Avoiding Axillary Sentinel Lymph Node Biopsy after Neoadjuvant Systemic Therapy in Breast Cancer: Rationale for the Prospective, Multicentric EUBREAST-01 Trial.

Currently, axillary surgery for breast cancer is considered only as staging procedure, since the risk of developing metastasis depends on the biological behavior of the primary. The postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement. Improvements in systemic treatments for breast cancer have increased the rates of pathologic complete response (pCR) in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to de-escalate surgery in patients who have a pCR. European Breast Cancer Research Association of Surgical Trialists (EUBREAST)-01 is a clinical trial in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included and type of surgery will be defined according to the response to NAST rather than on the classical T (for tumor size in the breast) and N (for axillary lymph node involvement) status. In the discussed trial, axillary surgery will be eliminated completely (no axillary sentinel lymph node biopsy) for initially clinical node-negative (cN0) patients with radiologic complete remission and a breast pCR in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (n = 267), which might give practice-changing results in a short period of time, sparing the time and the costs of a randomized comparison.

Dynamic Adjustments of Parenteral Support in Early Adult Intestinal Failure-Essential Role of Sodium.

Intestinal failure (IF) requires parenteral support (PS) substituting energy, water, and electrolytes to compensate intestinal losses and replenish deficits. Convalescence, adaptation, and reconstructive surgery facilitate PS reduction. We analyzed the effect of changes of PS on body mass index (BMI) in early adult IF. Energy, volume, and sodium content of PS and BMI were collected at the initial contact (FIRST), the time of maximal PS and BMI (MAX) and the last contact (LAST). Patients were categorized based on functional anatomy: small bowel enterostomy-group 1, jejuno-colic anastomosis-group 2. Analysis of variance was used to test the relative impact of changes in energy, volume, or sodium. Total of 50 patients were followed for 596 days. Although energy, volume, and sodium support were already high at FIRST, we increased PS to MAX, which was accompanied by a significant BMI increase. Thereafter PS could be reduced significantly, leading to a small BMI decrease in group 1, but not in group 2. Increased sodium support had a stronger impact on BMI than energy or volume. Total of 13 patients were weaned. Dynamic PS adjustments are required in the early phase of adult IF. Vigorous sodium support acts as an independent factor.

Validation of a Novel Clinical Score: The Rostock Functional and Cosmetic Cranioplasty Score.

With a rising number of cranioplasty (CP) procedures and an increasing percentage of patients with a good clinical outcome and prolonged survival after CP, looking at the functional and aesthetic outcome of these patients becomes more and more important. The aim of our study was to evaluate a novel score, combining functional and cosmetics aspects after CP, created at our institution: the Rostock Functional and Cosmetic Cranioplasty (RFCC-) Score. A total of 27 patients were enrolled, representing all indications for a secondary CP after decompressive craniectomy or extended temporal trephination with a complete separation of the temporalis muscle. Besides the clinical evaluation, five different already established clinical rating systems were tested and compared with our score. For reasons of objectivity, the score was also tested against the patient's own rating. Our findings showed that the RFCC-Score, derived from a health professional, is superior to other scoring systems, which only display a facet of the functional state of the patient. Our score is objective and independent of a disposition for a depression of the patient. It can be obtained without the need of a verbal communication, making it applicable for nearly all patients after CP. The score is time-saving, clearly arranged, and reliable, which are inevitable requirements for the comparing and evaluation of different surgical techniques and associated complications of CP.

Expression and clinicopathological correlations of retinoid acid receptor responder protein 1 in renal cell carcinomas.

AIM: To evaluate the expression and prognostic value of RARRES1 at protein level in renal cell carcinoma (RCC). MATERIALS & METHODS: Expression profile of RARRES1 was analyzed in 903 documented RCC followed by clinicopathological correlations and survival analysis. RESULTS: RARRES1 expression was seen in 72.5% of RCC. A stronger RARRES1 expression was seen in high grade compared with low grade RCC (p < 0.001). Logrank tests revealed shorter overall survival in RARRES1 positive RCC (p = 0.006) and in pT1/2 tumors with RARRES1 expression (p = 0.002). CONCLUSION: The variable expression profile in low and high grade RCC may reflect and confirm the differences of previous gene expression analysis. There was a significant prognostic value of RARRES1 expression in patients with RCC, especially in pT1/2 tumors.

Reduction of radiation exposure during ablation of atrial fibrillation.

AIMS: Pulmonary vein isolation (PVI) during ablation of atrial fibrillation (Afib) may be associated with long fluoroscopy duration. Although most current publications report on fluoroscopy time (FT), the dose-area product (DAP) may be a more valuable parameter for depicting radiation exposure. The aim of our study was to describe a method to reduce DAP by simple means during ablation of Afib. METHODS: Patients undergoing Afib ablation using a three-dimensional (3D) mapping system were assigned to two fluoroscopy protocols: (1) standard settings with 7.5 pictures/s and collimation to the heart, fluoroscopy as needed for the convenience of the operator (standard group, SG); and (2) strict collimation to the left atrium, a frame rate of 4 pictures/s, shortened pulmonary vein angiography sequences, and maximal orientation by the 3D mapping system (redDAP group). The primary endpoint was DAP. RESULTS: The study comprised 206 patients, who were assigned to the SG (n = 101, 49 %) or to the redDAP group (n = 105, 51 %). Mean FT was significantly reduced from 29.9 ± 11.3 min (SG) to 13.3 ± 8.3 min (redDAP group); mean DAP was reduced by approximately 90 % from 8,690 ± 5,727 to 837 ± 647 cGycm(2). The groups did not differ significantly in body mass index (28.8 ± 4.1 vs. 29.0 ± 5.0). PVI could be achieved in 98 of 101 patients (97 %) from the SG group and in all patients (100 %) from the redDAP group. Procedure time was significantly longer in the redDAP group (160.9 ± 35.7 vs. 138.1 ± 34.3 min). CONCLUSION: Radiation exposure during Afib ablation procedures can be reduced with simple means by strict collimation to the left atrium, a frame rate of 4 pictures/s, shortened pulmonary vein angiography sequences, and maximal 3D orientation.

Conditioning with treosulfan and fludarabine for patients with refractory or relapsed non-Hodgkin lymphoma.

The treatment of refractory or relapsed non-Hodgkin lymphoma (NHL) remains challenging. In this retrospective study, 88 patients with refractory or relapsed NHL received treosulfan and fludarabine as a reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Of the 88 intensely pre-treated patients, 73 experienced a relapse, with 18 of the 88 patients experiencing an early relapse (ER; <6 months from the last chemotherapy). At the time of allo-HSCT, 26 patients were in complete remission (CR) and 43 in partial remission (PR), 12 patients had progressive disease (PD) and 7 had stable disease (SD). A total of 47 patients received an autologous graft followed by allo-HSCT. Following allo-HSCT, 69 of the 88 patients were in CR and 7 were in PR, resulting in an overall response rate of 86.4% (76/88). A total of 33 patients achieved a CR from PR, as did 6 patients from PD and 5 from SD. Of the 88 patients, 43 (49%) were alive at the end of the follow-up period. The patients who directly underwent allo-HSCT without prior auto-HSCT exhibited a better disease-free survival (DFS; P=0.038) with a tendency (P=0.077) for a better overall survival (OS). The patients with ER exhibited a probability of OS of 0.35±0.12 after 3 and 7 years. Chronic graft-versus-host disease (cGvHD) exerted a positive effect on OS and DFS (for limited cGvHD vs. no cGvHD, P=0.002 and 0.004, respectively). In conclusion, allogeneic stem cell transplantation following conditioning with treosufan and fludarabine constitutes a viable therapeutic option for patients with refractory or relapsed NHL and should be considered early during the course of salvage treatment.

Hybrid aortic arch repair for complicated type B aortic dissection.

OBJECTIVE: This study analyzed the outcome of a combined endovascular and debranching procedure for hybrid aortic arch repair (HAR) in patients with complicated type B aortic dissection. METHODS: Between February 2006 and August 2012, HAR was performed in 75 consecutive patients, with retrospective analysis of a subgroup of 45 patients who underwent HAR with complicated acute (n = 10), subacute (n = 7), or chronic (n = 28) type B dissection as the underlying disease. Descriptive statistics were computed for continuous and categoric variables. The interval to death or last follow-up was estimated using the Kaplan-Meier method. RESULTS: The patients were a mean age of 59.9 ± 10.7 years (median, 59.2; range, 35-78 years). Complete supra-aortic debranching was performed in six (13%) in zone 0 (procedure time, 200 minutes; range, 185-365 minutes) and partial debranching in 39 (87%), comprising 16 (36%) in zone 1 (procedure time, 120 minutes; range, 75-250 minutes) and 23 (51%) in zone 2 (procedure time, 91 minutes; range, 70-210 minutes). Technical success was achieved in 86.7% (39 of 45). Thirty-day mortality was 4.4% (two of 45), with an in-hospital mortality of 11.1% (five of 45) as a result of three additional deaths after days 33, 35, and 111. Comparing HAR for type B dissection after complete debranching in six and partial debranching in 39, the overall in-hospital mortality was 67% (four of six) and 2.6% (one of 39), respectively. After a median follow-up of 20.8 months (range, 0.3-70 months), the overall mortality was 13.3% (six of 45), with Kaplan-Meier survival estimate of 85% at 1 year. Stroke rate was 8.8% (four of 45). Paraplegia developed in one patient (2.2%), with complete recovery after spinal drainage. Cardiac complications occurred in three patients (6.7%), pulmonary complications in 10 (22.2%), and renal insufficiency requiring dialysis developed in five (11%). Retrograde dissection occurred in one patient (2.2%) 14 days after complete debranching and zone 0 thoracic endovascular aortic repair, with fatal outcome. No bypass dysfunction was seen during follow-up. The overall early and late endoleak rates were 27% (12 of 44) and 43% (13 of 30), respectively. Eight patients (18%) required reintervention, with freedom of reintervention in 91% at 1 year and 81% at 2 years. CONCLUSIONS: HAR in zone 1 and 2 appears a viable alternative to conventional aortic arch surgery in patients with complicated type B dissection. Stroke and endoleaks remain complications that need to be addressed. Treatment of type B aortic dissection with complete supra-aortic debranching and thoracic endovascular aortic repair in zone 0, however, is associated with high mortality, which might be reduced by improved technology using branched stent grafts.

The dual kinase inhibitor NVP-BEZ235 in combination with cytotoxic drugs exerts anti-proliferative activity towards acute lymphoblastic leukemia cells.

BACKGROUND: Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches. MATERIALS AND METHODS: ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa). RESULTS: NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells. CONCLUSION: NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.

Impact of preoperative left ventricular function and time from infarction on the long-term benefits after intramyocardial CD133(+) bone marrow stem cell transplant.

OBJECTIVE: Our objective was to elucidate long-term clinical and functional effects of intramyocardial stem cell transplant and to identify patients who will show sustained benefit. METHODS: Long-term outcomes of 35 patients after intramyocardial CD133(+) bone marrow stem cell transplant during coronary artery bypass grafting were compared with those of a control group of 20 patients after coronary artery bypass grafting alone. Clinical effects were assessed with the New York Heart Association classification system and the Minnesota Living With Heart Failure questionnaire. Electrocardiography, 24-hour Holter monitoring, echocardiography, myocardial perfusion scanning, magnetic resonance imaging, and computed tomography were performed. Logistic regression analyses were used to identify prognostic factors for improvement in long-term left ventricular ejection fraction after stem cell treatment. RESULTS: The stem cell group revealed similar New York Heart Association and life quality scores to the control group. Myocardial perfusion score at the area of risk was significantly increased in the stem cell group after 36-month follow-up (P = .024 vs control). Multivariate logistic regression analysis revealed a 44-fold higher probability of at least 5% improvement in left ventricular ejection fraction for patients with preoperative left ventricular ejection fraction not greater than 40% than for patients with preoperative ejection fraction greater than 40% (P = .018). Furthermore, patients operated on between 7 and 12 weeks after myocardial infarction had a 56-fold higher chance of at least 5% improvement in left ventricular ejection fraction than patients treated later than 12 weeks after infarction (P = .023). CONCLUSIONS: Intramyocardial stem cell therapy was safe but lacked significant lasting benefits beyond 6 months in our study cohort with a limited number of patients. Preoperative left ventricular ejection fraction and time since myocardial infarction may be critical parameters for selection of patients who can benefit most from intramyocardial stem cell treatment during coronary artery bypass grafting.

Intramyocardial bone marrow stem cell transplantation during coronary artery bypass surgery: a meta-analysis.

OBJECTIVE: Experimental and clinical studies have suggested that intramyocardial bone marrow stem cell transplantation combined with coronary artery bypass grafting might improve left ventricular function in the setting of chronic ischemic heart disease. We therefore conducted a systematic review and meta-analysis of available publications regarding the efficacy and safety of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting. METHODS: The databases PUBMED, MEDLINE, Cochrane Controlled Trials Register, and ClinicalTrials.gov (all from their inception to May 2009) were searched for randomized controlled trials and cohort studies of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting to treat ischemic heart disease. Six studies were included. RESULTS: Compared with control groups, the bone marrow stem cell transplantation group showed a significant improvement of left ventricular ejection fraction from baseline to follow-up (5.40%; 95% confidence interval, 1.36-9.44; P = .009). Moreover, the overall change of left ventricular end-diastolic volume from baseline to follow-up favored the bone marrow stem cell therapy group (9.55 mL; 95% confidence interval, -2.82 to 21.92; P = .13). Major adverse cardiovascular events, including ventricular arrhythmia and the composite of other cardiovascular events, were not significantly different between the bone marrow stem cell therapy group and controls (relative risk for ventricular arrhythmia = 0.951; 95% confidence interval, 0.389-2.325; P = .913; relative risk for cardiovascular event = 1.134; 95% confidence interval, 0.28-4.6; P = .86). CONCLUSIONS: Clinical evidence suggests that intramyocardial bone marrow stem cell transplantation in combination with coronary artery bypass grafting is associated with improvements of functional parameters in patients with chronic ischemic heart disease. Furthermore, surgical intramyocardial bone marrow stem cell transplantation seems to be safe.

Autologous valve replacement-CD133+ stem cell-plus-fibrin composite-based sprayed cell seeding for intraoperative heart valve tissue engineering.

OBJECTIVE: The development of biological valve prostheses with lifetime native-like performance and optimal host engraftment is an ultimate goal of heart valve tissue engineering. We describe a new concept for autologous graft coating based on a CD133(+)-stem-cells-plus-fibrin (SC+F) complex processed from bone marrow and peripheral blood of a single patient. METHODS: CD133(+)-SC (1 × 10(6) cells/mL) from human bone marrow and autologous fibrin (20 mg/mL) were administered simultaneously via spray administration using the novel Vivostat Co-Delivery System. During static cultivation, SC+F performance was monitored for 20 days after delivery and compared with controls. For dynamic testing SC+F-composite was sprayed on a decellularized porcine pulmonary valve and transferred to a bioreactor under pulsatile flow conditions for 7 days. RESULTS: Static cultivation of SC+F-composite induced significant improvements in stem cell proliferation as compared with controls. For dynamic testing, microscopic analyses on a smooth engineered heart valve surface detected homogenous distribution of stem cells. Ultrasonic analysis revealed native-like valve performance. Applied CD133(+) stem cells differentiated into endothelial-like cells positive for CD31 and vascular endothelial growth factor receptor 2 and engrafted the valve. However, occasional delamination was observed. CONCLUSION: SC+F serves as an excellent autologous matrix for intraoperative tissue engineering of valve prostheses promising optimal in vivo integration. However, stability remains an issue.

The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells.

BACKGROUND: Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. METHODS: ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. RESULTS: Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. CONCLUSION: Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells.