In the treatment of patients with HCC awaiting liver transplantation (LT), local ablative treatments (LAT) are available either for downstaging or as bridging treatment. We present our clinical ...experience with both available radiation-based techniques, brachytherapy (BT), and stereotactic body radiotherapy (SBRT).
All patients diagnosed with HCC and who were treated with BT or SBRT at our institution between 2011 and 2018 were retrospectively reviewed. The current analysis included all patients who subsequently underwent LT.
A total of 14 patients (male=9; female=5) were evaluated. Seven underwent BT for bridging before LT, and seven were treated with SBRT. BT was performed with a prescribed dose of 1 × 15 Gy, while SBRT was applied with 37 Gy (65%-iso) in three fractions in six patients, and one patient was treated with 54 Gy (100%-iso) in nine fractions. The treatment was generally well tolerated. One case of grade 3 bleeding was reported after BT, and one case of liver failure occurred following SBRT. All patients underwent LT after a median time interval of 152 days (range 47-311) after BT and 202 days (range 44-775) following SBRT. In eight cases, no viable tumor was found in the explanted liver, while four liver specimens showed vital tumor. The median follow-up after SBRT was 41 months and 17 months following BT. Overall, no hepatic HCC recurrence occurred following LT.
Both SBRT and BT are feasible and well tolerated as bridging to LT when applied with caution in patients with impaired liver function. Radiation-based treatments can close the gap for patients not suitable for other locally ablative treatment options.
Extra-capsular growth (ECG) describes the extension of neoplastic cells beyond the lymph node capsule. Aim of this study was to investigate the prognostic value of ECG and its association with a stem ...cell like phenotype indicated by expression of the transcription factor SOX9 in gastric cancer.
By histological evaluation, 199 patients with nodal positive gastric cancer or adeoncarcinoma of the esophageal-gastric junction (AEG) were divided into two groups according to the presence (ECG) or absence (ICG) of extracapsular growth in at least one nodal metastasis. Of these, 194 patients were stained for SOX9 and SOX2 using immunohistochemistry. Seventeen nodal negative patients (pT3/4, pN0, pM0) served as controls.
Seventy-three patients (36.7%) showed ECG. ECG was associated with lower overall survival (p < 0.0001), advanced pT- (p = 0.03) and pN- category (p < 0.0001) and lymphovascular invasion (p = 0.014). In multivariate analysis, ECG was found to be an independent prognostic factor (HR = 2.1; 95% CI 1.7-3.4; p = 0.001). SOX9 expression correlated significantly with ECG (96% SOX9 high in ECG patients vs. 79% SOX9 high in patients with ICG; p = 0.002). Controls showed significantly reduced SOX9 expression compared to nodal positive carcinomas (59% vs. 85% high SOX9 expression; p = 0.006). No significant correlation of ECG and SOX2 (59% SOX2 negative in ECG patients vs. 64% in patients with ICG, p = 0.48) could be obtained.
Patients with ECG exhibit poorer prognosis and ECG was found to be an independent prognostic factor. Thus, ECG turns out to be a morphological biomarker for a more aggressive phenotype in gastric cancer. This is supported by the fact that ECG correlates with the expression of SOX9, which has been described in the context of pro-oncogenic properties of tumours. However, the fact that SOX2 failed to show significant results indicate that ECG is not associated with a distinct cancer stem cell phenotype in gastric cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
mmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome ...depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT).
We retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0-40% vs. 41-100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated.
Median OS was 14 months (range: 3-167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression < 1% on tumor cells was associated with improved OS, PFS and local control in patients treated with concurrent CRT. Univariate analysis showed a trend towards improved OS and local control in patients with low CD8+ TIL density. Evaluation of Tumor Immunity in the MicroEnvironment (TIME) appears to be an independent prognostic factor for local control, PFS and OS. The longest and shortest OS were achieved in patients with type I (PD-L1
/CD8
) and type IV (PD-L1
/CD8
) tumors (median OS: 57 ± 37 vs. 10 ± 5 months, p = 0.05), respectively.
Assessment of PD-L1 expression on tumor cells in combination with CD8+ TIL density can be a predictive biomarker in patients with inoperable LA-NSCLC treated with concurrent CRT.
Two-photon microscopy is indispensable for deep tissue and intravital imaging. However, current technology based on single-beam point scanning has reached sensitivity and speed limits because higher ...performance requires higher laser power leading to sample degradation. We utilize a multifocal scanhead splitting a laser beam into a line of 64 foci, allowing sample illumination in real time at full laser power. This technology requires charge-coupled device field detection in contrast to conventional detection by photomultipliers. A comparison of the optical performance of both setups shows functional equivalence in every measurable parameter down to penetration depths of 200
μm, where most actual experiments are executed. The advantage of photomultiplier detection materializes at imaging depths >300
μm because of their better signal/noise ratio, whereas only charge-coupled devices allow real-time detection of rapid processes (here blood flow). We also find that the point-spread function of both devices strongly depends on tissue constitution and penetration depth. However, employment of a depth-corrected point-spread function allows three-dimensional deconvolution of deep-tissue data up to an image quality resembling surface detection.
Glucocorticoid (GC) refractory relapses in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS), who are in potential need of treatment escalation, are a key challenge in ...routine clinical practice. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be an endogenous counter-regulator of GC, and potentiates autoimmune-mediated neuroinflammation. In order to evaluate whether MIF levels are elevated in the cerebrospinal fluid (CSF) of MS patients (CSF-MIF), and whether they are higher still during a GC refractory relapse, we compared CSF-MIF concentrations of CIS/MS patients with acute optic neuritis as their first inflammatory episode (ON, n = 20), CIS/MS patients with a stable disease progression/without relapse (CIS/MS w/o, n = 18), and healthy controls (HC, n = 20) using ANOVA. Mean CSF-MIF concentrations in CIS/MS w/o patients were significantly higher than in ON patients and HCs, whereas ON patients and HCs did not differ. A subgroup analysis of the ON group revealed 10 patients to be responsive to GC-treatment (GC-ON) and 10 patients refractory under GC-treatment (rGC-ON). However, mean CSF-MIF concentrations did not differ between GC-ON and rGC-ON cases. We therefore conclude that MIF is not suitable for distinguishing GC responders from non-responders in a group of patients with acute optic neuritis, but it rather mirrors the ongoing inflammation in long-term MS disease progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Tumor tissue as well as regional lymph nodes are removed during curative surgery for early-stage non-small cell lung cancer (NSCLC). These tissues provide a unique snapshot of the immune ...cell composition at the time of surgery. We investigated the immune landscape in matched tumor tissue, tumor bearing (tb) and non-tumor bearing (ntb) N1 as well as N2 lymph nodes (LNs) in patients with NSCLC and its relation to survival.
Methods
Internal hospital databases were screened for surgically treated NSCLC patients for whom tumor tissue, tbLNs as well as N1 and N2 ntbLNs were available. Clinical as well as demographic data were extracted from hospital records. Expression profiling of 770 immune-related genes was performed using the PanCancer IO 360 panel by NanoString Technologies.
Results
We identified 190 surgically treated patients of whom 16 fulfilled inclusion criteria and had sufficient archived tissue. The Tumor Immune Dysfunction and Exclusion (TIDE) score in N1 tumor-free lymph nodes was associated with OS. TIM-3 expression was inversely correlated with TIDE scores in affected LNs, N1 and N2 ntbLNs. Levels of CD8 expression were significantly higher in TIDE High compared to TIDE Low patients. TIM-3 and PD-L1 were selected for the final model for OS in multivariate regression in more than one tissue.
Conclusion
Levels of immune cell exhaustion markers may indicate a dysfunctional immune status and are associated with survival after curative surgery in NSCLC.
Background
Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper‐IgE syndrome (STAT3‐HIES). The aim of this ...study was to expand knowledge about lung disease in STAT3‐HIES.
Methods
The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3‐HIES patients were assessed.
Results
The patients’ quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive‐restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ATP‐binding cassette sub‐family A member 3 (ABCA3) positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long‐term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function.
Conclusions
Due to its severity, pulmonary disease in STAT3‐HIES patients requires strict monitoring and intensive therapy.
Pulmonary complications in STAT3‐HIES patients account for significant morbidity and mortality; patients are endangered by severe postinfectious pulmonary tissue damage including extensive pneumatocele or cyst formation. Strict monitoring and intensive acute and long‐term therapy is required including antimicrobial treatment, immunoglobulin replacement therapy (IGRT), inhalation therapy, and chest physiotherapy. Regular IGRT stabilized lung function. Preliminary data hint towards a healing defect associated with reduced ABCA3 expression in type 2 pneumocytes due to STAT3 malfunctioning.
The purpose of this paper is to investigate the influence of the engine position and mass as well as the pylon stiffness on the aeroelastic stability of a long-range wide-body transport aircraft. As ...reference configuration, DLR’s (German Aerospace Center/Deutsches Zentrum für Luft und Raumfahrt) generic aircraft configuration DLR-D250 is taken. The structural, mass, loads, and optimization models for the reference and a modified configuration with different engine and pylon parameters are set up using DLR’s automatized aeroelastic design process cpacs-MONA. At first, the cpacs-MONA process with its capabilities for parametric modeling of the complete aircraft and in particular the set-up of a generic elastic pylon model is unfolded. Then, the influence of the modified engine-wing parameters on the flight loads of the main wing is examined. The resulting loads are afterward used to structurally optimize the two configurations component wise. Finally, the results of post-cpacs-MONA flutter analyses performed for the two optimized aircraft configurations with the different engine and pylon characteristics are discussed. It is shown that the higher mass and the changed position of the engine slightly increased the flutter speed. Although the lowest flutter speeds for both configurations occur at a flutter phenomenon of the horizontal tail-plane outside of the aeroelastic stability envelope.
The development and progression of colorectal cancer (CRC) are known to be affected by the interplay between tumor and immune cells. However, the impact of CRC cells on the systemic immunity has yet ...to be elucidated. We aimed to comprehensively evaluate the circulating immune subsets and transcriptional profiles of CRC patients. In contrast to healthy controls (HCs), CRC patients had a lower percentage of B and T lymphocytes, T helper (Th) cells, non-classical monocytes, dendritic cells, and a higher proportion of polymorphonuclear myeloid-derived suppressor cells, as well as a reduced expression of CD69 on NK cells. Therefore, CRC patients exhibit a more evident systemic immune suppression than HCs. A diagnostic model integrating seven immune subsets was constructed to distinguish CRC patients from HCs with an AUC of 1.000. Moreover, NR3C2, CAMK4, and TRAT1 were identified as candidate genes regulating the number of Th cells in CRC patients. The altered composition of circulating immune cells in CRC could complement the regional immune status of the tumor microenvironment and contribute to the discovery of immune-related biomarkers for the diagnosis of CRC.
OBJECTIVE:Platelet activation has been implicated in microvascular thrombosis and organ failure. We tested the hypothesis that antiplatelet drugs favorably affect outcome in patients nonelectively ...admitted to an intensive care unit.
DESIGN:Retrospective cohort study.
SETTING:A 22-bed intensive care unit of a tertiary care center.
PATIENTS:Six hundred fifteen consecutive patients admitted to an intensive care unit within 24 hrs after hospitalization were enrolled, approximately 25% of whom received antiplatelet drugs (acetylsalicylic acid, clopidogrel) for secondary prevention of vascular disease. Impact of antiplatelet drugs and established risk factors on mortality were assessed by logistic regression and 2 × 2 table analysis.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Patients on antiplatelet drugs were markedly older and presented higher Acute Physiology and Chronic Health Evaluation II scores on intensive care unit admission. There was no significant difference in injury severity scores in trauma patients with (21 range, 13–29) or without antiplatelet drugs (18 range, 12–29). Using logistic regression analysis, a significant reduction of mortality was estimated for the use of antiplatelet drugs in various subgroups of patients with normal or high bleeding risk (odds ratios, 0.04–0.34). Significant benefit was also estimated by 2 × 2 table analysis of Acute Physiology and Chronic Health Evaluation II-matched samples (Acute Physiology and Chronic Health Evaluation II >20) of internal medicine patients and/or patients receiving medical treatment. No significant benefit but also no harm of antiplatelet drugs was estimated in Acute Physiology and Chronic Health Evaluation II-matched samples of patients with increased bleeding riskpatients from surgery departments overall, patients with surgical treatment, trauma, active bleeding, or transfusion (odds ratios, 0.51–0.88).
CONCLUSIONS:Our data are consistent with prevention of organ dysfunction by antiplatelet drugs, which may be masked in some patients by concomitant bleeding risk. Antiplatelet drugs might offer a novel therapeutic option to prevent organ failure, at least in the absence of active bleeding. This hypothesis warrants testing in a prospective trial.
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