Prospective multicentre cohort study of patient-reported outcomes and complications following major abdominal neoplastic surgery (PATRONUS) – study protocol for a CHIR-Net student-initiated German medical audit study (CHIR-Net SIGMA study)

Background: One of the most important aspects of designing a clinical trial is selecting appropriate outcomes. Patient-reported outcomes (PROs) can provide a personal assessment of the burden and impact of a malignant disease and its treatment. PROs comprise a wide range of outcomes including basic clinical symptom scores and complex metrics such as health-related quality of life (HRQoL). There is limited data on how postoperative complications following cancer surgery affect symptoms and HRQoL. For this reason the primary aim of the PATRONUS study is to investigate how perioperative complications affect cancer-related symptoms and HRQoL in patients undergoing abdominal cancer surgery. The PATRONUS study is designed and will be initiated and conducted by medical students under the direct supervision of clinician scientists based on the concept of inquiry-based learning. Methods: PATRONUS is a non-interventional prospective multicentre cohort study. Patients undergoing elective oncological abdominal surgery will be recruited at regional centres of the clinical network of the German Surgical Society (CHIR-Net) and associated hospitals. A core set of 12 cancer associated symptoms will be assessed via the PRO version of the Common Terminology Criteria for Adverse Events. The cancer-specific HRQoL will be measured via the computerised adaptive testing version of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. PROs will be measured eight times over a period of six months. The short-term clinical outcome measure is the rate of postoperative complications (grade II to V) within 30 days according to the Clavien-Dindo classification. The long-term clinical outcome is overall survival within six months postoperative. Discussion: PATRONUS will provide essential insights into the patients’ assessment of their well-being and quality of life in direct relation to clinical outcome parameters following abdominal cancer surgery. Furthermore, PATRONUS will investigate the feasibility of multicentre student-led clinical research. Trial registration German Clinical Trials Register: DRKS00013035 (registered on October 26, 2017). Universal Trial Number (UTN): U1111–1202-8863

Influence of patient and tumor characteristics on therapy persistence with letrozole in postmenopausal women with advanced breast cancer: results of the prospective observational EvAluate-TM study

Background: Treatment of postmenopausal, hormone receptor-positive metastatic breast cancer (MBC) patients varies despite clear therapy guidelines, favoring endocrine treatment (ET). Aim of this study was to analyze persistence of palliative aromatase inhibitor (AI) monotherapy in MBC patients. Methods: EvAluate-TM is a prospective, multicenter, noninterventional study to evaluate treatment with letrozole in postmenopausal women with hormone receptor–positive breast cancer. To assess therapy persistence, defined as the time from therapy start to the end of the therapy (TTEOT), two pre-specified study visits took place after 6 and 12 months. Competing risk survival analyses were performed to identify patient and tumor characteristics that predict TTEOT. Results: Out of 200 patients, 66 patients terminated treatment prematurely, 26 (13%) of them due to causes other than disease progression. Persistence rate for reasons other than progression at 12 months was 77.7%. Persistence was lower in patients who reported any adverse event (AE) in the first 30 days of ET (89.5% with no AE and 56% with AE). Furthermore, patients had a lower persistence if they reported compliance problems in the past before letrozole treatment. Conclusions: Despite suffering from a life-threatening disease, AEs of an AI will result in a relevant number of treatment terminations that are not related to progression. Some subgroups of patients have very low persistence rates. Especially with regard to novel endocrine combination therapies, these data imply that some groups of patients will need special attention to guide them through the therapy process. Trial registration Clinical Trials Number: CFEM345DDE1

Femoral Head and Liner Exchange in Patients with Atraumatic Dislocation. Results of a Retrospective Study with 6 Years Follow-Up

Background and Objectives: Femoral head and liner exchange is an established treatment for polyethylene wear but has had a more limited role in the treatment of other conditions including dislocation, because of concerns about an increased postoperative dislocation rate. Some authors have considered dislocation associated with polyethylene wear to be a contraindication for this procedure. Materials and Methods: Our retrospective review evaluated the outcome of head and liner exchange in a small consecutively operated heterogeneous cohort of 20 patients who presented with dislocation unrelated to trauma, component malposition or component loosening. Of this group, 12 had prior primary total hip arthroplasty, and 8 had prior revision total hip arthroplasty, and included 4 patients with prior revision for dislocation. Mean follow-up was 6 ± 3.5 years (range 1–145 months). Results: Kaplan–Meier analysis revealed a revision-free implant survival from any cause of 80% (confidence interval 95%:64.3–99.6%) at 5 years after head and liner exchange (index surgery). At final follow-up, 83.3% of patients (n = 10) with prior primary total hip arthroplasty and 62.5% of patients (n = 5) with prior revision total hip arthroplasty, had not required subsequent revision for any cause. None (0%) of the primary total hip arthroplasty group and 3 (38%) of the revision arthroplasty group had required revision for further dislocation. Of the eight revision arthroplasty patients, four had a prior revision for dislocation and three of these four patients required further revision for dislocation after index surgery. The fourth patient had no dislocation after index surgery. One additional patient who had prior revision surgery for femoral component fracture suffered dislocation after index surgery, but was successfully treated with closed reduction. Conclusions: In our study population, femoral head and liner exchange was an effective treatment option for patients with prior primary total hip arthroplasty and also for a highly select group of revision total arthroplasty patients with no prior history of dislocation. Femoral head and liner exchange does not appear to be a viable treatment option for patients who have had revision total arthroplasty after prior dislocations

Femoral Head and Liner Exchange in Patients with Atraumatic Dislocation. Results of a Retrospective Study with 6 Years Follow-Up

Background and Objectives: Femoral head and liner exchange is an established treatment for polyethylene wear but has had a more limited role in the treatment of other conditions including dislocation, because of concerns about an increased postoperative dislocation rate. Some authors have considered dislocation associated with polyethylene wear to be a contraindication for this procedure. Materials and Methods: Our retrospective review evaluated the outcome of head and liner exchange in a small consecutively operated heterogeneous cohort of 20 patients who presented with dislocation unrelated to trauma, component malposition or component loosening. Of this group, 12 had prior primary total hip arthroplasty, and 8 had prior revision total hip arthroplasty, and included 4 patients with prior revision for dislocation. Mean follow-up was 6 ± 3.5 years (range 1–145 months). Results: Kaplan–Meier analysis revealed a revision-free implant survival from any cause of 80% (confidence interval 95%:64.3–99.6%) at 5 years after head and liner exchange (index surgery). At final follow-up, 83.3% of patients (n = 10) with prior primary total hip arthroplasty and 62.5% of patients (n = 5) with prior revision total hip arthroplasty, had not required subsequent revision for any cause. None (0%) of the primary total hip arthroplasty group and 3 (38%) of the revision arthroplasty group had required revision for further dislocation. Of the eight revision arthroplasty patients, four had a prior revision for dislocation and three of these four patients required further revision for dislocation after index surgery. The fourth patient had no dislocation after index surgery. One additional patient who had prior revision surgery for femoral component fracture suffered dislocation after index surgery, but was successfully treated with closed reduction. Conclusions: In our study population, femoral head and liner exchange was an effective treatment option for patients with prior primary total hip arthroplasty and also for a highly select group of revision total arthroplasty patients with no prior history of dislocation. Femoral head and liner exchange does not appear to be a viable treatment option for patients who have had revision total arthroplasty after prior dislocations

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

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

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

BackgroundHealth-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. ObjectiveThis 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. MethodsA 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. ResultsThe 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. ConclusionsCompared 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

Evaluation of Repeated Web-Based Screening for Predicting Postpartum Depression: Prospective Cohort Study

BackgroundPostpartum depression (PPD) is a severe mental disorder that often results in poor maternal-infant attachment and negatively impacts infant development. Universal screening has recently been recommended to identify women at risk, but the optimal screening time during pregnancy has not been defined so far. Thus, web-based technologies with widespread use among women of childbearing age create new opportunities to detect pregnancies with a high risk for adverse mental health outcomes at an early stage. ObjectiveThe aim of this study was to stratify the risk for PPD and to determine the optimal screening time during pregnancy by using a web-based screening tool collecting electronic patient-reported outcomes (ePROs) as the basis for a screening algorithm. MethodsIn total, 214 women were repeatedly tested for depressive symptoms 5 times during and 3 times after pregnancy by using the Edinburgh Postnatal Depression Scale (EPDS), accessible on a web-based pregnancy platform, developed by the authors of this study. For each prenatal assessment, the area under the curve (AUC), sensitivity, specificity, and predictive values for PPD were calculated. Multivariate logistic regression analyses were applied to identify further potential predictors, such as age, education, parity, relationship quality, and anxiety, to increase predictive accuracy. ResultsDigitally collected data from 214 pregnant women were analyzed. The predictive accuracy of depressive symptoms 3 and 6 months postpartum was reasonable to good regarding the screening in the second (AUC=0.85) and third (AUC=0.75) trimester. The multivariate logistic regression analyses resulted in an excellent AUC of 0.93 at 3 months and a good AUC of 0.87 at 6 months postpartum. ConclusionsThe best predictive accuracy for PPD has been shown for screening between the 24th and the 28th gestational week (GW) and seems to be beneficial for identifying women at risk. In combination with the aforementioned predictive factors, the discriminatory power improved, particularly at 3 months postpartum. Screening for depression during pregnancy, combined with the women’s personal risk profile, can be used as a starting point for developing a digital screening algorithm. Thereby, web-based assessment tools constitute feasible, efficient, and cost-effective approaches. Thus, they seem to be beneficial in detecting high-risk pregnancies in order to improve maternal and infant birth outcomes in the long term

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

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

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

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

HER2-targeted therapy influences CTC status in metastatic breast cancer

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