Publications by authors named "Manuel Feisst"

48 Publications

Measuring the Time to Deterioration for Health-Related Quality of Life in Patients With Metastatic Breast Cancer Using a Web-Based Monitoring Application: Longitudinal Cohort Study.

JMIR Cancer 2021 Oct 12;7(4):e25776. Epub 2021 Oct 12.

Department of Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany.

Background: Health-related quality of life (HRQoL) is used to evaluate the treatment of metastatic breast cancer. In a long-term therapy setting, HRQoL can be used as an important benchmark for treatment success. With the help of digital apps, HRQoL monitoring can be extended to more remote areas and be administered on a more frequent basis.

Objective: This study aims to evaluate 3 common HRQoL questionnaires in metastasized breast cancer in terms of TTD in a digital, web-based setting. We further aim to examine the development of the HRQoL in different systemic treatment groups in each of these evaluation instruments.

Methods: A total of 192 patients with metastatic breast cancer were analyzed in this bicentric prospective online cohort study at two German university hospitals. Patients completed questionnaires on HRQoL (EuroQol Visual Analog Scale [EQ-VAS], EuroQol 5 Dimension 5 Level [EQ-5D-5L], European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 item [EORTC QLQ-C30]) via an online platform over a 6-month period. Treatment schedules and medical history were retrieved from medical records. Unadjusted Cox regression analysis on treatment-related factors was performed. We conducted subgroup analyses in regard to TTD events between different treatments.

Results: The EQ-VAS showed a higher rate of deterioration after 8 weeks (84/179, 46.9%) than the EQ-5D-5L (47/163, 28.8%) and EORTC QLQ-C30 (65/176, 36.9%). Unadjusted Cox regression revealed significant connections between known metastases in the liver (P=.03, HR 1.64, 95% CI 1.06-2.52) and pleura (P=.04, HR 0.42, 95% CI 0.18-0.96) in the EQ-VAS. Significant relations between EQ-VAS events and single EQ-5D-5L items and the EQ-5D-5L summary score were demonstrated. All treatment groups significantly differed from the CDK4/6 inhibition subgroup in the EQ-VAS.

Conclusions: Compared to the EQ-5D-5L and QLQ-C30, the EQ-VAS showed a higher rate of deterioration after 8 weeks. Significant connections to certain metastatic locations were only detected in the EQ-VAS. The EQ-VAS is capable of reflecting the distinctive HRQoL profiles of different systemic treatments as well as the different aspects of HRQoL presented in the EQ-5D-5L. TTD with the EQ-VAS is an adequate mean of examining longitudinal development of HRQoL among breast cancer patients.
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http://dx.doi.org/10.2196/25776DOI Listing
October 2021

Vacuum-Assisted Breast Biopsy After Neoadjuvant Systemic Treatment for Reliable Exclusion of Residual Cancer in Breast Cancer Patients.

Ann Surg Oncol 2021 Sep 28. Epub 2021 Sep 28.

Breast Unit, Department of Obstetrics and Gynecology, Heidelberg University Hospital, Heidelberg, Germany.

Background: About 40 % of women with breast cancer achieve a pathologic complete response in the breast after neoadjuvant systemic treatment (NST). To identify these women, vacuum-assisted biopsy (VAB) was evaluated to facilitate risk-adaptive surgery. In confirmatory trials, the rates of missed residual cancer [false-negative rates (FNRs)] were unacceptably high (> 10%). This analysis aimed to improve the ability of VAB to exclude residual cancer in the breast reliably by identifying key characteristics of false-negative cases.

Methods: Uni- and multivariable logistic regressions were performed using data of a prospective multicenter trial (n = 398) to identify patient and VAB characteristics associated with false-negative cases (no residual cancer in the VAB but in the surgical specimen). Based on these findings FNR was exploratively re-calculated.

Results: In the multivariable analysis, a false-negative VAB result was significantly associated with accompanying ductal carcinoma in situ (DCIS) in the initial diagnostic biopsy [odds ratio (OR), 3.94; p < 0.001], multicentric disease on imaging before NST (OR, 2.74; p = 0.066), and age (OR, 1.03; p = 0.034). Exclusion of women with DCIS or multicentric disease (n = 114) and classication of VABs that did not remove the clip marker as uncertain representative VABs decreased the FNR to 2.9% (3/104).

Conclusion: For patients without accompanying DCIS or multicentric disease, performing a distinct representative VAB (i.e., removing a well-placed clip marker) after NST suggests that VAB might reliably exclude residual cancer in the breast without surgery. This evidence will inform the design of future trials evaluating risk-adaptive surgery for exceptional responders to NST.
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http://dx.doi.org/10.1245/s10434-021-10847-9DOI Listing
September 2021

Is Negative Pressure Wound Therapy with Instillation Suitable for the Treatment of Acute Periprosthetic Hip Joint Infection?

J Clin Med 2021 Jul 23;10(15). Epub 2021 Jul 23.

Department of Orthopaedic and Trauma Surgery, University Hospital Heidelberg, Schlierbacher Landstrasse 200A, 69118 Heidelberg, Germany.

Background: Periprosthetic joint infection (PJI) can be devastating for the patient and demanding for the surgeon. In acute PJI, attempts are made to retain the prosthesis by debridement of the infected tissue, targeted antibiotic therapy and an exchange of modular components with implant retention (DAIR). There has been sparse research with adjunctive negative pressure wound treatment with wound irrigation (NPWTI) on the treatment outcome.

Questions/purposes: The goal was to assess the efficacy of our protocol of DAIR with adjunctive NPWTI in acute PJI and to reduce the need for later additional DAIR and Irrigation and Debridement (I and D).

Patients And Methods: Our cohort of 30 patients (31 hips) with acute PJI was divided into two groups based on symptom presentation up to 6 weeks or >6 weeks from prior (index) surgery (acute early or acute late groups, respectively). All received DAIR with an exchange of modular components and NPWTI with polyhexanide instillation, with the goal of bacterial elimination and biofilm elimination. Postoperatively, the patients were followed up clinically and radiographically for a mean of 4.3 years.

Results: Of the 31 PJI hips, 19 were early acute and 12 were late acute. In total, 21 hips had no evidence of residual infection, 10 required further surgical revision: 1 due to dislocation and 9 due to infection. Of these nine, seven had a removal of all the components and two were treated with irrigation and debridement (I and D), with the demise of one patient from pneumonia shortly after the procedure. The Kaplan-Meier 60-month revision free implant survival from infection was 73.2% (CI: 58.9-91.0%) and at the final follow up, the mean Harris Hip Score (HHS) was 81.1 ± 11.8 and the mean WOMAC score was 33.3 ± 20.1.

Conclusions: Our results are in line with those reported in prior studies. However, the utility of our protocol is inconclusive and needs further evaluation based on our small cohort and the lack of a control group.

Level Of Evidence: IV.
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http://dx.doi.org/10.3390/jcm10153246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347389PMC
July 2021

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

Ann Surg Oncol 2021 Jul 19. Epub 2021 Jul 19.

Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1245/s10434-021-10377-4DOI Listing
July 2021

Next-generation sequencing diagnostics of bacteremia in pediatric sepsis.

Medicine (Baltimore) 2021 Jun;100(25):e26403

Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen.

Introduction: Sepsis and septic shock are the most severe forms of infection affecting predominantly elderly people, preterm and term neonates, and young infants. Even in high-income countries sepsis causes about 8% of admissions to pediatric intensive care units (PICUs). Early diagnosis, rapid anti-infective treatment, and prompt hemodynamic stabilization are crucial for patient survival. In this context, it is essential to identify the causative pathogen as soon as possible to optimize antimicrobial treatment. To date, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care. However, they have 2 major problems: on the one hand, in the case of very small sample volumes (and thus usually in children), they are not sufficiently sensitive. On the other hand, with a time-to-result of 2 to 5 days, blood cultures need a relatively long time for the anti-infective therapy to be calculated. To overcome these problems, culture-independent molecular diagnostic procedures such as unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) have been tested successfully in adult septic patients. However, these results still need to be transferred to the pediatric setting.

Methods: The Next GeneSiPS-Trial is a prospective, observational, non-interventional, multicenter study used to assess the diagnostic performance of an NGS-based approach for the identification of causative pathogens in (preterm and term) neonates (d1-d28, n = 50), infants (d29 to <1 yr, n = 50), and toddlers (1 yr to <5 yr, n = 50) with suspected or proven severe sepsis or septic shock (according to the pediatric sepsis definition) by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard of care (culture-based) microbiological diagnostics. Potential changes in anti-infective treatment regimens based on these NGS results will be estimated retrospectively by a panel of 3 independent clinical specialists.

Discussion: Neonates, infants, and young children are significantly affected by sepsis. Fast and more sensitive diagnostic approaches are urgently needed. This prospective, observational, non-interventional, multicenter study seeks to evaluate an NGS-based approach in critically ill children suffering from sepsis.

Trial Registration: DRKS-ID: DRKS00015705 (registered October 24, 2018). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015705.
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http://dx.doi.org/10.1097/MD.0000000000026403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238315PMC
June 2021

Early intervention, treatment and rehabilitation of employees with common mental disorders by using psychotherapeutic consultation at work: study protocol of a randomised controlled multicentre trial (friaa project).

BMC Public Health 2021 06 22;21(1):1187. Epub 2021 Jun 22.

Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Background: Common mental disorders are one of the leading causes for sickness absence and early retirement due to reduced health. Furthermore, a treatment gap for common mental disorders has been described worldwide. Within this study, psychotherapeutic consultation at work defined as a tailored, module-based and work-related psychotherapeutic intervention will be applied to improve mental health care.

Methods: This study comprises a randomised controlled multicentre trial with 1:1 allocation to an intervention and control group. In total, 520 employees with common mental disorders shall be recruited from companies being located around five study centres in Germany. Besides care as usual, the intervention group will receive up to 17 sessions of psychotherapy. The first session will include basics diagnostics and medical indication of treatment and the second session will include work-related diagnostics. Then, participants of the intervention group may receive work-related psychotherapeutic consultation for up to ten sessions. Further psychotherapeutic consultation during return to work for up to five sessions will be offered where appropriate. The control group will receive care as usual and the first intervention session of basic diagnostics and medical indication of treatment. After enrolment to the study, participants will be followed up after nine (first follow-up) and fifteen (second follow-up) months. Self-reported days of sickness absence within the last 6 months at the second follow-up will be used as the primary outcome and self-efficacy at the second follow-up as the secondary outcome. Furthermore, a cost-benefit assessment related to costs of common mental disorders for social insurances and companies will be performed.

Discussion: Psychotherapeutic consultation at work represents a low threshold care model aiming to overcome treatment gaps for employees with common mental disorders. If successfully implemented and evaluated, it might serve as a role model to the care of employees with common mental disorders and might be adopted in standard care in cooperation with sickness and pension insurances in Germany.

Trial Registration: The friaa project was registered at the German Clinical Trial Register (DRKS) at 01.03.2021 (DRKS00023049): https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023049 .
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http://dx.doi.org/10.1186/s12889-021-11195-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218449PMC
June 2021

Do hospital type or caseload make a difference in chemotherapy treatment patterns for early breast cancer? Results from 104 German institutions, 2008-2017.

Breast 2021 Aug 23;58:63-71. Epub 2021 Apr 23.

Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: Over the past decade, chemotherapy has been used more selectively in early breast cancer (EBC) due to better risk stratification. Neoadjuvant chemotherapy (NACT) has evolved to the primary treatment option. The type and size of hospitals is known to have a substantial influence on the kinds of treatment they provide, and therefore on patient outcomes (e.g. rates for pathological complete response, pCR), but it is not yet known how this has affected delivery of chemotherapy for EBC in Germany.

Methods: This study analyzed chemotherapy use and pCR rates after NACT for EBC patients treated at 104 German institutions 2008-2017. Institutions were separated into associated hospital type (university hospital; teaching hospital; community hospital) and annual caseload (≤100; 101-250; >250 cases/year).

Results: Overall, 124,084 patients were included, of whom 11.6% were treated at university hospitals, 63.1% at teaching hospitals, and 25.3% at community hospitals. In total, 46,274 (37.3%) received chemotherapy, of whom 44,765 had information available about systemic treatment and surgery. From 2008 to 2017, chemotherapy use declined from 48.3% to 36.4% for university hospitals, from 40.7% to 30.3% for teaching hospitals, and from 42.4% to 33.7% for community hospitals. Furthermore, the proportion of NACT increased the most in university hospitals (from 32.0% to 68.1%); whereas, the rate of pCR (defined as ypT0 ypN0) increased irrespective of institutional type. Analyses regarding annual caseload did not show any differences.

Conclusions: The results from this large, nationwide cohort reflect a more selective use of chemotherapy in Germany, irrespective of institutional type or case load.
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http://dx.doi.org/10.1016/j.breast.2021.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102997PMC
August 2021

Gastric Venous Congestion After Total Pancreatectomy Is Frequent and Dangerous.

Ann Surg 2021 Mar 4. Epub 2021 Mar 4.

*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany ‡Department of Radiology, Heidelberg University Hospital, Heidelberg, Germany §Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany ||Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.

Objective: The aim of this study was to determine the role of gastric venous congestion (GVC) in mortality after total pancreatectomy (TP).

Background: Data from a nationwide administrative database revealed that TP is associated with a 23% mortality rate in Germany.

Methods: A total of 585 consecutive patients who had undergone TP (n = 514) or elective completion pancreatectomy (n = 71) between January 2015 and December 2019 were analyzed. Univariable and multivariable analyses were performed to identify risk factors for GVC and 90-day mortality.

Results: GVC was observed in 163 patients (27.9%) requiring partial or total gastrectomy. Splenectomy (OR 2.14, 95% CI 1.25-3.80, p = 0.007) and coronary vein resection (OR 5.49, 95% CI 3.19-9.64, p < 0.001) were independently associated with GVC. The overall 90-day mortality after TP was 4.1% (24 of 585 patients), 7.4% in patients with GVC and 2.8% in those without GVC (p = 0.014). Of the 24 patients who died after TP, 12 (50%) had GVC.

Conclusion: GVC is a frequent albeit not well-known finding after TP, especially when splenectomy and resection of the coronary vein are performed. Adequate decision making for partial gastrectomy during TP is crucial. Insufficient gastric venous drainage after TP is life-threatening.
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http://dx.doi.org/10.1097/SLA.0000000000004847DOI Listing
March 2021

Postoperative acute pancreatitis is a serious but rare complication after distal pancreatectomy.

HPB (Oxford) 2021 Sep 13;23(9):1339-1348. Epub 2021 Jan 13.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: The clinical relevance of hyperamylasemia after distal pancreatectomy (DP) remains unclear and no internationally accepted definition of postoperative acute pancreatitis (POAP) exists. The aim of this study was to characterize POAP after DP and to assess the role of serum amylase (SA) in POAP.

Methods: Outcomes of 641 patients who had undergone DP between 2015 and 2019 were analyzed. Postoperative SA was determined in all patients. POAP was defined based on contrast-enhanced computed tomography (CT) or intraoperative findings during relaparotomy.

Results: An elevation of SA on postoperative day 1 (hyperamylasemia) was found in 398 patients (62.1%). Twelve patients (1.87%) were identified with POAP. Ten patients demonstrated radiologic criteria for POAP and in two patients POAP was diagnosed during relaparotomy. Outcome of POAP patients was worse than that of patients with hyperamylasemia alone and that with normal SA without POAP evidence (postoperative pancreatic fistula 50% vs 30.6% vs 18.5%; length of hospital stay 26 days vs 12 vs 11, respectively). The overall 90-day mortality of all 641 patients was 0.6%.

Conclusion: POAP is a serious but rare complication after DP. Hyperamylasemia is of prognostic relevance after DP, but it seems not sufficient as a single parameter to diagnose POAP.
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http://dx.doi.org/10.1016/j.hpb.2021.01.004DOI Listing
September 2021

Diagnostic accuracy of axillary staging by ultrasound in early breast cancer patients.

Eur J Radiol 2021 Feb 4;135:109468. Epub 2020 Dec 4.

Department of Obstetrics and Gynecology, Breast Unit, University Hospital of Heidelberg, Germany. Electronic address:

Background: Axillary ultrasound (AUS) is a standard procedure in the preoperative clinical identification of axillary metastatic lymph node (LN) involvement. It guides decisions about local and systemic therapy for patients with early breast cancer (EBC). But there is only weak evidence on the diagnostic criteria and standard interpretation. The aim of this study was to assess the performance of AUS in the detection and exclusion of LN metastases.

Methods: In a retrospective single-center study, 611 consecutive EBC patients with 622 axillae underwent AUS +/- core needle biopsy (CNB) plus axillary surgery, i.e. sentinel lymph node biopsy and/or axillary lymph node dissection. For all patients, AUS image documentation of at least the most suspicious LN was saved during the initial diagnostic work-up. The diagnostic outcome measures were sensitivity, specificity, accuracy, Youden-index (YI), and diagnostic odds ratio (DOR) on the basis of the daily routine interpretation and on the basis of previously recommended diagnostic criteria by two blinded examiners.

Results: On the basis of the daily routine interpretation, AUS had a sensitivity (95 % CI) of 53.3 % (46.4-60.1), a specificity (95 % CI) of 93.6 % (90.8-95.8), an accuracy (95 % CI) of 79.7 % (76.4-82.8), a YI (95 % CI) of 0.47 (0.40 - 0.54), and a DOR (95 % CI) of 16.75 (10.37-27.05). Systematic application of previously recommended diagnostic criteria did not improve the diagnostic accuracy of routinely interpreted AUS.

Conclusion: AUS performance alone is not sufficient to accurately identify or exclude axillary metastatic disease in unselected patients with EBC.
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http://dx.doi.org/10.1016/j.ejrad.2020.109468DOI Listing
February 2021

A Phase II Trial of Nivolumab With Chemotherapy Followed by Maintenance Nivolumab in Patients With Pleural Mesothelioma After Surgery: The NICITA Study Protocol.

Clin Lung Cancer 2021 03 14;22(2):142-146. Epub 2020 Oct 14.

Department of Thoracic Oncology/Internal Medicine, Thoraxklinik, Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany.

Background: In selected patients with early-stage malignant pleural mesothelioma (MPM), a multimodal therapy that includes surgical cytoreduction, chemotherapy, and/or radiotherapy is recommended. Several clinical trials have demonstrated the beneficial effects of immune checkpoint inhibitors in pretreated MPM patients with advanced disease. Recent clinical data have suggested that the combination of chemotherapy and checkpoint inhibition might improve efficacy.

Trial Design: The NICITA (nivolumab with chemotherapy in pleural mesothelioma after surgery) trial is a prospective, 1:1 randomized, open-label, multicenter phase II clinical trial (ClinicalTrials.gov identifier, NCT04177953). Ninety-two patients with MPM epithelioid subtype, who had undergone extended pleurectomy and decortication with or without hyperthermic intrathoracic chemoperfusion, will be included to receive adjuvant treatment. All patients will receive ≤ 4 cycles of platinum-based chemotherapy with pemetrexed (arms A and B). Patients in arm B will additionally receive nivolumab, together with the adjuvant chemotherapy, and subsequently for ≤ 12 cycles as maintenance therapy. The primary endpoint of this study is the time-to-next-treatment. The secondary endpoints include progression-free survival, overall survival, proportion of patients with treatment beyond progression, duration of treatment beyond progression in this population, and quality of life.

Conclusion: This prospective trial will contribute data to assess the efficacy of standard chemotherapy combined with nivolumab in the context of multimodal management of early-stage MPM. The study is currently enrolling patients.
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http://dx.doi.org/10.1016/j.cllc.2020.10.005DOI Listing
March 2021

Arterial Resection in Pancreatic Cancer Surgery: Effective After a Learning Curve.

Ann Surg 2020 Jun 12. Epub 2020 Jun 12.

*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Institute for Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany.

Objective: To investigate the perioperative and oncologic long-term outcomes of patients with LAPC after surgical resection at a high-volume center for pancreatic surgery.

Background: The role of surgery in LAPC with arterial involvement is controversial.

Methods: We analyzed 385 consecutive patients undergoing PAR (n = 195) or PAD (n = 190) of the encased artery for LAPC between January 1, 2003 and April 30, 2019.

Results: There were 183 total pancreatectomies, 113 partial pancreatoduodenectomies, 79 distal pancreatectomies, and 10 resections for tumor recurrences, including 121 multivisceral resections and 171 venous resections. Forty-three patients (11.4%) had resectable oligometastatic disease. All of the 190 patients undergoing PAD (100%) and 95 of the 195 patients undergoing PAR (48.7%) received neoadjuvant chemotherapy. The R0 (circumferential resection margin negative) resection rate was 28%. The median hospital stay was 15 days (range: 3-236). The median survival after surgery for LAPC was 20.1 months and the overall 5-year survival rate 12.5%. In-hospital mortality was 8.8% for the entire patient cohort (n = 385). With increasing case load and growing expertise, there was a significant reduction of in-hospital mortality to 4.8% (n = 186) after 2013 (P = 0.005). The learning curve of experienced pancreatic surgeons for PAR was 15 such procedures.

Conclusion: Our data demonstrate that an arterial surgical approach is effective in LAPC with promising long-term survival. PAD after neoadjuvant treatment is safe. PAR is a technically demanding procedure and requires a high level of expertise.
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http://dx.doi.org/10.1097/SLA.0000000000004054DOI Listing
June 2020

Challenges in Acceptance and Compliance in Digital Health Assessments During Pregnancy: Prospective Cohort Study.

JMIR Mhealth Uhealth 2020 10 14;8(10):e17377. Epub 2020 Oct 14.

Department of Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany.

Background: Pregnant women are increasingly using mobile apps to access health information during the antenatal period. Therefore, digital health solutions can potentially be used as monitoring instruments during pregnancy. However, a main factor of success is high user engagement.

Objective: The aim of this study was to analyze engagement and factors influencing compliance in a longitudinal study targeting pregnant women using a digital health app with self-tracking.

Methods: Digitally collected data concerning demographics, medical history, technical aspects, and mental health from 585 pregnant women were analyzed. Patients filling out ≥80% of items at every study visit were considered to be highly compliant. Factors associated with high compliance were identified using logistic regression. The effect of a change in mental and physical well-being on compliance was assessed using a one-sample t test.

Results: Only 25% of patients could be considered compliant. Overall, 63% left at least one visit blank. Influential variables for higher engagement included higher education, higher income, private health insurance, nonsmoking, and German origin. There was no relationship between a change in the number of physical complaints or depressive symptoms and study dropout.

Conclusions: Maintaining high engagement with digital monitoring devices over a long time remains challenging. As cultural and socioeconomic background factors had the strongest influence, more effort needs to be directed toward understanding the needs of patients from different demographic backgrounds to ensure high-quality care for all patients. More studies need to report on compliance to disclose potential demographic bias.
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http://dx.doi.org/10.2196/17377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593860PMC
October 2020

Reply to Nezic.

Eur J Cardiothorac Surg 2021 04;59(4):923-924

Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1093/ejcts/ezaa340DOI Listing
April 2021

Hyperamylasemia and acute pancreatitis after pancreatoduodenectomy: Two different entities.

Surgery 2021 02 25;169(2):369-376. Epub 2020 Sep 25.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Background: Serum amylase activity greater than the institutional upper limit of normal (hyperamylasemia) on postoperative day 0-2 has been suggested as a criterion to define postoperative acute pancreatitis after pancreatoduodenectomy, but robust evidence supporting this definition is lacking.

Background: To assess the clinical impact of hyperamylasemia after pancreatoduodenectomy and to define postoperative acute pancreatitis.

Methods: Data of 1,235 consecutive patients who had undergone pancreatoduodenectomy between January 2010 and December 2014 were extracted from a prospective database and analyzed. Postoperative acute pancreatitis was defined based on the computed tomography severity index. Logistic regression modeling was used to calculate the postoperative acute pancreatitis rate of the entire study population.

Results: Hyperamylasemia on postoperative day 1 was found in 52% of patients after pancreatoduodenectomy. Patients with hyperamylasemia on postoperative day 1 had statistically significantly greater morbidity and mortality than patients with a normal serum amylase activity on postoperative day 1 with the rates of postoperative pancreatic fistula of 14.5% vs 2.1%, and 90-day mortality of 6.6% vs 2.2%, respectively. Of the 364 patients who underwent postoperative computed tomography, 103 (28%) had radiologic signs of acute pancreatitis, thus defining them as having postoperative acute pancreatitis by our definition. Logistic regression modeling showed a 14.7% rate of postoperative acute pancreatitis for the entire patient cohort and 29.2% for patients with hyperamylasemia on postoperative day 1. Outcomes of patients with postoperative acute pancreatitis defined based on the computed tomography severity index showed a rate of postoperative pancreatic fistula of 32.4% and a 90-day mortality rate of 11.8%, which were worse than those of patients with hyperamylasemia on postoperative day 1 alone.

Conclusion: Hyperamylasemia on postoperative day 1 is a frequent finding after pancreatoduodenectomy, but hyperamylasemia on postoperative day 1 alone is not synonymous with postoperative acute pancreatitis because only 29.2% of such patients have acute pancreatitis based on computed tomography findings. Postoperative acute pancreatitis is a dangerous complication after pancreatoduodenectomy, but its prevalence, according to the gold standard of CT, is not as high as reported previously. Our data suggest that hyperamylasemia on postoperative day 1 and postoperative acute pancreatitis are 2 different entities.
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http://dx.doi.org/10.1016/j.surg.2020.07.050DOI Listing
February 2021

Analyzing non-sentinel axillary metastases in patients with T3-T4 cN0 early breast cancer and tumor-involved sentinel lymph nodes undergoing breast-conserving therapy or mastectomy.

Breast Cancer Res Treat 2020 Nov 20;184(2):627-636. Epub 2020 Aug 20.

Department of Gynecology and Obstetrics, Heidelberg University Hospital, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.

Purpose: In the ACOSOG Z0011 trial, completing axillary lymph node dissection (cALND) did not benefit patients with T1-T2 cN0 early breast cancer and 1-2 positive sentinel lymph nodes (SLN) undergoing breast-conserving surgery (BCT). This paper reports cALND rates in the clinical routine for patients who had higher (T3-T4) tumor stages and/or underwent mastectomy but otherwise met the ACOSOG Z0011 eligibility criteria. Aim of this study is to determine cALND time trends and non-sentinel axillary metastases (NSAM) rates to estimate occult axillary tumor burden.

Methods: Data were included from patients treated in 179 German breast cancer centers between 2008 and 2015. Time-trend rates were analyzed for cALND of patients with T3-T4 tumors separated for BCT and mastectomy and regarding presence of axillary macrometastases or micrometastases.

Results: Data were available for 188,909 patients, of whom 19,009 were identified with 1-2 positive SLN. Those 19,009 patients were separated into 4 cohorts: (1) Patients with T1-T2 tumors receiving BCT (ACOSOG Z0011 eligible; n = 13,741), (2) T1-T2 with mastectomy (n = 4093), (3) T3-T4 with BCT (n = 269), (4) T3-T4 with mastectomy (n = 906). Among patients with T3-T4 tumors, cALND rates declined from 2008 to 2015: from 88.2 to 62.6% for patients receiving mastectomy and from 96.6 to 58.1% in patients receiving BCT. Overall rates for any NSAM after cALND for cohorts 1-4 were 33.4%, 42.3%, 46.9%, 58.8%, respectively.

Conclusions: The cALND rates have decreased substantially in routine care in patients with 'extended' ACOSOG Z0011 eligibility criteria. Axillary tumor burden is higher in these patients than in the ACOSOG Z0011 trial.
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http://dx.doi.org/10.1007/s10549-020-05876-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599150PMC
November 2020

Reply to Sartipy.

Eur J Cardiothorac Surg 2021 01;59(1):282-283

Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1093/ejcts/ezaa249DOI Listing
January 2021

Cross-lagged analyses of the bidirectional relationship between depression and markers of chronic heart failure.

Depress Anxiety 2020 09 16;37(9):898-907. Epub 2020 Jun 16.

Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.

Background: Depression is common in patients with chronic heart failure (CHF) and is a predictor of rehospitalization and mortality. However, the complex bidirectional relationships between these two conditions are barely understood. We investigated the course of depression and markers of CHF (New York Heart Association [NYHA] functional class, N-terminal-prohormone B-type natriuretic peptide [NT-proBNP], and left ventricular ejection fraction [LVEF]) in a longitudinal study over a period of 2 years, using three assessment points.

Methods: Data of n = 446 patients with documented CHF were analyzed using structural equation modeling. Specifically, a Bayesian cross-lagged structural equation model was applied.

Results: Our study revealed that an aggravation of depression predicted an increase in NYHA functional class (significant cross-lagged effect γ  = 0.103, 95% confidence interval [CI] [0.017; 0.194]), whereas an increase in NYHA functional class did not predict an aggravation of depression (γ  = 0.002 95% CI [-0.057; 0.194]). This association was found only for NYHA functional class and depression-not for NT-proBNP and LVEF.

Conclusions: Experiencing depression and associated symptoms, such as lack of energy and fatigue, may lead to a further decrease of functional capacity, and consequently to a higher NYHA functional class in CHF patients. As NYHA functional class is associated with higher mortality, this may be a critical development for affected patients. Further studies are required to investigate whether or not this association could be an essential key that explains the pathway from depression to increased mortality in heart failure patients.
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http://dx.doi.org/10.1002/da.23041DOI Listing
September 2020

Prediction of mortality rate in acute type A dissection: the German Registry for Acute Type A Aortic Dissection score.

Eur J Cardiothorac Surg 2020 10;58(4):700-706

Department of Cardiovascular Surgery, University Heart Center Freiburg, Bad Krozingen, Germany.

Objectives: The goal was to develop a scoring system to predict the 30-day mortality rate for patients undergoing surgery for acute type A aortic dissection on the basis of the German Registry for Acute Type A Aortic Dissection (GERAADA) data set and to provide a Web-based application for standard use.

Methods: A total of 2537 patients enrolled in GERAADA who underwent surgery between 2006 and 2015 were analysed. Variable selection was performed using the R-package FAMoS. The robustness of the results was confirmed via the bootstrap procedure. The coefficients of the final model were used to calculate the risk score in a Web-based application.

Results: Age [odds ratio (OR) 1.018, 95% confidence interval (CI) 1.009-1.026; P < 0.001; 5-year OR: 1.093], need for catecholamines at referral (OR 1.732, 95% CI 1.340-2.232; P < 0.001), preoperative resuscitation (OR 3.051, 95% CI 2.099-4.441; P < 0.001), need for intubation before surgery (OR 1.949, 95% CI 1.465-2.585; P < 0.001), preoperative hemiparesis (OR 1.442, 95% CI 0.996-2.065; P = 0.049), coronary malperfusion (OR 1.870, 95% CI 1.386-2.509; P < 0.001), visceral malperfusion (OR 1.748, 95% CI 1.198-2.530; P = 0.003), dissection extension to the descending aorta (OR 1.443, 95% CI 1.120-1.864; P = 0.005) and previous cardiac surgery (OR 1.772, 95% CI 1.048-2.903; P = 0.027) were independent predictors of the 30-day mortality rate. The Web application based on the final model can be found at https://www.dgthg.de/de/GERAADA_Score.

Conclusions: The GERAADA score is a simple, effective tool to predict the 30-day mortality rate for patients undergoing surgery for acute type A aortic dissection. We recommend the widespread use of this Web-based application for standard use.
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http://dx.doi.org/10.1093/ejcts/ezaa156DOI Listing
October 2020

HER2-targeted therapy influences CTC status in metastatic breast cancer.

Breast Cancer Res Treat 2020 Jul 20;182(1):127-136. Epub 2020 May 20.

Department of Gynecology and Obstetrics, University Hospital Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.

Purpose: As an independent, negative-prognostic biomarker for progression-free survival (PFS) and overall survival (OS), circulating tumor cells (CTCs) constitute a promising component for developing a liquid biopsy for patients with metastatic breast cancer (MBC). The effects of HER2-targeted therapy such as trastuzumab, pertuzumab, T-DM1, and lapatinib on CTC status and longitudinal enumeration were assessed in this trial.

Methods: CTC status of 264 patients with MBC was analyzed prior to and after 4 weeks of a new line of palliative systemic therapy. CTCs were assessed using CellSearch®. Three groups were compared: patients with HER2-positive MBC receiving ongoing HER2-targeted therapy (n = 28), patients with de novo HER2-positive MBC and no HER2-targeted therapy in the last 12 months prior to enrollment and start of HER2-targeted therapy (n = 15), and patients with HER2-nonamplified disease and no HER2-targeted therapy (n = 212).

Results: Positive CTC status (≥ 5 CTC/7.5 ml blood) at enrollment was observed in the 3 groups for 17.9, 46.7, and 46.2% (p = 0.02) of patients, respectively. At least one CTC/7.5 ml was seen in 28.6, 53.3, and 67.0% (p < 0.001) of these patients. Furthermore, 3.6, 40.0, and 3.3% (p < 0.001) of the patients had at least one HER2-positive CTC. After 4 weeks of therapy 7.1, 0.0, and 31.1% (p = 0.001) of patients had still a positive CTC status (≥ 5 CTC/7.5 ml blood). At least one CTC/7.5 ml was still observed in 25.0, 20.0, and 50.5% (p = 0.004) of the patients. Furthermore, 7.1, 0.0, and 1.9% (p = 0.187) had at least one HER2-positive CTC. After 3 months of therapy, 35.7, 20.0, and 28.3% (p = 0.536) showed disease progression.

Conclusions: HER2-targeted therapy seems to reduce the overall CTC count in patients with MBC. This should be taken into account when CTC status is used as an indicator for aggressive or indolent metastatic tumor disease.
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http://dx.doi.org/10.1007/s10549-020-05687-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274999PMC
July 2020

Reduction in physical activity significantly increases depression and anxiety in the perinatal period: a longitudinal study based on a self-report digital assessment tool.

Arch Gynecol Obstet 2020 07 5;302(1):53-64. Epub 2020 May 5.

Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.

Purpose: Physical activity can reduce pregnancy-related complications and contributes substantially to improving maternal mental health. A reduction in activity encompassing exercise and daily household tasks throughout the course of pregnancy increases the risk of depression and anxiety. The following research examines the longitudinal interaction between exercise, general physical activity, and mental health outcomes in pregnant women.

Methods: This prospective longitudinal study was conducted at the maternity departments of two major university hospitals in Germany. Self-reported data of 597 women were digitally assessed every 4 weeks from the second trimester until birth as well as 3 and 6 months postnatally. Depressive and anxiety symptoms were assessed using the EPDS, PRAQ, and STAI and physical activity levels were measured using the PPAQ questionnaire. Cross-sectional and longitudinal analyses using Pearson's correlation coefficient and multiple regression models were conducted.

Results: We found a significant reduction in general physical activity in the period from the 20th to 32nd gestational week. Women who reported a greater decline during pregnancy showed significantly higher depression and anxiety scores. In stratified analyses, only baseline mental health scores proved to be variables with stronger impact on postnatal depression and anxiety outcomes.

Conclusion: General physical activity and maternal mental health significantly influence each other during and after pregnancy. Both physical activity and the prevention of perinatal mental disorders should be systematically encouraged during perinatal care to prevent adverse maternal and fetal birth outcomes.
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http://dx.doi.org/10.1007/s00404-020-05570-xDOI Listing
July 2020

Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer.

Cancers (Basel) 2020 Apr 24;12(4). Epub 2020 Apr 24.

Department of Gynecology and Obstetrics, University Hospital Heidelberg, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch system. A cut-off analysis was performed using Youden's J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4-92) vs. 7 (2-43) months ( < 0.001). Median intact CTC count at enrollment was 15.0 (5-2760) vs. 30.5 (5-200000) cells ( = 0.39) and 2.5 (0-420) vs. 8.5 (0-15000) cells after one cycle of systemic therapy ( = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0-1500) vs. 9 (0-800) cells ( = 0.475) and 1 (0-200) vs. 3 (0-250) cells after one cycle of systemic therapy ( = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression.
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http://dx.doi.org/10.3390/cancers12041055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226373PMC
April 2020

Postoperative complications and mobilisation following major abdominal surgery with vs. without fitness tracker-based feedback (EXPELLIARMUS): study protocol for a student-led multicentre randomised controlled trial (CHIR-Net SIGMA study group).

Trials 2020 Mar 23;21(1):293. Epub 2020 Mar 23.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Postoperative complications following major abdominal surgery are frequent despite progress in surgical technique and perioperative care. Early and enhanced postoperative mobilisation has been advocated to reduce postoperative complications, but it is still unknown whether it can independently improve outcomes after major surgery. Fitness trackers (FTs) are a promising tool to improve postoperative mobilisation, but their effect on postoperative complications and recovery has not been investigated in clinical trials.

Methods: This is a multicentre randomised controlled trial with two parallel study groups evaluating the efficacy of an enhanced and early mobilisation protocol in combination with FT-based feedback in patients undergoing elective major abdominal surgery. Participants are randomly assigned (1:1) to either the experimental group, which receives daily step goals and a FT giving feedback about daily steps, or the control group, which is mobilised according to hospital standards. The control group also receives a FT, however with a blackened screen; thus no FT-based feedback is possible. Randomisation will be stratified by type of surgery (laparoscopic vs. open). The primary endpoint of the study is postoperative morbidity within 30 days measured via the Comprehensive Complication Index. Secondary endpoints include number of steps as well as a set of functional, morbidity and safety parameters. A total of 348 patients will be recruited in 15 German centres. The study will be conducted and organised by the student-led German Clinical Trial Network SIGMA.

Discussion: Our study aims at investigating whether the implementation of a simple mobilisation protocol in combination with FT-based feedback can reduce postoperative morbidity in patients undergoing major abdominal surgery. If so, FTs would offer a cost-effective intervention to enhance postoperative mobilisation and improve patient outcomes.

Trial Registration: Deutsches Register Klinischer Studien (DRKS, German Clinical Trials Register): DRKS00016755, UTN U1111-1228-3320. Registered on 06.03.2019.
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http://dx.doi.org/10.1186/s13063-020-4220-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092422PMC
March 2020

Novel Liquid Biomarker Panels for A Very Early Response Capturing of NSCLC Therapies in Advanced Stages.

Cancers (Basel) 2020 Apr 12;12(4). Epub 2020 Apr 12.

Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), INF 156, 69120 Heidelberg, Germany.

Computed tomography (CT) scans are the gold standard to measure treatment success of non-small cell lung cancer (NSCLC) therapies. Here, we investigated the very early tumor response of patients receiving chemotherapy or targeted therapies using a panel of already established and explorative liquid biomarkers. Blood samples from 50 patients were taken at baseline and at three early time points after therapy initiation. DNA mutations, a panel of 17 microRNAs, glycodelin, glutathione disulfide, glutathione, soluble caspase-cleaved cytokeratin 18 (M30 antigen), and soluble cytokeratin 18 (M65 antigen) were measured in serum and plasma samples. Baseline and first follow-up CT scans were evaluated and correlated with biomarker data. The detection rate of the individual biomarkers was between 56% and 100%. While only keratin 18 correlated with the tumor load at baseline, we found several individual markers correlating with the tumor response to treatment for each of the three time points of blood draws. A combination of the five best markers at each time point resulted in highly significant marker panels indicating therapeutic response (R = 0.78, R = 0.71, and R = 0.71). Our study demonstrates that an early measurement of biomarkers immediately after therapy start can assess tumor response to treatment and might support an adaptation of treatment to improve patients' outcome.
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http://dx.doi.org/10.3390/cancers12040954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226444PMC
April 2020

Symptomatic marginal ulcer after pancreatoduodenectomy.

Surgery 2020 07 7;168(1):67-71. Epub 2020 Apr 7.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Germany.

Background: Marginal ulcer is a well-known complication after pancreatoduodenectomy. In light of increasing long-term survival after pancreatoduodenectomy, the identification of risk factors and preventive strategies are of utmost importance. We assessed the incidence, clinical impact, and potential risk factors of marginal ulcer after pancreatoduodenectomy.

Methods: A prospectively maintained database of patients undergoing pancreatoduodenectomy was analyzed retrospectively. Univariate and bivariate competing-risk Cox regression analyses were performed to identify risk factors for marginal ulcer.

Results: Two hundred and fifty-five consecutive patients underwent pancreatoduodenectomy. The median follow-up was 35.7 months. Marginal ulcer was diagnosed in 19 patients (7.5%), and the median time from pancreatoduodenectomy to marginal ulcer diagnosis was 450 days. Thirteen of these 19 patients presented with abdominal pain, melena, or anemia. In all these 13 patients, marginal ulcer resolved with proton pump inhibitor therapy and endoscopic surveillance. Six patients with marginal ulcer presented with an acute abdomen and underwent emergency laparotomy for marginal ulcer perforation and peritonitis. There was no marginal ulcer-related mortality. Univariate and bivariate competing-risk analyses showed an increased risk for marginal ulcer with discontinuation of proton pump inhibitor therapy, smoking, alcohol intake, and the use of non-steroidal anti-inflammatory drugs. Discontinuation of proton pump inhibitor therapy was an independent risk factor for marginal ulcer development.

Conclusion: Marginal ulcer is a relevant long-term complication after pancreatoduodenectomy that occurs more frequently after proton pump inhibitor therapy is discontinued. Based on our data, permanent use of proton pump inhibitor after pancreatoduodenectomy is strongly recommended especially for those patients who smoke, consume alcohol, or use non-steroidal anti-inflammatory drugs.
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http://dx.doi.org/10.1016/j.surg.2020.02.012DOI Listing
July 2020

The Lack of Evidence for an Association between Cancer Biomarker Conversion Patterns and CTC-Status in Patients with Metastatic Breast Cancer.

Int J Mol Sci 2020 Mar 21;21(6). Epub 2020 Mar 21.

Department of Gynecology and Obstetrics, Heidelberg University Hospital, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.

Circulating tumor cell (CTC) detection is a prognostic factor in the metastatic breast cancer (MBC) setting. Discrepancies in primary (PT) and metastatic tumor (MT) genetic profiles are also of prognostic importance. Our study aimed to compare the CTC statuses and prognoses between those with subtype stable MBCs and MBCs with specific biomarker conversions. The study enrolled 261 MBC patients, treated at the National Center for Tumor Diseases, Heidelberg, Germany in a five-year period. All underwent PT and MT biopsies and subsequent CTC enumeration before the initiation of systemic therapy. ER and HER2 statuses of the PTs and MTs were determined and progression free survivals (PFSs) and overall survivals (OSs) were recorded. We compared CTC statuses, CTC counts, PFSs and OSs between subgroups of patients with different receptor change patterns. Patients who had tumors that converted to triple negative MTs had the shortest median OSs, while HER2 expression was not associated with a shorter median OS. No significant differences in PFSs and OSs have been demonstrated by Kaplan-Meier curve comparisons in any of the subgroup analyses. CTC counts were similar in all subgroups. CTCs were comparably less frequently detected in patients with a stable HER2 expression. Similar proportions of CTC positives were observed in all other subtype change pattern subgroups, barring the aforementioned HER2 stable subgroup. The detection of CTCs was of no appreciable prognostic value in different receptor change pattern subgroups in our cohort.
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http://dx.doi.org/10.3390/ijms21062161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139918PMC
March 2020

Incorporating historical two-arm data in clinical trials with binary outcome: A practical approach.

Pharm Stat 2020 09 30;19(5):662-678. Epub 2020 Mar 30.

Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.

The feasibility of a new clinical trial may be increased by incorporating historical data of previous trials. In the particular case where only data from a single historical trial are available, there exists no clear recommendation in the literature regarding the most favorable approach. A main problem of the incorporation of historical data is the possible inflation of the type I error rate. A way to control this type of error is the so-called power prior approach. This Bayesian method does not "borrow" the full historical information but uses a parameter 0 ≤ δ ≤ 1 to determine the amount of borrowed data. Based on the methodology of the power prior, we propose a frequentist framework that allows incorporation of historical data from both arms of two-armed trials with binary outcome, while simultaneously controlling the type I error rate. It is shown that for any specific trial scenario a value δ > 0 can be determined such that the type I error rate falls below the prespecified significance level. The magnitude of this value of δ depends on the characteristics of the data observed in the historical trial. Conditionally on these characteristics, an increase in power as compared to a trial without borrowing may result. Similarly, we propose methods how the required sample size can be reduced. The results are discussed and compared to those obtained in a Bayesian framework. Application is illustrated by a clinical trial example.
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http://dx.doi.org/10.1002/pst.2023DOI Listing
September 2020

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.

Arch Gynecol Obstet 2020 04 9;301(4):1037-1045. Epub 2020 Mar 9.

Department of Gynecology, Breast Center, Heidelberg University, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1007/s00404-020-05481-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103012PMC
April 2020

Hernia reduction following laparotomy using small stitch abdominal wall closure with and without mesh augmentation (the HULC trial): study protocol for a randomized controlled trial.

Trials 2019 Dec 16;20(1):738. Epub 2019 Dec 16.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Incisional hernias are among the most frequent complications following abdominal surgery and cause substantial morbidity, impaired health-related quality of life and costs. Despite improvements in abdominal wall closure techniques, the risk for developing an incisional hernia is reported to be between 10 and 30% following midline laparotomies. There have been two recent innovations with promising results to reduce hernia risks, namely the small stitches technique and the placement of a prophylactic mesh. So far, these two techniques have not been evaluated in combination.

Methods: The HULC trial is a multicentre, randomized controlled, observer- and patient-blinded surgical effectiveness trial with two parallel study groups. A total of 812 patients scheduled for elective abdominal surgery via a midline laparotomy will be randomized in 12 centres after informed consent. Patients will be randomly assigned to the control group receiving closure of the midline incision with a slowly absorbable monofilament suture in the small stitches technique or to the intervention group, who will receive a small stitches closure followed by augmentation with a light-weight polypropylene mesh in the onlay technique. The primary endpoint will be the occurrence of incisional hernias, as defined by the European Hernia Society, within 24 months after surgery. Further perioperative parameters, as well as patient-reported outcomes, will be analysed as secondary outcomes.

Discussion: The HULC trial will address the yet unanswered question of whether a combination of small stitched fascial closure and onlay mesh augmentation after elective midline laparotomies reduces the risk of incisional hernias. The HULC trial marks the logical and innovative next step in the development of a safe abdominal closure technique.

Trial Registration: German Clinical Trials Register, DRKS00017517. Registered on 24th June 2019.
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http://dx.doi.org/10.1186/s13063-019-3921-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915967PMC
December 2019
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