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Purpose: To review the role of radiotherapy (RT) in the treatment of renal cell cancer (RCC) in the curative and palliative setting.
Content: Details related to the clinical outcomes of primary, preoperative, postoperative and palliative RT are discussed, along with a presentation of the established role of surgery and systemic therapy. An overview of data derived from mono- and multi-institutional trials is provided.
Conclusion: Radiotherapy has been shown to provide good symptom palliation and local control in RCC depending on the dose that can be delivered. There is emerging data suggesting that with the use of high-precision RT methods the indication spectrum of RT can be exploited covering different clinical situations particularly for unresectable local recurrences and oligometastatic disease.
Background: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The management of affected patients contains unique challenges because of the rarity of this tumor entity and its critical location at the porta hepatis, which can make achievement of a radical resection very difficult.
Methods: In a retrospective chart analysis we analysed children suffering from biliary RMS who were registered in three different CWS trials (CWS-96, CWS-2002P, and SoTiSaR registry).
Results: Seventeen patients (12 female, 5 male) with a median age of 4.3 years were assessed. The median follow-up was 42.2 months (10.7–202.5). The 5-year overall (OS) and event free survival (EFS) rates were 58% (45–71) and 47% (34–50), respectively. Patients > 10 years of age and those with alveolar histology had the worst prognosis (OS 0%). Patients with botryoid histology had an excellent survival (OS 100%) compared to those with non-botryoid histology (OS 38%, 22–54, p = 0.047). Microscopic complete tumor resection was achieved in almost all patients who received initial tumor biopsy followed by chemotherapy and delayed surgery.
Conclusion: Positive predictive factors for survival of children with biliary RMS are age ≤ 10 years and botryoid tumor histology. Primary surgery with intention of tumor resection should be avoided.
Objectives: The present randomized clinical trial assesses the six-month outcomes following surgical regenerative therapy of periimplantitis lesions using either an electrolytic method (EC) to remove biofilms or a combination of powder spray and electrolytic method (PEC).
Materials and Methods: 24 patients with 24 implants suffering from peri-implantitis with any type of bone defect were randomly treated by EC or PEC. Bone defects were augmented with a mixture of natural bone mineral and autogenous bone and left for submerged healing. The distance from implant shoulder to bone was assessed at six defined points at baseline (T0) and after six months at uncovering surgery (T1) by periodontal probe and standardized x-rays.
Results: One implant had to be removed at T1 because of reinfection and other obstacles. None of the other implants showed signs of inflammation. Bone gain was 2.71 ± 1.70 mm for EC and 2.81 ± 2.15 mm for PEC. No statistically significant difference between EC and PEC was detected. Significant clinical bone fill was observed for all 24 implants. Complete regeneration of bone was achieved in 12 implants. Defect morphology impacted the amount of regeneration.
Conclusion: EC needs no further mechanical cleaning by powder spray. Complete re-osseointegration in peri-implantitis cases is possible.
Objective: Novel treatments are needed to control treatment‐resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE).
Methods: A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation.
Results: In total, TPM was used in 106 of 854 patients having a mean age of 67.4 ± 18.1 years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5 days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100 mg/d, which was uptitrated to a median maintenance dose of 400 mg/d. Treatment with TPM was continued for a median time of 12 days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment‐emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty‐four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n = 24).
Significance: The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than 8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.
Background: Until now, a few studies have addressed the accuracy of intraoral scanners (IOSs) in implantology. Hence, the aim of this in vitro study was to assess the accuracy of 5 different IOSs in the impressions of single and multiple implants, and to compare them.
Methods: Plaster models were prepared, representative of a partially edentulous maxilla (PEM) to be restored with a single crown (SC) and a partial prosthesis (PP), and a totally edentulous maxilla (TEM) to be restored with a full-arch (FA). These models were scanned with a desktop scanner, to capture reference models (RMs), and with 5 IOSs (CS 3600®, Trios3®, Omnicam®, DWIO®, Emerald®); 10 scans were taken for each model, using each IOS. All IOS datasets were loaded into a reverse-engineering software where they were superimposed on the corresponding RMs, to evaluate trueness, and superimposed on each other within groups, to determine precision. A statistical analysis was performed.
Results: In the SC, CS 3600® had the best trueness (15.2 ± 0.8 μm), followed by Trios3® (22.3 ± 0.5 μm), DWIO® (27.8 ± 3.2 μm), Omnicam® (28.4 ± 4.5 μm), Emerald® (43.1 ± 11.5 μm). In the PP, CS 3600® had the best trueness (23 ± 1.1 μm), followed by Trios3® (28.5 ± 0.5 μm), Omnicam® (38.1 ± 8.8 μm), Emerald® (49.3 ± 5.5 μm), DWIO® (49.8 ± 5 μm). In the FA, CS 3600® had the best trueness (44.9 ± 8.9 μm), followed by Trios3® (46.3 ± 4.9 μm), Emerald® (66.3 ± 5.6 μm), Omnicam® (70.4 ± 11.9 μm), DWIO® (92.1 ± 24.1 μm). Significant differences were found between the IOSs; a significant difference in trueness was found between the contexts (SC vs. PP vs. FA). In the SC, CS 3600® had the best precision (11.3 ± 1.1 μm), followed by Trios3® (15.2 ± 0.8 μm), DWIO® (27.1 ± 10.7 μm), Omnicam® (30.6 ± 3.3 μm), Emerald® (32.8 ± 10.7 μm). In the PP, CS 3600® had the best precision (17 ± 2.3 μm), followed by Trios3® (21 ± 1.9 μm), Emerald® (29.9 ± 8.9 μm), DWIO® (34.8 ± 10.8 μm), Omnicam® (43.2 ± 9.4 μm). In the FA, Trios3® had the best precision (35.6 ± 3.4 μm), followed by CS 3600® (35.7 ± 4.3 μm), Emerald® (61.5 ± 18.1 μm), Omnicam® (89.3 ± 14 μm), DWIO® (111 ± 24.8 μm). Significant differences were found between the IOSs; a significant difference in precision was found between the contexts (SC vs. PP vs. FA).
Conclusions: The IOSs showed significant differences between them, both in trueness and in precision. The mathematical error increased in the transition from SC to PP up to FA, both in trueness than in precision.
University hospital research
(2019)
Weltweit stellt das kolorektale Karzinom die dritthäufigste Krebsdiagnose bei Männern und die zweithäufigste bei Frauen dar. Von den bekannten beeinflussbaren Risikofaktoren sind Ernährung, Rauchen und körperliche Aktivität zu nennen, hingegen gelten Alter, familiäre Belastung und männliches Geschlecht als nicht beeinflussbare Risikofaktoren. Neben Genmutationen, welche beispielsweise bei der Familiären Adenomatösen Polyposis coli und beim “Lynch Syndrom” eine wichtige Rolle spielen, kann auch die pathologisch verstärkte Expression von tumorrelevanten Proteinen wie z.B. induzierbare COX-2, Cyclin A, B und D, c-Fos, EGF, MMP-9, VEGF sowie das ubiquitäre RNA-Bindeprotein HuR maßgeblich zur Entstehung des Kolonkarzinoms beitragen. Viele der bislang identifizierten Zielgene des HuRs sind an der Regulation tumorpromovierender Eigenschaften wie Proliferation, Invasion, Metastasierung und Apoptose beteiligt, was HuR zu einem hochattraktiven Target der molekularen Tumortherapie macht. Bislang ist bekannt, dass eine gesteigerte HuR-Bindung an AREs in der 3’UTR vieler Zielgene entweder zur Stabilisierung und/oder
Translationsveränderung von kurzlebigen mRNAs von tumorrelevanten Genprodukten führen kann. Eine pathologisch erhöhte zytosolische HuR Akkumulation, welche bekanntlich oft mit einer ungünstigen Prognose der Tumorpatienten korreliert, wird jedoch im Wesentlichen als Folge eines fehlerhaft regulierten erhöhten Exportes des überwiegend im Zellkern lokalisierten HuR Proteins ins Zytoplasma (sogenanntes “HuR-Shuttling”) betrachtet, während genomische oder epigenetische Mechanismen vermutlich nur eine untergeordnete Rolle spielen. Der Gegenstand der vorliegenden Arbeit war die Aufklärung der bisher nur wenig bekannten zugrunde liegenden Mechanismen des erhöhten HuR-Shuttlings in der Kolonkarzinom-Zelllinie DLD-1 unter besonderen Berücksichtigung PKCδ-abhängiger Signalwege. Durch Zugabe des pharmakologischen PKCδ-Inhibitors Rottlerin konnte die subzelluläre HuR-Lokalisation in den Kolonkarzinom Zelllinien DLD-1 und SW-620 deutlich reduziert werden, wobei die maximale Wirkung erst nach einer Inhibitionszeit von 16 Stunden erreicht wurde. Diese Beobachtung lässt vermuten, dass Rottlerin die PKCδ Aktivität in DLD-1 Zellen hemmt. Hingegen konnten Inhibitoren von verschiedenen MAPK-Kinasen (SB203580, SP600125, PD98059, Raf-1-Inhibitor) die basale zytoplasmatische HuR Lokalisation nicht beeinflussten, ebensowenig der pharmakologische Inhibitor der Calcium-abhängigen PKCs (PKCα und PKCβ) Gö6976. Auf der anderen Seite bewirkte das Phorbolester PMA eine deutliche Steigerung der PKC-Aktivität. Des Weiteren wurde in dieser Arbeit nach tumorrelevanten Genen gesucht, deren Expression in humanen Kolonkarzinomzellen posttranskriptionell von HuR und gleichzeitig von PKCδ kontrolliert wird. Mit Hilfe von RNA-Pulldown Experimenten konnte gezeigt werden, dass die Hemmung der PKCδ funktionell zu einer starken Reduktion der an HuR-gebundenen mRNAs wie c-myc, cyclin A und D sowie COX-2 führt. Schließlich haben Aktivitätsmessungen der Gesamt-PKC-Aktivität gezeigt, dass diese in Kolonkarzinom-Zelllinien nachweisbar und damit basal aktiv ist. Die Untersuchungsergebnisse dieser Arbeit können zum besseren Verständnis der pathophysiologischen Bedeutung des ubiquitären RNA-Bindeproteins HuR für die Kolonkarzinogenese sowie der prokarzinogenen Rolle der PKCδ im Kolongewebe beitragen.
uORF-tools—workflow for the determination of translation-regulatory upstream open reading frames
(2019)
Ribosome profiling (ribo-seq) provides a means to analyze active translation by determining ribosome occupancy in a transcriptome-wide manner. The vast majority of ribosome protected fragments (RPFs) resides within the protein-coding sequence of mRNAs. However, commonly reads are also found within the transcript leader sequence (TLS) (aka 5’ untranslated region) preceding the main open reading frame (ORF), indicating the translation of regulatory upstream ORFs (uORFs). Here, we present a workflow for the identification of translation-regulatory uORFs. Specifically, uORF-Tools uses Ribo-TISH to identify uORFs within a given dataset and generates a uORF annotation file. In addition, a comprehensive human uORF annotation file, based on 35 ribo-seq files, is provided, which can serve as an alternative input file for the workflow. To assess the translation-regulatory activity of the uORFs, stimulus-induced changes in the ratio of the RPFs residing in the main ORFs relative to those found in the associated uORFs are determined. The resulting output file allows for the easy identification of candidate uORFs, which have translation-inhibitory effects on their associated main ORFs. uORF-Tools is available as a free and open Snakemake workflow at https://github.com/Biochemistry1-FFM/uORF-Tools. It is easily installed and all necessary tools are provided in a version-controlled manner, which also ensures lasting usability. uORF-Tools is designed for intuitive use and requires only limited computing times and resources.
For many years, small but significant advancements have been made time and again in the prevention and treatment of early breast cancer. The so-called panel gene analyses are becoming more and more important in prevention, since the risk due to the tested genes is better understood and as a result, concepts for integration in health care can be developed. In the adjuvant situation, the first study in the so-called post-neoadjuvant situation was able to demonstrate a clear improvement in the prognosis with an absent pathological complete remission following trastuzumab or pertuzumab + trastuzumab. Additional studies with this post-neoadjuvant therapeutic concept are still being conducted at present. The CDK4/6 inhibitors which had shown a significant improvement in progression-free survival in a metastatic situation are currently being tested in the adjuvant situation in large therapeutic studies. These and other new data for the treatment or prevention of primary breast cancer are presented in this review against the backdrop of current studies.
The treatment of patients with advanced breast cancer has developed further in recent years. In addition to therapeutic progress in the established subgroups (hormone receptor and HER2 status), there are now therapies which are geared to individual molecular characteristics, such as PARP inhibitor therapy in BRCA-mutated patients. In addition to this, tests are being developed which are intended to establish additional markers within subgroups in order to predict the efficacy of a therapy. PI3K mutation testing in HER2-negative, hormone-receptor-positive tumours and PD-L1 testing of immune cells in triple-negative tumours are expected to become established in clinical practice in order to select patients for the respective therapies. With new therapeutic approaches, new adverse effects also appear. The management of these adverse effects, just as those of classical therapy (supportive therapy), is essential with the introduction of new treatments in order to preserve patientsʼ quality of life. Knowledge regarding measures to preserve and improve quality of life has significantly increased in recent years. Lifestyle factors should be taken into account, as should modern therapeutic methods. This review summarises the latest studies and publications and evaluates them in regard to the relevance for clinical practice.