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BACKGROUND: Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial.
PATIENTS AND METHODS: PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT.
RESULTS: Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups.
CONCLUSIONS: Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies.
Background: The management of intraductal papilloma without atypia (IDP) in breast needle biopsy remains controversial. This study investigates the upgrade rate of IDP to carcinoma and clinical and radiologic features predictive of an upgrade. Methods: Patients with a diagnosis of IDP on image-guided (mammography, ultrasound, magnetic resonance imaging) core needle or vacuum-assisted biopsy and surgical excision of this lesion at a certified breast center between 2007 and 2017 were included in this institutional review board-approved retrospective study. Appropriate statistical tests were performed to assess clinical and radiologic characteristics associated with an upgrade to malignancy at excision. Results: For 60 women with 62 surgically removed IDPs, the upgrade rate to malignancy was 16.1% (10 upgrades, 4 invasive ductal carcinoma, 6 ductal carcinoma in situ). IDPs with upgrade to carcinoma showed a significantly greater distance to the nipple (63.5 vs. 36.8 mm; p = 0.012). No significant associations were found between upgrade to carcinoma and age, menopausal status, lesion size, microcalcifications, BI-RADS descriptors, initial BI-RADS category, and biopsy modality. Conclusion: The upgrade rate at excision for IDPs diagnosed with needle biopsy was higher than expected according to some guideline recommendations. Observation only might not be appropriate for all patients with IDP, particularly for those with peripheral IDP.
Background: Transient elastography (TE) has been validated as an effective noninvasive tool for the assessment of liver fibrosis. The XL probe is a new probe that was initially designed for use in patients with obesity. A meta-analysis was performed to assess the feasibility and efficacy of TE using the XL probe.
Methods: In September 2016, we systematically searched the PubMed and Science Direct search engines. The feasibility of TE was evaluated based on the failure rate and the results of the unreliable liver stiffness measurement (LSM). The efficacy of TE was measured using sensitivity, specificity, and summary receiver-operating characteristic as measures/indices assessed in different stages of fibrosis. Heterogeneity was measured using the chi-squared test and the Q-statistic. We used the 95% confidence interval (95% CI) as an effect measure.
Results: We included 8 studies in the meta-analysis. When the XL was compared to the M probe, the former showed a lower risk of failure rate [relative risk (RR) 0.24, 95% CI 0.14–0.38]. In patients with a body mass index ≥30 kg/m2, the XL probe showed a statistically significantly lower risk of failure rate (RR 0.16, 95% CI 0.08–0.32) but no significant improvement (RR 0.76, 95% CI 0.50–1.16) in the unreliable LSM result. In patients showing liver fibrosis stage ≥F2, the XL probe showed a sensitivity of 0.56 (95% CI 0.39–0.72), specificity of 0.71 (95% CI 0.61–0.79), and an area under the curve (AUC) of 0.71. The results observed in patients with liver fibrosis stage F4 were more promising with a sensitivity of 0.84 (95% CI 0.76–0.90), specificity of 0.78 (95% CI 0.70–0.84), and an AUC of 0.88.
Conclusion: TE using the XL probe demonstrates significant diagnostic utility in patients with liver fibrosis and is likely to be more reliable than the M probe in patients with obesity. Large prospective multicenter studies are, however, necessary to establish the new cut-off values to be used for the XL probe in patients with obesity.
Zielsetzung: Beteiligung von Medizinstudierenden im Rahmen der konzeptionellen Entwicklung eines zielgruppenspezifischen und attraktiven allgemeinmedizinischen Lehrangebots im ländlichen Raum.
Methodik: Es wurde ein Fragebogen entwickelt, der die Bewertung der Studierenden hinsichtlich des aktuellen Ablaufs ihres Studiums, den späteren Berufswunsch sowie die Anforderungen an ein zu entwickelndes allgemeinmedizinisches Schwerpunktprogramm im ländlichen Raum erfasst. Mittels einer Online-Befragung wurden im Sommer 2015 alle Medizinstudierende ab dem vierten vorklinischen Semester (n=2.150) der Goethe-Universität Frankfurt einmalig befragt. Die statistische Auswertung erfolgte primär deskriptiv. Die persönliche Einstellung hinsichtlich der Bereitschaft, als Hausarzt tätig zu werden, wurde auf statistische Signifikanz überprüft. Zudem wurde erhoben, ob ein messbarer Zusammenhang zwischen der eigenen Herkunft und dem späteren Wunscharbeitsort besteht.
Ergebnisse: Von insgesamt 2.150 kontaktierten Studierenden nahmen 617 an der Befragung teil (Rücklaufquote=28,7%). Die Ergebnisse repräsentieren eine große Bandbreite an Ideen und Anregungen, die sowohl die Meinung von Befürwortern als auch eher kritisch gegenüber der Lehre in der Allgemeinmedizin eingestellten Medizinstudierenden widerspiegeln. Von dem geplanten Schwerpunktprogramm erwarten die Studierenden einen starken Praxisbezug ebenso wie das Kennenlernen administrativer sowie wirtschaftlicher Hintergründe zum Führen einer Praxis.
Schlussfolgerungen: Durch die Einbeziehung der Zielgruppe am Entwicklungsprozess bestand die Möglichkeit, das zu entwickelnde Schwerpunktprogramm auf die späteren Teilnehmer passgenauer zuzuschneiden. Zudem ist zu erwarten, dass die Beteiligung der Studierenden zu einer höheren Akzeptanz des Programms führt. Die gewonnenen Ergebnisse zur Gestaltung eines Lehrangebots können als Orientierung für die mögliche Entwicklung ähnlicher Schwerpunktprogramme an anderen medizinischen Fakultäten dienen.
Aim: Participation of medical students in the conceptual development of targeted and attractive teaching content for rural areas.
Method: A questionnaire was developed to gather information on students' views of their current medical studies, career interests, and what requirements should be met by an optional rural health program in general practice. By means of an online survey in summer 2015, all medical students from the fourth preclinical semester onwards (n=2,150) at Goethe University Frankfurt were surveyed on one occasion. Statistical analysis was mainly descriptive. Personal attitudes towards a career as a family practitioner were examined for statistical significance. Further information was gathered on whether a measurable correlation exists between personal background and desired work location.
Results: Of the 2,150 students that were contacted, 617 participated in the survey (response rate=28.7%). The results covered a wide range of ideas and recommendations and were representative both of medical students with a positive attitude toward general practice, as well as those that were rather critical of teaching in general practice. The students expected the planned health program to be of strong practical relevance and to acquaint them with the administrative and economic aspects of running a practice.
Conclusions: By including the target group in the development process, it was possible to tailor the health program to meet the needs of future participants more precisely. Student participation can also be expected to result in greater acceptance of the program. The results on teaching content may also provide other medical faculties with orientation when developing comparable programs.
Vorhofflimmern entsteht unter anderem durch ein Ungleichgewicht zwischen sympathischem und parasympathischem autonomen Nervensystem. Sowohl invasive Ansätze via Ablation oder Denervierung als auch minimalinvasive Ansätze via Elektrostimulation liefern erfolgsversprechende Ergebnisse in Bezug auf Beeinflussung eines bestehenden Vorhofflimmerns.
Interessanterweise konnte durch Akupunktur des Tragus eine Reduktion von Vorhofflimmer-Rezidiven nach Kardioversion erreicht werden. Ziel dieser Studie war die Evaluation von Akupunktur-induzierten kardialen (vegetativen) Effekten bei gesunden Probanden.
Herzgesunde männliche Probanden (n=24) wurden im Bereich des Vagus-Innervationsgebietes an der Concha inferior des Ohres (Herzpunkt 100, OHR) sowie an einem klassischen Akupunktur-Punkt des Herzens (ventralen Unterarm, P6/Neiguan, ARM) akupunktiert. Eine „Placebo“-Akupunktur eines Punktes, der gegen Gonarthrose-Schmerzen helfen soll (Magenpunkt 35), diente als Kontrolle. Die Hälfte der Probanden erhielt eine zusätzliche Messung ohne Akupunktur, um Effekte durch das alleinige Platzieren einer Nadel zu untersuchen.
Um eine Aktivierung des ANS zu bewirken und Veränderungen quantifizieren zu können, wurden 12-Kanal Langzeit-EKG Messungen wie folgt durchgeführt: 30 Minuten (min) in liegender Position unter Akupunktur, Entfernung der Akupunkturnadel, 5 min liegend, 5 min sitzend, 5 min stehend, 5 min sitzend.
Es erfolgten Analysen folgender Parameter der Herzfrequenzvariabilität: Herzfrequenz, SDNN, RMSSD, HF, LF, LF/HF. Des Weiteren wurden Periodic Dynamics Repolarization und Deceleration Capacity untersucht.
Verglichen mit Placebo-Akupunktur wurde sowohl durch Akupunktur am OHR als auch am ARM die Herzfrequenz in liegender und sitzender Körperpositionen signifikant gesenkt (Phasen 30L, 5S1, 5S2, ∆5L-5S1, ∆5S1-5ST).
Während die Akupunktur am OHR vor allem die SDNN signifikant erhöhte, führte die Akupunktur am ARM zu einer signifikanten Steigerung von RMSSD und dem parasympathischen Leistungsdichtespektrum-Parameter HF. Der Quotient LF/HF wurde ebenfalls signifikant gesenkt.
Kein Unterschied bestand zwischen Placebo-Akupunktur und Messung ohne Akupunktur, sodass postuliert werden kann, dass das alleinige Platzieren einer Nadel keinen nennenswerten Effekt auf das autonome Nervensystem besitzt.
Die Ergebnisse der Studie zeigen, dass eine Akupunktur an Orten, die mit dem autonomen Nervensystem verschaltet sind, zu einer Modulation des parasympathischen kardialen autonomen Nervensystems führen kann.
Eine Modulation der parasympathisch-sympathischen Balance durch minimalinvasive Zusatzbehandlung, wie in unserer Studie, könnte möglicherweise bei Patienten mit Vorhofflimmern zusätzlich zu medikamentöser oder nach invasiver Behandlung wie der Pulmonalvenenisolation das Therapieresultat verbessern und die Rezidivrate verringern.
Continuous blood glucose monitoring reveals enormous circadian variations in pregnant diabetic rats
(2018)
Aim: Diabetes in pregnancy is a major burden with acute and long-term consequences. Its treatment requires adequate diagnosis and monitoring of therapy. Many experimental research on diabetes during pregnancy has been performed in rats. Recently, continuous blood glucose monitoring of non-pregnant diabetic rats revealed an increased circadian variability of blood glucose that made a single blood glucose measurement per day inappropriate to reflect glycemic status. Continuous blood glucose measurement has never been performed in pregnant rats. We wanted to perform continuous blood glucose monitoring in pregnant rats to decipher the influence of pregnancy on blood glucose in diabetic and normoglycemic status.
Methods: We used the transgenic Tet29 diabetes rat model with an inducible knock down of the insulin receptor via RNA interference upon application of doxycycline (DOX) leading to insulin resistant type II diabetes. All Tet29 rats received a HD-XG telemetry implant (Data Sciences International, USA) that measured blood glucose and activity continuously. Rats were divided into four groups and blood glucose was monitored until end of pregnancy or the corresponding period: Tet29 + DOX (diabetic) non-pregnant, Tet29 + DOX (diabetic) pregnant, Tet29 (normoglycemic) non-pregnant, Tet29 (normoglycemic) pregnant.
Results: All analyzed rats displayed a circadian variation in blood glucose concentration. Circadian variability was much more pronounced in pregnant diabetic rats than in normoglycemic pregnant rats. Pregnancy ameliorated variation in blood glucose in diabetic situation. Pregnancy continuously decreased blood glucose during normoglycemic pregnancy. Diabetic rats were less active than normoglycemic rats. We performed a calculation showing that application of continuous blood glucose measurement reduces animal numbers needed to detect a given effect in experimental setting by decreasing variability and SD.
Interpretation: Continuous blood glucose monitoring via a telemetry device in pregnant rats provides a more informative picture of the glycemic situation in comparison to single measurements. This could improve diagnosis and therapy of diabetes, decrease animal numbers within experimental settings, and add another physiological parameter (activity) to the analysis that could be helpful in testing therapeutic concepts targeting blood glucose levels and peripheral muscle function. We propose continuous glucose monitoring as a new tool for the evaluation of pregnant diabetic rats.
The genetic mutation of the coagulation factor VIII (fVIII) results in a defective or missing protein, leading to a malfunctioning blood coagulation. The resulting disease is called hemophilia A. Depending on the severity of the mutation, affected patients experience an increased risk of pathologic bleeding after minor trauma or even sudden bleeding events. Substitution therapies with extrinsic fVIII exist using plasmatic or recombinant fVIII products. Due to an insufficient immune tolerance towards substituted fVIII, about 30 % of patients develop allogenic neutralizing antibodies (inhibitors) against substituted fVIII products. The gold standard of treating inhibitors is the immune tolerance induction (ITI), where patients are given frequent, high doses of fVIII to induce an immune tolerance. ITI therapy fails in about 30 % of patients. Mechanisms of action of ITI are part of research, as insufficient knowledge about mechanisms and prognostic factors complicate treatment. For example, the development of anti-idiotypic antibodies, which occur naturally as a regulatory mechanism of the immune system, are being studied. Such anti-idiotypes have been detected in immunoglobuline preparations and in patients after successful ITI.
Inhibitors interfere with fVIII function in coagulation by binding functional epitopes within fVIII domains. Inhibitors against the A2 and C2 domain are predominantly found, however also the C1 domain has been shown to be highly immunogenic in some patients. The polyclonality of inhibitors aggravates the understanding and treatment of these. The present project therefore focusses on the selection of synthetic anti-idiotypic antibodies to target inhibitors in patients. The phage display method was applied to, for one, isolate anti-idiotypic single chain variable fragments (scFvs) specific against human polyclonal anti-fVIII antibodies and second against two C1 domain-specific inhibitory monoclonal antibodies (mAbs).
In the first project, anti-fVIII antibodies were purified from human plasma to serve as target molecules. A previous project showed that using full plasma as a target did not yield anti-idiotypic antibodies from phage display. For the purification, protein A chromatography and fVIII coupled Affi Gel® chromatography were applied. The isolated antibodies were next used as targets for the selection of anti-idiotypic scFvs. Analysis revealed that none of the selected phages solely bound the anti-fVIII antibody target. Consequently, the test protocol was modified, which resulted in a reduction of unspecific binders. Yet, no target-specific binders were isolated from phage pools. Reason for this may have been the high diversity of the polyclonal antibody target and the limited diversity of the phage libraries.
The aim of the second project, was the selection and characterization of scFvs, that target the paratopes of C1 domain-specific mAbs GMA8011 and LE2E9. From a therapeutic viewpoint, the preparation of an anti-idiotypic antibody pool, tailored to each patient’s inhibitor population, could help neutralize inhibitors in patients. Ultimately, one GMA8011-specific scFv-carrying phage clone (H2C1) and two specifics to LE2E9 (H3G7, H3F10) were isolated. In further experiments, only the GMA8011-specific scFv showed competitive behavior in presence of fVIII, pointing towards an anti-idiotypic binding to the inhibitor paratope. The LE2E9-specific scFvs did not prevent binding of the inhibitor to fVIII. Hence, no anti-idiotypic behavior could be determined. For further characterization, selected scFvs were genetically fused to Fc antibody fragments and recombinantly produced. In this antibody format, all three scFvs showed concentration dependent binding to the target and the isotype control. The binding specificity to the target, observed in phage context, could not be reproduced. Competition experiments with fVIII confirmed that none of the scFvs bound the paratope of their target inhibitor.
The selection of anti-idiotypic scFvs from phage display libraries proves to be effortful. Polyclonal anti-fVIII antibodies purified from hemophilic plasma appear to be unsuitable as a target for phage display, likely due to the high diversity of the target molecules. Furthermore, the preparation of an individualized anti-idiotypic pools for patients by selecting scFvs against single inhibitory mAbs proves to be difficult. The selection of scFvs against anti-C1 inhibitors GMA8011 and LE2E9 produced three promising scFv-carrying phages. However, analysis could not detect anti-idiotypic behavior. Further research with inhibitors, monoclonal and polyclonal, and anti-idiotypic antibodies should be performed to bring better insight into the highly complex paratope-epitope interaction.
nzidenz und Mortalität von Gebärmutterhalskrebs (C53 nach ICD-10) müssen signifikant nach oben korrigiert werden, wenn aus der betrachteten Referenzbevölkerung die Frauen ausgeschlossen werden, deren Gebärmutter operativ entfernt wurde. Diese Arbeit stützt sich auf die Studie zur Gesundheit Erwachsener in Deutschland (DEGS1), nach der die Hysterektomie-Prävalenz in Deutschland 2011 bei über 18-jährigen Frauen bei 17,4% lag. Auf Grundlage der Altersverteilung dieser Prävalenz werden die Inzidenz- und Mortalitätsraten von Gebärmutterhalskrebs entsprechend korrigiert. Maximale Korrekturen resultieren bei 70–79-jährigen Frauen mit einer Inzidenzkorrektur von 13,6 auf 22,5, d.h. um 65,4% und einer Mortalitätskorrektur von 7,5 auf 12,4, d.h. um 65,3%. Die mögliche Prävention durch eine HPV-Impfung gewinnt damit an Relevanz.