapy
Author(s): J. DeCunha, C. Janicki, S.A. Enger
PurposeCoronary artery disease involves the deposition of plaque along the walls of a coronary artery leading to narrowed or blocked vessels (stenosis) and is one of the main causes of death in developed countries. Percutaneous transluminal coronary angioplasty (PTCA) is used to reverse stenosis. Restenosis (renarrowing) of the treated vessel is a major complication of PTCA. A metal mesh tube (stent) can be placed inside the vessel to prevent restenosis. Tissue stress incurred during PTCA and stenting can provoke neointimal cell proliferation leading to in-stent restenosis (ISR). Intravascular brachytherapy (IVBT), a form of internal radiotherapy, is used to treat ISR. Renewed interest in IVBT is being expressed as a treatment for patients with ISR in drug-eluting stents. Current treatment planning (TP) of IVBT is extremely limited and assumes human tissue can be approximated by water. The interactions of arterial plaque, guidewires, and the stent have been shown to attenuate radiation significantly but are ignored in TP. Other models have determined the degree of attenuation by each factor in isolation. For the first time, we create a model with several inhomogenities present to determine whether attenuation by multiple inhomogenities combines linearly or if a larger dose reduction than anticipated is realized. We are also able to evaluate a spatial distribution of dose around the source and in arterial walls.Methods and MaterialsA dosimetric analysis of two commercially available IVBT systems was performed in a Monte Carlo–based particle simulation (Geant4). Absorbed dose was calculated using a model of a human coronary artery with a calcified plaque and stent. Dose delivered in water was also calculated to evaluate the accuracy of a water approximation.ResultsDose as a function of θ shows significant variation around IVBT sources. For the Guidant Galileo, dose is reduced by 20% behind stent struts and as much as 66% in a region occluded by the guidewire, plaque, and stent. For the Novoste Beta Cath device, delivered dose is reduced by 19% and 58%, respectively, in the same regions.ConclusionSOur findings show that the water approximation used in clinical practice to calculate dose is inaccurate when inhomogeneities are present. Methods proposed for calculating dose perturbations in IVBT may underestimate the magnitude of dose reduction. Increasing source dwell time seems unlikely to resolve dosimetric issues in IVBT. The effectiveness of currently existing β-emitting devices may be reduced in patients with complex lesions at the treatment site. Investigation of new radioisotopes and off-centering devices should be considered to improve dose outcomes.

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Intraoperative factors associated with stranded source placement accuracy in low–dose rate prostate brachytherapy

Publication date: Available online 10 February 2017
Source:Brachytherapy
Author(s): M.F. Jamaluddin, S. Ghosh, M.P. Waine, M. Tavakoli, J. Amanie, A.D. Murtha, D. Yee, N. Usmani
PurposeThe quality of a low–dose rate prostate brachytherapy implant depends on the accurate placement of sources in their planned locations. This study investigates intraoperative factors that potentially contribute to stranded source placement inaccuracy in prostate brachytherapy.Methods and MaterialsIntraoperative video images of the brachytherapist's hand motions and needle insertions during the implant procedure were acquired for analysis. Using video analysis software, maximum and average needle insertion velocities were determined. The number of needle insertion attempts and the use of the brachytherapist's other hand to manipulate the needle direction were also recorded. Sources misplacements were analyzed using an ultrasound-based method described elsewhere.ResultsFifteen patients agreed to undergo this study; 1619 ¹²⁵I seeds were inserted using 357 needles; 1197 seeds were confidently identified using ultrasound images and included in the analysis. The mean overall misplacement was 0.49 cm (0–2 cm, 95% CI = 0.47–0.51); 614 seeds were delivered with a single pass and 583 seeds with >1 passes (range 2–6). The mean maximum needle velocity was 12.34 cm s⁻¹ (range 4–28 cm s⁻¹) and mean average velocity was 4.76 cm s⁻¹ (range 0.4–17.4 cm s⁻¹); 747 seeds were delivered with manipulation of the needle. The generalized linear model test was used to analyze factors contributing to seed misplacement, and it was found that a maximum speed <12 cm s⁻¹ was associated with a decrease in seed misplacement by 0.049 cm vs. a maximum speed >12 cm s⁻¹, p = 0.0121). Other evaluated factors were found to have no statistically significant correlation with seed misplacement: average speed (p = 0.4947), manual manipulation of needle (p = 0.9264), and number of needle passes (p = 0.8907).ConclusionsThis study identified that needles inserted with lower maximum velocity were associated with less seed misplacement. Manual manipulation of the needle, number of passes, and average speed did not show statistically significant correlation with seed misplacement.

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Asymmetric Configurations in a Reengineered Homodimer Reveal Multiple Subunit Communication Pathways in Protein Allostery [Molecular Biophysics]

Many allosteric proteins form homo-oligomeric complexes to regulate a biological function. In homo-oligomers, subunits establish communication pathways that are modulated by external stimuli like ligand binding. A challenge for dissecting the communication mechanisms in homo-oligomers is identifying intermediate liganded states, which are typically transiently populated. However, their identities provide the most mechanistic information on how ligand-induced signals propagate from bound to empty subunits. Here, we dissected the directionality and magnitude of subunit communication in a reengineered, single-chain version of the homodimeric transcription factor cAMP Receptor Protein (CRPSC). By combining wild-type and mutant subunits in various asymmetric configurations, we revealed a linear relationship between the magnitude of cooperative effects and the number of mutant subunits. We found that a single mutation is sufficient to change the global allosteric behavior of the dimer even when one subunit was wild-type. Dimers harboring two mutations with opposite cooperative effects had different allosteric properties depending on the arrangement of the mutations. When the two mutations were placed in the same subunit, the resulting cooperativity was neutral. In contrast, when placed in different subunits, the observed cooperativity was dominated by the mutation with strongest effects over cAMP affinity relative to wild-type. These results highlight the distinct roles of intrasubunit interactions and intersubunit communication in allostery. Finally, dimers bound to either one or two cAMP molecules had similar DNA affinities, indicating that both asymmetric and symmetric liganded states activate DNA interactions. These studies have revealed the multiple communication pathways that homo-oligomers employ to transduce signals.

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Cytosolic DNA Promotes Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation by TANK-binding kinase 1 (TBK1) to Restrain STAT3 Activity [Signal Transduction]

Cytosolic DNA can elicit beneficial as well as undesirable immune responses. For example, viral or microbial DNA triggers cell-intrinsic immune responses to defend against infections, whereas aberrant cytosolic accumulation of self-DNA results in pathological conditions, such as autoimmunity. Given the importance of these DNA-provoked responses, a better understanding of their molecular mechanisms is needed. Cytosolic DNA engages stimulator of interferon genes (STING) to activate TANK-binding kinase 1 (TBK1), which subsequently phosphorylates the transcription factor interferon regulatory factor 3 (IRF3) to promote interferon expression. Recent studies have reported that additional transcription factors, including nuclear factor kappa-B (NF-κB) and signal transducer and activator of transcription 6 (STAT6), are also activated by cytosolic DNA, suggesting that cytosolic DNA-induced gene expression is orchestrated by multiple factors. Here we show that cytosolic DNA activates STAT3, another member of the STAT family, via an autocrine mechanism involving interferon β (IFNβ) and IL-6. Additionally, we observed a novel cytosolic DNA-induced phosphorylation at serine 754 in the transactivation domain of STAT3. Upon cytosolic DNA stimulation, S754 is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, S754 phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity, and selectively reduces STAT3 target genes that are upregulated in response to cytosolic DNA. Taken together, our results suggest that cytosolic DNA-induced STAT3 activation via IFNβ and IL-6 is restrained by S754 phosphorylation of STAT3. Our findings reveal a new signaling axis downstream of the cytosolic DNA pathway and suggest potential interactions between innate immune responses and STAT3-driven oncogenic pathways.

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Negative-stain single particle EM of the maltose transporter in nanodiscs reveals asymmetric closure of MalK2 and catalytic roles of ATP, MalE and maltose [Membrane Biology]

The Escherichia coli MalE-MalFGK2 complex is one of the best characterized members of the large and ubiquitous family of ATP-binding cassette (ABC) transporters. It is composed of a membrane-spanning heterodimer, MalF-MalG; a homodimeric ATPase, MalK2; and a periplasmic maltose receptor, MalE. Opening and closure of MalK2 is coupled to conformational changes in MalF-MalG and the alternate exposition of the substrate-binding site to either side of the membrane. To further define this alternate access mechanism and the impact of ATP, MalE and maltose on the conformation of the transporter during the transport cycle, we have reconstituted MalFGK2 in nanodiscs and analyzed its conformations under 10 different biochemical conditions using negative stain single particle EM. EM map results (at 15-25 Å resolution) indicate that binding of ATP to MalK2 promotes an asymmetric, semi-closed conformation in accordance with the low ATPase activity of MalFGK2. In the presence of MalE, the MalK dimer becomes fully closed; gaining the ability to hydrolyze ATP. In the presence of ADP or maltose, MalE·MalFGK2 remains essentially in a semi-closed symmetric conformation indicating that release of these ligands is required for the return to the initial state. Taken together, this structural information provides a rationale for the stimulation of MalK ATPase activity by MalE as well as by maltose.

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Improving theatre turnaround time

The NHS Institute for Innovation and Improvement has determined that a £7 million saving can be achieved per trust by improving theatre efficiency. The aim of this quality improvement project was to improve orthopaedic theatre turnaround without compromising the patient safety.

We process mapped all the stages from application of dressing to knife to skin on the next patient in order to identify potential areas for improvement. Several suggestions arose which were tested in multiple PDSA cycles in a single theatre. These changes were either adopted, adapted or rejected on the basis of run chart data and theatre team feedback.

Successful ideas which were adopted included, the operating department practitioner (ODP) seeing and completing check-in paperwork during the previous case rather than during turnaround, a 15 minute telephone warning to ensure the next patient was fully ready, a dedicated cleaning team mobilised during wound closure, sending for the next patient as theatre cleaning begins.

Run charts demonstrate that as a result of these interventions the mean turnaround time almost halved from 66.5 minutes in July to 36.8 minutes over all PDSA cycles. This improvement has been sustained and rolled out into another theatre. As these improvements become more established we hope that additional cases will be booked, improving theatre output. The PDSA cycle continues as we believe that further gains may yet be made, and our improvements may be rolled out across other surgical specialities.

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Health Education and Activity - Lessening The Inequalities in mental health (HEA - LTI mental health)

Patients suffering from mental health illness have considerably more physical health disease burden than the rest of the population and are more likely to die 10 to 20 years younger compared with their peers. Diabetes, cardiovascular and respiratory disease have been recognised as contributing factors to premature death. Furthermore patients with severe mental illness undertake lower levels of physical activity.

The aim of the project was therefore to address the inequalities in physical health that affect patients with mental health illness through designing and implementing a sustainable, transferable, patient-centred education and activity intervention.

The objective of the project was to increase patient motivation to change behaviour as a result of physical health interventions by increasing patients' physical health understanding, motivation to change their physical health behaviour, motivation to do exercise and by reducing their anxiety.

The method used was a prospective cohort study in four eighteen bed psychosis inpatient units. The units were across two large London hospitals in one Hospital Trust involving male and female inpatients with a range of mental health issues.

The intervention was comprised of two components. The first component was a weekly 45 minute teaching group designed in collaboration with patients focusing on the key domains that affect the physical health of mental health patients. Four discussion domains (heart health, diabetes and weight, smoking and lung disease, cancer screening and substance misuse) were undertaken, with each cycle lasting four weeks. The second component was a weekly 45 minute exercise group (‘normalisation activity’) in collaboration with patients and the multidisciplinary team.

The intervention was evaluated at the end of each cycle and four cycles in total took place.

Weekly pre and post intervention measures were undertaken comprising of a self reported change in understanding, motivation to change physical health behaviours, confidence to change, anxiety and motivation to exercise.

The result was a 26% improvement in self-reported understanding across the four domains following teaching. Furthermore patient anxiety reduced by on average 35%, self-reported motivation to change increased by 20%, motivation to do exercise by 26% and confidence to change by 16% as a result of the intervention.

The authors conclude that a collaborative approach to education and activity between the Multidisciplinary Team (MDT) and service user results in sustained improvement in understanding of physical health, motivation to change behaviour and to do exercise. It also results in improved confidence and reduced anxiety.

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Convulxin, a C-type lectin-like protein, inhibits HCASMCs functions via WAD-motif/integrin-αv interaction and NF-κB-independent gene suppression of GRO and IL-8

Publication date: Available online 10 February 2017
Source:Experimental Cell Research
Author(s): Chun-Ho Shih, Tin-Bin Chiang, Wen-Jeng Wang
Convulxin (CVX), a C-type lectin-like protein (CLPs), is a potent platelet aggregation inducer. To evaluate its potential applications in angiogenic diseases, the multimeric CVX were further explored on its mode of actions toward human coronary artery smooth muscle cells (HCASMCs). The N-terminus of β-chain of CVX (CVX-β) contains a putative disintegrin-like domain with a conserved motif upon the sequence comparison with other CLPs. Importantly, native CVX had no cytotoxic activity as examined by electrophoretic pattern. A Trp-Ala–Asp (WAD)-containing octapeptide, MTWADAEK, was thereafter synthesized and analyzed in functional assays. In the case of specific integrin antagonists as positive controls, the anti-angiogenic effects of CVX on HCASMCs were investigated by series of functional analyses. CVX showed to exhibit multiple inhibitory activities toward HCASMCs proliferation, adhesion and invasion with a dose- and integrin αvβ3-dependent fashion. However, the WAD-octapeptide exerting a minor potency could also work as an active peptidomimetic. In addition, flow cytometric analysis demonstrated both the intact CVX and synthetic peptide can specifically interact with integrin-αv on HCASMCs and CVX was shown to have a down-regulatory effect on the gene expression of CXC-chemokines, such as growth-related oncogene and interleukin-8. According to nuclear factor-κB (NF-κB) p65 translocation assay and Western blotting analysis, the NF-κB activation was not involved in the signaling events of CVX-induced gene expression. In conclusion, CVX may act as a disintegrin-like protein via the interactions of WAD-motif in CVX-β with integrin-αv on HCASMCs and it also is a gene suppressor with the ability to diminish the expression of two CXC-chemokines in a NF-κB-independent manner. Indeed, more extensive investigations are needed and might create a new avenue for the development of a novel angiostatic agent.

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Perineal resuturing versus expectant management following vaginal delivery complicated by a dehisced wound (PREVIEW): a pilot and feasibility randomised controlled trial

Objective

To establish the feasibility of conducting a definitive randomised controlled trial (RCT) comparing the effectiveness of resuturing versus expectant management for dehisced perineal wounds.

Design

A multicentre pilot and feasibility RCT.

Setting

Ten UK maternity units from July 2011 to July 2013.

Population

Eligible women with a dehisced perineal wound within 2 weeks of childbirth.

Methods

The interventions were resuturing or expectancy. Randomisation was via web or telephone, stratified by participating centre. Blinding was not possible due to the nature of the interventions. Analysis was by intention-to-treat.

Outcome

The primary outcome measure was wound healing at 6–8 weeks.

Results

The study revealed a number of feasibility issues, particularly strong patient and clinician preference for treatment options at recruiting centres and the timing of the primary outcome measure. Thirty-four women were randomised (17 in each arm). Data from 33 women were analysed on an intention-to-treat analysis to obtain preliminary estimates of effect size. There was a difference in wound healing at 2 weeks favouring resuturing (OR 20.00, 95% CI 2.04 to 196.37, p=0.004). However, by 6–8 weeks all but one wound in both groups had healed.

Conclusions

PREVIEW revealed a number of feasibility issues, which impacted on recruitment rate. These will have to be taken into account in the design of any future definitive study. In this feasibility study, resuturing was associated with quicker wound healing and women reported higher satisfaction rates with the outcome at 3 months.

Trial registration number

ISRCTN05754020.

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What are the decision-making preferences of patients in vascular surgery? A mixed-methods study

Objectives

Shared decision-making (SDM) has been advocated as the preferred method of choosing a suitable treatment option. However, patient involvement in treatment decision-making is not yet common practice in the field of vascular surgery. The aim of this mixed-methods study was to explore patients' decision-making preferences and to investigate which facilitators and barriers patients perceive as important for the application of SDM in vascular surgery.

Design and setting

Patients were invited to participate after visiting the vascular surgical outpatient clinic of an Academic Medical Center in the Netherlands. A treatment decision was made during the consultation for an abdominal aortic aneurysm or peripheral arterial occlusive disease. Patients filled in a number of questionnaires (quantitative part) and a random subgroup of patients participated in an in-depth interview (qualitative part).

Results

A total of 67 patients participated in this study. 58 per cent of them (n=39) indicated that they preferred a shared role in decision-making. In more than half of the patients (55%; n=37) their preferred role was in disagreement with what they had experienced. 31 per cent of the patients (n=21) preferred a more active role in the decision-making process than they had experienced. Patients indicated a good patient–doctor relationship as an important facilitator for the application of SDM.

Conclusions

The vast majority of vascular surgical patients preferred, but did not experience a shared role in the decision-making process, although the concept of SDM was insufficiently clear to some patients. This emphasises the importance of explaining the concept of SDM and implementing it in the clinical encounter.

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Multisite musculoskeletal pain in adolescence and later mental health disorders: a population-based registry study of Norwegian youth: the NAAHS cohort study

Objectives

To examine the association between multisite musculoskeletal pain in adolescence and mental health disorders in young adulthood.

Design and setting

Data were obtained from a linkage between the Norwegian Patient Registry (2008–2012) and the Norwegian Arctic Adolescent Health Study, a school-based survey conducted among 10th grade students in North Norway (2003–2005).

Participants

In total, 3987 (68%) of all 5877 invited participants consented to the registry linkage.

Outcome measures

Mental healthcare use and disorders from age 18–20 to 23–25 years (5 years).

Methods

Musculoskeletal pain was measured by the number of musculoskeletal pain sites. Multivariable logistic regression was used to explore the association with later mental healthcare use and disorders.

Results

Multisite adolescent musculoskeletal pain was significantly associated with an increase in mental healthcare use and mental health disorders in young adulthood. The relationship was stronger for anxiety and mood disorders, in both genders. Overall, the association between musculoskeletal pain and later mental health problems was attenuated after controlling for adolescent psychosocial and mental health problems, not by physical or sedentary activity. This could be due to confounding or mediation. However, when examining different mental health disorders, we found musculoskeletal pain to be significantly associated with anxiety disorders, and showing a strong trend in mood disorders, when adjusted for the adolescent factors.

Conclusions

Physicians should be aware that multisite adolescent pain is associated with mental health problems in adolescence, and that these adolescents are at increased risk of mental health disorders in young adulthood. As youth troubled by mental health problems commonly present physical symptoms it is important to examine for psychosocial problems in order to offer early interventions.

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Perineal resuturing versus expectant management following vaginal delivery complicated by a dehisced wound (PREVIEW): a nested qualitative study

Objective

To explore women's lived experiences of a dehisced perineal wound following childbirth and how they felt participating in a pilot and feasibility randomised controlled trial (RCT).

Design

A nested qualitative study using semistructured interviews, underpinned by descriptive phenomenology.

Participants and setting

A purposive sample of six women at 6–9 months postnatal who participated in the RCT were interviewed in their own homes.

Results

Following Giorgi's analytical framework the verbatim transcripts were analysed for key themes. Women's lived experiences revealed 4 emerging themes: (1) Physical impact, with sub-themes focusing upon avoiding infection, perineal pain and the impact of the wound dehiscence upon daily activities; (2) Psychosocial impact, with sub-themes of denial, sense of failure or self-blame, fear, isolation and altered body image; (3) Sexual impact; and (4) Satisfaction with wound healing. A fifth theme ‘participating in the RCT’ was ‘a priori’ with sub-themes centred upon understanding the randomisation process, completing the trial questionnaires, attending for hospital appointments and acceptability of the treatment options.

Conclusions

To the best of our knowledge, this is the first qualitative study to grant women the opportunity to voice their personal experiences of a dehisced perineal wound and their views on the management offered. The powerful testimonies presented disclose the extent of morbidity experienced while also revealing a strong preference for a treatment option.

Trial registration number

ISRCTN05754020; results.

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ESPACOMP Medication Adherence Reporting Guidelines (EMERGE): a reactive-Delphi study protocol

Introduction

Medication adherence is fundamental to achieving optimal patient outcomes. Reporting research on medication adherence suffers from some issues—including conceptualisation, measurement and data analysis—that thwart its advancement. Using the ABC taxonomy for medication adherence as the conceptual basis, a steering committee of members of the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) launched an initiative to develop ESPACOMP Medication Adherence Reporting Guidelines (EMERGE). This paper is a protocol for a Delphi study that aims to build consensus among a group of topic experts regarding an item list that will support developing EMERGE.

Methods and analysis

This study uses a reactive-Delphi design where a group of topic experts will be asked to rate the relevance and clarity of an initial list of items, in addition to suggesting further items and/or modifications of the initial items. The initial item list, generated by the EMERGE steering committee through a structured process, consists of 26 items distributed in 2 sections: 4 items representing the taxonomy-based minimum reporting criteria, and 22 items organised according to the common reporting sections. A purposive sample of experts will be selected from relevant disciplines and diverse geographical locations. Consensus will be achieved through predefined decision rules to keep, delete or modify the items. An iterative process of online survey rounds will be carried out until consensus is reached.

Ethics and dissemination

An ethics approval was not required for the study according to the Swiss federal act on research involving human beings. The participating experts will be asked to give an informed consent. The results of this Delphi study will feed into EMERGE, which will be disseminated through peer-reviewed publications and presentations at conferences. Additionally, the steering committee will encourage their endorsement by registering the guidelines at the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network and other relevant organisations.

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Randomised trial assessing the impact of framing of fracture risk and osteoporosis treatment benefits in patients undergoing bone densitometry

Objectives

The accuracy of patients' perception of risk is important for decisions about treatment in many diseases. We framed the risk of fracture and benefits of treatment in different ways and assessed the impact on patients' perception of fracture risk and intentions to take medication.

Design

Randomised trial of 4 different presentations of fracture risk and likely benefits from osteoporosis treatment.

Setting

Academic centre.

Participants

200 patients undergoing bone densitometry.

Intervention

Presentation that framed the patient's absolute fracture risk either as the chance of having or not having an event, with their likely benefits from osteoporosis treatment in natural frequencies or numbers needed to treat.

Outcomes

Participants' views about their fracture risk and the need for osteoporosis treatment.

Results

The median 5-year fracture risk threshold participants regarded as high enough to consider preventative medication was 50–60%, and did not change substantially after the presentation. The median (Q1, Q3) 5-year risk initially estimated by participants was 20% (10, 50) for any fracture and 19% (10, 40) for hip fracture. 61% considered their fracture risk was low or very low, and 59–67% considered their fracture risk was lower than average. These participant estimates were 2–3 times higher than Garvan calculator estimates for any fracture, and 10–20 times higher for hip fracture. Participant estimates of fracture risk halved after the presentation, but remained higher than the Garvan estimates (1.5–2 times for any fracture, 5–10 times for hip fracture). There was no difference in these outcomes between the randomised groups. Participants' intentions about taking medication to prevent fractures were not substantially affected by receiving information about fracture risk and treatment benefits.

Conclusions

Altering the framing of estimated fracture risks and treatment benefits had little effect on participants' perception of the need to take treatment or their individual fracture risk.

Trial registration number

ACTRN12613001081707; Pre-results.

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Feasibility of peer assessment and clinical audit to self-regulate the quality of physiotherapy services: a mixed methods study

Objectives

To evaluate the feasibility of a quality improvement programme aimed to enhance the client-centeredness, effectiveness and transparency of physiotherapy services by addressing three feasibility domains: (1) acceptability of the programme design, (2) appropriateness of the implementation strategy and (3) impact on quality improvement.

Design

Mixed methods study.

Participants and setting

64 physiotherapists working in primary care, organised in a network of communities of practice in the Netherlands.

Methods

The programme contained: (1) two cycles of online self-assessment and peer assessment (PA) of clinical performance using client records and video-recordings of client communication followed by face-to-face group discussions, and (2) clinical audit assessing organisational performance. Assessment was based on predefined performance indicators which could be scored on a 5-point Likert scale. Discussions addressed performance standards and scoring differences. All feasibility domains were evaluated qualitatively with two focus groups and 10 in-depth interviews. In addition, we evaluated the impact on quality improvement quantitatively by comparing self-assessment and PA scores in cycles 1 and 2.

Results

We identified critical success features relevant to programme development and implementation, such as clarifying expectations at baseline, training in PA skills, prolonged engagement with video-assessment and competent group coaches. Self-reported impact on quality improvement included awareness of clinical and organisational performance, improved evidence-based practice and client-centeredness and increased motivation to self-direct quality improvement. Differences between self-scores and peer scores on performance indicators were not significant. Between cycles 1 and 2, scores for record keeping showed significant improvement, however not for client communication.

Conclusions

This study demonstrated that bottom-up initiatives to improve healthcare quality can be effective. The results justify ongoing evaluation to inform nationwide implementation when the critical success features are addressed. Further research is necessary to explore the sustainability of the results and the impact on client outcomes in a full-scale study.

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Multilayered and digitally structured presentation formats of trustworthy recommendations: a combined survey and randomised trial

Objectives

To investigate practicing physicians' preferences, perceived usefulness and understanding of a new multilayered guideline presentation format—compared to a standard format—as well as conceptual understanding of trustworthy guideline concepts.

Design

Participants attended a standardised lecture in which they were presented with a clinical scenario and randomised to view a guideline recommendation in a multilayered format or standard format after which they answered multiple-choice questions using clickers. Both groups were also presented and asked about guideline concepts.

Setting

Mandatory educational lectures in 7 non-academic and academic hospitals, and 2 settings involving primary care in Lebanon, Norway, Spain and the UK.

Participants

181 practicing physicians in internal medicine (156) and general practice (25).

Interventions

A new digitally structured, multilayered guideline presentation format and a standard narrative presentation format currently in widespread use.

Primary and secondary outcome measures

Our primary outcome was preference for presentation format. Understanding, perceived usefulness and perception of absolute effects were secondary outcomes.

Results

72% (95% CI 65 to 79) of participants preferred the multilayered format and 16% (95% CI 10 to 22) preferred the standard format. A majority agreed that recommendations (multilayered 86% vs standard 91%, p value=0.31) and evidence summaries (79% vs 77%, p value=0.76) were useful in the context of the clinical scenario. 72% of participants randomised to the multilayered format vs 58% for standard formats reported correct understanding of the recommendations (p value=0.06). Most participants elected an appropriate clinical action after viewing the recommendations (98% vs 92%, p value=0.10). 82% of the participants considered absolute effect estimates in evidence summaries helpful or crucial.

Conclusions

Clinicians clearly preferred a novel multilayered presentation format to the standard format. Whether the preferred format improves decision-making and has an impact on patient important outcomes merits further investigation.

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Enzymatic cleavage of myoferlin releases a dual C2-domain module linked to ERK signalling

Publication date: Available online 10 February 2017
Source:Cellular Signalling
Author(s): Ann-Katrin Piper, Samuel E. Ross, Gregory M. Redpath, Frances A. Lemckert, Natalie Woolger, Adam Bournazos, Peter A. Greer, Roger B. Sutton, Sandra T. Cooper
Myoferlin and dysferlin are closely related members of the ferlin family of Ca²⁺-regulated vesicle fusion proteins. Dysferlin is proposed to play a role in Ca²⁺-triggered vesicle fusion during membrane repair. Myoferlin regulates endocytosis, recycling of growth factor receptors and adhesion proteins, and is linked to the metastatic potential of cancer cells. Our previous studies establish that dysferlin is cleaved by calpains during membrane injury, with the cleavage motif encoded by alternately-spliced exon 40a. Herein we describe the cleavage of myoferlin, yielding a membrane-associated dual C2 domain ‘mini-myoferlin’. Myoferlin bears two enzymatic cleavage sites: a canonical cleavage site encoded by exon 38 within the C2DE domain; and a second cleavage site in the linker adjacent to C2DE, encoded by alternately-spliced exon 38a, homologous to dysferlin exon 40a. Both myoferlin cleavage sites, when introduced into dysferlin, can functionally substitute for exon 40a to confer Ca²⁺-triggered calpain cleavage in response to membrane injury. However, enzymatic cleavage of myoferlin is complex, showing both constitutive or Ca²⁺-enhanced cleavage in different cell lines, that is not solely dependent on calpains-1 or -2. The functional impact of myoferlin cleavage was explored through signalling protein phospho-protein arrays revealing specific activation of ERK1/2 by ectopic expression of cleavable myoferlin, but not an uncleavable isoform. In summary, we molecularly define two enzymatic cleavage sites within myoferlin and demonstrate ‘mini-myoferlin’ can be detected in human breast cancer tumour samples and cell lines. These data further illustrate that enzymatic cleavage of ferlins is an evolutionarily preserved mechanism to release functionally specialized mini-modules.

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Prostate Cancer Heterogeneity: Discovering Novel Molecular Targets for Therapy

Prostate cancer (PCa) is among the most common adult malignancies [1], marked by a broad heterogeneous spectrum of biological and clinical behavior ranging from indolent undiagnosed forms up to aggressive metastatic and rapidly lethal tumors. This complex variety of PCa behavior represents the epiphenomenon of the extreme mutational heterogeneity of this cancer type.

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Adjuvant therapy in patients with Ductal Carcinoma in Situ of the breast: The Pandora’s box

Ductal carcinoma in situ (DCIS) currently accounts for approximately one fifth of newly-diagnosed breast cancers [1]. The actual rate of approximately 1.6-2.0 per 1,000 women screened [1,2] has increased fivefold in the last 25 years both in the U.S. and in Europe [1,3–5], mostly due to the expanded use of screening mammography. However, the natural history of screen-detected DCIS is unclear. Some forms of DCIS remain indolent throughout the lifespan of a patient, whereas other forms have a higher propensity to advance into life-threatening invasive disease.

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Targeting the Programmed Death-1 Pathway in Lymphoid Neoplasms

T cell activation is explained by the two-signal model proposed by Bretscher and Cohn (Fig. 1).[1] The first signal, which triggers T cell receptor (TCR) signaling, occurs when the major histocompatibility complex (MHC) molecule of an antigen-presenting cell (APC) presents a processed antigen to the TCR of a T cell. The second signal, which is an antigen-independent, co-stimulatory or co-inhibitory signal delivered by the APCs, modulates TCR signaling and determines the T cell’s fate. The prototypical molecule of the second signal is CD28, which constitutively expressed in resting naïve T-cells.

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The Expanding Role of Immunotherapy

The development of therapeutic agents that modulate the immune system (IS) to induce or potentiate its anti-tumour activity has revolutionized cancer treatment in recent years. Focusing on the IS of the host rather than the tumour has proven to be an effective strategy in a number of tumours. However, this approach is not new. In the late 19th century, William Coley noticed that some patients affected by sarcoma had tumour response when injected locally with bacteria-derived toxins in what seemed to be an immune-driven effect [1].

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Targeting the Programmed Death-1 Pathway in Lymphoid Neoplasms

Prostate Cancer Heterogeneity: Discovering Novel Molecular Targets for Therapy

Adjuvant therapy in patients with Ductal Carcinoma in Situ of the breast: The Pandora’s box

The Expanding Role of Immunotherapy

Locally Advanced Colon Cancer: Evaluation of Current Clinical Practice and Treatment Outcomes at the Population Level

Background: The goal of this study was to evaluate current clinical practice and treatment outcomes regarding locally advanced colon cancer (LACC) at the population level. Methods: Data were used from the Dutch Surgical Colorectal Audit from 2009 to 2014. A total of 34,527 patients underwent resection for non-LACC and 6,918 for LACC, which was defined as cT4 and/or pT4 stage. LACC was divided into those with multivisceral resection (LACC-MV; n=3,385) and without (LACC-noMV; n=1,595). Guideline adherence, treatment strategy, and short-term outcomes were evaluated. Results: Guideline adherence was >90% regarding preoperative imaging and ≥80% regarding preoperative multidisciplinary team (MDT) discussion. In the elective setting, neoadjuvant chemoradiotherapy (chemoRT) was applied in 6.2% of the cT4 cases, and neoadjuvant chemotherapy in 4.0%. R0 resection rates were 99%, 91%, and 87% in patients with non-LACC, LACC-noMV, and LACC-MV, respectively (P<.001). A postoperative complicated course occurred in 17%, 25%, and 29% of patients (P<.001), and the 30-day/in-hospital mortality rate was 3.6%, 6.0%, and 5.4% (P<.001) in the non-LACC, LACC-noMV, and LACC-MV groups, respectively. Discussion/Conclusions: This population-based study suggests that there is room for improvement in the treatment of LACC, with regard to short-term surgical outcomes and oncologic outcomes (ie, radicality of resection). Improvement might be expected from optimized preoperative imaging, routine MDT discussions, and further specialization and centralization of care. Optimized use of neoadjuvant treatment strategies based on already available and upcoming evidence is likely to result in a better margin status and thereby a better long-term prognosis. Furthermore, lower R0 resection rates in an emergency setting suggest a potential role for bridging strategies in order to enable optimal staging, neoadjuvant treatment, and elective surgery by a surgical team most optimally qualified for the procedure.

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Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology

Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.

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Oncology Research Program

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Identifying Educational Needs of the Multidisciplinary Cancer Team in the Treatment of Metastatic Breast Cancer

Background: Rapid advancements in the field of metastatic breast cancer (mBC) add to the complexity of managing patients with this disease. An educational needs assessment of multidisciplinary mBC clinicians was executed to identify practice performance gaps and recommend educational strategies aimed at closing these gaps. Methods: To ensure a collection of reliable data for assessment, a systematic process was used to design, develop, and validate the tools that were used. This grounded theory approach included assessment and confirmation by clinical experts and validation testing within the target audiences. A mixed-methods approach was used to identify practice performance gaps in care, using both qualitative in-depth interviews and quantitative surveying. The quantitative survey assessment consisted of 2 main sections: the Clinician Change Readiness Inventory tool and a Clinical Knowledge and Practice Assessment. Results: The study included 42 clinicians in the interview phase and 186 clinicians in the survey phase from 36 different states. Five key practice performance gaps were identified: (1) selecting optimal treatment, (2) personalizing therapy, (3) monitoring mBC, (4) engaging in effective communication, and (5) balancing patient access and time. Most of the gaps overlap and are related to the integral role communication plays in management decision-making in mBC. Conclusions: Awareness of the key practice performance gaps is critical to inform improvements in quality care.

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Mad About MACRA

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NCCN News

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Response to PD-1 Blockade in Microsatellite Stable Metastatic Colorectal Cancer Harboring a POLE Mutation

Recent clinical evidence has demonstrated that microsatellite instability (MSI) or defective mismatch repair (MMR) and high tumor mutational load can predict response to the programmed cell death 1 (PD-1) receptor inhibitor pembrolizumab in metastatic colorectal cancer (mCRC). Mutations in polymerase (POLE), a DNA polymerase involved in DNA replication and repair, contribute to an ultramutated but microsatellite stable (MSS) phenotype in colorectal tumors that is uniquely distinct from MSI tumors. This report presents the first case in the literature describing a clinical response to pembrolizumab in an 81-year-old man with treatment-refractory mCRC characterized by an MSS phenotype and POLE mutation identified on genomic profiling by next-generation sequencing. On tumor immunostaining, a large amount of CD8-positive tumor infiltrating lymphocytes (TILs) were present, with >90% of these expressing PD-1. More than 99% of PD-L1 expression was identified on nontumor cells in the tumor microenvironment that were close to the PD-1–positive CD8 TILs. mCRC tumors harboring POLE mutations represent a hypermutated phenotype that may predict response to anti–PD-1 therapy.

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Vascular Invasion and Metastasis is Predictive of Outcome in Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma

Background: Patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) have variable long-term outcomes. Better delineation of prognosis is important for clinical trial enrollment and clinical practice in an era of precision medicine. We hypothesized that stratification of patients with BCLC stage C HCC by presence of vascular invasion and/or metastasis improves prognostic discrimination. Methods: Using a prospectively maintained database, we identified 234 patients diagnosed with BCLC stage C HCC between 2005 and 2015. Patients were stratified into 3 groups based on tumor characteristics: (1) vascular invasion alone, (2) metastasis alone, and (3) vascular invasion and metastasis. Overall survival (OS) was compared using a Cox model. A subgroup analysis was performed based on extent of vascular invasion and site of metastasis. Results: The cohort comprised 123 patients (53%) with vascular invasion alone, 34 (15%) with metastasis alone, and 77 (33%) with both vascular invasion and metastasis. Median survival was 5.7, 3.9, and 3.0 months, respectively (P<.01). Patients with vascular invasion or metastasis alone had significantly better survival compared with those with vascular invasion and metastasis (adjusted hazard ratio [HR],0.68; 95% CI, 0.49–0.94, and HR, 0.61; 95% CI, 0.39–0.96, respectively). Compared with tumoral invasion of branch portal veins, involvement of the main portal vein was associated with worse survival (HR, 2.13; 95% CI, 1.29–3.49). OS did not differ by site of metastasis. Conclusions: Stratification of patients within the BCLC stage C staging subgroup by vascular invasion and presence of metastasis further discriminates patient prognosis. This substratification may have implications for therapy and more accurate prognostic features.

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NCCN Guidelines Insights: Bone Cancer, Version 2.2017

The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.

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Payer Coverage for Hereditary Cancer Panels: Barriers, Opportunities, and Implications for the Precision Medicine Initiative

Background: Hereditary cancer panels (HCPs), testing for multiple genes and syndromes, are rapidly transforming cancer risk assessment but are controversial and lack formal insurance coverage. We aimed to identify payers' perspectives on barriers to HCP coverage and opportunities to address them. Comprehensive cancer risk assessment is highly relevant to the Precision Medicine Initiative (PMI), and payers' considerations could inform PMI's efforts. We describe our findings and discuss them in the context of PMI priorities. Methods: We conducted semi-structured interviews with 11 major US payers, covering >160 million lives. We used the framework approach of qualitative research to design, conduct, and analyze interviews, and used simple frequencies to further describe findings. Results: Barriers to HCP coverage included poor fit with coverage frameworks (100%); insufficient evidence (100%); departure from pedigree/family history–based testing toward genetic screening (91%); lacking rigor in the HCP hybrid research/clinical setting (82%); and patient transparency and involvement concerns (82%). Addressing barriers requires refining HCP-indicated populations (82%); developing evidence of actionability (82%) and pathogenicity/penetrance (64%); creating infrastructure and standards for informing and recontacting patients (45%); separating research from clinical use in the hybrid clinical-research setting (44%); and adjusting coverage frameworks (18%). Conclusions: Leveraging opportunities suggested by payers to address HCP coverage barriers is essential to ensure patients' access to evolving HCPs. Our findings inform 3 areas of the PMI: addressing insurance coverage to secure access to future PMI discoveries; incorporating payers' evidentiary requirements into PMI's research agenda; and leveraging payers' recommendations and experience to keep patients informed and involved.

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Electronic Rapid Fitness Assessment: A Novel Tool for Preoperative Evaluation of the Geriatric Oncology Patient

Background: The American College of Surgeons and American Geriatrics Society recommend performing a geriatric assessment (GA) in the preoperative evaluation of older patients. To address this, we developed an electronic GA, the Electronic Rapid Fitness Assessment (eRFA). We reviewed the feasibility and clinical utility of the eRFA in the preoperative evaluation of geriatric patients. Methods: We performed a retrospective review of our experience using the eRFA in the preoperative assessment of geriatric patients. The rate and time to completion of the eRFA were recorded. The first 50 patients who completed the assessment were asked additional questions to assess their satisfaction. Descriptive statistics of patient-reported geriatric-related data were used for analysis. Results: In 2015, 636 older patients with cancer (median age, 80 years) completed the eRFA during preoperative evaluation. The median time to completion was 11 minutes (95% CI, 11–12 minutes). Only 13% of patients needed someone else to complete the assessment for them. Of the first 50 patients, 88% (95% CI, 75%–95%) responded that answering questions using the eRFA was easy. Geriatric syndromes were commonly identified through the performance of the GA: 16% of patients had a positive screening for cognitive impairment, 22% (95% CI, 19%–26%) needed a cane to ambulate, and 26% (95% CI, 23%–30%) had fallen at least once during the previous year. Conclusions: Implementation of the eRFA was feasible. The eRFA identified relevant geriatric syndromes in the preoperative setting that, if addressed, could lead to improved outcomes.

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Lean: Targeted Therapy for Care Delivery

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Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Mette S. van Ramshorst, Erik van Werkhoven, Ingrid A.M. Mandjes, Margaret Schot, Jelle Wesseling, Marie-Jeanne T.F.D. Vrancken Peeters, Jetske M. Meerum Terwogt, Monique E.M. Bos, Hendrika M. Oosterkamp, Sjoerd Rodenhuis, Sabine C. Linn, Gabe S. Sonke
AimTo determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer.Patients and methodsPatients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m²), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml⁻¹ min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla.ResultsOne hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33–52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82–94), and the 3-year overall survival was 92% (95% CI: 88–98). The most common grade 3–4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment.ConclusionAn anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity.

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Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Lea Schroeder, Paolo Boscolo-Rizzo, Elisa Dal Cin, Salvatore Romeo, Lorena Baboci, Gerhard Dyckhoff, Jochen Hess, Carlota Lucena-Porcel, Anne Byl, Nikolaus Becker, Laia Alemany, Xavier Castellsagué, Miquel Quer, Xavier León, Manuel Wiesenfarth, Michael Pawlita, Dana Holzinger
Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment.In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16^INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome.A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998–2004 to 23% during 2005–2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008).Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP.

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Second- and third-generation drugs for immuno-oncology treatment—The more the better?

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Wolfram C.M. Dempke, Klaus Fenchel, Peter Uciechowski, Stephen P. Dale
Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to ‘step on the gas’ while ‘cutting the brakes’, although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field.

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Transplantations-Richtlinien – Wie hat sich der Richtlinienprozess für die Allokation von Spenderorganen seit dem Transplantationsskandal entwickelt?

Dtsch med Wochenschr 2017; 142: 227-228
DOI: 10.1055/s-0043-103124

Article in Thieme eJournals:
Table of contents | Full text

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Stenting bei Carotisstenose

Dtsch med Wochenschr 2017; 142: 152-156
DOI: 10.1055/s-0042-116620

Aktuelle Studiendaten Die 10-Jahresdaten der CREST-Studie (CEA vs. CAS bei symptomatischen und asymptomatischen Karotisstenosen) sowie die 5-Jahresdaten der ACT I- Studie (asymptomatische Karotisstenosen) zeigen, dass beide Verfahren hinsichtlich ihres Langzeiterfolges (Schlaganfallverhinderung) vergleichbar und sicher sind. Sowohl die Restenoserate als auch die Reinterventionsraten nach CAS sind gegenüber der CEA nicht signifikant unterschiedlich. Echogenität der Plaques/Nachweis von Mikroembolie In einer Metaanalyse zur Echogenität der Karotissplaques im Ultraschall fanden Jashari et al. heraus, dass Patienten mit echoarmen Plaques ein fast 3fach erhöhtes Risiko für einen Schlaganfall aufweisen als Patienten mit echogenen Plaques. Zusätzliche Information liefert die Detektion von „high intense transient signals“ (HITS) mittels transkranieller Duplexsonografie. Technische Weiterentwicklung von Stents und Protektionsystemen Eine Innovation im Bereich der Protektionssysteme ist der monorail-PTA-Ballon, verbunden mit einem oberhalb des Ballons montierten feinporigen Filtersystem. Die Porengröße beträgt lediglich 40 µm (Standardfilter ≥ 100 µm) und lässt sich zudem an die benötigten Gefäßdiameter anpassen. Um einer Plaque-Protrusion während des Stentings entgegenzuwirken, haben Micromesh-Stents auf der endoluminalen oder abluminalen Seite des eigentlichen Stentgerüsts ein weiteres feines Netz. Ziel beider Weiterentwicklungen ist die Verhinderung von Minor-Strokes.
[...]

Article in Thieme eJournals:
Table of contents | Abstract | Full text

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Moderne Therapie der Obstipation

Dtsch med Wochenschr 2017; 142: 205-208
DOI: 10.1055/s-0042-116460

Therapie im Stufenschema Die interdisziplinäre „S2k-Leitlinie Chronische Obstipation: Definition, Pathophysiologie, Diagnostik und Therapie“ fasst die aktuelle wissenschaftliche Evidenz zusammen. Chronische Obstipationsbeschwerden bedürfen eines gewissen Maßes an Diagnostik. Insbesondere sollten ggf. auslösende Ursachen rasch identifiziert werden, um zwischen Stuhlentleerungsstörungen und Transitstörungen zu differenzieren. Zur Therapie der chronischen Obstipation empfiehlt sich die Anwendung eines Stufenschemas, das Allgemeinmaßnahmen, konventionelle Laxanzien, moderne medikamentöse Ansätze sowie ggf. chirurgische Interventionen umfasst. Prucaloprid Mit Prucaloprid, einem 5-HT4-Rezeptor-Agonisten, steht ein wirksames Prokinetikum für konventionell therapierefraktäre Obstipationspatienten zur Verfügung. Linaclotid Linaclotid, ein in Deutschland für das obstipationsprädominante Reizdarmsyndrom zugelassener Guanylatcyclase-C-Rezeptoragonist, kann bei chronischer Obstipation ohne weitere Reizdarmbeschwerden bei ansonsten ausgeschöpfter medikamentöser Therapie eine Behandlungsoption als Off-label-Use darstellen. µ-Opioid-Rezeptor-Antagonisten (PAMORA) Durch selektive Blockade der Opioidwirkung am Darm konnte das Behandlungsspektrum der opioidinduzierten Obstipation (OIC) erweitert und wesentlich verbessert werden. Neben Naloxon (das in der oral retardierten Form nahezu nicht systemisch wirkt) stehen heute mit dem subkutan zu applizierenden Methylnaltrexon und dem neuen, oral verfügbaren Naloxegol auch „echte“, rein peripher wirksame µ-Opioid-Rezeptorantagonisten zur Verfügung. Sakralnervenstimulation Die Wirksamkeit der Sakralnervenstimulation bei der chronischen Obstipation konnte bisher nicht hinreichend nachgewiesen werden. Dennoch kann sie bei ausgesuchten therapierefraktären Patienten, besonders vor einer subtotalen Kolektomie, versucht werden.
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Was soll ich tun bzw. lassen bei einem zufällig entdeckten Nebennierenknoten?

Dtsch med Wochenschr 2017; 142: 158-161
DOI: 10.1055/s-0042-121731

Welche Bildgebung ist die beste? Zur Dignitätsbeurteilung ist das native CT aktuell das am besten validierte Verfahren. Liegen die Hounsfield Units bei ≤ 10, ist die Nebennierenraumforderung benigne und benötigt keinerlei weitere Bildgebung. Welche Hormondiagnostik ist notwendig? Jeder Patient bekommt einen 1mg-Dexamethason-Test, der die Diagnose einer „autonomen Cortisolsekretion“ erlaubt. Das weitere Management dieser Patienten hängt dann aber wesentlich von den Komorbiditäten ab, die in jedem Fall adäquat zu behandeln sind. Zusätzlich wird bei allen Nebennieren-Inzidentalomen ein Phäochromozytom und Conn-Syndrom ausgeschlossen. Welches Operationsverfahren für welchen Patienten? Die meisten Nebennieren-Inzidentalome müssen nicht operiert werden. Wenn eine Operation notwendig ist, kann meist laparoskopisch operiert werden (Tumoren < 6 cm ohne Hinweis auf Lokalinvasion). Vor der Operation erfolgt bei allen Patienten die Vorstellung in einem interdisziplinären Tumorboard. Welcher Patient benötigt welche Nachsorge? Bei endokrin-inaktiven, eindeutig benignen Tumoren bedarf es keinerlei Nachsorge mehr und auch sonst kann aufgrund der genaueren Diagnostik bei Erstdiagnose diese deutlich vereinfacht werden.
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Jürgen Schölmerich neuer Vorsitzender der Deutschen Stiftung Innere Medizin

Dtsch med Wochenschr 2017; 142: 231-231
DOI: 10.1055/s-0043-103128

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Neue Entwicklungen in der geriatrischen Onkologie

Dtsch med Wochenschr 2017; 142: 163-168
DOI: 10.1055/s-0042-122556

Vulnerabilitätsabschätzende Diagnostik Die Abschätzung der Vulnerabilität eines alten Krebspatienten sollte über eine bloße Sichtung anamnestisch bekannter Komorbiditäten und klinische Beurteilung des „Performance Status“ hinausgehen. Geboten ist stattdessen eine lückenlose Fahndung nach geriatrischen Syndromen, weil daraus Änderungen sowohl des onkologischen als auch geriatrischen Therapieplans resultieren können. Eine systematische Erfassung gelingt mittels geriatrischer Konsultation, Screenings und Assessments. Vulnerabilitätsangepasste onkologische Therapie Kontinuierliche Fortschritte bei onkologischen Therapieverfahren führen dazu, dass alte Krebspatienten heute häufiger und differenzierter als früher tumorspezifisch behandelt werden können. Jüngst wurden zahlreiche neue monoklonale Antikörper, Kinasenhemmer sowie andere zielgerichtete Therapeutika zugelassen, wobei der Nutzengewinn zum Teil auch spezifisch bei alten Krebspatienten dokumentiert wurde. Dennoch sind diese Medikamente nicht frei von Nebenwirkungen und das Toxizitätsrisiko bleibt oft gegenüber jüngeren Patienten erhöht. Auch das Risiko von Wechselwirkungen solcher Präparate mit der häufig vielfachen Begleitmedikation eines alten Krebspatienten muss von allen Mitbehandlern jetzt zunehmend beachtet werden. Vulnerabilitätsmildernde geriatrische Therapie Mit dem Ziel, die Vulnerabilität alter Krebspatienten zu senken und dadurch die Verträglichkeit und Durchführbarkeit der onkologischen Therapie sowie das Gesamtüberleben zu verbessern, sollten geriatrische Syndrome bei solchen Patienten häufiger als bisher üblich behandelt werden. Für ein standardisiertes, onkogeriatrisches Syndrom-Management ist die interdisziplinäre Zusammenarbeit zwischen Onkologen, Geriatern und anderen Mitbehandlern weiter zu stärken.
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Dentogener Fokus als Ursache für eine nekrotisierende Fasziitis

Dtsch med Wochenschr 2017; 142: 212-215
DOI: 10.1055/s-0042-121849

Anamnese und klinischer Befund Wir berichten von einem 72-jährigen Patienten, der mit einer schmerzhaften Schwellung des Unterkiefers vorstellig wurde. Untersuchungen und Diagnose In der klinischen Untersuchung fanden sich Krepitationen der Halsweichteile. In der anschließend durchgeführten Computertomografie zeigten sich flächig-konfluierende Lufteinschlüsse subkutan und intramuskulär in den zervikalen Weichteilen beidseits im Sinne eines ausgeprägten Weichteilemphysems. Anatomisch bestand eine enge räumliche Beziehung der oral angrenzenden subkutanen Lufteinschlüsse zu den Zähnen des linken Ober- und Unterkiefers, sodass von einer dentogenen Ursache ausgegangen wurde. Therapie und Verlauf Aufgrund von Klinik und Bildgebung wurde die Diagnose einer nekrotisierenden Fasziitis bei Infektion mit gasbildenden Bakterien mit beginnender Absenkung der Infektion in das Mediastinum gestellt. Als Therapie erfolgte noch am selben Abend ein aggressives chirurgisches Vorgehen mit Sternotomie und Débridement der ausgedehnten Nekroseareale. Folgerung: Bei subkutanem Emphysem und Verdachtsdiagnose nekrotisierender Fasziitis im Kopf-Hals-Bereich ist ein dentogener Fokus als häufigste Ursache zu bedenken. Eine rasche Diagnosefindung ermöglicht eine zeitnahe Einleitung der notwendigen therapeutischen Maßnahmen und ist essenziell für eine optimale Patientenversorgung.
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Akute lymphatische Leukämie des Erwachsenen

Dtsch med Wochenschr 2017; 142: 170-175
DOI: 10.1055/s-0042-121436

Diagnostik und Risikofaktoren Die Bedeutung konventioneller Risikofaktoren tritt im Verhältnis zu der prognostischen Relevanz des individuellen Verlaufs der minimalen Resterkrankung immer mehr in den Hintergrund. Intensivierte Chemotherapie Eine Intensivierung der Chemotherapie auf Basis pädiatrischer Protokolle ist auch bei erwachsenen ALL-Patienten möglich und verbessert das Gesamtüberleben. Essenziell ist für alle Altersgruppen eine konsequente Durchführung der Erhaltungstherapie. Stammzelltransplantation Die Optimierung der Stammzelltransplantation (SZT) hat zu einer deutlichen Verbesserung des Gesamtüberlebens bei Hochrisiko-Patienten beigetragen. Neue Optionen der SZT umfassen dosisreduzierte Konditionierungsschemata für ältere Patienten sowie die haploidente Transplantation bei Patienten ohne passenden Spender. Ph/BCR-ABL-positive ALL Neue Therapien der Ph/BCR-ABL-positiven ALL basieren in allen Altersgruppen auf einer dosisreduzierten Chemotherapie in Kombination mit einem Tyrosinkinaseinhibitor (TKI). Bei jüngeren Patienten ist die SZT in Erstremission weiterhin indiziert. Bei älteren Patienten sollte die Möglichkeit einer SZT mit dosisreduzierter Konditionierung erwogen werden. Immuntherapie bei ALL Die Kombination von zielgerichteter Therapie mit Chemotherapie kann zu einer Verbesserung des Gesamtüberlebens beitragen. In der Erstlinientherapie spielen vor allem der CD20-Antikörper Rituximab sowie im Rahmen von Studien das T-Zell-spezifische Purinanalog Nelarabin einen Rolle. Bei Patienten aller Altersgruppen mit molekularem Therapieversagen oder molekularem Rezidiv sollten die Möglichkeiten auch experimenteller, zielgerichteter Therapien erwogen werden. Altersadaptierte Therapie Die Prognose der ALL ist streng mit dem Alter korreliert. Doch auch bei Patienten über 55 – 65 Jahren können durch spezifische, altersadaptierte Protokolle Heilungschancen verbessert werden. Neue Studien, die auf der Kombination einer Immuntherapie mit dosisreduzierter Chemotherapie beruhen, sollen in Deutschland in Kürze anlaufen. Rezidivtherapie Die Prognose von Rezidivpatienten ist weiterhin ungünstig. Eine Heilung kann nur durch SZT erreicht werden. Neue Immuntherapien stehen für die Behandlung von Rezidiven der B-Vorläufer-ALL zur Verfügung und sind bei Frührezidiven und refraktären Rezidiven den Standardtherapien überlegen. Spätfolgen der Therapie Aufgrund der immer besseren Heilungschancen überleben viele ALL-Patienten langfristig. Die Nachsorge auch im hausärztlichen Bereich sollte die potenziellen Spätfolgen im Blick behalten.
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DGIM schreibt 10 Peter Scriba-Promotionsstipendien 2017 aus

Dtsch med Wochenschr 2017; 142: 230-230
DOI: 10.1055/s-0043-103126

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Antibiotic Stewardship (ABS) in Akutkrankenhäusern – neue Erfahrungen und Empfehlungen

Dtsch med Wochenschr 2017; 142: 177-182
DOI: 10.1055/s-0042-121745

Neue ABS-Leitlinien und strukturelle Empfehlungen Neue Leitlinien für „Antibiotic Stewardship“ (ABS) und EU-Empfehlungen raten zur Einrichtung von ABS-Teams an Krankenhäusern. Mit einer personellen Ausstattung von (mindestens) einer Vollkraft pro 500 Betten scheint damit ein Basisbündel von ABS-Maßnahmen kostenneutral durchführbar. Empfohlen werden nun, je nach Versorgungschwerpunkt, ein bis drei Vollkräfte pro 500 Betten, darunter Infektiologiefachärzte und Apotheker, um eine verbesserte Versorgung von Patienten mit Infektionskrankheiten zu erreichen. Antiinfektivavisiten als wichtiges ABS-Instrument Wichtiges Instrument für eine optimierte Antibiotikaverordnungsqualität und die Vermeidung von Medikationsfehlern sind spezielle Infektionsvisiten. Mit diesen kann meistens auch eine Verkürzung der Therapie sowie eine Reduktion des Verbrauchs von Antibiotika erreicht werden. Antibiotikaverbrauch in deutschen Akutkrankenhäusern Nach einer aktualisierten Querschnittsanalyse des Antibiotikaeinsatzes in mehr als 100 Akutkrankenhäusern zeigte der Gesamtverbrauch 2013/2014 mit rund 40 Tagesdosen/100 Pflegetage wenige Änderungen gegenüber dem Vorjahr. Cephalosporine wurden im Vergleich zu anderen europäischen Ländern immer noch relativ viel eingesetzt. Beispiele für eine sinnvolle Reduktion des Antibiotikaverbrauchs im Krankenhaus Neue Studien unterstreichen die Empfehlungen, nach denen eine perioperative Antibiotikaprophylaxe nicht länger als 24 Stunden durchgeführt werden soll – dies gilt auch für ICD- und Schrittmacherimplantationen. Antibiotika zur Pneumonieprophylaxe bei Schlaganfall sind nicht wirksam. Bisherige Studien zur kritischen Indikationsstellung für Cephalosporine und zum reduzierten Verbrauch von Fluorchinolonen zeigen mäßige Effekte auf die Häufigkeit multiresistenter gramnegativer Bakterien.
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MEDICA EDUCATION CONFERENCE 2016 – Gelungene Vermittlung von Wissenschaft und Medizintechnik

Dtsch med Wochenschr 2017; 142: 232-232
DOI: 10.1055/s-0043-103130

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Nierenersatztherapie bei Intensivpatienten: Ist ein früher Beginn sinnvoll?

Dtsch med Wochenschr 2017; 142: 184-188
DOI: 10.1055/s-0042-119242

Wann ist der optimale Zeitpunkt? Unklarheit besteht, ob ein früher Beginn eines Nierenersatzverfahrens bei Intensivpatienten sinnvoll sein kann. Ein früher Beginn kann Komplikationen vermeiden helfen, umgekehrt benötigen viele Patienten mit Nierenversagen am Ende gar kein Ersatzverfahren und würden dann nur einem unnötigen Trauma unterzogen werden. Früh oder nicht früh? Studienlage nicht einheitlich Zwei neue große randomisiert-kontrollierte Studien zum optimalen Beginn eines Nierenersatzverfahrens kommen zu unterschiedlichen Ergebnissen. Grund dafür sind die verschiedenen Vorgehensweisen der beiden Studien. Beide Studien können wichtige, neue Informationen jedoch keine definitiven Antworten liefern. Die Entscheidung zum Beginn muss daher weiter immer individuell unter Abwägung des Nutzens aber auch des Risikos einer Nierenersatztherapie getroffen werden.
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64-jährige Frau mit Dyspnoe und verkürzten Phalangen

Dtsch med Wochenschr 2017; 142: 209-209
DOI: 10.1055/s-0042-122504

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ESC-Leitlinien 2016 – Prävention kardiovaskulärer Erkrankungen in der klinischen Praxis

Dtsch med Wochenschr 2017; 142: 189-192
DOI: 10.1055/s-0042-113928

Bevölkerungsbezogene Prävention Die Leitlinien von 2016 beinhalten erstmals Empfehlungen zur Umsetzung präventiver Maßnahmen in öffentlichen Bereichen durch Politik, Wirtschaft, Schule und Arbeitsplatz. Ein Beispiel ist die Empfehlung, Nichtraucherschutzgesetze sowie die Besteuerung von Tabakwaren zu verstärken. Individuelle Risikoeinschätzung Zur Risikoeinschätzung wird die Messung der Intima-Media-Dicke der Karotiden nicht mehr empfohlen. Zusätzlich zu klassischen Risikofaktoren, wie Rauchen und Cholesterin, sollen weitere Risikomodifikatoren (wie psychosoziales Umfeld) und das Risiko besonderer Patientengruppen (frauenspezifische Erkrankungen, EU-Immigranten) in die Bewertung einfließen Individuelle Prävention Neue Studien, wie IMPROVE-IT (Ezetimib) und EMPA-REG OUTCOME (Empagliflozin) haben die Empfehlungen zur Intervention bei zahlreichen Risikofaktoren modifiziert. In den aktuellen Leitlinien werden zudem neue Entwicklungen wie die elektronische Zigarette oder PCSK9-Inhibitoren diskutiert.
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Prävention von Infekten der oberen Atemwege

Dtsch med Wochenschr 2017; 142: 217-224
DOI: 10.1055/s-0042-120574

Because of its high prevalence acute respiratory diseases have a significant impact on the population. The focus of this review was the current state of knowledge for the prophylactic efficacy of: zinc, vitamin C, Echinacea preparations, garlic and carrying out physical measures. Furthermore, the benefits of pneumococcal and influenza vaccine were elicited. In the synopsis, the physical measures proved to be the most effective, cost-effective method to prevent infections. The intake of zinc, Echinacea preparations (for example: E. purpurea), vitamin C and garlic showed moderate success in the prevention of infection and must be elicited individually. Pneumococcal and annual influenza vaccines in family practice should be given furthermore accordingly topical STIKO-recommendation. Nevertheless, the prophylactic effect from influenza vaccines on usual cold illnesses is unsettled.
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Chronisches Nierenversagen

Dtsch med Wochenschr 2017; 142: 193-196
DOI: 10.1055/s-0042-123170

Neue Endpunkte zur Progressionsverzögerung diabetischer Spätschäden Das Fortschreiten diabetischer Nierenschäden kann derzeit auf eine Progressionsrate von 3 – 4 ml/min/Jahr GFR gesenkt werden. Neue Endpunkte als Alternative zum terminalen Nierenversagen werden geprüft, z. B. ein 40 %iger eGFR-Abfall, eGFR-slopes oder ein 30 %iger Rückgang der Albuminurie. Renale und kardiovaskuläre Protektion bei Niereninsuffizienz Therapiestandard bei kardiovaskulären Hochrisiko-Patienten ist die Gabe von Statin, RAS-Hemmer und Acetylsalicylsäure. Änderungen in Sichtweise und Therapie sind aber zurzeit durch Erkenntnisse aus Studien mit Empagliflozin und Liraglutid zu erwarten. Aktuelle Studienlage Die Blockade des Natrium-Glukose-Cotransporters 2 beim kardiovaskulär kranken Typ-2-Diabetiker mit Empagliflozin führt zu einer Verzögerung der Progression einer diabetischen Nephropathie (EMPA-REG-OUTCOME-Studie). Glucagon-like-Peptid-1-Rezeptor-Agonisten wie Liraglutid und Semaglutid reduzieren vor allem die Albuminurie (LEADER- und SUSTAIN-6-Studie), haben aber das Potenzial für Nephroprotektion im Langzeitverlauf. Neue Optionen der Diabetestherapie bei Niereninsuffizienz Die zunehmende Glukoneogenese bei erhöhter Nierenfunktionseinschränkung stellt Patienten und Ärzte vor große Herausforderungen, da sukzessiv die Insulindosis reduziert werden muss. Neue Therapieansätze werden von Nephrologen daher begrüßt. ESC-Leitlinien 2016 zur LDL-Cholesterinsenkung Die European Society of Cardiology (ESC) hat eine neue Leitlinie zur LDL-Cholesterinsenkung veröffentlicht. Niereninsuffiziente wurden dort als Antwort auf die KDIGO-Leitlinien in die Gruppe der Hoch- und Höchstrisiko-Patienten aufgenommen. Biomarker zur Präzisierung in klinischen Studien Zur Auswahl des Patientenkollektivs sollen zukünftig neue Panels an Biomarkern erstellt werden, um zu selektieren, wer dem Wirkungsprofil des neuen Medikaments am besten entspricht. NTproBNP eignet sich z. B. zur Selektion von Patienten für Herzinsuffizienzstudien.
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DGIM-Generalsekretär geehrt – Professor Ulrich R. Fölsch mit Walter-Siegenthaler-Medaille ausgezeichnet

Dtsch med Wochenschr 2017; 142: 229-229
DOI: 10.1055/s-0043-103125

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Chronischer idiopathischer Husten

Dtsch med Wochenschr 2017; 142: 197-200
DOI: 10.1055/s-0042-121765

Klassifizierung des Hustens Die Klassifizierung ist jetzt dreistufig: Chronischer idiopathischer Husten – eine neue Hypothese Der chronische idiopathische Husten (CIH, in früheren Leitlinien: chronisch persistierender Husten) wird durch eine Hypersensitivität des Hustenreflexes verursacht. Häufig wird diese Hypersensitivität durch einen unscheinbaren viralen Infekt ausgelöst, sie kann Jahre oder Jahrzehnte anhalten. Frauen sind doppelt so häufig betroffen wie Männer. Gastroösophagealer Reflux, chronische Rhinosinusitis, laryngeale Hyperreagibilität sind nicht die Auslöser, sondern nur Trigger des Hustens. Die Therapie einzelner Trigger kann häufig eine Linderung, aber keine völlige Resolution des Hustens bewirken. Therapeutische Aspekte beim chronischen idiopathischen Husten Sekretomotorika und Antitussiva sind für die symptomatische Therapie des CIH nur wenig wirksam. Meistens bringt die Behandlung identifizierter Trigger wie Reflux oder chronische Rhinosinusitis eine Erleichterung. Die Hypothese der Neuropathie des Hustenreflexes bei CIH führte zur Empfehlung eines Heilversuches mit Gabapentin, Pergabalin und Amitryptilin. Alle 3 Substanzen sind für diese Indikation nicht zugelassen.
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Πληροφορίες

Παρασκευή 10 Φεβρουαρίου 2017

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