TP53 is not a prognostic markerâ clinical consequences of a generally disregarded fact

Technological progress within the last 15â 20 years has significantly increased our knowledge about the molecular basis of cancer development, tumor progression, and treatment response. As a consequence, a vast number of biomarkers have been proposed, but only a small fraction of them have found their way into clinical use. The aim of this paper is to describe the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. We name this procedure the â tripleâ R principleâ : robustness, reproducibility, and relevance. The usefulness of this principle is illustrated with the marker TP53. Since it is mutated in a broad spectrum of cancer entities, TP53 can be considered a very promising marker. Thus, TP53 has been studied in detail but there is still no explicit consensus about its clinical value. By considering our own experience and reviewing the literature, we demonstrate that a major problem of current biomarker research is disregard of whether the biomarker is prognostic or predictive. As an example, it is demonstrated that TP53 is not a prognostic marker, but rather a purely predictive marker, and that disregard of this fact has made this otherwise strong biomarker appear as not being clinically useful so far.Many biomarkers have been proposed for cancer, but only a small fraction of them are clinically useful. This paper describes the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. This is illustrated with the marker TP53, which has been studied in detail but for which there is still no explicit consensus about its clinical value.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146810/1/nyas13947.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146810/2/nyas13947_am.pd

Methods for non-proportional hazards in clinical trials: A systematic review

For the analysis of time-to-event data, frequently used methods such as the log-rank test or the Cox proportional hazards model are based on the proportional hazards assumption, which is often debatable. Although a wide range of parametric and non-parametric methods for non-proportional hazards (NPH) has been proposed, there is no consensus on the best approaches. To close this gap, we conducted a systematic literature search to identify statistical methods and software appropriate under NPH. Our literature search identified 907 abstracts, out of which we included 211 articles, mostly methodological ones. Review articles and applications were less frequently identified. The articles discuss effect measures, effect estimation and regression approaches, hypothesis tests, and sample size calculation approaches, which are often tailored to specific NPH situations. Using a unified notation, we provide an overview of methods available. Furthermore, we derive some guidance from the identified articles. We summarized the contents from the literature review in a concise way in the main text and provide more detailed explanations in the supplement (page 29)

Critical Appraisal of Randomized Clinical Trials: Can We Have Faith in the Conclusions?

Randomized clinical trials (RCTs) are the most appropriate research design for studying the effectiveness of a specific intervention. Its results are considered as the highest ‘level of evidence'. Published reports on RCTs have already succeeded in a peer review process, but still there can be undetected major deficiencies of the study that may question the reported outcome. It is still up to the readers to assess the quality of publications and to question if the published results apply to their patients. The major points of such a critical appraisal process are reviewed and discussed with a focus on breast cancer studies

International Journal of Geriatric Psychiatry / SSRI comedication with NOAC or VKA does not increase hospitalisation for bleeding: A retrospective nationwide cohort study in Austria 20102015

Objectives Nonvitamin K oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) are used for the prophylaxis and treatment of thromboembolic events. A potential drugdrug interaction and increased bleeding events have been reported with comedication of selective serotonin receptor inhibitors (SSRIs) and VKA. The aim of this study was to investigate the bleeding risk of a coprescription of NOAC or VKA with SSRI. Methods Patients with prescription of NOAC or VKA and an antidepressant drug therapy (ADTx) were selected from the drug reimbursement database of 13 Austrian health insurance funds. For this cohort, hospital discharge diagnoses for gastrointestinal bleeding, cerebral haemorrhage, and bleeding anaemia between 2010 and 2015 were analysed. Results Data were available from 50 196 female and 31 308 male patients. Among these, 892 patients had 987 hospitalisations with bleeding events. The most frequent bleeding cases were gastrointestinal bleedings with 588 events (59.6%), followed by cerebral haemorrhage with 344 (34.8%), and bleeding anaemia with 55 events (5.6%), respectively. The risk of bleeding events was similar between SSRI and other ADTx, when combined with oral anticoagulants (p = 0.51). Concomitant treatment of patients with SSRI or other ADTx and NOAC was associated with an increased bleeding risk compared with cotreatment with VKA (1.21, 95% CI: 1.051.40; p = 0.0097). Conclusion Comedication of SSRI with VKA or NOAC has little if any impact on hospital discharge diagnoses for bleeding events compared with cotreatment of those anticoagulants with other antidepressant medications.(VLID)510236

Minimal-invasive approach for penetrating Crohns disease is not associated with increased complications

Background Laparoscopic surgery for penetrating Crohns disease (CD) still remains highly conflicting due to a lack of sufficient data. Therefore, the following large study was designed to compare postoperative outcomes after minimal-invasive resections for penetrating and non-penetrating CD. Methods Consecutive patients, who underwent laparoscopic intestinal resection for symptomatic CD at a tertiary academic referral center, were included. Patients were divided according to perioperative findings in penetrating and non-penetrating type of disease. All clinical data were obtained from an institutional database and analyzed retrospectively. Results Of 234 patients enrolled, 101 patients [females: n = 54 (53.5 %)] were operated on for non-penetrating CD and 133 patients [females: n = 50 (37.6 %)] for penetrating CD. Fistulas (p < 0.001), inflammatory mass (p < 0.001) and abscess formation (p < 0.001) were observed more frequently in the perforating group. Ileocolic resections were performed predominantly in both groups [perforating CD: n = 110 (82.7 %), non-perforating CD: n = 82 (81.2 %)], with more complex resections (>1 intestinal resection) found in perforating CD (p < 0.001). Conversion rates did not differ significantly. Notably, 30-day postoperative morbidity was comparable for both groups [perforating CD: n = 20 (15 %), non-perforating CD: n = 19 (18.8 %), p = 0.44]. Postoperative complication rates graded according to the ClavienDindo classification showed no difference too (p = 0.49). Conclusion Laparoscopic surgery can be conducted safely in selected patients with penetrating CD without increasing the risk of postoperative complications. This finding needs to be implemented in future guidelines.(VLID)348927

The modified Glasgow prognostic score in Crohns diseasedoes it predict short-term outcome?

Background The modified Glasgow prognostic score (mGPS) has recently gained increased attention as a prognostic marker for malignant disease survival and postoperative short-term complications. Due to lacking data, the present study was conducted to correlate the mGPS with the postoperative course in patients following surgery for Crohns disease. Methods We enrolled 341 patients who underwent intestinal resection for symptomatic Crohns disease at a tertiary referral centre between 2000 and 2014. All relevant data were obtained from the institutional database and individual chart review. Thirty-day morbidity was defined according to the ClavienDindo classification. Results A total of 79 (23.17%) postoperative complications were identified (grade I and II: n = 54, 15.84%; grade III and IV: n = 23, 6.74%; grade V: n = 2, 0.59%). The mGPS did not show any correlation with an eventful postoperative course following surgery (no complication: median mGPS: 1, range 02; complications: median mGPS: 1, range 02; p = 0.8521). In addition, the occurrence of an anastomotic leakage was not associated with a higher mGPS (p = 0.8592). Patients with an acute indication for surgery (n = 29, 11.44%) had higher median mGPS (median: 2, range 02) in contrast to patients who were operated on electively (median: 1, range 02; p = 0.0003). No other correlation between surgical characteristics and mGPS was detected. Conclusions In the present study, we could clearly demonstrate that an acute indication for surgery in symptomatic Crohns disease is associated with higher mGPS scores. However, the mGPS did not correlate with postoperative complications. Further studies are required to define the prognostic value of mGPS in Crohns disease patients.(VLID)359159

Survival rate of autotransplanted teeth after 5 years : A retrospective cohort study

Background: Autotransplantation of teeth (TX) is a predictable treatment option, although this type of therapy is often overlooked compared to other types of restorations. Purpose: As current literature contains few long-term studies concerning the outcome of auto-transplanted immature molars, the aim was to evaluate results after a follow-up period of 5 years. Material and methods: This retrospective study enrolled all patients treated with immature auto-transplanted molars after a follow-up period of 5 years. In order to ensure comparable results, survival rate was investigated as well as clinical and radiological parameters. Contralateral teeth (TC) were used as controls for further assessments and for ensuring comparable future results. Results: 52 patients with 66 TX were examined. Mean age at the time of surgery was 19.64 years. Tooth survival rate after 5 years was 89.39%. The results for parameters such as PPD, BOP, mobility, dental caries, periapical pathologies and endodontic treatments showed no differences. In contrast, dental restorations (p < 0.001), occlusal contacts (p = 0.003) and sensitivity (p < 0.001) differed significantly between TX and TC. Conclusions: The current findings clearly confirm that TX is an effective alternative treatment option to fixed prosthodontic restorations and dental implants, and provides for results equivalent to those with the patients' natural teeth. (C) 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved

Providing the best chest compression quality: Standard CPR versus chest compressions only in a bystander resuscitation model.

AIM OF THE STUDY:Bystander-initiated basic life support (BLS) for the treatment of prehospital cardiac arrest increases survival but is frequently not performed due to fear and a lack of knowledge. A simple flowchart can improve motivation and the quality of performance. Furthermore, guidelines do recommend a chest compression (CC)-only algorithm for dispatcher-assisted bystander resuscitation, which may lead to increased fatigue and a loss of compression depth. Consequently, we wanted to test the hypothesis that CCs are more correctly delivered in a flowchart-assisted standard resuscitation algorithm than in a CC-only algorithm. METHODS:With the use of a manikin model, 84 laypersons were randomized to perform either flowchart-assisted standard resuscitation or CC-only resuscitation for 5min. The primary outcome was the total number of CCs. RESULTS:The total number of correct CCs did not significantly differ between the CC-only group and the standard group (63 [±81] vs. 79 [±86]; p = 0.394; 95% CI of difference: 21-53). The total hand-off time was significantly lower in the CC-only group than in the standard BLS group. The relative number of correct CCs (the fraction of the total number of CCs achieving 5-6cm) and the level of exhaustion after BLS did not significantly differ between the groups. CONCLUSION:Standard BLS did not lead to an increase in correctly delivered CCs compared to CC-only resuscitation and exhibited significantly more hand-off time. The low rate of CCs in both groups indicates the need for an increased focus on performance during BLS training