Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-ß.

Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-ß (TGF-ß) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-ß, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-ß signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-ß.

Human tissue cultures of lung cancer predict patient susceptibility to immune-checkpoint inhibition.

Despite novel immunotherapies being approved and established for the treatment of non-small cell lung cancer (NSCLC), ex vivo models predicting individual patients' responses to immunotherapies are missing. Especially immune modulating therapies with moderate response rates urge for biomarkers and/or assays to determine individual prediction of treatment response and investigate resistance mechanisms. Here, we describe a standardized ex vivo tissue culture model to investigate individual tumor responses. NSCLC tissue cultures preserve morphological characteristics of the baseline tumor specimen for up to 12 days ex vivo and also maintain T-cell function for up to 10 days ex vivo. A semi-automated analysis of proliferating and apoptotic tumor cells was used to evaluate tissue responses to the PD-1 inhibitor nivolumab (n = 12), from which two cases could be successfully correlated to the clinical outcome. T-cell responses upon nivolumab treatment were investigated by flow cytometry and multispectral imaging. Alterations in the frequency of the Treg population and reorganization of tumor tissues could be correlated to nivolumab responsiveness ex vivo. Thus, our findings not only demonstrate the functionality of T cells in NSCLC slice cultures up to 10 days ex vivo, but also suggests this model for stratifying patients for treatment selection and to investigate in depth the tumor-associated T-cell regulation.

Procedural times in early non-intubated VATS program - a propensity score analysis.

BACKGROUND: Non-intubated video-assisted thoracic surgery (NiVATS) has been introduced to surgical medicine in order to reduce the invasiveness of anesthetic procedures and avoid adverse effects of intubation and one-lung ventilation (OLV). The aim of this study is to determine the time effectiveness of a NiVATS program compared to conventional OLV. METHODS: This retrospective analysis included all patients in Leipzig University Hospital that needed minor VATS surgery between November 2016 and October 2019 constituting a NiVATS (n = 67) and an OLV (n = 36) group. Perioperative data was matched via propensity score analysis, identifying two comparable groups with 23 patients. Matched pairs were compared via t-Test. RESULTS: Patients in NiVATS and OLV group show no significant differences other than the type of surgical procedure performed. Wedge resection was performed significantly more often under NiVATS conditions than with OLV (p = 0,043). Recovery time was significantly reduced by 7 min (p = 0,000) in the NiVATS group. There was no significant difference in the time for induction of anesthesia, duration of surgical procedure or overall procedural time. CONCLUSIONS: Recovery time was significantly shorter in NiVATS, but this effect disappeared when extrapolated to total procedural time. Even during the implementation phase of NiVATS programs, no extension of procedural times occurs.

Prognostic Factors for Iatrogenic Tracheal Rupture: A Single-Center Retrospective Cohort Study.

Iatrogenic tracheal ruptures are rare but severe complications of medical interventions. The main goal of this study was to explore prognostic factors for all-cause mortality and rupture-related (adjusted) mortality. We retrospectively analyzed patients admitted to an academic referral center over a 15-year period (2004-2018). Fifty-four patients met the inclusion criteria, of whom 36 patients underwent surgical repair and 18 patients were treated conservatively. In a 90-day follow-up, the all-cause mortality was 50%, while the adjusted mortality was 13%. Rupture length was identified as a predictor for all-cause mortality (area under the curve, 0.84; 95% confidence interval (CI) 0.74-0.94) with a cutoff rupture length of 4.5 cm (sensitivity, 0.70; specificity, 0.81). Multivariate analysis confirmed rupture length as a prognostic factor for all-cause mortality (adjusted hazard ratio (HR) 1.5; 95% CI 1.2-1.9; p = 0.001), but not for adjusted mortality (HR 1.5; 95% CI 0.97-2.3; p = 0.068), while mediastinitis predicted adjusted mortality (HR 5.8; 95% CI 1.1-31.7; p = 0.042), but not all-cause mortality (HR 1.6; 95% CI 0.7-3.5; p = 0.243). The extent of iatrogenic tracheal rupture and mediastinitis might be relevant prognostic factors for all-cause mortality and adjusted mortality, respectively.

Thoracotomy for emergency repair of iatrogenic tracheal rupture: single center analysis of perioperative management and outcomes.

BACKGROUND: Iatrogenic tracheal ruptures are rare but life-threatening airway complications that often require surgical repair. Data on perioperative vital functions and anesthetic regimes are scarce. The goal of this study was to explore comorbidity, perioperative management, complications and outcomes of patients undergoing thoracotomy for surgical repair. METHODS: We retrospectively evaluated adult patients who required right thoracotomy for emergency surgical repair of iatrogenic posterior tracheal ruptures and were admitted to a university hospital over a 15-year period (2004-2018). The analyses included demographic, diagnostic, management and outcome data on preinjury morbidity and perioperative complications. RESULTS: Thirty-five patients who met the inclusion criteria were analyzed. All but two patients (96%) presented with critical underlying diseases and/or emergency tracheal intubations. The median time (interquartile range) from diagnosis to surgery was 0.3 (0.2-1.0) days. The durations of anesthesia, surgery and one-lung ventilation (OLV) were 172 (128-261) min, 100 (68-162) min, and 52 (40-99) min, respectively. The primary airway management approach to OLV was successful in only 12 patients (34%). Major complications during surgery were observed in 10 patients (29%). Four patients (11%) required cardiopulmonary resuscitation, one of whom received extracorporeal membrane oxygenation, and another one of these patients died during surgery. Major complications were associated with significantly higher all-cause 30-day mortality (p = 0.002) and adjusted mortality (p = 0.001) compared to patients with minor or no complications. CONCLUSIONS: Surgical repair of iatrogenic tracheal ruptures requires advanced perioperative care in a specialized center due to high morbidity and potential complications. Airway management should include early anticipation of alternative OLV approaches to provide acceptable conditions for surgery.

In-depth characterization of the Wnt-signaling/ß-catenin pathway in an in vitro model of Barrett's sequence.

BACKGROUND: An altered Wnt-signaling activation has been reported during Barrett's esophagus progression, but with rarely detected mutations in APC and ß-catenin (CTNNB1) genes. METHODS: In this study, a robust in-depth expression pattern analysis of frizzled receptors, co-receptors, the Wnt-ligands Wnt3a and Wnt5a, the Wnt-signaling downstream targets Axin2, and CyclinD1, as well as the activation of the intracellular signaling kinases Akt and GSK3ß was performed in an in vitro cell culture model of Barrett's esophagus. Representing the Barrett's sequence, we used normal esophageal squamous epithelium (EPC-1, EPC-2), metaplasia (CP-A) and dysplasia (CP-B) to esophageal adenocarcinoma (EAC) cell lines (OE33, OE19) and primary specimens of squamous epithelium, metaplasia and EAC. RESULTS: A loss of Wnt3a expression was observed beginning from the metaplastic cell line CP-A towards dysplasia (CP-B) and EAC (OE33 and OE19), confirmed by a lower staining index of WNT3A in Barrett's metaplasia and EAC, than in squamous epithelium specimens. Frizzled 1-10 expression analysis revealed a distinct expression pattern, showing the highest expression for Fzd2, Fzd3, Fzd4, Fzd5, Fzd7, and the co-receptor LRP5/6 in EAC cells, while Fzd3 and Fzd7 were rarely expressed in primary specimens from squamous epithelium. CONCLUSION: Despite the absence of an in-depth characterization of Wnt-signaling-associated receptors in Barrett's esophagus, by showing variations of the Fzd- and co-receptor profiles, we provide evidence to have a significant role during Barrett's progression and the underlying pathological mechanisms.

Correction to: Predictive risk factors for lymph node metastasis in patients with resected non-small cell lung cancer: a case control study.

The original article [1] contains slight errors whereby several terms in the first column of Tables 1, 2, and 3 have an erroneous 'p' preceding them.

Predictive risk factors for lymph node metastasis in patients with resected non-small cell lung cancer: a case control study.

BACKGROUND: Estimation of lymph node status is essential in order to determine precise therapy for patients with non-small cell lung cancer (NSCLC). Furthermore, lymph node involvement is a very powerful prognostic factor in these patients. In this analysis, we aim to evaluate the predictive factors for lymph node metastasis in NSCLC-patients. METHODS: In a prospectively-established database, we analyzed all data of patients with NSCLC, who underwent oncological surgical resections from 01/2007 to 12/2016, retrospectively. The correlation between clinicopathological parameters and lymph node metastasis was investigated by using univariate and binary logistic regression analysis. RESULTS: In this study, we operated on 204 consecutive patients, 142 men (71.7%) and 56 women (28.3%). Lymph node metastases were detected in 38.2% (78/204). Preoperatively, central tumor localization (OR = 2.6, 95% CI = 1.3-5.1, P = 0.005) and tumor size > 3 cm (OR = 2.5, 95% CI = 1.3-4.4, P = 0.005) were found to be significant predictive factors for lymph node metastasis. Postoperatively, multivariate analysis showed that intratumoral lymph vessel invasion (L1-status) (OR = 17.3, 95% CI = 5.1-58.4, P <  0.001) along with the central tumor localization (OR = 2.8, 95% CI = 1.4-5.8, P = 0.004) were significantly associated with lymph node metastasis. In small size tumors (≤3 cm), two predictive factors for lymph node metastasis were found: central tumor localization (OR = 19.4, 95% = 2.1-186.4, P = 0.01) and L1-status (OR = 43.9, 95% CI = 3.6-529.4, P = 0.003). CONCLUSIONS: A precise pre- and intraoperative assessment of the lymph node status is essential in patients with larger sized tumors and central localization. Furthermore, L1-status is a highly significant risk factor for lymph node metastasis in NSCLC-Patients. Therefore, an adjuvant therapy in patients with L1-status and pNX category should be considered.

TIE2-expressing monocytes and M2-polarized macrophages impact survival and correlate with angiogenesis in adenocarcinoma of the pancreas.

INTRODUCTION: M2-polarized tumor-associated macrophages (TAMs) and TIE2-expressing monocytes (TEMs) are associated with angiogenesis and have been identified as a potential prognostic marker in several solid tumors, including hepatobiliary malignancies. However, little is known regarding their influence on tumor progression and patient survival in pancreatic ductal adenocarcinoma (PDAC). RESULTS: Patients with tumors characterized by the presence of CD163+ TAMs or TEMs in TCA or TIF, respectively, showed a significantly decreased 1-, 3- and 5-year overall and recurrence-free survival compared to patients without CD163+ TAMs or TEMs (all ρ < 0.05). Patients with TEMs in TCA showed a higher incidence of tumor recurrence (ρ < 0.05). Furthermore, the presence of CD163+ TAMs was associated with a higher tumor MVD (ρ < 0.05). CONCLUSIONS: Presence of M2-polarized TAMs and TEMs is associated with a decreased overall and recurrence-free survival of patients with PDAC. MATERIALS AND METHODS: The localization and density of CD163+ M2-polarized TAMs and TEMs were quantified in the tumor central area (TCA) and tumor-infiltrating front (TIF) in human PDAC tissue (n = 106) and correlated to clinicopathological characteristics, tumor recurrence rates and patient survival. In parallel, tumor microvascular density (MVD) and the density of angiopoietin-positive tumor cells were quantified. Statistical analysis was performed using SPSS software.

Response to TNF-α Is Increasing Along with the Progression in Barrett's Esophagus.

BACKGROUND AND AIMS: Barrett's esophagus, a metaplasia resulting from a long-standing reflux disease, and its progression to esophageal adenocarcinoma (EAC) are characterized by activation of pro-inflammatory pathways, induced by cytokines. METHODS: An in vitro cell culture system representing the sequence of squamous epithelium (EPC1 and EPC2), Barrett's metaplasia (CP-A), dysplasia (CP-B) to EAC (OE33 and OE19) was used to investigate TNF-α-mediated induction of interleukin-8 (IL-8). RESULTS: IL-6 and IL-8 expressions are increasing with the progression of Barrett's esophagus, with the highest expression of both cytokines in the dysplastic cell line CP-B. IL-8 expression in EAC cells was approx. 4.4-fold (OE33) and eightfold (OE19) higher in EAC cells than in squamous epithelium cells (EPC1 and EPC2). The pro-inflammatory cytokine TNF-α increased IL-8 expression in a time-, concentration-, and stage-specific manner. Furthermore, TNF-α changed the EMT marker profile in OE33 cells by decreasing the epithelial marker E-cadherin and increasing the mesenchymal marker vimentin. The anti-inflammatory compound curcumin was able to repress proliferation and to activate apoptosis in both EAC cell lines. CONCLUSION: The increased basal expression levels of IL-8 with the progression of Barrett's esophagus constrain NFκB activation and its contribution in the manifestation of Barrett's esophagus. An anti-inflammatory compound, such as curcumin, could create an anti-inflammatory microenvironment and thus potentially support an increase chemosensitivity in EAC cells.

Therapeutic options to prevent recurrence of an aggressive aneurysmatic bone cyst of the cervical spine of a 16 year old boy - a case report.

The aneurysmatic bone cyst (ABC) is a benign primary bone tumour. If located in the cervical spine, its expansive growth and destructive behaviour may lead to instability and serious neurological impairment. We report a case of a 16-year-old boy with an aggressive ABC in the 7th cervical vertebra. Computertomographic and magnetic resonance imaging revealed the envelopment of the left 7th and 8th spinal nerve along with the anterior displacement of the left vertebral artery. The interdisciplinary surgical strategy consisted of a partially incomplete cyst resection, subtotal spondylectomy with posterior screw-and-rod fixation from C6-Th1, iliac crest bone grafting and anterior plating from C6-Th1. With regard to the high rate of recurrence after incomplete resection published in the recent literature, the patient was postoperatively treated by megavoltage radiotherapy with a total dose of 30Gy (daily dose of 1.8 Gy for 3 weeks). The clinical and radiographic follow-up showed complete recovery of all neurologic impairments and no signs of tumour recurrence at 3, 6 and 12 months after surgery. This case highlights diverse treatment regimens and shall outline the challenge and the problems of the interdisciplinary decision-making in adolescents presenting with ABC in high-demanding anatomical regions.

Iatrogenic tracheobronchial ruptures - treatment and outcomes.

In the present paper we discuss the indication and follow-up of 42 patients with iatrogenic tracheobrochial ruptures. Thirty-five patients were treated by operation and 7 patients were treated conservatively. In the operated patients, four developed an insufficiency of the tracheal closure and the rupture related mortality was 2.8%. A significant effect on suture dehiscence was seen for mediastinitis (P<0.005) prior to operation, prior resection of the esophagus (P<0.001), and a long delay between injury and diagnosis (P=0.004). In the conservatively treated group the rupture related mortality was 29%. In conclusion to our results we suggest a surgical procedure whenever a tracheobronchial rupture is diagnosed and the patient's constitution allows the surgical procedure or anesthesia.

Video-assisted thoracoscopic surgery for pulmonary nodules after computed tomography-guided marking with a spiral wire.

PURPOSE: Peripheral pulmonary nodules are preferably removed by minimally invasive techniques, such as video-assisted thoracoscopic (VATS) surgery. These nodules should be marked preoperatively for better intraoperative detection and removal. DESCRIPTION: Twenty-two cases with a single pulmonary nodule requiring surgical removal for histologic examination were included in a prospective study. Guided by computed tomography, nodules were marked preoperatively using a laser marker system and fixed with a spiral wire. The marked nodules were removed by VATS surgery immediately after the marking. EVALUATION: The marking wire was placed in all 22 patients without any complications. The marked nodule was completely removed by VATS surgery in 19 patients. Conversion to thoracotomy was necessary in 3 patients, twice because of thoracoscopy-related problems and once because of a marking failure. The average times for the marking procedure and operation were 24 minutes and 32 minutes, respectively. CONCLUSIONS: This new method of computed tomography-guided nodule marking with a spiral wire and subsequent VATS surgery is very efficient in terms of localization and stable fixation of subpleural pulmonary nodules.

Determination of temperature elevation in tissue during the application of the harmonic scalpel.

The temperature elevation in tissue during the application of the harmonic scalpel (UltraCision, operating frequency 55 kHz; Ethicon Endo-Surgery, Norderstedt, Germany) was determined using thermocouples of a specific design. In experiments with and without perfusion, two different scalpel blades were applied to three different kinds of pig tissue (lung parenchyma, tongue, parotid gland) in various configurations. Temperature elevations by more than 40 degrees C were found at 1 mm distance from the blade, whereas at distances of more than 5 mm, perfusion removed the heat very efficiently. The differences in the heating potential of the two blades were small and, at a distance of 2 mm, the temperature elevation did not exceed 6 degrees C at all. In histological investigations, the damaged area between blade and parenchyma was determined. No morphologic indications of thermal damage were found at a distance of more than 2 mm. It is concluded that, during application of the harmonic scalpel, a safety margin of 3 mm from sensitive structures should be kept.