Right ventricular to pulmonary artery coupling in patients with different types of aortic stenosis undergoing TAVI.

BACKGROUND: Right ventricular (RV) dysfunction in patients undergoing transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) has long been disregarded. We aimed to assess the predictive value of RV to pulmonary artery coupling (RV/PAc), defined as tricuspid annular plane systolic excursion to systolic pulmonary artery pressure, on mortality in different flow types of AS after TAVI. METHODS: All patients undergoing TAVI for AS at our centre between 2018 and 2020 were assessed; 862 patients were analysed. The cohort was dichotomized using a ROC analysis (cut-off 0.512 mm/mmHg), into 429 patients with preserved and 433 patients with reduced RV/PAc. RESULTS: Reduced RV/PAc was associated with male sex and a higher rate of comorbidities. Short-term VARC-3 endpoints and NYHA classes at follow-up were comparable. Reduced RV/PAc was associated with higher 2-year all-cause mortality (35.0% [30.3-39.3%] vs. 15.4% [11.9-18.7%], hazard ratio 2.5 [1.9-3.4], p < 0.001). Cardiovascular mortality was almost tripled. Results were consistent after statistical adjustment and in a multivariate model. Sub-analyses of AS flow types revealed lower RV/PAc in classical and paradoxical low-flow low-gradient AS, with the majority having reduced RV/PAc (74% and 59%). RV/PAc retained its predictive value in these subgroups. CONCLUSIONS: RV dysfunction defined by low RV/PAc is a strong mortality predictor after TAVI independent of flow group. It should be incorporated in future TAVI risk assessment.

Influence of intestinal microbial metabolites on the abscopal effect after radiation therapy combined with immune checkpoint inhibitors.

Background: Most clinical studies failed to elicit a strong antitumor immune response and subsequent systemic tumor regression after radiation therapy (RT), even in combination with the immune checkpoint inhibitors (ICI) anti-CTLA4 or anti-PD1. Mechanistically, type I interferon (IFN-I) activation is essential for the development of such abscopal effects (AE); however, mechanisms driving or limiting IFN-I activation are ill defined. Groundbreaking discoveries have shown that antibiotics (ABx) can affect oncological outcomes and that microbiota-derived metabolites can modulate systemic antitumor immunity. Recent studies have demonstrated that the bacterial metabolites desaminotyrosine (DAT) and indole-3-carboxaldehyde (ICA) can enhance IFN-I activation in models of inflammatory diseases. Materials and Methods: The subcutaneous bilateral MC38 tumor model is a widely used experimental tool to study the AE in mice. We applied it to explore the influence of broad-spectrum ABx, DAT and ICA on the AE after radioimmunotherapy (RIT). We performed 1x8 Gy of the primary tumor ± anti-CTLA4 or anti-PD1, and ± daily oral application of ABx or metabolites. Result: Combinatory ABx had neither a significant effect on tumor growth of the irradiated tumor nor on tumor progression of the abscopal tumor after RIT with anti-CTLA4. Furthermore, DAT and ICA did not significantly impact on the AE after RIT with anti-CTLA4 or anti-PD1. Surprisingly, ICA even appears to reduce outcomes after RIT with anti-CTLA4. Conclusion: We did not find a significant impact of combinatory ABx on the AE. Experimental application of the IFN-I-inducing metabolites DAT or ICA did not boost the AE after combined RIT. Additional studies are important to further investigate whether the intestinal microbiota or specific microbiota-derived metabolites modulate the AE.

Tumor Contact With Internal Mammary Perforator Vessels as Risk Factor for Gross Internal Mammary Lymph Node Involvement in Patients With Breast Cancer.

PURPOSE: The identification of internal mammary lymph node metastases and the assessment of associated risk factors are crucial for adjuvant regional lymph node irradiation in patients with breast cancer. The current study aims to investigate whether tumor contact with internal mammary perforator vessels is associated with gross internal mammary lymph node involvement. METHODS AND MATERIALS: We included 297 patients with primary breast cancer and gross internal mammary (IMN+) and/or axillary metastases as well as 230 patients without lymph node metastases. Based on pretreatment dynamic contrast-enhanced magnetic resonance imaging, we assessed contact of the tumor with the internal mammary perforating vessels (IMPV). RESULTS: A total of 59 patients had ipsilateral IMN+ (iIMN+), 10 patients had contralateral IMN+ (cIMN+), and 228 patients had ipsilateral axillary metastases without IMN; 230 patients had node-negative breast cancer. In patients with iIMN+, 100% of tumors had contact with ipsilateral IMPV, with 94.9% (n = 56) classified as major contact. In iIMN- patients, major IMPV contact was observed in only 25.3% (n = 116), and 36.2% (n = 166) had no IMPV contact at all. Receiver operating characteristic analysis revealed that "major IMPV contact" was more accurate in predicting iIMN+ (area under the curve, 0.85) compared with a multivariate model combining grade of differentiation, tumor site, size, and molecular subtype (area under the curve, 0.65). Strikingly, among patients with cIMN+, 100% of tumors had contact with a crossing contralateral IMPV, whereas in cIMN- patients, IMPVs to the contralateral side were observed in only 53.4% (iIMN+) and 24.8% (iIMN-), respectively. CONCLUSIONS: Tumor contact with the IMPV is highly associated with risk of gross IMN involvement. Further studies are warranted to investigate whether this identified risk factor is also associated with microscopic IMN involvement and whether it can assist in the selection of patients with breast cancer for irradiation of the internal mammary lymph nodes.

The association of off-hour vs. on-hour intensive care unit admission time with mortality in patients with cardiogenic shock: a retrospective multi-centre analysis.

AIMS: Studies have shown a so-called off-hour effect for many different diseases, but data are scarce concerning cardiogenic shock. We therefore assessed the association of off-hour vs. on-hour intensive care unit admission with 30-day mortality in patients with cardiogenic shock. METHODS AND RESULTS: In total, 1720 cardiogenic shock patients (666 admitted during off-hours) from two large university hospitals in Germany were included in retrospect. An admission during off-hours was associated with increased 30-day mortality compared to an admission during on-hours [crude mortality 48% vs. 41%, HR 1.17 (1.03-1.33), P = 0.017]. This effect remained significant after propensity score matching (P = 0.023). Neither patients with a combined SCAI stage D and E (P = 0.088) or C (P = 0.548) nor those requiring cardiopulmonary resuscitation (P = 0.114) had a higher mortality at off-hour admission. In contrast, those without veno-arterial extracorporeal membrane oxygenation [HR 1.17 (1.00-1.36), P = 0.049], without acute myocardial infarction [HR 1.27 (1.02-1.56), P = 0.029] or a with combined SCAI stage A and B [HR 2.23 (1.08-4.57), P = 0.025] had an increased mortality at off-hour admission. CONCLUSION: Our study showed an increased mortality in patients with cardiogenic shock admitted during off-hours, especially in those with a milder onset of disease. This stresses the importance of a thorough workup of each patient, especially at times of limited resources, the menace of underestimating the severity of cardiogenic shock, and the need for an improved 24×7 available risk stratification.

Association of Skin Microbiome Dynamics With Radiodermatitis in Patients With Breast Cancer.

Importance: The interindividual differences in severity of acute radiation dermatitis are not well understood. To date, the pathomechanism and interplay of microbiome and radiodermatitis before and during treatment remain largely unknown. Objective: To assess the association of skin microbiome baseline composition and dynamics with severity of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer. Design, Setting, and Participants: A longitudinal prospective pilot observational study was conducted between January 2017 and January 2019. Sequencing results were received in March 2021, and the data were analyzed from August 2021 to March 2023. This study was performed at an urban academic university cancer center. A total of 21 female patients with breast cancer after surgery were consecutively approached, of which 1 patient withdrew consent before the study started. Exposure: Adjuvant radiotherapy for breast cancer for 7 weeks. Main Outcomes and Measures: The main outcome was the association of baseline skin microbiome composition and its dynamics with the severity of radiodermatitis. A total of 360 skin microbiome samples from patients were analyzed, taken before, during, and after radiotherapy, from both the treated and contralateral healthy sides. The skin microbiome samples were analyzed using 16S (V1-V3) amplicon sequencing and quantitative polymerase chain reaction bacterial enumeration. Results: Twenty female patients with breast cancer after surgery who underwent radiotherapy enrolled in the study had a median (range) age of 61 (37-81) years. The median (range) body mass index of the patients was 24.2 (17.6-38.4). The 16S sequencing revealed that low (<5%) relative abundance of commensal skin bacteria (Staphylococcus epidermidis, Staphylococcus hominis, Cutibacterium acnes) at baseline composition was associated with the development of severe radiodermatitis with an accuracy of 100% (sensitivity and specificity of 100%, P < .001). Furthermore, in patients with severe radiodermatitis, quantitative polymerase chain reaction bacterial enumeration revealed a general non-species-specific overgrowth of skin bacterial load before the onset of severe symptoms. Subsequently, the abundance of commensal bacteria increased in severe radiodermatitis, coinciding with a decline in total bacterial load. Conclusions and Relevance: The findings of this observational study indicated a potential mechanism associated with the skin microbiome for the pathogenesis of severe radiodermatitis, which may be a useful biomarker for personalized prevention of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer.

Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation.

The microbiome is a predictor of clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT). Microbiota-derived metabolites can modulate these outcomes. How bacteria, fungi and viruses contribute to the production of intestinal metabolites is still unclear. We combined amplicon sequencing, viral metagenomics and targeted metabolomics from stool samples of patients receiving allo-SCT (n = 78) and uncovered a microbiome signature of Lachnospiraceae and Oscillospiraceae and their associated bacteriophages, correlating with the production of immunomodulatory metabolites (IMMs). Moreover, we established the IMM risk index (IMM-RI), which was associated with improved survival and reduced relapse. A high abundance of short-chain fatty acid-biosynthesis pathways, specifically butyric acid via butyryl-coenzyme A (CoA):acetate CoA-transferase (BCoAT, which catalyzes EC 2.8.3.8) was detected in IMM-RI low-risk patients, and virome genome assembly identified two bacteriophages encoding BCoAT as an auxiliary metabolic gene. In conclusion, our study identifies a microbiome signature associated with protective IMMs and provides a rationale for considering metabolite-producing consortia and metabolite formulations as microbiome-based therapies.

Atrial Functional Tricuspid Regurgitation in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: Knowledge about atrial functional tricuspid regurgitation (afTR) in transcatheter aortic valve replacement (TAVR) patients is scarce. OBJECTIVES: The aim of the study was to analyze the association between the entity and the development of tricuspid regurgitation (TR) in patients undergoing TAVR for aortic stenosis and concomitant TR. METHODS: We analyzed patients undergoing TAVR for severe aortic stenosis from January 2013 to December 2020 and concomitant at least moderate TR at baseline. afTR was defined as enlargement of the right atrium in relation to the right ventricle. TR development after TAVR and 3-year all-cause mortality were evaluated. RESULTS: Out of 3,474 TAVR patients, we identified 420 patients with concomitant at least moderate TR. A total of 363 patients were included in the study, with 178 patients stratified in the afTR and 185 in the non-afTR group based on a receiver-operating characteristic curve cutoff of 1.132 of the right atrial/right ventricular area ratio. TR improvement after TAVR was observed in significantly less patients with afTR compared with non-afTR (31.1% vs 60.6%; P < 0.001). Multivariate regression analysis confirmed afTR as independent predictor for TR persistence (adjusted OR: 2.80; 95% CI: 1.66-4.76; P < 0.001). Moreover, afTR was associated with aggravation of TR after TAVR (17.0% vs 6.8%; P = 0.013). Three-year all-cause mortality was significantly higher in patients with persistence compared with patients with improvement of TR (P < 0.001). CONCLUSIONS: In TAVR patients, afTR is an independent predictor for TR persistence. Moreover, TR persistence is associated with increased 3-year all-cause mortality.

Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation.

PURPOSE: Preoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT), which combines simultaneous radiochemotherapy with additional courses of chemotherapy, has emerged as an effective approach. TNT achieves a pathologic complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-programmed cell death protein 1 immunotherapy can induce clinical complete responses in patients with specific genetic alterations. There is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to immunotherapy remain poorly understood. METHODS AND MATERIALS: We developed a novel orthotopic mouse model of rectal cancer based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT and validated rectal tumor growth and response rates to therapy using small-animal magnetic resonance imaging and endoscopic follow-up. RESULTS: Rectal tumor formation was successfully induced in all mice after 2 organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, long-term survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiologic tumor staging and histopathologic examination. CONCLUSIONS: Our novel mouse model combines orthotopic tumor growth via noninvasive and precise rectal organoid injection and small-animal RT. This model holds significant promise for investigating the effect of tumor cell-intrinsic aspects, genetic alterations of the host, and exogenous factors (eg, nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving chemotherapy, immunotherapy, or novel targeted therapies.

Concomitant percutaneous coronary intervention in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Patients undergoing transcatheter aortic valve implantation (TAVI) frequently have coronary artery disease requiring percutaneous coronary intervention (PCI). Usually, PCI and TAVI are performed in two separate procedures and current studies are investigating potential benefits regarding the order. However, the two interventions may also be performed simultaneously, thereby limiting the risk associated with repeated vascular access. Data evaluating benefit and harm of concomitant procedures are scarce. AIMS: Therefore, this study aimed to evaluate concomitant PCI (coPCI) in TAVI patients regarding Valve Academic Research Consortium 3 (VARC-3) endpoints and long-term mortality. METHODS: A total of 2233 consecutive TAVI patients from the EVERY-VALVE registry were analyzed according to the VARC-3 endpoint definitions. A total of 274 patients had undergone TAVI and concomitant PCI (coPCI group). They were compared to 226 TAVI patients who had received PCI within 60 days before TAVI in a stepwise approach (swPCI group) and to the remaining 1733 TAVI patients who had not undergone PCI recently (noPCI group). RESULTS: Overall median age was 81.4 years, median Society of Thoracic Surgeons score was 4.0%. Patients in the coPCI and in the swPCI group were predominantly male with reduced left-ventricular ejection fraction. Rates of VARC-3 composite endpoints technical success and 30-day device success were comparable between all three groups. Mortality rates at 3 years after TAVI were similar (coPCI, 34.2% vs. swPCI, 31.9% vs. noPCI, 34.0% p = 0.84). CONCLUSIONS: coPCI during TAVI seems comparable in a retrospective analysis. Compared to a stepwise approach, it has similar rates of composite endpoints technical success and device success as well as long-term mortality.

Cardio-hepatic syndrome in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Cardiohepatic syndrome (CHS) has been identified as an important but underrecognized survival predictor in multiple cardiovascular disease entities. The objectives of this study were to evaluate the prevalence and prognostic value of CHS in patients undergoing TAVR for severe aortic stenosis (AS). METHODS: The study included patients with available laboratory parameters of hepatic function who underwent TAVR from July 2013 until December 2019 at our center. CHS was defined as an elevation of at least two of three laboratory cholestasis parameters above the upper limit of normal (bilirubin, alkaline phosphatase, and gamma glutamyl transferase). Study endpoints were three-year survival, technical and device failure (VARC 3), as well as New York Heart Association (NYHA) functional class at follow-up. RESULTS: Among a total of 953 analyzed patients (47.6% females, median age 80.0 [76.0-85.0] years) CHS was present in 212 patients (22.4%). In patients with vs. without CHS, rates of technical (6.1% vs. 8.4%, p = 0.29) and device failure (18.9% vs. 17.3%, p = 0.59) were comparable. NYHA functional class at baseline and follow-up was more severe in patients with CHS. Nevertheless, heart failure symptoms improved from baseline to follow-up irrespective of hepatic function. Three-year survival rates were significantly lower in patients with CHS (49.4 vs. 65.4%, p < 0.001). The predictive value of CHS persisted after adjustment in a multivariable analysis (hazard ratio 1.58, p < 0.01). CONCLUSION: In patients undergoing TAVR, CHS is prevalent in 22% of patients and is associated with increased postinterventional mortality. Thus, CHS should be included in the decision-making process within the TAVR heart team. Cardiohepatic syndrome (CHS) as defined by an elevation of at least two of three laboratory cholestasis parameters above the upper limit of normal was prevalent in 22% of patients undergoing TAVR for severe AS. The presence of CHS was associated with more severe heart failure symptoms and worse three-year survival.

Impact of mitral regurgitation aetiology on the outcomes of transcatheter aortic valve implantation.

BACKGROUND: Concomitant moderate/severe mitral regurgitation (MR) is observed in 17-35% of patients undergoing transcatheter aortic valve implantation (TAVI) and contributes to a worse prognosis. Studies analysing outcomes in patients undergoing TAVI with different MR aetiologies, including atrial functional MR (aFMR), are lacking. AIMS: We aimed to analyse outcomes and changes in MR severity in patients with aFMR, ventricular functional (vFMR) and primary mitral regurgitation (PMR) following TAVI. METHODS: We analysed all consecutive patients with at least moderate MR undergoing TAVI between January 2013 and December 2020 at the Munich University Hospital. Characterisation of MR aetiology was performed by detailed individual echocardiographic assessment. Three-year mortality, changes in MR severity and New York Heart Association (NYHA) Functional Class at follow-up were assessed. RESULTS: Out of 3,474 patients undergoing TAVI, 631 patients showed MR ≥2+ (172 with aFMR, 296 with vFMR, 163 with PMR). Procedural characteristics and endpoints were comparable between groups. The rate of MR improvement was 80.2% in aFMR patients, which was significantly higher compared to both other groups (vFMR: 69.4%; p=0.03; PMR: 40.8%; p<0.001). The estimated 3-year survival rates did not differ between aetiologies (p=0.57). However, MR persistence at follow-up was associated with increased mortality (hazard ratio 1.49, 95% confidence interval: 1.04-2.11; p=0.027), mainly driven by the PMR subgroup of patients. NYHA Class improved significantly in all groups. In patients with baseline MR ≥3+, the PMR aetiology was associated with the lowest MR improvement, the lowest survival rates and least symptomatic improvement. CONCLUSIONS: TAVI reduces MR severity and symptoms in patients with aFMR, vFMR and less-pronounced PMR. The presence of aFMR was associated with the greatest MR severity improvement.

Quantification of physical activity with prospective activity tracking after transfemoral aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a well-established, safe and effective therapy for severe symptomatic aortic stenosis (AS). The aim of this study was to objectively quantify improvement of physical activity after TAVR, with consideration of different low-gradient AS subtypes. METHODS AND RESULTS: All patients undergoing TAVR for severe AS were screened. Participants received a wearable activity tracker (Fitbit®) at hospital discharge following TAVR and 6 months thereafter. The difference of median daily steps was defined as surrogate outcome for physical activity. For analysis, patients were grouped into high-gradient (HG) AS (dPmean ≥40 mmHg), classical low-flow low-gradient (LFLG) AS (dPmean <40 mmHg, EF <50%), paradoxical LFLG-AS (dPmean <40 mmHg, EF ≥50%, SVi ≤35 ml/m2) and normal-flow low-gradient (NFLG) AS (dPmean <40 mmHg, EF ≥50%, SVi >35 ml/m2) according to mean transvalvular pressure gradient (dPmean), stroke volume index (SVi) and left-ventricular ejection fraction (LVEF). RESULTS AND CONCLUSIONS: The analysis is based on 230 patients. The median daily step count was 4409 [IQR 2581-7487] after hospital discharge and 5326 [IQR 3045-8668] 6 months thereafter. Median difference of daily steps was ∆529 [IQR -702-2152]). Patients with HG-AS and paradoxical LFLG-AS showed a significant improvement of daily steps (∆951 [IQR -378-2323], p <0.001 and (∆1392 [IQR -609-4444], p = 0.02, respectively). Patients with classical LFLG-AS showed no statistically relevant improvement of daily steps (∆192 [IQR -687-770], p = 0.79). Patients with NFLG-AS showed a numerical decline in daily steps without statistical significance (∆-300 [IQR -1334-1406], p = 0.67). This first prospective study of this sample size shows significant improvement of physical activity after TAVR with an objective and reproducible method. This was mainly driven by an improvement in patients with HG-AS and paradoxical LFLG-AS.

Short-Term Changes in Arterial Stiffness Measured by 2D Speckle Tracking in Patients Undergoing Transcatheter Aortic Valve Implantation.

Arterial stiffness has received increasing interest as a cardiovascular marker in patients with aortic valve stenosis (AS). So far, studies on the impact of aortic valve replacement (AVR) on arterial stiffness have been equivocal. Two-dimensional speckle tracking (2DST) is a novel, non-invasive method to measure the motion of the vessel wall. In this prospective observational study, we aimed to assess the change in arterial stiffness of the common carotid artery (CCA) measured by 2DST in patients undergoing transcatheter aortic valve implantation (TAVI). A total of 47 patients were included in the study (age 80.04 ± 6.065 years). Peak circumferential strain (CS) was significantly improved after TAVI (4.50 ± 2.292 vs. 5.12 ± 2.958, p = 0.012), as was the peak strain rate (CSR) (0.85 ± 0.567 vs. 1.35 ± 0.710, p = 0.002). Body mass index (BMI), mean arterial pressure (MAP) and hemodynamic parameters were associated with this change. 2DST results did not correlate with aortic pulse wave velocity (aPWV) or augmentation index normalized to heart rate (AIx@75), suggesting a distinct difference between arterial stiffness of the CCA and other stiffness parameters. 2DST seems to be a promising new tool to assess arterial stiffness in TAVI patients.

Emergency transcatheter aortic valve implantation for acute heart failure due to severe aortic stenosis in critically ill patients with or without cardiogenic shock.

AIMS: Severe aortic stenosis can cause acute heart failure and cardiogenic shock (CS). Transcatheter aortic valve implantation (TAVI) is the standard therapy for aortic stenosis in inoperable patients. However, its role in this setting is poorly evaluated. The study purpose was to explore clinical characteristics of these patients and to assess predictors of mortality. METHODS AND RESULTS: All 2930 patients undergoing transfemoral TAVI at our centre between 2013 and 2019 were screened for critically ill patients, receiving intensive care therapy and emergency TAVI. Selected patients were subdivided into two groups, according to the presence or absence of CS. Remaining patients undergoing elective TAVI served as a comparison. Primary outcome was 90-day mortality. Out of 179 critically ill patients, 47 fulfilled criteria of CS (shock group) and 132 did not despite a severe decompensation (no shock group). Shock patients were more often male and had higher Society of Thoracic Surgeons scores [15.6, interquartile range (8.0-32.1) vs. 5.5 (3.9-8.5), P < 0.01] compared with severely decompensated patients. Ninety-day mortality was: shock group, 42.6%, vs. no shock group, 15.9%, vs. elective group, 5.3% (P < 0.01). A landmark analysis from day 90 showed similar mortality (P = 0.29). Compared with elective patients, 30-day composite endpoint device failure was higher in critically ill groups [shock group, odds ratio, 2.86 (1.43-5.36), no shock group, odds ratio, 1.74 (1.09-2.69)]. Multivariable regression revealed mechanical ventilation, haemofiltration, elevated C-reactive protein or bilirubin, and hypotension before TAVI as 90-day mortality predictors. CONCLUSION: Ninety-day mortality after TAVI in critically ill patients is increased but survivors have similar outcomes as elective patients.

Experimental investigation of skin toxicity after immune checkpoint inhibition in combination with radiation therapy.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, structured knowledge to mitigate a patient's specific risk of developing adverse events are limited. Nevertheless, there is an exponential growth of clinical studies combining conventional therapies such as radiation therapy (RT) with ICIs. Cutaneous reactions are among the most common adverse events after monotherapy with either ICIs or RT. So far, little is known about interindividual differences for the risk of developing severe tissue toxicity after the combination of RT with ICIs, and the underlying biological mechanisms are ill defined. We used experimental models of RT-induced skin injury to analyze skin toxicity after simultaneous application of ICIs. We compared different RT regimens such as fractionated or stereotactic RT with varying dose intensity. Strikingly, we found that simultaneous application of RT and ICIs did not significantly aggravate acute skin injury in two different mouse strains. Detailed examination of long-term tissue damage of the skin revealed similar signs of epidermal hyperplasia, dermal fibrosis, and adnexal atrophy. In summary, we here present the first experimental study demonstrating the excellent safety profiles of concurrent treatment with RT and ICIs. These findings will help to interpret the development of adverse events of the skin after radioimmunotherapy and guide the design of new clinical trials and clinical decision-making in individual cases. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pneumonitis after Stereotactic Thoracic Radioimmunotherapy with Checkpoint Inhibitors: Exploration of the Dose-Volume-Effect Correlation.

Thoracic stereotactic body radiation therapy (SBRT) is extensively used in combination with immune checkpoint blockade (ICB). While current evidence suggests that the occurrence of pneumonitis as a side effect of both treatments is not enhanced for the combination, the dose-volume correlation remains unclear. We investigate dose-volume-effect correlations for pneumonitis after combined SBRT + ICB. We analyzed patient clinical characteristics and dosimetric data for 42 data sets for thoracic SBRT with ICB treatment (13) and without (29). Dose volumes were converted into 2 Gy equivalent doses (EQD2), allowing for dosimetric comparison of different fractionation regimes. Pneumonitis volumes were delineated and corresponding DVHs were analyzed. We noticed a shift towards lower doses for combined SBRT + ICB treatment, supported by a trend of smaller areas under the curve (AUC) for SBRT+ ICB (median AUC 1337.37 vs. 5799.10, p = 0.317). We present a DVH-based dose-volume-effect correlation method and observed large pneumonitis volumes, even with bilateral extent in the SBRT + ICB group. We conclude that further studies using this method with enhanced statistical power are needed to clarify whether adjustments of the radiation dose constraints are required to better estimate risks of pneumonitis after the combination of SBRT and ICB.

Systolic or diastolic CT image acquisition for transcatheter aortic valve replacement - An outcome analysis.

BACKGROUND: Computed tomography (CT) imaging is the standard of care before transcatheter aortic valve replacement (TAVR). The aortic annulus undergoes conformational changes during the heart cycle. Therefore, the image acquisition time point can impact prosthesis sizing and fit. Clinical outcome data are lacking. The aim of this study was to compare systolic and diastolic cardiac CT data acquisition with regard to procedural and clinical outcomes in patients undergoing TAVR for severe aortic stenosis (AS). METHODS: Preprocedural high-pitch helical CT datasets were analyzed in 1954 patients undergoing TAVR between 2013 and 2018 â€‹at our center. Patients were stratified into two groups according to the acquisition heart phase (979 systolic and 975 diastolic). The study was approved by the local ethics committee. RESULTS: Median age was 81.6 [interquartile range 77.5-85.8] years and 964 (49.3%) patients were male. No significant difference was found for the Valve Academic Research Consortium-3 (VARC-3) endpoints of technical failure (systolic, 5.1% vs. diastolic, 5.2%, p â€‹= â€‹0.94) or device failure (systolic, 13.7% vs. diastolic, 13.5%, p â€‹= â€‹0.92). There was no difference in paravalvular regurgitation. All-cause 30-day mortality was comparable (systolic, 3.6% [95% confidence interval, 2.4-4.7%] vs. diastolic, 3.6% [2.4-4.8%], p â€‹= â€‹1.00), while 3-year mortality rates were higher in the diastolic group (Society of Thoracic Surgeons score adjusted hazard ratio, 1.25 [1.07-1.46], p â€‹< â€‹0.01). CONCLUSIONS: While the 30-day technical and clinical outcomes after TAVR are comparable between systolic and diastolic CT imaging, diastolic imaging was associated with higher long-term mortality. Therefore, the data support the guideline recommendation of systolic imaging.

TAVI in patients with low-flow low-gradient aortic stenosis-short-term and long-term outcomes.

OBJECTIVES: The study objective was to characterize different groups of low-flow low-gradient (LFLG) aortic stenosis (AS) and determine short-term outcomes and long-term mortality according to Valve Academic Research Consortium-3 (VARC-3) endpoint definitions. BACKGROUND: Characteristics and outcomes of patients with LFLG AS undergoing transcatheter aortic valve implantation (TAVI) are poorly understood. METHODS: All patients undergoing TAVI at our center between 2013 and 2019 were screened. Patients were divided into three groups according to mean pressure gradient (dPmean), ejection fraction (LVEF), and stroke volume index (SVi): high gradient (HG) AS (dPmean ≥ 40 mmHg), classical LFLG (cLFLG) AS (dPmean < 40 mmHg, LVEF < 50%), and paradoxical LFLG (pLFLG) AS (dPmean < 40 mmHg, LVEF ≥ 50%, SVi ≤ 35 ml/m2). RESULTS: We included 1776 patients (956 HG, 447 cLFLG, and 373 pLFLG patients). Most baseline characteristics differed significantly. Median Society of Thoracic Surgeons (STS) score was highest in cLFLG, followed by pLFLG and HG patients (5.0, 3.9 and 3.0, respectively, p < 0.01). Compared to HG patients, odds ratios for the short-term VARC-3 composite endpoints, technical failure (cLFLG, 0.76 [95% confidence interval, 0.40-1.36], pLFLG, 1.37 [0.79-2.31]) and device failure (cLFLG, 1.06 [0.74-1.49], pLFLG, 0.97 [0.66-1.41]) were similar, without relevant differences within LFLG patients. NYHA classes improved equally in all groups. Compared to HG, LFLG patients had a higher 3-year all-cause mortality (STS score-adjusted hazard ratios, cLFLG 2.16 [1.77-2.64], pLFLG 1.53 [1.22-193]), as well as cardiovascular mortality (cLFLG, 2.88 [2.15-3.84], pLFLG, 2.08 [1.50-2.87]). CONCLUSIONS: While 3-year mortality remains high after TAVI in LFLG compared to HG patients, symptoms improve in all subsets after TAVI.

Histopathological Tumor and Normal Tissue Responses after 3D-Planned Arc Radiotherapy in an Orthotopic Xenograft Mouse Model of Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. Innovative treatment concepts may enhance oncological outcome. Clinically relevant tumor models are essential in developing new therapeutic strategies. In the present study, we used two human PDAC cell lines for an orthotopic xenograft mouse model and compared treatment characteristics between this in vivo tumor model and PDAC patients. Tumor-bearing mice received stereotactic high-precision irradiation using arc technique after 3D-treatment planning. Induction of DNA damage in tumors and organs at risk (OARs) was histopathologically analyzed by the DNA damage marker γH2AX and compared with results after unprecise whole-abdomen irradiation. Our mouse model and preclinical setup reflect the characteristics of PDAC patients and clinical RT. It was feasible to perform stereotactic high-precision RT after defining tumor and OARs by CT imaging. After stereotactic RT, a high rate of DNA damage was mainly observed in the tumor but not in OARs. The calculated dose distributions and the extent of the irradiation field correlate with histopathological staining and the clinical example. We established and validated 3D-planned stereotactic RT in an orthotopic PDAC mouse model, which reflects the human RT. The efficacy of the whole workflow of imaging, treatment planning, and high-precision RT was proven by longitudinal analysis showing a significant improved survival. Importantly, this model can be used to analyze tumor regression and therapy-related toxicity in one model and will allow drawing clinically relevant conclusions.

Bright Purcell Enhanced Single-Photon Source in the Telecom O-Band Based on a Quantum Dot in a Circular Bragg Grating.

The combination of semiconductor quantum dots with photonic cavities is a promising way to realize nonclassical light sources with state-of-the-art performances regarding brightness, indistinguishability, and repetition rate. Here we demonstrate the coupling of InGaAs/GaAs QDs emitting in the telecom O-band to a circular Bragg grating cavity. We demonstrate a broadband geometric extraction efficiency enhancement by investigating two emission lines under above-band excitation, inside and detuned from the cavity mode, respectively. In the first case, a Purcell enhancement of 4 is attained. For the latter case, an end-to-end brightness of 1.4% with a brightness at the first lens of 23% is achieved. Using p-shell pumping, a combination of high count rate with pure single-photon emission (g(2)(0) = 0.01 in saturation) is achieved. Finally, a good single-photon purity (g(2)(0) = 0.13) together with a high detector count rate of 191 kcps is demonstrated for a temperature of up to 77 K.