Enhancing Data Protection via Auditable Informational Separation of Powers Between Workflow Engine Based Agents: Conceptualization, Implementation, and First Cross-Institutional Experiences.

German best practice standards for secondary use of patient data require pseudonymization and informational separation of powers assuring that identifying data (IDAT), pseudonyms (PSN), and medical data (MDAT) are never simultaneously knowable by any party involved in data provisioning and use. We describe a solution meeting these requirements based on the dynamic interaction of three software agents: the clinical domain agent (CDA), which processes IDAT and MDAT, the trusted third party agent (TTA), which processes IDAT and PSN, and the research domain agent (RDA), which processes PSN and MDAT and delivers pseudonymized datasets. CDA and RDA implement a distributed workflow by employing an off-the-shelf workflow engine. TTA wraps the gPAS framework for pseudonym generation and persistence. All agent interactions are implemented via secured REST-APIs. Rollout to three university hospitals was seamless. The workflow engine allowed meeting various overarching requirements, including auditability of data transfer and pseudonymization, with minimal additional implementation effort. Using a distributed agent architecture based on workflow engine technology thus proved to be an efficient way to meet technical and organizational requirements for provisioning patient data for research purposes in a data protection compliant way.

The Effect of Postoperative Complications After Minimally Invasive Esophagectomy on Long-term Survival: An International Multicenter Cohort Study.

BACKGROUND: Esophagectomy is a technically challenging procedure, associated with significant morbidity. The introduction of minimally invasive esophagectomy (MIE) has reduced postoperative morbidity. OBJECTIVE: Although the short-term effect on complications is increasingly being recognized, the impact on long-term survival remains unclear. This study aims to investigate the association between postoperative complications following MIE and long-term survival. METHODS: Data were collected from the EsoBenchmark Collaborative composed by 13 high-volume, expert centers routinely performing MIE. Patients operated between June 1, 2011 and May 31, 2016 were included. Complications were graded using the Clavien-Dindo (CD) classification. To correct for short-term effects of postoperative complications on mortality, patients who died within 90 days postoperative were excluded. Primary endpoint was 5-year overall survival. RESULTS: A total of 915 patients were included with a mean follow-up time of 30.8 months (standard deviation 17.9). Complications occurred in 542 patients (59.2%) of which 50.2% had a CD grade ≥III complication [ie, (re)intervention, organ dysfunction, or death]. The incidence of anastomotic leakage (AL) was 135 of 915 patients (14.8%) of which 84 patients were classified as a CD grade ≥III. Multivariable analysis showed a significantly deteriorated long-term survival in all patients with AL [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.25-2.24]. This inverse relation was most distinct when AL was scored as a CD grade ≥III (HR 1.83, 95% CI 1.30-2.58). For all other complications, no significant association with long-term survival was found. CONCLUSION: The occurrence and severity of AL, but not overall complications, after MIE negatively affect long-term survival of esophageal cancer patients.

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study.

BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007). CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.

Anastomotic Techniques and Associated Morbidity in Total Minimally Invasive Transthoracic Esophagectomy: Results From the EsoBenchmark Database.

OBJECTIVE: The aim of this study was to describe anastomotic techniques used for total minimally invasive transthoracic esophagectomy (ttMIE) and to analyze the associated morbidity. BACKGROUND: ttMIE faces increasing application in surgical treatment of esophageal cancer. For esophagogastric reconstruction, different anastomotic techniques are currently used, but their effect on postoperative anastomotic leakage and morbidity has not been investigated. PATIENTS AND METHODS: Patients were selected from a basic dataset, collected during a 5-year period from 13 international surgical high-volume centers. Endpoints were anastomotic leakage rate and postoperative morbidity in correlation to anastomotic techniques, measured by the Clavien-Dindo classification and the Comprehensive Complication Index (CCI). RESULTS: Five anastomotic techniques were identified in 966 patients after ttMIE: intrathoracic end-to-side circular-stapled technique in 427 patients (double-stapling n = 90, purse-string n = 337), intrathoracic (n = 109) or cervical (n = 255) side-to-side linear-stapled, and cervical end-to-side hand-sewn (n = 175). Leakage rates were similar in intrathoracic and cervical anastomoses (15.9% vs 17.2%, P = 0.601), but overall complications (56.7%% vs 63.7%, P = 0.029) and median 90-day CCI {21 [interquartile range (IQR) 0-36] vs 29 [IQR 0-40], P = 0.019} favored intrathoracic reconstructions. Leakage rates after intrathoracic end-to-side double-stapling (23.3%) and cervical end-to-side hand-sewn (25.1%) techniques were significantly higher compared with intrathoracic side-to-side linear (15.6%), end-to-side purse-string (13.9%), and cervical side-to-side linear-stapled esophagogastrostomies (11.8%) (P < 0.001). Multivariable analysis confirmed anastomotic technique as independent predictor of leakage after ttMIE. CONCLUSION: Results of this analysis present the current status of the technical evolution of ttMIE with anastomotic leakage as predominant surgical complication. However, technique-related morbidity requires cautious interpretation considering the long learning curve of this complex surgical procedure.

Approaching Clinical Data Transformation from Disparate Healthcare IT Systems Through a Modular Framework.

Many healthcare IT systems in Germany are unable to interoperate with other systems through standardised data formats. Therefore it is difficult to store and retrieve data and to establish a systematic collection of data with provenance across systems and even healthcare institutions. We outline the concept for a Transformation Pipeline that can act as a processor for proprietary medical data formats from multiple sources. Through a modular construction, the pipeline relies on different data extraction and data enrichment modules as well as on interfaces to external definitions for interoperability standards. The developed solution is extendable and reusable, enabling data transformation independent from current format definitions and entailing the opportunity of collaboration with other research groups.

Defining Benchmarks for Transthoracic Esophagectomy: A Multicenter Analysis of Total Minimally Invasive Esophagectomy in Low Risk Patients.

OBJECTIVE: To define "best possible" outcomes in total minimally invasive transthoracic esophagectomy (ttMIE). BACKGROUND: TtMIE, performed by experts in patients with low comorbidity, may serve as a benchmark procedure for esophagectomy. PATIENTS AND METHODS: From a cohort of 1057 ttMIE, performed over a 5-year period in 13 high-volume centers for esophageal surgery, we selected a study group of 334 patients (31.6%) that fulfilled criteria of low comorbidity (American Society of Anesthesiologists score ≤2, WHO/ECOG score ≤1, age ≤65 years, body mass index 19-29 kg/m). Endpoints included postoperative morbidity measured by the Clavien-Dindo classification and the comprehensive complication index. Benchmark values were defined as the 75th percentile of the median outcome parameters of the participating centers to represent best achievable results. RESULTS: Benchmark patients were predominantly male (82.9%) with a median age of 58 years (53-62). High intrathoracic (Ivor Lewis) and cervical esophagogastrostomy (McKeown) were performed in 188 (56.3%) and 146 (43.7%) patients, respectively. Median (IQR) ICU and hospital stay was 0 (0-2) and 12 (9-18) days, respectively. 56.0% of patients developed at least 1 complication, and 26.9% experienced major morbidity (≥grade III), mostly related to pulmonary complications (25.7%), anastomotic leakage (15.9%), and cardiac events (13.5%). Benchmark values at 30 days after hospital discharge were ≤55.7% and ≤30.8% for overall and major complications, ≤18.0% for readmission, ≤3.1% for positive resection margins, and ≥23 for lymph node yield. Benchmarks at 30 and 90 days were ≤1.0% and ≤4.6% for mortality, and ≤40.8 and ≤42.8 for the comprehensive complication index, respectively. CONCLUSION: This outcome analysis of patients with low comorbidity undergoing ttMIE may serve as a reference to evaluate surgical performance in major esophageal resection.

Accelerated Recovery Within Standardized Recovery Pathways After Esophagectomy: A Prospective Cohort Study Assessing the Effects of Early Discharge on Outcomes, Readmissions, Patient Satisfaction, and Costs.

BACKGROUND: After esophagectomy, some patients exceed targeted discharge goal within enhanced recovery after surgery programs. This study reviews the demographics, outcomes, cost, readmission rates, and patient satisfaction for the accelerated recovery (AR) group. METHODS: Between 2010 and 2013, 137 consecutive esophagectomy patients were compared according to the length of hospital stay: AR 5 to 6 days, targeted recovery (TR) 7 to 8 days, and delayed recovery (DR) 9 days or more. RESULTS: The AR patients increased from 3% to 46% during the study period. The AR patients were younger, but all groups were comparable regarding comorbidities (Charlson, American Society of Anesthesiologists, and Eastern Cooperative Oncology Group score), cancer stage, and treatment approach. The AR patients were more likely to have neoadjuvant therapy, shorter operations, and less blood loss. The DR patients were more likely to have complications (40% AR versus 45% TR versus 90% DR, p < 0.001). Inhospital and 90-day mortality was 1.5%. All AR patients were discharged home (100% AR versus 87% TR versus 63% DR, p < 0.001), and 30-day readmission rates were comparable between groups (14% AR versus 19% TR versus 5% DR, p = 0.122). Overall mean costs ($38,385 AR versus $41,607 TR versus $61,199 DR, p < 0.001) as well as readmission costs ($7,470 AR versus $27,695 TR versus $33,398 DR, p = 0.202) were lower in the AR group. Patient satisfaction scores were comparable between groups. CONCLUSIONS: Accelerated recovery is achievable in a significant proportion of patients undergoing esophagectomy. Accelerated recovery is associated with decreased treatment costs but does not lead to increased readmissions or decreased patient satisfaction. Enhanced recovery after surgery programs should be designed to accommodate patients appropriate for AR.

Multidisciplinary treatment of T1a adenocarcinoma in Barrett's esophagus: contemporary comparison of endoscopic and surgical treatment in physiologically fit patients.

BACKGROUND: Previous reports comparing endoscopic therapy (ET) and surgical therapy (ST) have predominantly assessed patients with high-grade dysplasia. The study aim was to compare ET to ST in physiologically fit patients with cT1a adenocarcinoma (EAC). METHODS: Review of two prospective databases yielded 100 patients presenting with clinical cT1a EAC between 2000 and 2013. Only physiologically fit patients who were candidates for either treatment were analyzed. RESULTS: Presenting patient characteristics were similar between ET (n = 36) and ST groups (n = 49). Surgical patients were less likely to be staged with EMR (43 vs 100 %) and were associated with mass lesions >1 cm at EGD (p = 0.01), multifocal EAC (p = 0.03), and positive margins for EAC on EMR (p < 0.05). On multivariate analysis, only multifocal HGD was an independent factor for surgery. Following esophagectomy, R0 resection rates for Barrett's esophagus and cancer were 100 %. Incidence of surgery decreased over the study period from 85 to 25 %. All ET patients had EMR, and 28 patients underwent additional ablative therapies for Barrett's esophagus. Following ET, eradication rates of EAC, dysplasia, and BE were 92, 81, and 53 %, respectively. Morbidity rates were comparable between groups (ST 51 % vs ET 39 %, p = 0.31). In-hospital mortality rate was zero in each group. Recurrence rates in ST and ET group were 2 and 11 % (p = 0.08). In the ET group, two patients with endoluminal cancer recurrence after complete eradication underwent esophagectomy. Age-adjusted overall survival was comparable. CONCLUSION: In high-volume esophageal centers, ST and ET provide equally safe and effective treatment for cT1a EAC in medically fit patients. While the results of this study provide a historical perspective and clearly demonstrate an evolution toward ET over time, the appropriate treatment modality is best selected in a multidisciplinary fashion with EMR providing the most accurate staging. In endoscopically treated patients, indefinite endoscopic follow-up required, however, standardized long-term follow-up protocols are needed.

Thoracic multidisciplinary tumor board routinely impacts therapeutic plans in patients with lung and esophageal cancer: a prospective cohort study.

BACKGROUND: National and subspecialty guidelines for lung and esophageal cancers recommend treatment decisions to be made in a multidisciplinary tumor board (MTB). This study prospectively analyzes the actual impact of presentation at the thoracic tumor board on decision making in thoracic cancer cases. METHODS: During the electronic submission process for presentation at MTB managing physicians documented their current treatment plan. The initial treatment plan was compared with the MTB final recommendation. Patient demographics, physician's proposed treatment plan, MTB recommendation, and documentation of application of MTB recommendations were prospectively recorded in an Institutional Review Board approved database. RESULTS: Between June 2010 and December 2012, 185 patients with esophageal and 294 patients with lung cancer were presented at the MTB. One hundred sixty-six patients were presented on more than 1 occasion, resulting in 724 assessments of 479 patients. In 48 esophageal cancer patients (26%) and 118 lung cancer patients (40%) MTB recommendations differed from the initial treatment plan. Overall, a differing MTB recommendation from the primary treatment plan occurred in 330 of 724 case presentations (46%). The MTB recommendations changed treatment plans in 40% and staging and assessment plans in 60% of patients. Follow-up in a cohort of 249 patients confirmed that MTB recommendations were followed in 97% of cases. CONCLUSIONS: This study validates the impact of the thoracic MTB. Recommendations will differ from the managing providers' initial plan in 26% to 40% of cases. However, MTB recommendations can be successfully initiated in the majority of patients. Complex thoracic cancer patients will benefit from multidisciplinary review and should ideally be presented at tumor board.

Solitary syringoma. Report of five cases and clinicopathologic comparison with microcystic adnexal carcinoma of the skin.

Five cases of solitary syringoma (SS) were found by the authors in a search of adnexal neoplasms seen over an 18-year period. These tumors all occurred in adults as mobile, flesh-colored, circumscribed papules of the facial skin, measuring < or = 5 mm in greatest dimension. Each was cured by simple punch or shave biopsy excision. Comparison with nine histologically similar variants of microcystic adnexal carcinoma (MAC) showed that the latter lesions differed from SS in that they showed much deeper invasion, with regular involvement of the underlying subcutis and perineural or vascular-adventitial infiltration. Moreover, SS was wider than it was deep on microscopic examination, whereas the converse pertained to MAC. Knowledge of the typical clinicopathologic attributes of these two tumor types should prevent clinicians and pathologists from confusing them with each other.

A quinine-induced drug reaction of photosensitive distribution with histological features mimicking mycosis fungoides.

Drug reactions simulating mycosis fungoides have been described most frequently for phenytoin, angiotensin-converting enzyme inhibitors, and carbamazepine. The first reported case of a quinine-induced drug reaction that histologically mimicked mycosis fungoides is described.