[68Ga]DOTA-TATE PET for the detection of early transplant rejection in a heterotopic allograft heart transplantation model of the rat: a pilot study.

BACKGROUND: The most important cause of heart transplant loss is early acute allograft rejection, caused by the infiltration of lymphocytes, development of edema and myocardial necrosis. It has been propagated that [68Ga]DOTA-TATE PET might be suitable to quantify the presence of SSTR over-expressing lymphocytes. With heterotopic allogenic heart transplant models in the rat readily available, we aimed to investigate, if monitoring and quantification of acute allograft rejection after heterotopic allogenic heart transplantation was feasible by non-invasive serial [68Ga]DOTA-TATE PET. METHODS: Seventeen Lewis rats (9 for serial PET imaging, 8 for histological correlation) received allogenic heterotopic heart transplants from 17 Brown-Norway rats. On days 4, 6 and 7 a [68Ga]DOTA-TATE PET scan was performed. RESULTS: Imaging of acute transplant rejection until 7 days after allogenic heart transplantation in the rat is feasible. Heterotopic allografts showed significantly increased tracer uptake on day 4 until day 7 after transplantation, reflecting the process of histologically detected myocardial lymphocytic infiltration. Both the area of infarction and the amount of necrosis increased over the course of 7 days, with necrosis reaching statistical significance. CONCLUSIONS: We purport that the detected PET signal is primarily a specific marker of lymphocyte infiltration and only to a lesser extent an unspecific marker of infarction and necrosis. Thus, [68Ga]DOTA-TATE PET might be a suitable tool for serial imaging and quantification of lymphocyte infiltration as a direct mediator of acute allograft rejection at an early stage after heart transplantation.

Transcatheter mitral valve implantation versus conventional redo surgery for degenerated mitral valve prostheses and rings in a multicenter registry.

OBJECTIVES: Degeneration of mitral prostheses/rings may be treated by redo surgery, and, recently, by transcatheter valve-in-valve/ring implantation. This multicenter registry presents results of transcatheter valve-in-valve and repeat surgery for prostheses/rings degeneration. METHODS: Data provided by 10 German heart centers underwent propensity score-matched retrospective analysis. The primary endpoint was 30-day/midterm mortality. Perioperative outcome was assessed according to the Mitral Valve Academic Research Consortium criteria. Further, the influence of moderate or greater tricuspid regurgitation (TR) on 30-day/midterm mortality was analyzed. RESULTS: Between 2014 and 2019, 273 patients (79 transcatheter mitral valve-in-valve [TM-ViV] and 194 redo mitral valve replacement [Re-MVR]) underwent repeat procedure for mitral prosthesis/ring degeneration. Propensity score matching distinguished 79 patient pairs. European System for Cardiac Operative Risk Evaluation (EuroSCORE) II-predicted risk was 15.7 ± 13.7% in the TM-ViV group and 15.0% ± 12.7% in the Re-MVR group (P = .5336). TM-ViV patients were older (74.73 vs 72.2 years; P = .0030) and had higher incidence of atrial fibrillation (54 vs 40 patients; P = .0233). Severe TR incidence was similar (17.95% in TM-ViV vs 14.10%; P = .1741). Sixty-eight TM-ViV patients previously underwent mitral valve replacement, whereas 41 Re-MVR patients underwent valve repair (P < .0001). Stenosis was the leading degeneration mechanism in 42 TM-ViV versus 22 Re-MVR patients (P < .0005). The 30-day/midterm mortality did not differ between groups. Moderate or greater TR was a predictor of total (odds ratio [OR], 4.36; P = .0011), 30-day (OR, 3.76; P = .0180), and midterm mortality (OR, 4.30; P = .0378), irrespective of group. CONCLUSIONS: In both groups, observed mortality was less than predicted. Redo surgery enabled treatment of concomitant conditions, such as atrial fibrillation or TR. TR was shown to be a predictor of total, 30-day, and midterm mortality in both groups.

Bridging patients in cardiogenic shock with a paracorporeal pulsatile biventricular assist device to heart transplantation-a single-centre experience.

OBJECTIVES: We evaluated the outcome of patients in cardiogenic shock receiving a paracorporeal pulsatile biventricular assist device as a bridge to transplantation. METHODS: We performed a retrospective single-centre analysis of all patients who received a Berlin Heart Excor® at our institution between 2004 and 2019. RESULTS: A total of 97 patients (90 adults, 7 paediatric) were analysed. Eighty-four patients were in Interagency Registry for Mechanically Assisted Circulatory Support level 1 (80 adults, 4 paediatric). Diagnoses were dilated cardiomyopathy (n = 41), ischaemic cardiomyopathy (n = 17) or myocardial infarction (n = 4), myocarditis (n = 15), restrictive cardiomyopathy (n = 2), graft failure after heart transplant (n = 7), postcardiotomy heart failure (n = 5), postpartum cardiomyopathy (n = 3), congenital heart disease (n = 1), valvular cardiomyopathy (n = 1) and toxic cardiomyopathy (n = 1). All patients were in biventricular heart failure and had secondary organ dysfunction. The mean duration of support was 63 days (0-487 days). There was a significant decrease in creatinine values after assist device implantation (from 1.83 ± 0.79 to 1.12 ± 0.67 mg/dl, P = 0.001) as well as a decrease in bilirubin values (from 3.94 ± 4.58 to 2.65 ± 3.61 mg/dl, P = 0.084). Cerebral stroke occurred in 16 patients, bleeding in 15 and infection in 13 patients. Forty-eight patients died on support, while 49 patients could be successfully bridged to transplantation. Thirty-day survival and 1-year survival were 70.1% and 41.2%, respectively. CONCLUSIONS: A pulsatile biventricular assist device is a reasonable therapeutic option in cardiogenic shock, when immediate high cardiac output is necessary to rescue the already impaired kidney and liver function of the patient.

Treatment of a massive pseudoaneurysm originating from the ascending aorta with an off-the-shelf stent graft.

A 73-year-old patient who underwent an emergency coronary bypass surgery in our institution and who required postoperative extracorporeal membrane oxygenation support in December 2019 presented in August 2020 with a rapidly growing subxiphoidal, pulsating swelling. A computed tomography scan revealed a massive mediastinal pseudoaneurysm originating from an 8-mm Dacron graft that was sutured to the ascending aorta during the index surgery for arterial extracorporeal membrane oxygenation cannulation. Due to the location and extent of the pseudoaneurysm, an open surgical revision was deemed high risk. Because no bypass conduit originated from the ascending aorta, we decided to occlude the entry of the pseudoaneurysm with a stent graft. Also, urgency did not allow for the manufacturing of a custom-made device, so an off-the-shelf stent graft had to be implanted. Currently, the only off-the-shelf thoracic stent graft with a length suitable for the ascending aorta (<7 cm) is the Medtronic Valiant Navion prosthesis, of which 2 prostheses (37 mm × 52 mm; covered seal) were successfully implanted to exclude the pseudoaneurysm. A follow-up computed tomography scan performed 4 months postoperatively showed no perfusion and regression of the pseudoaneurysm. With the growing number of reports describing stent graft placement in the ascending aorta, more off-the-shelf stent grafts suitable for the ascending aorta are desirable.

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency.

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.

Pig-to-non-human primate heart transplantation: The final step toward clinical xenotransplantation?

BACKGROUND: The demand for donated human hearts far exceeds the number available. Xenotransplantation of genetically modified porcine organs provides an alternative. In 2000, an Advisory Board of the International Society for Heart and Lung Transplantation set the benchmark for commencing clinical cardiac xenotransplantation as consistent 60% survival of non-human primates after life-supporting porcine heart transplantations. Recently, we reported the stepwise optimization of pig-to-baboon orthotopic cardiac xenotransplantation finally resulting in consistent success, with 4 recipients surviving 90 (n = 2), 182, and 195 days. Here, we report on 4 additional recipients, supporting the efficacy of our procedure. RESULTS: The first 2 additional recipients succumbed to porcine cytomegalovirus (PCMV) infections on Days 15 and 27, respectively. In 2 further experiments, PCMV infections were successfully avoided, and 3-months survival was achieved. Throughout all the long-term experiments, heart, liver, and renal functions remained within normal ranges. Post-mortem cardiac diameters were slightly increased when compared with that at the time of transplantation but with no detrimental effect. There were no signs of thrombotic microangiopathy. The current regimen enabled the prolonged survival and function of orthotopic cardiac xenografts in altogether 6 of 8 baboons, of which 4 were now added. These results exceed the threshold set by the Advisory Board of the International Society for Heart and Lung Transplantation. CONCLUSIONS: The results of our current and previous experimental cardiac xenotransplantations together fulfill for the first time the pre-clinical efficacy suggestions. PCMV-positive donor animals must be avoided.

Rare Association between Giant Right Ventricular Myxoma and Right Coronary Artery Tumour Blush with Complicating Pulmonary Tumour Embolism.

Cardiac myxoma is a benign primary cardiac tumour which can present with nonspecific symptoms of right heart failure, syncope, exertional dyspnea, and pulmonary embolism. We describe a case of a right ventricular myxoma complicated with bilateral pulmonary embolism, with an incidental right coronary artery fistula but otherwise normal coronary anatomy on coronary angiogram. This case report emphasizes the importance of performing a transesophageal echo in the setting of pulmonary embolism to search for the origin of thrombus/tumour, and performing a comprehensive assessment is also necessary to rule out coronary artery disease, coronary artery fistula that may also represent a tumour blush.

Author Correction: Consistent success in life-supporting porcine cardiac xenotransplantation.

In this Letter, Mayuko Kurome and Valeri Zakhartchenko have been added to the author list (affiliated with Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany). The author list and 'Author contributions' section have been corrected online; see accompanying Amendment.

Consistent success in life-supporting porcine cardiac xenotransplantation.

Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1-3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.

HER4 expression in estrogen receptor-positive breast cancer is associated with decreased sensitivity to tamoxifen treatment and reduced overall survival of postmenopausal women.

BACKGROUND: The sensitivity of estrogen receptor-positive breast cancers to tamoxifen treatment varies considerably, and the molecular mechanisms affecting the response rates are manifold. The human epidermal growth factor receptor-related receptor HER2 is known to trigger intracellular signaling cascades that modulate the activity of coregulators of the estrogen receptor which, in turn, reduces the cell sensitivity to tamoxifen treatment. However, the impact of HER2-related receptor tyrosine kinases HER1, HER3, and, in particular, HER4 on endocrine treatment is largely unknown. METHODS: Here, we retrospectively evaluated the importance of HER4 expression on the outcome of tamoxifen- and aromatase inhibitor-treated estrogen receptor-positive breast cancer patients (n = 258). In addition, we experimentally analyzed the efficiency of tamoxifen treatment as a function of HER4 co-expression in vitro. RESULTS: We found a significantly improved survival in tamoxifen-treated postmenopausal breast cancer patients in the absence of HER4 compared with those with pronounced HER4 expression. In accordance with this finding, the sensitivity to tamoxifen treatment of estrogen and HER4 receptor-positive ZR-75-1 breast cancer cells can be significantly enhanced by HER4 knockdown. CONCLUSION: We suggest an HER4/estrogen receptor interaction that impedes tamoxifen binding to the estrogen receptor and reduces treatment efficiency. Whether the sensitivity to tamoxifen treatment can be enhanced by anti-HER4 targeting needs to be prospectively evaluated.

Regional to tertiary inter-hospital transfer versus in-house percutaneous coronary intervention in acute coronary syndrome.

RATIONALE: To address the inaccessibility of interventional cardiac services in North Queensland a new cardiac catheterisation laboratory (CCL) was established in Mackay Base Hospital (MBH) in February 2014. OBJECTIVE: To determine whether the provision of in-house angiography and/or percutaneous coronary intervention (PCI) 1) minimises treatment delays 2) further reduces the risk of mortality, recurrent myocardial infarction (MI) and recurrent ischaemia 3) improves patient satisfaction and 4) minimises cost expenditure compared with inter-hospital transfer for patients with acute coronary syndrome (ACS). METHODS: We compared ACS patients who were transferred to tertiary centres from July 2012 to June 2013 with those who received in-house angiography and/or PCI from February 2015 to January 2016. The primary outcome was the composite of all-cause mortality, recurrent myocardial infarction (MI) or recurrent ischaemia at six months. Pre-specified secondary outcomes were the composite of all-cause mortality, recurrent MI or recurrent ischaemia at one month, a summated patient satisfaction score and the proportional cost savings generated between 2015 and 2016. RESULTS: We included consecutive samples of 203 patients from July 2012 to June 2013 and 229 patients from February 2015 to January 2016. There was a reduction in the median time to treatment of 3.2 days and a reduction in the median length of stay of four days amongst all ACS patients receiving in-house angiography and/or PCI. The primary outcome occurred in 14 (6.9%) patients in the 2012 to 2013 group, as compared with 18 (7.9%) patients in the 2015 to 2016 group (OR = 0.71, 95% CI 0.24-2.1, P = 0.54). The secondary outcome at one month occurred in four (2.0%) patients in the 2012 to 2013 group, as compared with three (1.3%) patients in the 2015 to 2016 group (OR = 1.2, 95% CI 0.11-13.1, P = 0.87). There was a statistically significant improvement in the summated patient satisfaction score amongst patients who received in-house angiography and/or PCI (U = 1918, P <0.05 two tailed). A calculation of estimated cost savings showed a reduction in proportional cost of $14 481 (51%) per ACS patient receiving in house angiography and/or PCI between 2015 and 2016. CONCLUSION: This study suggests that the provision of regional in-house angiography and/or PCI for the treatment of ACS minimises delays to invasive treatment by 3.2 days, minimises the median length of stay by four days, significantly improves patient satisfaction and reduces proportional treatment costs by $14 481 (51%) per patient. Currently, however, it appears that that in-house treatment does not further reduce the risk of mortality, recurrent MI and recurrent ischaemia at one and six months.

Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.

BACKGROUND: In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. METHODS: Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. RESULTS: In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group. CONCLUSIONS: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).

Large-Animal Biventricular Working Heart Perfusion System with Low Priming Volume-Comparison between in vivo and ex vivo Cardiac Function.

BACKGROUND: Existing large-animal, ex vivo, cardiac perfusion models are restricted in their ability to establish an ischemia/reperfusion condition as seen in cardiac surgery or transplantation. Other working heart systems only challenge one ventricle or require a substantially larger priming volume. We describe a novel biventricular cardiac perfusion system with reduced priming volume. METHODS: Juvenile pig hearts were cardiopleged, explanted, and reperfused ex vivo after 150 minutes of cold ischemia. Autologous whole blood was used as perfusate (minimal priming volume 350 mL). After 15 minutes of Langendorff perfusion (LM), the system was switched into a biventricular working mode (WM) and studied for 3 hours. RESULTS: During reperfusion, complete unloading of both ventricles and constant-pressure coronary perfusion was achieved. During working mode perfusion, the preload and afterload pressure of both ventricles was controlled within the targeted physiologic range. Functional parameters such as left ventricular work index were reduced in ex vivo working mode (in vivo: 787 ± 186 vs. 1 h WM 498 ± 66 mm Hg·mL/g·min; p < 0.01), but remained stable throughout the following study period (3 h WM 517 ± 103 mm Hg·mL/g·min; p = 0.63). Along with the elevated workload during WM, myocardial metabolism and oxygen consumption increased compared with LM (0.021 ± 0.08 vs. 0.06 ± 0.01 mL/min/g; 1 h after reperfusion). Histologic examination of the myocardium revealed no structural damage. CONCLUSION: In the ex vivo perfusion system, stable hemodynamic and metabolic conditions can be established for a period of 3 hours while functional and blood parameters are easily accessible. Moreover, because of the minimal priming volume, the novel ex vivo cardiac perfusion circuit allows for autologous perfusion, using the limited amount of blood available from the organ donating animal.

Remote ECLS-Implantation and Transport for Retrieval of Cardiogenic Shock Patients.

OBJECTIVE: Extracorporeal life support (ECLS) emerges as a salvage option in therapy refractory cardiogenic shock but is limited to highly specialized tertiary care centers. Critically ill patients are often too unstable for conventional transport. Mobile ECLS programs for remote implantation and subsequent air or ground-based transport for patient retrieval could solve this dilemma and make full-spectrum advanced cardiac care available to patients in remote hospitals in whom shock otherwise might be fatal. METHODS: From December 2012 to March 2016, 40 patients underwent venoarterial ECLS implantation in remote hospitals with subsequent transport to our center and were retrospectively analyzed. The mobile ECLS team was available 24/7, implantation was performed percutaneously bedside, and compact support systems designed for transport were used. RESULTS: Twenty percent of the patients were female; the mean age was 55 ± 10 years, and the mean Interagency Registry for Mechanically Assisted Circulatory Support score was 1.3 ± 0.5. Patient retrieval was accomplished via ground-based (n = 29, 72.5%, mean distance = 27.9 ± 29.7 km [range, 5.6-107.1 km]) or air (n = 11, mean distance = 62.4 ± 27.2 km [range, 38.9-116.4 km]) transport. No ECLS-related complications occurred during transport. The ECLS system could be explanted in 65.0% (n = 26) of patients, and the 30-day survival rate was 52.5% (n = 21). CONCLUSION: Remote ECLS implantation and interfacility transport on ECLS are feasible and effective. Interdisciplinary teams and full-spectrum cardiac care are essential to achieve optimal outcomes. Rapid-response ECLS networks have the potential to substantially increase the survival of cardiogenic shock patients.

Early Versus Delayed Invasive Strategies in High-Risk Non-ST Elevation Acute Coronary Syndrome Patients - A Systematic Literature Review and Meta-Analysis of Randomised Controlled Trials.

RATIONALE: It is unclear whether it is beneficial to perform angiography and/or percutaneous coronary intervention (PCI) as an early or delayed invasive strategy amongst high-risk non-ST elevation acute coronary syndrome (NSTEACS) patients. OBJECTIVE: To determine whether an early invasive strategy could further reduce recurrent myocardial infarction (MI) and early mortality compared to a delayed invasive strategy. METHODS AND RESULTS: We searched MEDLINE, CINAHL and SCOPUS and performed a meta-analysis of nine RCTs with a total of 5274 patients. No statistically significant difference in recurrent MI (RR=0.56, 95% CI 0.17-1.87, p=0.35), early mortality (RR=0.81, 95% CI 0.62-1.05, p=0.11) and major bleeding (RR=0.85, 95% CI 0.66-1.09, p=0.21) was found between groups. A statistically significant reduction in recurrent ischaemia was found amongst patients treated with an early invasive strategy (RR 0.45, 95% CI 0.26-0.78, p=0.004). Subgroup analysis for recurrent MI showed a statistically significant reduction in risk amongst patients treated <24hours compared to≥24hours (RR=0.31, 95% CI 0.11-0.89, p=0.03). CONCLUSION: This study suggests that an early invasive strategy may not further reduce recurrent MI and early mortality, but may significantly reduce recurrent ischaemia. However, the recurrent MI endpoint was associated with heterogeneity due to inconsistent MI definitions and strategy timings amongst the included trials. Furthermore, subgroup analysis demonstrated a significant reduction in recurrent MI amongst patients treated <24hours. Therefore, large clinical trials with consistent inclusion criteria are required to confirm whether intervention within 24hours reduces the rate of spontaneous and post-discharge recurrent MI. Future studies with long-term follow-up data are required to detect relevant differences in early mortality. Currently, it appears that stabilised high-risk NSTEACS patients may be safely delayed up to 24hours before undergoing an early invasive strategy.

Hemopericardium Due to Idiopathic Coronary Artery Rupture Treated with Saphenous Vein Patch Plasty.

We report a case of an idiopathic coronary artery rupture in a 41-year-old male patient who was admitted to the hospital with cardiac tamponade. On opening the chest via a median sternotomy and establishing cardiopulmonary bypass the hemopericardium's cause could be identified as a perforation of the right posterior descending coronary artery which was treated with a saphenous vein patch plasty. With idiopathic coronary artery rupture being a rare diagnosis, one should always consider it in a young patient presenting with cardiac tamponade.

Early dissemination seeds metastasis in breast cancer.

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.

Interplay of demographic variables, birth experience, and initial reactions in the prediction of symptoms of posttraumatic stress one year after giving birth.

BACKGROUND: There has been increasing research on posttraumatic stress disorder (PTSD) following childbirth in the last two decades. The literature on predictors of who develops posttraumatic stress symptoms (PSS) suggests that both vulnerability and birth factors have an influence, but many studies measure predictors and outcomes simultaneously. OBJECTIVE: In this context, we aimed to examine indirect and direct effects of predictors of PSS, which were measured longitudinally. METHOD: We assessed women within the first days (n=353), 6 weeks, and 12 months (n=183) after having given birth to a healthy infant. The first assessment included questions on demographics, pregnancy, and birth experience. The second and third assessments contained screenings for postpartum depression, PTSD, and general mental health problems, as well as assessing social support and physical well-being. We analysed our data using structural equation modelling techniques (n=277). RESULTS: Our final model showed good fit and was consistent with a diathesis-stress model of PSS. Women who had used antidepressant medication in the 10 years before childbirth had higher PSS at 6 weeks, independent of birth experiences. Subjective birth experience was the early predictor with the highest total effect on later PSS. Interestingly, a probable migration background also had a small but significant effect on PSS via more episiotomies. The null results for social support may have been caused by a ceiling effect. CONCLUSIONS: Given that we measured predictors at different time points, our results lend important support to the etiological model, namely, that there is a vulnerability pathway and a stress pathway leading to PSS. PSS and other psychological measures stayed very stable between 6 weeks and 1 year postpartum, indicating that it is possible to identify women developing problems early. HIGHLIGHTS OF THE ARTICLE: Our results are consistent with a diathesis-stress model: vulnerability (antidepressant use in the previous 10 years) influenced posttraumatic stress symptoms at 6 weeks and 1 year, independently of stress (birth-related variables). The strongest predictor of posttraumatic stress symptoms 1 year postpartum was posttraumatic stress symptoms 6 weeks postpartum. This means that women who develop problems could be identified during routinely offered postpartum care. Women with a probable migration background experienced more PSS 1 year after the birth, which was an indirect effect through more episiotomies and more PSS after 6 weeks.

Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique.

BACKGROUND: As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions. METHODS: Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/± thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. RESULTS: In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI. CONCLUSIONS: Longer-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.

The Coronary Microcirculation in Hamster-to-Rat Cardiac Xenografts.

BACKGROUND: The aim of this study was to establish a new experimental model to directly analyse the coronary microcirculation in cardiac xenografts. METHODS: Intravital fluorescence microscopy (IVM) of the subepicardial microcirculation in heterotopically transplanted hamster-to-rat cardiac xenografts was performed at 30 and 90 min of reperfusion. We quantitatively assessed the microcirculatory perfusion characteristics as well as the interactions of leukocytes and platelets with the endothelium of postcapillary coronary venules in non-sensitised as well as sensitised recipients. RESULTS: In this first experimental IVM study of cardiac xenografts, we successfully visualised the subepicardial microcirculation, i.e. feeding arterioles, nutritive capillaries and draining postcapillary venules, during reperfusion. Leukocyte-endothelial and platelet-endothelial cell interactions could be quantified. In the non-sensitised group, the myocardial microcirculation remained stable during the observation period of 90 min, whereas in the sensitised group, xenografts were rejected immediately. CONCLUSIONS: We established a model for the assessment of the microcirculatory dysfunction and inflammation during ischaemia/reperfusion injury in hamster-to-rat cardiac xenografts.