Anti-Inflammatory Characteristics of Local Anesthetics: Inhibition of TNF-α Secretion of Lipopolysaccharide-Stimulated Leucocytes in Human Blood Samples

Background. Local anesthetics (LAs) have potent anti-inflammatory properties. Inflammatory down-regulation is crucial in diseases with overactive immune reactions, such as acute respiratory distress syndrome (ARDS) and chronic inflammation. We investigated the influence of four LAs, procaine, lidocaine, mepivacaine, and bupivacaine, on the reduction of tumor necrosis factor-alpha (TNF-α) secretion in lipopolysaccharide (LPS)-activated human leucocytes. Methods. Blood samples of 28 individuals were stimulated with LPS. The reduction of TNF-α production by each of the four LAs added (0.5 mg/mL) was measured and correlated with biometric variables. A response was defined as reduction to <85% of initial levels. Results. All four LAs down-regulated the TNF-α secretion in 44–61%: Bupivacaine (44.4%), lidocaine (61.5%), mepivacaine (44.4%), and procaine (50% of the individuals, “responders”). The TNF-α secretion was reduced to 67.4, 68.0, 63.6, and 67.1% of the initial values in responders. The effects in both patients and healthy persons were the same. Interindividual responses to LAs were not correlated with the duration or type of complaints, basal TNF-α serum level, sex, BMI, or age of responders. Conclusions. Four clinically relevant LAs (amid-LA and ester-LA) attenuate the inflammatory response provoked by LPS. They are potential candidates for drug repositioning in treating overactive immune reactions and chronic inflammation

Refining scores based on patient reported outcomes – statistical and medical perspectives

Background: Patient Reported Outcomes (PRO) are gaining more and more importance in the context of clinical trials. The assessment of PRO is frequently performed by questionnaires where the multiple items of a questionnaire are usually pooled within summarizing scores. These scores are used as variables to measure subjective aspects of treatments and diseases. In clinical research, the calculation of these scores is mostly kept very simple, e.g. by a simple summation of item values. In the medical literature, there is hardly any guidance for performing a refinements of questionnaires and for deducing adequate scores. In contrast, in psychometric literature, there are plenty of more sophisticated methods, which overcome typical assumptions made in traditional (sum) scores, however to the prize of more complicated algorithms, which might be difficult to communicate. When faced with the practical task to refine an existing questionnaire, there exist a clear gap of guidance for applied medical researchers. By this article we try to fill this important gap between psychometric theory and medical application by illustrating our methodological choices on the example of a clinical PRO questionnaire. Methods: Based on our experiences with the refinement of the BCTOS, a PRO questionnaire to assess aesthetic and function after breast conserving therapy in breast cancer patients, we present the following general steps that we performed by refining the BCTOS questionnaire and its scores: 1. Refinement of the length of the questionnaire and the (item-factor) structure. 2. Selection of the factor score estimation method. 3. Validation of the refined questionnaire and scores with respect to validity, reliability and structure based on a validation cohort. Results: Our step-step-step procedure helped us to shorten the current form of the BCTOS and to redefine the factor structure. By this, the compliance of patients can be increased and the interpretation of the results becomes more coherent. Conclusions: We present a step-by-step procedure to refine an existing medical questionnaire along with its scores illustrated and discussed by the refinement of the BCTOS. Trial registration: Due to the character of the study (no intervention study), no registration was performed

Incorporating of Historical Two-Arm Data in Clinical Trials with Binary Outcome

Das Ziel dieser Arbeit war es, zu untersuchen, ob und wie Daten einer bereits durchgeführten (historischen) zweiarmigen klinischen Studie in eine neue klinische Studie eingebunden werden können. Es wurde überprüft, ob diese Einbindung mit einem Mehrwert im Sinne einer Erhöhung der Power beziehungsweise einer Reduzierung des erforderlichen Stichprobenumfangs einer neuen klinischen Studie im Vergleich zu einer konventionellen Studie ohne Einbindung historischer Daten einhergehen kann. Eine Reduzierung des erforderlichen Stichprobenumfangs reduziert in der Regel auch den zeitlichen Aufwand und die Kosten einer neuen klinischen Studie. Dies kann daher aus operativer Sicht als sehr wünschenswert angesehen werden. Darüber hinaus kann eine Reduzierung des Stichprobenumfangs und der Dauer einer klinischen Studie auch aus Sicht der Patienten als vorteilhaft angesehen werden, da wirksame Behandlungen schneller ihren Weg in die klinische Praxis finden können. In einem regulatorischen Kontext ist eine notwendige Bedingung für die erfolgreiche Einbindung historischer Daten in eine neue Studie die Kontrolle der Wahrscheinlichkeit eines Fehlers 1. Art unterhalb eines vorgegebenen Signifikanzniveaus. Im Allgemeinen vergrößert sich jedoch die Wahrscheinlichkeit des Fehlers 1.Art mit steigendem Anteil an eingebundenen historischen Daten. Daher wurden in dieser Arbeit Ansätze entwickelt, die auf einer der sogenannten Power-Prior-Methode beruhen, welche es erlaubt, den Anteil der in die neue Studie einfließenden historischen Daten zu kontrollieren. Diese Bayes'sche Methode wurde in einen frequentistischen Rahmen überführt, da die statistischen Konzepte des Fehlers 1. Art und der Power ursprünglich innerhalb der Inferenztheorie eines frequentistischen Settings entwickelt wurden. Im Rahmen dieser Arbeit wurde gezeigt, dass für ein zweiseitiges statistisches Testproblem mit steigendem Anteil an historischen Daten aus zwei Studienarmen die Wahrscheinlichkeit eines Fehlers 1. Art zunächst abnimmt, bevor er zunimmt. Dadurch war es möglich, bei gleichzeitiger Kontrolle der Wahrscheinlichkeit eines Fehlers 1. Art zum vorgegebenen Signifikanzniveau, einen entsprechenden Anteil an historischen Daten in eine neue Studie einzubinden. Es wurde gezeigt, dass das Ausmaß dieses Anteils von verschiedenen Parametern abhängt. Unter der Berücksichtigung dieser sogenannten Störparameter, wurden drei verschiedene Ansätze entwickelt um den Anteil der einzubeziehenden historischen Daten zu bestimmen. Im weiteren Verlauf dieser Arbeit wurden diese drei Ansätze insbesondere bezüglich der Möglichkeit Stichprobenumfang einzusparen untersucht und miteinander verglichen. Es konnte gezeigt werden, dass durch die Einbeziehung historischer Daten in vielen Szenarien die Power zur Aufdeckung des gleichen Effekts, wie er in den historischen Daten beobachtet wurde, erhöht werden kann. Folglich kann der erforderliche Stichprobenumfang für eine neue Studie für viele praktisch relevante Situationen reduziert werden. Es wurden jedoch auch einige Szenarien identifiziert, in denen die Einbeziehung historischer Daten nicht mit einem Mehrwert verbunden ist. Die in dieser Arbeit entwickelten Ansätze sind mit einem hohen Rechenaufwand verbunden. Es wurden daher praktische Empfehlungen gegeben, um diesen zu verringern. Darüber hinaus wurde ein Algorithmus für die Bestimmung des optimalen Stichprobenumfangs entwickelt, der den Rechenaufwand bei den entwickelten Verfahren deutlich reduziert. Zusammenfassend wurde in dieser Arbeit gezeigt, dass die Einbeziehung historischer Daten aus zwei Studienarmen in eine neue Studie mit einem Mehrwert verbunden sein kann. Dieser Mehrwert spiegelt sich im Sinne eine Erhöhung der Power zugunsten des Effekts, wie er in den historischen Daten beobachtet wurde beziehungsweise in einer Reduzierung des erforderlichen Stichprobenumfangs wider. Gleichzeitig wird dabei die Wahrscheinlichkeit eines Fehlers 1. Art durch das vorgegebene Signifikanzniveau eingehalten. Die Existenz und das Ausmaß dieses Mehrwerts hängt jedoch maßgeblich von den zugrundeliegenden historischen Daten ab. Es wurden sowohl Szenarien identifiziert, die mit einem hohen als auch solche, die mit gar keinem Mehrwert einhergehen

Long-Term Patient Satisfaction and Quality of Life After Breast-Conserving Therapy: A Prospective Study Using the BREAST-Q

Background!#!Poor patient-reported satisfaction after breast-conserving therapy (BCT) has been associated with impaired health-related quality of life (HRQOL) and subsequent depression in retrospective analysis. This prospective cohort study aimed to assess the HRQOL of patients who have undergone BCT using the BREAST-Q, and to identify clinical risk factors for lower patient satisfaction.!##!Methods!#!Patients with primary breast cancer undergoing BCT were asked to complete the BREAST-Q preoperatively (T1) for baseline evaluation, then 3 to 4 weeks postoperatively (T2), and finally 1 year after surgery (T3). Clinicopathologic data were extracted from the patients' charts. Repeated measures analysis of variance (ANOVA) was used to determine significant differences in mean satisfaction and well-being levels among the test intervals. Multiple linear regression was used to evaluate risk factors for lower satisfaction.!##!Results!#!The study enrolled 250 patients. The lowest baseline BREAST-Q score was reported for 'satisfaction with breast' (mean, 61 ± 19), but this increased postoperatively (mean, 66 ± 18) and was maintained at the 1 year follow-up evaluation (mean, 67 ± 21). 'Physical well-being' decreased from T1 (mean, 82 ± 17) to T2 (mean, 28 ± 13) and did not recover much by T3 (mean, 33 ± 13), being the lowest BREAST-Q score postoperatively and in the 1-year follow-up evaluation. In multiple regression, baseline psychosocial well-being, body mass index (BMI), and type of incision were risk factors for lower 'satisfaction with breasts.'!##!Conclusion!#!Both the aesthetic/surgery-related and psychological aspects are equally important with regard to 'satisfaction with breasts' after BCT. The data could serve as the benchmark for future studies

Surgeon’s preference of subcutaneous tissue resection: most important factor for short-term complications in subcutaneous implant placement after mastectomy—results of a cohort study

Purpose!#!Little is known about the reason of high short-term complication rates after the subcutaneous placement of breast implants or expanders after mastectomy without biological matrices or synthetic meshes. This study aims to evaluate complications and their risk factors to develop guidelines for decreasing complication rates.!##!Methods!#!We included all cases of mastectomy followed by subcutaneous implant or expander placement between 06/2017 and 05/2018 (n = 92). Mean follow-up time was 12 months.!##!Results!#!Explantation occurred in 15 cases (16.3%). The surgeon's preference for moderate vs. radical subcutaneous tissue resection had a significant influence on explantation rates (p = 0.026), impaired wound healing or infection (requiring surgery) (p = 0.029, p = 0.003 respectively) and major complications (p = 0.018). Multivariate analysis revealed significant influence on complication rates for radical subcutaneous tissue resection (p up to 0.003), higher implant volume (p up to 0.023), higher drain volume during the last 24 h (p = 0.049), higher resection weight (p = 0.035) and incision type (p = 0.011).!##!Conclusion!#!Based on the significant risk factors we suggest the following guidelines to decrease complication rates: favoring thicker skin envelopes after surgical preparation, using smaller implants, removing drains based on a low output volume during the last 24 h and no use of periareolar incision with extension medial or lateral. We should consider ADMs for subcutaneous one-stage reconstructions. The individual surgeon's preference of subcutaneous tissue resection is of highest relevance for short-term complications-this has to be part of internal team discussions and should be considered in future trials for comparable results

Primary Care Disease Management for Venous Leg Ulceration in German Healthcare: Results of the Ulcus Cruris Care Pilot Study

Despite proven effectiveness, compression therapy is applied in only 20–40% of patients with venous leg ulceration, leading to avoidable chronification and morbidity. The Ulcus Cruris Care project was established to develop a new disease-management concept comparable to existing programs for chronic diseases to support evidence-based treatment of venous leg ulceration. This prospective controlled study assessed its first implementation. Interventional elements comprised online training for general practitioner practices, software support for case management, and educational materials for patients. A total of 20 practices and 40 patients were enrolled in a 1:1 ratio to the intervention and control group. Guideline-conform compression therapy was applied more frequently in the intervention group (19/20 [95%] vs. 11/19 [58%]; p = 0.006). For patients with ulcers existing ≤ 6 months, the healing rate at 12 weeks was 8/11 [73%] (intervention) compared to 4/11 [36%] (control; p = 0.087). Patients after intervention had higher scores for self-help and education in the PACIC-5A questionnaire (42.9 ± 41.6 vs. 11.4 ± 28.8; p = 0.044). Treatment costs were EUR 1.380 ± 1.347 (intervention) and EUR 2.049 ± 2.748 (control; p = 0.342). The results of this study indicate that the Ulcus Cruris Care intervention may lead to a significant improvement in care. Consequently, a broader rollout in German healthcare seems warranted

Conventional partial pancreatoduodenectomy versus an extended pancreatoduodenectomy (triangle operation) for pancreatic head cancers—study protocol for the randomised controlled TRIANGLE trial

Abstract Background Pancreatic ductal carcinoma (PDAC) is the fourth most frequent cause of cancer-related death in the Western world, and its incidence is rising. In patients that undergo curative resection, local recurrence (LR) is frequent. A recently described surgical technique of extended pancreatoduodenectomy (PD) termed the TRIANGLE operation has been proposed as a promising approach to reduce LR and improve disease-free survival in PDAC patients. Methods The TRIANGLE trial is a multicentre confirmatory randomised controlled superiority trial with two parallel study groups. A total of 270 patients with suspected or histologically confirmed pancreatic head cancer scheduled for PD will be included in the trial and randomly assigned to the intervention group (extended PD defined as Inoue level 3 dissection along the superior mesenteric and celiac artery as well as removal of all soft tissue in the so-called triangle between the celiac artery, the SMA and the mesenterico-portal axis) or the control group (conventional PD with lymphadenectomy and removal of soft tissue according to current guidelines). The primary endpoint of the trial will be the disease-free survival of patients. Other perioperative outcomes as well as oncological parameters and patient-reported outcomes will be analysed as secondary outcomes. Discussion Despite multimodal treatment, LR remains high and disease-free survival is limited following PD for PDAC. The TRIANGLE operation could address these shortcomings of conventional PD as indicated in several retrospective studies. However, this technique could be associated with more adverse events for patients including intractable diarrhoea. The TRIANGLE trial will close the evidence gap as well as offer a risk-benefit assessment of this more radical approach to PD. Trial registration German Clinical Trials Register DRKS00030576 (UTN U1111-1243-4412) 19th December 2022

Overall morbidity after total minimally invasive keyhole oesophagectomy versus hybrid oesophagectomy (the MICkey trial): study protocol for a multicentre randomized controlled trial

Background: Oesophageal cancer (EC) is the sixth leading cause of cancer death worldwide. Oesophageal resection is the only curative treatment option for EC which is frequently performed via an abdominal and right thoracic approach (Ivor-Lewis operation). This 2-cavity operation is associated with a high risk of major complications. To reduce postoperative morbidity, several minimally invasive techniques have been developed that can be broadly classified into either hybrid oesophagectomy (HYBRID-E) via laparoscopic/robotic abdominal and open thoracic surgery or total minimally invasive oesophagectomy (MIN-E). Both, HYBIRD-E and MIN-E, compare favourable to open oesophagectomy. However, there is still an evidence gap comparing HYBRID-E with MIN-E with regard to postoperative morbidity. Methods: The MICkey trial is a multicentre randomized controlled superiority trial with two parallel study groups. A total of 152 patients with oesophageal cancer scheduled for elective oesophagectomy will be randomly assigned 1:1 to the control group (HYBRID-E) or to the intervention group (MIN-E). The primary endpoint will be overall postoperative morbidity assessed via the comprehensive complication index (CCI) within 30 days after surgery. Specific perioperative parameters, as well as patient-reported and oncological outcomes, will be analysed as secondary outcomes. Discussion: The MICkey trial will address the yet unanswered question whether the total minimally invasive oesophagectomy (MIN-E) is superior to the HYBRID-E procedure regarding overall postoperative morbidity. Trial registration: DRKS00027927 U1111-1277-0214