The Burden of Obesity in Cardiac Surgery: A 14 years' Follow-Up of 14.754 Patients.

Aims: The prevalence of obesity is rapidly increasing during the past decades. While previous research has focused on the early outcome after cardiac surgery or specific complications, the current study covers the whole burden of obesity in the field of cardiac surgery over short term and long term. Endpoints of the study were all-cause mortality, perioperative outcome, and wound-healing disorders (WHDs). Methods: 14.754 consecutive patients who underwent cardiac surgery over a 14 years' time period were analyzed. BMI classifications were used according to the WHO definition. Results: Mean survival was 11.95 years ± 0.1; CI 95% [12.04-12.14]. After adjustment for clinical baseline characteristics, obesity classes' I-III (obesity) did not affect 30-day mortality or all-cause mortality during the whole observational period. After adjustment for known risk factors, the risk for WHDs doubled at least in obesity patients as follows: obesity I (OR = 2.06; CI 95% [1.7-2.5]; p < 0.0001), obesity II (OR = 2.5; CI 95% [1.83-3.41]; p < 0.0001), and obesity III (OR = 4.12; CI 95% [2.52-6.74]; p < 0.0001). The same applies to the risk for sternal reconstruction that is substantially elevated in obesity I (OR = 2.23; CI 95% [1.75-2.83]; p < 0.0001), obesity II (OR = 2.81; CI 95% [1.91-4.13]; p < 0.0001), and obesity III (OR = 2.31; CI 95% [1.08-4.97]; p=0.03). No significant correlation could be found between obesity and major adverse events in the perioperative course like renal failure, ventilation >24 h, re-exploration, or cerebrovascular events. Conclusions: Cardiac surgery is safe in obesity as short- and long-term mortality are not increased, and major adverse events during the perioperative course are similar to control patients. The burden of obesity lies in substantially increased rates of wound-healing disorders and sternal reconstructions.

A Standardized Treatment Pathway for Telehealth-Based Care of Chronic Wounds in Austria.

Chronic wounds present a significant healthcare challenge in Austria as well as in other countries. The interdisciplinary approach to wound treatment involving various caregivers, doctors, and relatives, poses challenges in documentation and information exchange. To overcome these barriers and promote patient-centered care, a new telehealth-supported treatment pathway for chronic wounds has been developed. The primary focus was to regularly update the status of the chronic wound by responding to predefined questions and transmitted images of the chronic wound. This was achieved by an interdisciplinary team of experts in chronic wound care, providing a new perspective for digital implementation in the healthcare system.

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT).

BACKGROUND: Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy. CASE PRESENTATION: A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events. CONCLUSION: This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable.

No association of malignant B-cell non-Hodgkin lymphomas with ipsilateral SARS-CoV-2 vaccination.

PURPOSE: SARS-CoV-2 vaccines cause acute ipsilateral lymph node swelling in an important proportion of vaccines. Thus far, no malignant lymphadenopathies have been reported in temporal context to vaccination in the ipsilateral draining lymph node areas. EXPERIMENTAL DESIGN: Prompted by two cases with unilateral axillary lymphomas that occurred ipsilaterally to prior SARS-CoV-2 vaccination, we systematically retrieved all B-cell non-Hodgkin lymphomas at two German University Medical Centers diagnosed before and after introduction of SARS-CoV-2 vaccines in Germany. Available lymphoma tissue (n=19) was subjected to next-generation immunosequencing of the IGH locus. Malignant clonotypes were mined in the CoVabDab database and published data sets from 342 uninfected individuals, 55 individuals 28 days after anti-SARS-CoV-2 vaccination and 139 individuals with acute COVID-19 together encompassing over 1 million CDR3 sequences in total. RESULTS: Of 313 newly diagnosed cases in the two centers and observation periods, 27 unilateral manifestations in the defined deltoid draining regions were identified. The majority thereof were diffuse large B-cell lymphomas (18 of 27 cases). Eleven unilateral cases were diagnosed in the era of SARS-CoV-2 vaccination and 16 in the control period before introduction of such vaccines. Of the 11 unilateral lymphomas that occurred during the vaccination period, ten had received a SARS-CoV-2 vaccine prior to lymphoma diagnosis. These cases were further evaluated. While left-sided were more frequent than right-sided lymphomas (19 vs 8 cases), no statistically significant association of vaccination site and laterality of the lymphoma manifestation was found. The unilateral lymphomas showed a normal range of B-cell receptors typically found in these lymphoma subtypes with no evidence for anti-SARS-CoV-2 sequences in the malignant clonotype. CONCLUSIONS: Together, we found no evidence that the current SARS-CoV-2 vaccines could serve as a trigger for lymphomagenesis in the draining lymph node areas of the deltoid region used for vaccination.

Efficacy and Safety of Vedolizumab in Patients with Inflammatory Bowel Disease in Association with Vedolizumab Drug Levels.

BACKGROUND: Vedolizumab (VDZ) is a well-established and important therapeutic option in the treatment of patients with inflammatory bowel disease (IBD). However, the significance of therapeutic drug monitoring (TDM) with VDZ remains a contradictory field in daily clinical practice. Our study aims to clarify the predictive impact of VDZ drug levels in long-term clinical outcomes in a real-world cohort. METHODS: Patients with moderate to severe ulcerative colitis (UC) and Crohn's disease (CD) from a tertiary IBD referral center at the University Hospital Augsburg, Germany, were enrolled in this single-center retrospective data analysis. Clinical and endoscopic data were collected at month 6, month 12, and at the last time of follow-up, and outcomes were correlated with VDZ levels at week 6. RESULTS: This study included 95 patients, 68.4% (n = 65) with UC, 24.2% (n = 23) with CD, and 7.4% (n = 7) with indeterminate colitis (CI). Patients with a mean VDZ treatment time of 17.83 months ± 14.56 showed clinical response in 29.5% (n = 28) and clinical remission in 45.3% (n = 43) at the end of the study. Endoscopic response occurred in 20.0% (n = 19) and endoscopic remission in 29.5% (n = 28) at the end of the study. The sustained beneficial effect of VDZ was also reflected in a significant change in biomarker levels. VDZ trough level at week 6 was determined in 48.4% (n = 46) with a mean of 41.79 µg/mL ± 24.58. A significant association between VDZ level at week 6 and both short and long-term outcomes could not be demonstrated. However, numerically higher VDZ levels were seen in patients with endoscopic and clinical improvement at month 6 and at the time of last follow-up. CONCLUSIONS: This study demonstrated efficacy and safety for VDZ in a real-world cohort. Although, for some parameters, a clear trend for higher VDZ levels at week 6 was seen, the efficacy of VDZ was not significantly correlated to VDZ level at week 6, which questions the predictive value of VDZ levels in the real world.

Progressive multifocal leukoencephalopathy associated with chemotherapy induced lymphocytopenia in solid tumors - case report of an underestimated complication.

Background: JC virus reactivation causing progressive multifocal leukoencephalopathy (PML) occurs preferentially in human immunodeficiency virus (HIV) positive individuals or patients suffering from hematologic neoplasms due to impaired viral control. Reactivation in patients suffering from solid malignancies is rarely described in published literature. Case Presentation: Here we describe a case of PML in a male patient suffering from esophageal cancer who underwent neoadjuvant radiochemotherapy and surgical resection in curative intent resulting in complete tumor remission. The radiochemotherapy regimen contained carboplatin and paclitaxel (CROSS protocol). Since therapy onset, the patient presented with persistent and progredient leukopenia and lymphopenia in absence of otherwise known risk factors for PML. Symptom onset, which comprised aphasia, word finding disorder, and paresis, was apparent 7 months after therapy initiation. There was no relief in symptoms despite standard of care PML directed supportive therapy. The patient died two months after therapy onset. Conclusion: PML is a very rare event in solid tumors without obvious states of immununosuppression and thus harbors the risk of unawareness. The reported patient suffered from lymphopenia, associated with systemic therapy, but was an otherwise immunocompetent individual. In case of neurologic impairment in patients suffering from leukopenia, PML must be considered - even in the absence of hematologic neoplasia or HIV infection.

Integrated Platform for the Management of Chronic Low Back Pain.

BACKGROUND: Chronic low back pain is a global health problem having a tremendous effect on the quality of life of patients. OBJECTIVES: An online therapy management system (TMS) is developed for comprehensive management of chronic low back pain patients. METHODS: A smartphone and a web app are built based on the Keep-In-Touch Telehealth Platform. The smartphone app allows entering patient reported outcomes and connection to third party devices to monitor physiological data and parameters of therapy. RESULTS: The TMS has been realized and a wearable auricular vagus nerve stimulation device has been integrated. The TMS is currently evaluated in a randomized clinical trial.

Interobserver Variability in the Assessment of Tumor Budding in pT 3/4 Colon Cancer: Improvement by Supporting Immunohistochemistry?

The prognostic significance of tumor budding in colon cancer is unequivocally documented, and the recommendations of the International Tumor Budding Consensus Conference (ITBCC) are currently the accepted basis for its assessment. Up to now, it is unknown whether the general use of a supporting cytokeratin immunohistochemistry can improve the interobserver variability and prognostic significance. Six investigators with different levels of experience reassessed 229 cases of colon carcinoma (pT3/4, N+/-, M0) with a supporting cytokeratin immunohistochemistry. The results were compared to previous assessments, which have been performed only on H & E. Bd3 was significantly associated with the occurrence of distant metastases according to the assessments of three out of six investigators (p < 0.05). Only one single investigator reached significant results concerning the cancer specific survival (p = 0.01). The pairwise kappa values range between a poor and moderate level of agreement (range 0.17-0.45; median 0.21). In conclusion, the results show no superiority of the use of an additional cytokeratin immunohistochemistry compared to the conventional analysis on sole H & E slides. Therefore, the general supporting use of a cytokeratin immunohistochemical staining seems to be inadvisable in colon cancer in consideration of necessary resources and costs.

Neoadjuvant and Definitive Radiochemotherapeutic Approaches in Esophageal Cancer: A Retrospective Evaluation of 122 Cases in Daily Clinical Routine.

INTRODUCTION: Esophageal cancer (EC) is a common malignant tumor entity with increasing occurrence. The incidence of esophageal adenocarcinoma (AC), particularly, is constantly rising in the Western world. The mainstays of therapy with curative intent for EC in advanced stages are neoadjuvant radiochemotherapy (neoRCT) with surgery and definitive radiochemotherapy (defRCT). METHODS: We examined our internal files to identify patients suffering from EC. Palliative cases were excluded. Statistical testing was performed by χ2 test, Student's t test, Kaplan-Meier analyses, and the Mann-Whitney U test. RESULTS: One hundred and twenty-two cases were included. Histology revealed squamous cell carcinoma in 92 cases and AC in 23 cases. Ninety-five patients underwent defRCT, 27 underwent neoRCT, and 114 (in both therapy regimes) received simultaneous chemotherapy. There was no difference in the overall survival (OS) (p = 0.654; HR 1.145; 95% CI 0.629-2.086) or and progression-free survival (PFS) (p = 0.912) of patients who underwent neoRCT or defRCT. Median OS was 13.5 (2-197) months for defRCT patients and 19.5 (2-134) months for neoRCT patients (p = 0.751). Karnofsky index (KI) with a cut-off of 70% was strongest, but not a significant parameter for OS (p = 0.608) or PFS (p = 0.137). CONCLUSION: defRCT is a valid and an equal alternative to neoRCT for patients suffering from EC. Selection of patients for therapy is of crucial relevance. Further studies and improvements in follow-up are needed when neoRCT has been completed before surgery, in order to spare the patient undergoing operative treatment if there is complete remission. The identification of valid markers urgently needed to limit treatment side effects.

Tumor proportion in colon cancer: results from a semiautomatic image analysis approach.

The tumor stroma ratio (TSR) is a promising prognostic biomarker in colon cancer, which could provide additional risk stratification for therapy adaption. The objective of our study was the investigation of the prognostic significance of TSR at different tumor sites in a simple semiautomatic approach with the open-source program ImageJ. We investigated 206 pT3 and pT4 adenocarcinomas of no special type. According to our established thresholds, 31 tumors (15%) were classified as low tumor proportion (TP) (≤ 15% TP), 42 tumors (20%) were classified as high TP (≥ 54% TP), and 133 tumors (65%) were classified as medium TP. High and low TP were associated with an adverse overall survival in comparison to medium TP (p = 0.001 and p = 0.03). Furthermore, the TP was an independent risk factor of occurrence of distant metastasis next to T status, microsatellite status, and tumor budding. The 5-year survival rate was 49% in patients with high TP, 48% in patients with low TP, and 68% in patients with medium TP (p = 0.042, n = 160). Patients with a high TP had less often tumor budding (p = 0.012), lymphovascular invasion (p = 0.049), and less harvested lymph nodes (p = 0.042) in comparison to low TP tumors. The results provide first evidence that a high tumor proportion/low stroma proportion is also associated with an adverse prognosis and that this subgroup might be difficult to identify with other classical histopathologic characteristics that are linked to an adverse prognosis.

Predicting factors for long-term survival in patients with out-of-hospital cardiac arrest - A propensity score-matched analysis.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death worldwide, with acute coronary syndromes accounting for most of the cases. While the benefit of early revascularization has been clearly demonstrated in patients with ST-segment-elevation myocardial infarction (STEMI), diagnostic pathways remain unclear in the absence of STEMI. We aimed to characterize OHCA patients presenting to 2 tertiary cardiology centers and identify predicting factors associated with survival. METHODS: We retrospectively analyzed 519 patients after OHCA from February 2003 to December 2017 at 2 centers in Munich, Germany. Patients undergoing immediate coronary angiography (CAG) were compared to those without. Multivariate regression analysis and inverse probability treatment weighting (IPTW) were performed to identify predictors for improved outcome in a matched population. RESULTS: Immediate CAG was performed in 385 (74.1%) patients after OHCA with presumed cardiac cause of arrest. As a result of multivariate analysis after propensity score matching, we found that immediate CAG, return of spontaneous circulation (ROSC) at admission, witnessed arrest and former smoking were associated with improved 30-days-survival [(OR, 0.46; 95% CI, 0.26-0.84), (OR, 0.21; 95% CI, 0.10-0.45), (OR, 0.50; 95% CI, 0.26-0.97), (OR, 0.43; 95% CI, 0.23-0.81)], and 1-year-survival [(OR, 0.39; 95% CI, 0.19-0.82), (OR, 0.29; 95% CI, 0.12-0.7), (OR, 0.43; 95% CI, 0.2-1.00), (OR, 0.3; 95% CI, 0.14-0.63)]. CONCLUSIONS: In our study, immediate CAG, ROSC at admission, witnessed arrest and former smoking were independent predictors of survival in cardiac arrest survivors. Improvement in prehospital management including bystander CPR and best practice post-resuscitation care with optimized triage of patients to an early invasive strategy may help ameliorate overall outcome of this critically-ill patient population.

Malignancies associated with GIST: a retrospective study with molecular analysis of KIT and PDGFRA.

PURPOSE: Gastrointestinal stromal tumors (GISTs) are the most common soft tissue tumors of the GI tract. Studies have been published reporting additional neoplasms in GIST patients. This study aimed to evaluate possible associations of mutation type, morphology, and clinical aspects of GISTs. METHODS: All cases of GIST were identified from our pathology files. Coding exons of KIT and PDGFRA in GISTs with additional malignancies were sequenced. RESULTS: A total of 70 of 188 (37%) retrieved patients with confirmed diagnosis of GIST showed at least one additional malignant neoplasm. Fifty of these GISTs were located in the stomach (71%), 8 in the small intestine (11%), 5 in the colon/rectum (7%), and 7 cases (6.2%) were of undetermined sites of origin. The distribution of identified mutations was similar to that described in GISTs without secondary malignancies. A total of 37 of 57 cases (65%) showed mutations in the KIT gene exon 11, 3 (5%) cases in exon 9, and 1 (2%) case in exon 13. Nine tumors (16%) had mutations of the PDGFRA gene. KIT and PDGFRA wild-type status were found in seven cases (12%). Most of the secondary neoplasms were located within the GI tract (34%), in the urogenital system (24%), or the breast/female genital tract (20%). CONCLUSION: This study confirms the high rate of additional malignant tumors in GIST patients. GIST features in these cases are very similar to those with sole GIST.

Level of interobserver variability estimation as a valuable tool: assessment of tumour budding in colon cancer.

AIMS: Tumour budding is considered to be a good marker for progression and prognosis in colorectal carcinomas. A uniform classification system has been established recently. The natural element of uncertainty in the practice of human medicine is also exhibited in the assessment of tumour budding. We tested the hypothesis that interobserver variability can be estimated during the assessment process and investigated its potential clinical implication. METHODS AND RESULTS: Six investigators with different levels of experience could perceive different levels of difficulty (LOD) and estimated different levels of interobserver variability (LOIV) (Li1, lower than average; Li2, average; Li3, higher than average) during the assessment of tumour budding in 244 cases of colon cancer (pT3/4). In total, the LOIV showed following distribution: Li1: 36.1%, Li2: 43.9% and Li3: 20.0%. The LOIV was correlated significantly with the LOD given by the investigator. In total, the agreement rates with the final consensus classification were: Li1: 93.4%, Li2: 78.5% and Li3: 58.4%. The relative risk of disagreement with the final consensus classification was more than six times higher when a case was estimated to have a high rather than a low interobserver variability. CONCLUSION: Our data show that the investigator can estimate the interobserver variability during the ongoing rating process in pT3/4 colon cancer. The LOIV/LOD seems to be a valuable parameter of the assessment quality. For Li3 cases further measures seem mandatory.

HEALTHeBIKES - Smart E-Bike Prototype for Controlled Exercise in Telerehabilitation Programs.

E-Bikes in telerehabilitation programs could be a new intervention for more sustainable rehabilitation results. The aim is to design and build a prototype of an E-Bike usable for rehabilitation - a HEALTHeBIKE. It should avoid over-exercising, work independently of the environment and it should enable cycling in a group despite different reference exercise intensities. To achieve these goals, requirements for this system architecture have been identified. A system architecture including an Arduino microcontroller, an Android smartphone and a telemonitoring platform was presented. A power output regulated proportional-integral controller to adjust the motor assistance has been implemented. A feasibility study with two subjects cycling in a group was performed. Seven test rides on varying terrain (flat, hilly, mountainous and uphill) with the same and different exercise intensities were completed. The mean power output was close to or below the target power output of the cyclist for all test rides with a maximal error of 6.7% above and 27.6% below the target. Although the exercise intensities of the two subjects were clearly different, cycling in a group was possible without over-exercising.

Interobserver variability in the H&E-based assessment of tumor budding in pT3/4 colon cancer: does it affect the prognostic relevance?

Tumor budding is a mostly accepted adverse prognostic factor in colorectal carcinoma. It is on the cusp of a widespread use after agreement was reached recently on uniform assessment criteria. We investigated whether the interobserver variability has a direct influence on the prognostic relevance in pT3/4 colon cancer in the background of different levels of experience of the investigators. In total, six investigators with different levels of experience evaluated tumor budding on H&E slides in 244 cases with primary diagnosed (2002-2011) colon carcinoma (pT3/4, N+/-, M0). High-grade tumor budding/budding grade 3 (defined as majority assessment among the investigators) was significantly associated with an adverse outcome (overall survival p = 0.03, cancer-specific survival p = 0.08) and the occurrence of distant metastasis (p = 0.009). However, a detailed analysis of the rating results of the individual investigators revealed that only ratings of one investigator (advanced resident) were associated with an adverse outcome (p = 0.01 cancer-specific survival, overall survival p = 0.09, distant metastasis p = 0.002). The results of another investigator (consultant) were significantly associated with distant metastasis (p = 0.007). The kappa values among the investigators have a range between 0.077 and 0.357 (median 0.166). Total agreement of all investigators existed in 109 cases (44.7%). Our results demonstrate that the evaluation of tumor budding on H&E slides in pT3/4 colon cancer goes along with a considerable interobserver variability among investigators of different levels of experience. Furthermore, our results reveal that these findings directly influence the prognostic value.

Multicenter Comparison of Novel Self-Expanding Versus Balloon-Expandable Transcatheter Heart Valves.

OBJECTIVES: This study sought to compare 2 next-generation transcatheter heart valves (THV), the self-expanding ACURATE neo (NEO) and the balloon-expandable SAPIEN 3 (S3), in terms of device failure and early safety at 30 days. BACKGROUND: Deployment of these THV showed promising initial clinical results. However, no comparative data are available. METHODS: Of 1,121 treated patients at 3 centers, a 1-to-2 nearest neighbor matching was performed to identify 2 patients treated with S3 (n = 622) for each patient treated with NEO (n = 311). RESULTS: In-hospital complications were comparable between NEO and S3, including stroke (1.9% vs. 2.4%; p = 0.64), major vascular complications (10.3% vs. 8.5%; p = 0.38), or life-threatening bleeding (4.2% vs. 3.7%; p = 0.72). Device failure with NEO was comparable with S3 (10.9% vs. 9.6%; odds ratio: 1.09 [95% confidence interval: 0.69 to 1.73]; p = 0.71) with more paravalvular leakage (PVL II+, 4.8% vs. 1.8%; p = 0.01), but less elevated gradients (≥20 mm Hg, 3.2% vs. 6.9%; p = 0.02) and pacemaker implantations (9.9% vs. 15.5%; p = 0.02). Thirty-day mortality (2.3% vs. 1.9%; p = 0.74) and the early safety composite endpoint (15.8% vs. 15.6%; hazard ratio: 0.97 [95% confidence interval: 0.68 to 1.39]; p = 0.88) were similar with NEO and S3. CONCLUSIONS: Very high success rates were achieved for both valves, and the clinical and procedural results were comparable. Compared with S3, NEO was associated with less new pacemaker implantations and less elevated gradients, but with more paravalvular leakage.