Search

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 17 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.

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.

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.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.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.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.

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.

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 (

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., Metastatic dissemination in breast cancer patients occurs early in malignant transformation, raising questions about how disseminated cancer cells (DCC) progress at distant sites. Here, the authors show that DCCs in bone marrow are activated via IL6-trans-signaling and thereby acquire stemness traits relevant for metastasis formation.

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 profiled rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identified IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lacked membranous IL6 receptor expression and mechanistic dissection revealed IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals was found to be niche-dependent as bone marrow stromal and endosteal cells down-regulated gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation rendered cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we found 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.

Der konventionell therapierefraktare Herz-Kreislauf-Stillstand verlauft in aller Regel letal. Die „Extracorporeal Life Support“(ECLS)-Therapie hat das Potenzial der sofortigen, vollen kardiopulmonalen Unterstutzung und wird zunehmend im Rahmen der kardiopulmonalen Reanimation (Extracorporeal Cardiopulmonary Resuscitation, ECPR) eingesetzt. Diese Arbeit soll Einblicke in die aktuelle Studienlage und eine Ubersicht uber das Verfahren der ECPR geben. Es erfolgt ein systematischer Uberblick uber die vorhandenen Daten und Empfehlungen zur ECPR-Therapie in Kombination mit einer fokussierten Darstellung von Schlusselelementen des Verfahrens. Die ECPR kann im Fall der frustranen konventionellen CPR zur Etablierung einer suffizienten Zirkulation dienen. Daten aus prospektiven, randomisierten kontrollierten Studien sind bisher nicht verfugbar. Es handelt sich um ein hochinvasives Verfahren, das entsprechende Expertise erfordert. Parameter zur Patienten-Triage konnen Alter und Vorerkrankungen, den beobachteten Herz-Kreislauf-Stillstand, die Ischamiezeit, Qualitat und Dauer der Reanimation, einschlieslich Einsatz einer mechanischen Kompressionshilfe, umfassen. Vor Implantation liefern pH-Wert und Lactatkonzentration wertvolle Zusatzinformationen uber den metabolischen Zustand des Patienten und die Perfusion wahrend der Reanimation. Das Verfahren der ECPR sollte auf Zentren der Maximalversorgung beschrankt sein, die uber das volle Spektrum der modernen interdisziplinaren Herzmedizin verfugen, einschlieslich Kunstherzimplantation und thorakaler Organtransplantation. Randomisierte kontrollierte Studien und umfassende entsprechende Leitlinien sind dringend erforderlich. Die Definition minimaler Fallzahlen und die Etablierung von Kompetenzzentren werden zu diskutieren sein.

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.To determine whether an early invasive strategy could further reduce recurrent myocardial infarction (MI) and early mortality compared to a delayed invasive strategy.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 treated24hours compared to≥24hours (RR=0.31, 95% CI 0.11-0.89, p=0.03).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 treated24hours. 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.

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.

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 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.

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.

Purpose Major hurdles in oXHTx are the delayed xenograft rejection, the early perioperative cardiac xenograft dysfunction (PCXD) and the pig heart overgrowth, which were solved in this study with a costimulation blockade, a new non-ischemic cold preservation and a growth inhibition by anti-proliferative drugs. Aim was to achieve a 90-days-survival of minimal 60% (6 of 10 baboons) in this life-supporting orthotopic pig-to-baboon model (oXHTx), because this is the recommendation of the ISHLT to begin a clinical cardiac XT program. Methods We transplanted 8 GalKO/hCD46/hTM transgenic (tg) pig hearts orthotopically into baboons with using a basic immunosuppression consisting of ATG, rituximab, mycophenolate (MMF), cortisone and a costimulation blockade CD40mAb (high dose: 50 mg/kg). To prevent PCXD, we used instead of the crystalloid solution a new non-ischemic 8°C cold perfusion technique with oxygenated erythrocytes. Additional antihypertensive drugs and an mTOR inhibitor (temsirolimus) were applied to inhibit pig xenograft growth and hypertrophy. Results In comparison to our previous group with crystalloid cardioplegia (Langin et al. Nature. 2018;564:430-433) in this group with cold perfusion preservation (non-ischemic) no PCXD was found. One baboon died of a pancreatitis on day 14, another of sepsis on day 26. By using the antiproliferative therapy, 6 of 8 recipient baboons reached the end of study, were long-term surviving (4 were actively terminated after 90 days according to the guidelines of our government). With special permit two further experiments could be prolonged to half a year and the animals were terminated on day 182 and 195. All baboons lived under excellent physical conditions and no hyperacute rejection or DXR occurred. Conclusion First time in a life-supporting oXHT of multi-tg pig hearts here was a consistent reproduceable long-term survival of 3 - 6 months achieved, which is a major progress after 25 years of research. This is an essential milestone and breakthrough and meets the prerequisite according to the ISHLT to begin a clinical phase I study with patients in terminal heart failure. This paves the way to clinical cardiac XT in the next 2 to 5 years.

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

End-stage heart failure is associated with significant morbidity and mortality. Heart transplantation has the potential to offer a return to daily activities for critically ill patients and is the gold standard therapy. However, heart transplantations are decreasing yearly with a historic low in Germany in 2017. By striking contrast, both waiting list numbers and waiting time have increased owing to a lack of acceptable donor organs. Ventricular assist devices (VAD) represent a reasonable therapeutic alternative for patients on heart transplantation waiting lists. Patients ineligible for transplantation may undergo VAD implantation as a destination therapy. However, the necessity for life-long anticoagulation must be weighed against bleeding complications in potential VAD candidates. VAD-dependent patients also face risks of driveline infections, in addition to restricted activities of daily living owing to limited battery capacities. Given Germany's low transplantation rate, VAD implantation may serve as a middle ground. With the recent events in transplantation medicine, trust among the German population has declined. Transplant centers must ensure graft quality and ongoing care, define minimum caseload for accreditation, and implement specialty care units in heart failure. Furthermore, the legislation shift from extended consent to dissent solution has the potential to end donor organ shortage.

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.

Background It is uncertain if the addition of OFS to adjuvant endocrine therapy with T improves outcomes in premenopausal HR+ BC. The SOFT trial was designed to determine the value of OFS in women who remain premenopausal and are treated with T (OFS question) and also to test whether an AI improves outcome in premenopausal women with HR+ BC treated with OFS (AI question). In the combined analysis of the TEXT and SOFT trials (AI question), the group treated with the AI exemestane+OFS had a significantly better disease-free survival (DFS) than those with T+OFS. This abstract presents the results of the OFS question (n=2,045). Patients and Methods Between November 2003 and January 2011, the SOFT phase 3 trial randomized 3066 premenopausal women with HR+ BC to 5 years of adjuvant endocrine therapy with exemestane+OFS versus T+OFS versus T alone, with OFS initiated by choice of GnRH agonist triptorelin, oophorectomy or ovarian irradiation. Prior chemotherapy was allowed, provided women had confirmed premenopausal estradiol levels within 8 months of completing chemotherapy. The primary end point was DFS which included invasive local, regional, distant and contralateral breast events, second non-breast malignancies and deaths without prior cancer. Because of a lower-than expected overall event rate and to ensure results within a reasonable time-frame, a protocol amendment in 2011 changed the originally event-driven analysis plan. The amendment (1) designated the comparison of T+OFS versus T alone as the primary analysis for SOFT (n=2045), recognizing that the statistical power for the original three pairwise comparisons would be substantially reduced and (2) specified that the primary analysis of T+OFS versus T be undertaken when median follow-up was at least 5 years. The comparison would be tested at the 2-sided 0.05 level with no interim analysis. Based on the projected number of events at the lower rates, the estimated power to detect hazard ratios of 0.75, 0.70, and 0.66 for the comparison would be 52%, 69%, and 80%. Results The SOFT trial completed planned patient enrollment with an international collaboration involving 426 centres from BIG and NABCG led by the International Breast Cancer Study Group (IBCSG). Numbers of patients randomized, randomization strata, and pt age are summarized in the Table. The database lock for the primary analysis of the OFS question will occur in September 2014 and the final analysis will be completed by October 15, 2014. SOFT Patients (%)Tamoxifen alone1021 (33%)Tamoxifen+OFS1024 (33%)Exemestane+OFS1021 (33%)* Prior Chemotherapy54%Lymph node positive35%Median age (% < 40 years)43 years (30%)*Patients randomized to Exemestane+OFS are not part of the current analysis Conclusions We will present the primary analysis of outcomes and toxicities by treatment for women randomized to receive T+OFS versus T and address the value of OFS in addition to T as adjuvant endocrine therapy for premenopausal women with HR+ BC. Citation Format: Aron Goldhirsch, Richard D Gelber, Prudence A Francis, Meredith M Regan, Gini F Fleming, Istvan Lang, Eva M Ciruelos, Meritxell Bellet, Herve Bonnefoi, Miguel A Climent, Lorenzo Pavesi, Harold J Burstein, Silvana Martino, Nancy E Davidson, Charles E Geyer Jr, Barbara A Walley, Robert E Coleman, Pierre Kerbrat, Manuela Rabaglio-Poretti, Alan S Coates. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Analysis of the SOFT trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-08.

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.

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.

Die Nachsorge bei Patientinnen mit abgeschlossener Therapie des fruhen Mammakarzinoms ist gut etabliert und wird im Bereich der Brustzentren bzw. der betreuenden Gynakologen analog der S3-Leitlinie zur Diagnostik, Therapie und Nachsorge des fruhen Mammakarzinoms durchgefuhrt. Diese wird symptombasiert vorgenommen. Die apparative Diagnostik steht nicht im Mittelpunkt. Ziel ist es, neben der Detektion eines moglichen lokalen Rezidivs die Patientin hinsichtlich der Nebenwirkungen und moglicher supportiver Masnahmen zur Verbesserung der Lebensqualitat zu beraten. Neue Strategien, die beispielsweise in Form einer verlangerten adjuvanten endokrinen Therapie umgesetzt werden, werden zurzeit diskutiert und finden Einzug in die tagliche Praxis. Dies entspricht aber einer Therapiephase und nicht der klassischen Definition der Nachsorge. Individualisierung, auch in Bezug auf Therapien, kann moglicherweise Einfluss auf die Gestaltung der Nachsorge haben.

Objective Local application of estradiol (E2) to treat vulvovaginal atrophy in postmenopausal breast cancer patients receiving aromatase inhibitors is known to elevate serum estradiol levels and thereby might counteract breast cancer therapy. Thus, vaginal application of estriol (E3) has been recommended for these patients. However, it is unclear to what extent E3 stimulates breast cancer cell growth. In this study, we examined the effect of E3 on growth and gene expression of two human breast cancer cell lines. Methods We used an established in vitro cell culture assay and compared the effect of E2 and E3 on growth of the estrogen receptor alpha-positive breast cancer cell lines MCF-7 and T-47D testing a wide range of hormone concentrations of 10−12–10−7 M. E3 effects on gene expression were examined by means of reporter gene assays, RT-qPCR and Western blot analysis. Results E3 acted as a potent estrogen and exerted a mitogenic effect on T-47D and MCF-7 cells at concentrations of 10−9 M (288 pg/ml) and higher. With regard to activation of an estrogen response element (ERE) in breast cancer cells, effects of E3 were visible at 10−10 M. The same concentrations of E3 activated expression of the estrogen-responsive gene PR and of the proliferation genes cyclin A2, cyclin B1, Ki-67, c-myc and b-myb, providing molecular mechanisms underlying the observed growth increase. Conclusions Like E2, low levels of E3 were able to trigger a robust estrogenic response in breast cancer cells. Thus, our data suggest caution regarding use of E3 by breast cancer survivors.

Carbon dioxide can be used in various ways as a cheap C1 source. However, the utilization of CO2 requires energy or energy-rich reagents, which leads to further emissions, and therefore, diminishes the CO2-saving potential. Therefore, life cycle assessment (LCA) is required for each process that uses CO2 to provide valid data for CO2 savings. Carbon dioxide can be incorporated into epoxidized fatty acid esters to provide the corresponding carbonates. A robust catalytic process was developed based on simple halide salts in combination with a phase-transfer catalyst. The CO2-saving potential was determined by comparing the carbonates as a plasticizer with an established phthalate-based plasticizer. Although CO2 savings of up to 80 % were achieved, most of the savings arose from indirect effects and not from CO2 utilization. Furthermore, other categories have been analyzed in the LCA. The use of biobased material has a variety of impacts on categories such as eutrophication and marine toxicity. Therefore, the benefits of biobased materials have to be evaluated carefully for each case. Finally, interesting properties as plasticizers were obtained with the carbonates. The volatility and water extraction could be improved relative to the epoxidized system.

While thousands of breast cancer cells disseminate and home to bone marrow (BM) until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. Signals and mechanisms determining failure or success of disseminated cancer cells (DCCs) are largely unknown and there is no in vivo model available to study the spontaneous progression and genomic evolution from early bone marrow infiltration to manifestation of bone metastasis, as spontaneous or transgenic mouse models do not generate bone metastases. We therefore profiled DCCs from BM of breast cancer patients long before manifestation of metastasis by RNAseq to identify signals supporting survival or outgrowth of DCCs and identified IL6/PTEN/PI3K signaling as candidate pathway for DCC activation. Since early DCCs often display close-to-normal genomes we used mammary epithelial cells ex vivo isolated from reduction mammoplasties and immortalized pre-malignant breast cancer cell lines as model for functional testing in vitro. Using specific activators and inhibitors of IL6 signaling revealed that IL6 trans, but not classical signaling, regulates stemness of mammary epithelial cells. Moreover, knock-down of PTEN revealed that PI3K/PTEN pathway activation renders cells independent of IL6 trans-signaling. Interestingly, gp130 expression, a pre-requisite for IL6 trans-signaling was found to be down-regulated by bone marrow stromal and endosteal, but not vascular niche cells, and as a consequence the number of cells with stem-like ability was significantly reduced. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic DCCs and CTCs while generally absent in early DCCs. Our data suggest that the initial steps of metastasis formation depend on microenvironmental signals and are not cancer cell-autonomous. Citation Format: Melanie Werner-Klein, Ana Grujovic, Milan Obradovic, Martin Hoffmann, Xin Lu, Stefan Kirsch, Steffi Treitschke, Cäcilia Köstler, Kathrin Weidele, Christoph Irlbeck, Catherine Botteron, Christian Werno, Bernhard Polzer, Miodrag Guzvic, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John, Christoph A. Klein. Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-312.

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.

a Transregio Collaborative Research Center 127, Ludwig-Maximilians University, Munich, Germany b Department of Cardiovascular Surgery, Ludwig-Maximilians University, Munich, Germany c Revivicor, Blacksburg, VA, USA d Living Cell Technologies, Auckland, New Zealand e Chair of Livestock Biotechnology, Weihenstephan, Technical University, Munich, Germany f Department of Anaesthesiology and Intensive Medicine, Ludwig-Maximilians University, Munich, Germany

Die Therapie klimakterischer Beschwerden bei Patientinnen mit gynakologischen Malignomen und Mammakarzinom ist eine Herausforderung fur den Arzt. Die Beschwerden beeinflussen die Lebensqualitat der Patientinnen deutlich. Da eine Reihe der gynakologischen Malignome, vor allem das Mammakarzinom, Steroidhormonrezeptoren exprimieren, ist der Einsatz der Sexualsteroide nicht unbedenklich. Im Vordergrund steht das therapiebedingte erhohte Rezidivrisiko. Dennoch ist der Einsatz einer Hormontherapie bei Patientinnen mit gynakologischen Malignomen in seltenen Fallen moglich.

Introduction: Intra-vaginal estradiol (E2) is effective to treat symptomatic vaginal atrophy. However, in postmenopausal (PM) women on aromatase inhibitors (AI), this increases serum E2 levels. We here report pharmacokinetic (PK), efficacy and safety results of a phase I study using vaginal tablets with lyophilized lactobacilli and 0.03 mg estriol (E3) (Gynoflor®) in PM breast cancer (BC) survivors on AI reporting atrophic vaginitis. Patients and Methods: In this open label phase I PK study, women being treated for ≥6 months with a non-steroidal AI and reporting non-hormone treatment-resistant vaginal atrophy were recruited. The primary objective was absorption and serum concentration of estrone (E1), E2, E3, FSH, LH and SHBG during initial therapy with one vaginal tablet of Gynoflor® daily for 28 days and during subsequent maintenance therapy of a daily tablet 3x per week for another 8 weeks. The secondary objective was to evaluate clinical symptoms, changes in vaginal pH, epithelium and microflora. Patients were assessed 6 times for endpoints. Blood was taken pre-insertion (baseline samples) at study entry, week 2, 4, 8, 12. At entry and week 4, multiple PK blood samples were drawn 0.5 hours pre-insertion and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-insertion. Serum samples were assayed by highly sensitive GC/MS. Results: The interim results of 8 of 16 enrolled patients who have completed the 12 week study period are presented. Basline estrogen concentrations of all women were below the levels of quantitation (E3: < 10–20 pg/ml; E2: < 1 pg/ml; E1: < 2 pg/ml). After first insertion, E3 serum levels transiently increased in 7 of 8 women; the single maximum concentration of all women was 132 pg/ml and highest levels (12–132 pg/ml) were observed usually 3 hours post-insertion. After 4 weeks of daily application, PK results showed an increase in E3 levels as compared to baseline in only 5 of 8 women. In addition, the single maximum concentration of all women was lower, 44 pg/ml, which was only reached after 8 hours. The baseline E3 concentrations did not change over the complete period of 12 weeks and were in the range of the limit of quantitation. The serum concentrations of E2 and E1 did not increase at any time point in any of the women. Clinical symptoms, vaginal pH and maturation index improved already after 2 weeks of therapy. Global efficacy and tolerability were rated by the investigators in at least 75% of the cases as (very) good, and by at least 87.5 % of the women. No serious adverse events were observed. Conclusions: Gynoflor® vaginal tablet is an effective and safe option to treat vaginal atrophy in PM patients with early BC on AI. Our data showed only a transient increase in E3 serum concentration after first application, and this increase was lower after 4 weeks. Baseline E3 concentrations did not increase demonstrating that no accumulation occurred. Serum E2 and E1 concentrations did not change and were always below limit of quantitation. The clinical significance of transient vaginal E3 absorption is unknown, however the absence of elevated E2 and E1 serum levels is compatible with the desired effect for BC patients taking an AI. *The first and second author have shared first authorship. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-06.

Treatment of colon cancer with an antagonist of growth hormone-releasing hormone (GHRH), JMR-132, results in a cell cycle arrest in S-phase of the tumor cells. Thus, we investigated the effect of JMR-132 in combination with S-phase-specific cytotoxic agents, 5-FU, irinotecan and cisplatin on the in vitro and in vivo growth of HT-29, HCT-116 and HCT-15 human colon cancer cell lines. In vitro, every compound inhibited proliferation of HCT-116 cells in a dose-dependent manner. Treatment with JMR-132 (5 μM) combined with 5-FU (1.25 μM), irinotecan (1.25 μM) or cisplatin (1.25 μM) resulted in an additive growth inhibition of HCT-116 cells in vitro as shown by MTS assay. Cell cycle analyses revealed that treatment of HCT-116 cells with JMR-132 was accompanied by a cell cycle arrest in S-phase. Combination treatment using JMR-132 plus a cytotoxic drug led to a significant increase of the sub-G1 fraction, suggesting apoptosis. In vivo, daily treatment with GHRH antagonist JMR-132 decreased the tumor volume by 40–55% (p < 0.001) of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice. Combined treatment with JMR-132 plus chemotherapeutic agents 5-FU, irinotecan or cisplatin resulted in an additive tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts to 56–85%. Our observations indicate that JMR-132 enhances the antiproliferative effect of S-phase-specific cytotoxic drugs by causing accumulation of tumor cells in S-phase.