Delivery of the second twin: influence of presentation on neonatal outcome, a case controlled study.

BACKGROUND: Spontaneous vaginal twin delivery after 32nd week of gestation is safe when first twin presenting cephalic. Aim of this study is to identify obstetric factors influencing the condition of second twin and to verify whether non-cephalic presentation and vaginal breech delivery of the second twin is safe. METHODS: This is a retrospective case controlled cohort study of 717 uncomplicated twin deliveries ≥32 + 0 weeks of gestation from 2005 to 2014 in two tertiary perinatal centers. Obstetric parameters were evaluated in three groups with descriptive, univariate logistic regression analysis for perinatal outcome of second twins. RESULTS: The three groups included twins delivered by elective cesarean section ECS (n = 277, 38.6%), by unplanned cesarean section UPC (n = 233, 32.5%) and vaginally (n = 207, 28.9%). Serious adverse fetal outcome is rare and we found no differences between the groups. Second twins after ECS had significant better umbilical artery UA pH (p < 0.001) and better Apgar compared to UPC (p = 0.002). Variables for a fetal population "at risk" for adverse neonatal outcome after vaginal delivery (UA pH < 7.20, Apgar 5´ < 9) were associated with higher gestational age (p = 0.001), longer twin-twin interval (p = 0.05) and vacuum extraction of twin A (p = 0.04). Non-cephalic presentation of second twins was not associated (UA pH < 7.20 OR 1.97, CI 95% 0.93-4.22, p = 0.07, Apgar 5´ < 9 OR 1.63, CI 95% 0.70-3.77, p = 0.25, Transfer to neonatal intermediate care unit p = 0.48). Twenty-one second twins (2,9%) were delivered by cesarean section following vaginal delivery of the first twin. Even though non-cephalic presentation was overrepresented in this subgroup, outcome variables were not significantly different compared to cephalic presentation. CONCLUSIONS: Even though elective cesarean means reduced stress for second twins this seems not to be clinically relevant. Non-cephalic presentation of the second twin does not significantly influence the perinatal outcome of the second twin but might be a risk factor for vaginal-cesarean birth.

European cost-effectiveness study of uPA/PAI-1 biomarkers to guide adjuvant chemotherapy decisions in breast cancer.

BACKGROUND: This study investigated the cost effectiveness of guideline-recommended (American Society of Clinical Oncology, European Society of Medical Oncology) urokinase plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) biomarkers to guide adjuvant chemotherapy decisions for hormone receptor-positive, node-negative early breast cancer patients at intermediate risk of relapse, in France, Germany, and The Netherlands. METHODS: uPA/PAI-1 testing was compared to chemotherapy for all patients and to no chemotherapy in two age-related subgroups (35-49 and 50-75 years). A partitioned survival analysis was performed using patient-level data for survival outcomes and secondary sources. Mean quality-adjusted life years (QALYs) and costs were estimated over a lifetime horizon to calculate the incremental net monetary benefit (INMB) at a willingness-to-pay of €50,000/QALY. Uncertainty was explored through bootstrap and probabilistic sensitivity analysis using 5000 replicates. RESULTS: In the 35-49 year age group, INMBs were negative when uPA/PAI-1 testing was compared to chemotherapy for all patients but positive when it was compared to no chemotherapy for the three countries. In the 50-75 year age group, INMBs of uPA/PAI-1 testing compared to both reference strategies were positive in the three countries, with cost-effectiveness probabilities for the uPA/PAI-1 strategy of 65%, 70%, and 59% for France, Germany, and the Netherlands, respectively, compared with chemotherapy for all patients, and 64%, 58%, and 65%, respectively, compared with no chemotherapy. CONCLUSIONS: uPA/PAI-1 testing could allow the selection of patients older than 50 years requiring chemotherapy in this population, but the cost effectiveness of this strategy is uncertain. Chemotherapy for all patients is the most cost-effective strategy for patients younger than 50 years.

Concordance rates of biomarkers uPA and PAI-1 results in primary breast cancer vs. consecutive tumor board decision and therapy performed in clinical hospital routine: Results of a prospective multi-center study at certified breast centers.

OBJECTIVE: Biomarkers uPA and PAI-1 are guideline recommended by ASCO (USA) and AGO (Germany) in primary breast cancer to avoid unnecessary CTX in patients at medium risk for recurrence. For clinical quality assurance of uPA/PAI-1 testing, analysis of test-therapy concordance was performed. METHODS: Prospective non-interventional multi-center study over 2 years among six Certified Breast Centers in Germany to investigate uPA/PAI-1 results in consecutive decision making for tumor board recommendation and actual therapy in uninfluenced clinical setting. Concordance and discordance rates of uPA/PAI-1 testing were calculated and individual reasons for decision making analyzed. RESULTS: Among n = 93 uPA/PAI-1 tests evaluated n = 42/93 (45.2%) were uPA + PAI-1 negative and n = 51/93 (54.8%) uPA and/or PAI-1 positive. In uPA + PAI-1 negative test results in n = 35/42 (83.3%) CTX was avoided as recommended. But in n = 7/42 (16.7%) CTX was performed despite, resulting in over treatment. In uPA and/or PAI-1 positive test results in n = 26/51 (51.0%) CTX was performed but in n = 25/51 (49.0%) not despite recommendation for CTX which is under treatment. The conformity of uPA/PAI-1 test result vs. tumor board decision was n = 73/93 (78.5%). The overall concordance of uPA/PAI-1 test result vs. consecutive therapy was n = 61/93 (65.6%). A variety of reasons for individual result-deviating decisions were identified. CONCLUSIONS: Clinical quality assurance of uPA/PAI-1 biomarker testing showed inconsistency of test results with consecutive tumor board decision and/or final therapy performed in up to 1/3 of patients. To close this clinical quality gap in application of uPA/PAI-1 biomarkers, individual analysis of deviations is suggested with process optimization accordingly.

Mesonephric adenocarcinoma of the vagina : Diagnosis and multimodal treatment of a rare tumor and analysis of worldwide experience.

BACKGROUND: Mesonephric adenocarcinoma of the vagina is an extremely rare tumor of the female genital tract, with only a few cases reported so far worldwide. Consequently, there is no established standard treatment and limited knowledge about the prognosis and biologic behavior of vaginal mesonephric adenocarcinoma. METHODS: This report documents a new case of vaginal mesonephric adenocarcinoma diagnosed in a 54-year-old woman, and analyzes this in the context of all previously published cases. RESULTS: MRI demonstrated that the 2.5 × 1.8 cm tumor of the vaginal wall was invading urethra and bladder. Following surgical excision, histologic analysis determined mesonephric adenocarcinoma of the vagina, stage pT2 R1. In order to avoid the mutilating extended surgery which would be required to reach R0 and considerable impairment of quality of life, adjuvant radiochemotherapy was administered with external radiation and brachytherapy, including 5 cycles of cisplatin (40 mg/m²) for radiosensitization. After 4 years of continuous oncologic follow-up, the patient is alive and clinically free of disease. CONCLUSION: In this case it was shown that adjuvant radiochemotherapy with radiation and brachytherapy was effective to manage the surgical R1 situation and maintain the patient's life quality. More published cases reports are needed to gradually substantiate optimal treatment strategies.

Mechanical fibrinogen-depletion supports heparin-free mesenchymal stem cell propagation in human platelet lysate.

BACKGROUND: Pooled human platelet lysate (pHPL) is an efficient alternative to xenogenic supplements for ex vivo expansion of mesenchymal stem cells (MSCs) in clinical studies. Currently, porcine heparin is used in pHPL-supplemented medium to prevent clotting due to plasmatic coagulation factors. We therefore searched for an efficient and reproducible medium preparation method that avoids clot formation while omitting animal-derived heparin. METHODS: We established a protocol to deplete fibrinogen by clotting of pHPL in medium, subsequent mechanical hydrogel disruption and removal of the fibrin pellet. After primary culture, bone-marrow and umbilical cord derived MSCs were tested for surface markers by flow cytometry and for trilineage differentiation capacity. Proliferation and clonogenicity were analyzed for three passages. RESULTS: The proposed clotting procedure reduced fibrinogen more than 1000-fold, while a volume recovery of 99.5 % was obtained. All MSC types were propagated in standard and fibrinogen-depleted medium. Flow cytometric phenotype profiles and adipogenic, osteogenic and chondrogenic differentiation potential in vitro were independent of MSC-source or medium type. Enhanced proliferation of MSCs was observed in the absence of fibrinogen but presence of heparin compared to standard medium. Interestingly, this proliferative response to heparin was not detected after an initial contact with fibrinogen during the isolation procedure. CONCLUSIONS: Here, we present an efficient, reproducible and economical method in compliance to good manufacturing practice for the preparation of MSC media avoiding xenogenic components and suitable for clinical studies.

Breech delivery in the all fours position: a prospective observational comparative study with classic assistance.

OBJECTIVE: Vaginal delivery of fetal breech presentation is considered to be a challenge for obstetricians. The purpose of this study was to show that vaginal delivery in all fours position is feasible and safe for mother and child compared with vaginal breech and classic support. METHODS: A single-center prospective observational case series of breech delivery (n=41) in all fours position was compared to a retrospective cohort of breech deliveries in the form of a matched-pair analysis. RESULTS: Deliveries in the all fours position successfully took place without obstetric intervention in 70.7% of deliveries (n=29/41), and those including intervention in 90.2% (n=37/41). The rate of maternal perineal injuries was reduced (14.6% vs. 58.5%, P<0.001). Newborns delivered in all fours position had increased prenatal hypoxic stress with a pH of 7.19 [95% confidence interval (CI) 7.16-7.22] vs. a pH of 7.24 (95% CI 7.21-7.27; P=0.016). With n=24 vs. n=16, a higher number of newborns had a pH of <7.20 (P=0.03) and decreased base excess of -7.2 mmol/L (95% CI -8.2-6.2) vs. -4.8 mmol/L (95% CI -5.7-4.0; P<0.001). However, this had no clinical consequences for the newborns (5 min Apgar score <9: n=5 vs. n=4, not significant; transfer rate to neonatal intensive care unit n=7 vs. n=6, not significant). CONCLUSION: This is the first clinical evaluation of breech delivery in the all fours position. It is a feasible non-interventional obstetric delivery method. It seems to be safe for the fetus with reduced maternal morbidity. Vaginal delivery of fetal breech presentation, even in the all fours position, creates stress for the newborn.

Local foreign body reaction of peritoneum after rupture of cystic partially immature teratoma.

This is a pictorial report of rare sequelae after an unintended intraoperative rupture of a cystic teratoma. A 30-year-old woman was operated on for a mature cystic teratoma of the right ovary with an unintended intraoperative rupture of the ovarian tumor during the procedure. Postoperatively, the final immune histologic report showed partial neuroendocrine differentiation of an immature origin. At relaparoscopy for staging 7 weeks later, several suspicious peritoneal lesions of up to a 2.5-cm diameter were discovered and excised for which malignancy could not be excluded macroscopically. However, the final histologic report revealed a foreign body reaction related to spilling of the content of the mature teratoma. It is important to distinguish local peritoneal reaction from chemical peritonitis. The postoperative follow-up regarding symptomatic recurrence was uneventful.

Comparison of fetal outcome in premature vaginal or cesarean breech delivery at 24-37 gestational weeks.

PURPOSE: To compare the fetal outcome of preterm breech infants delivered vaginally (VD) or by cesarean section (CS). METHODS: A monocentric, retrospective consecutive case series of preterm breech deliveries between 24-37 gestational weeks over 10 years from 1/2000 to 12/2009 was performed in a perinatal care center (Level 1) at the University Clinic of Salzburg, Austria. Data from hospital database were statistically analyzed and compared regarding birth weight, head circumference, parity, transfer rate to neonatal intensive care unit (NICU), arterial and venous cord blood pH and base excess (BE), arterial cord blood pH ≤ 7.10 and BE ≤ -11. Special focus was on fetal outcome of elective CS preterm breech deliveries with a non-urgent medical indication compared to VD. RESULTS: Among 22.115 deliveries, there were 346 live-born preterm singletons and twins in breech presentation (1.56 %), born between 24 + 0 and 37 + 0 gestational weeks. 180 CS and 36 vaginally delivered preterm breech infants were statistically evaluated. On comparing CS vs. VD for premature breech singletons, arterial cord blood pH and BE were lower in the VD group. VD twins had a lower arterial cord blood pH than CS twins. All other parameters were comparable. In preterm breech singletons with non-urgent CS, a statistical analysis was not possible due to small numbers. The VD twin group revealed lower values in birth weight, head circumference, arterial cord blood pH and BE, but no significant difference in venous cord blood pH and BE and transfer rate to NICU. CONCLUSIONS: Although general recommendations regarding a superior mode of delivery for improved fetal outcome of preterm breech infants cannot be given, these data do not support a policy of routine CS.

Prospective multi-center study for quantification of chemotherapies and CTX-related direct medication costs avoided by use of biomarkers uPA and PAI-1 in primary breast cancer.

Biomarkers uPA/PAI-1 as recommended by ASCO and AGO are used in primary breast cancer to avoid unnecessary CTX in medium risk-recurrence patients. This study verified how many CTX cycles and CTX-related direct medication costs can be avoided by uPA/PAI-1 testing. A prospective, non-interventional, multi-center study was performed among six Certified Breast Centers to analyze application of uPA/PAI-1 and consecutive decision-making. CTX avoided were identified and direct costs for CTX, CTX-related concomitant medication and febrile neutropenia (FN) prophylaxis with G-CSF calculated. In n = 93 breast cancers n = 35 CTX (37.6%) with 210 CTX cycles were avoided according to uPA/PAI-1 test result. uPA/PAI-1 testing saved direct medication costs for CTX of 177,453 €, CTX-related concomitant medication of 27,482 € and FN prophylaxis of 20,599 €, overall 225,534 €. At test costs at 287.50 € uPA/PAI-1 testing resulted in additional costs of 26,737.50 €. uPA/PAI-1 has proven to be cost-effective at a return-on-investment ratio of 8.4:1. Indirect cost savings further increase this ROI. These results support decision-making for cost-effective diagnostics and therapy in breast cancer.

Health economic impact of risk group selection according to ASCO-recommended biomarkers uPA/PAI-1 in node-negative primary breast cancer.

Invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy (CTX) in women with primary breast cancer. They define a high-risk group with strong benefit from adjuvant CTX and a low-risk group with uncertain benefit and excellent survival without CTX. In a target population (age > 35/N0/G2/HR+/HER2-), administration of adjuvant CTX is not mandatory in Germany and other countries. Based on existing data, this economic model was developed to determine for the first time health economic impact of uPA/PAI-1 testing. Incremental cost-effectiveness ratio (ICER) resulting from uPA/PAI-1 testing was estimated for the target population by Markov modeling and sensitivity analysis. Survival data, CTX-uPA/PAI-1 interactions, and uPA/PAI-1 hazard ratios were derived from the Chemo N0 trial and other evidence. Incremental costs were computed from a payer's perspective appropriate to the German setting. Incremental effectiveness in life years (ly) was estimated taking into account age-adjusted life expectancy, disease-free survival (with/without CTX), and 2 years post-relapse survival. Sensitivity analysis was performed by varying residual adjuvant CTX benefit in the low-risk group, denoted HR_CTX(LR), in range 0.8-0.99. All patients receive adjuvant endocrine therapy. Test is restricted to patients willing to forgo CTX if both markers are below specific cut-off values and to undergo CTX otherwise. For a typical 55-year-old patient, comparing to an "all-CTX" strategy without the test, ICER (all-CTX vs. test) > 50,000 if HR_CTX(LR) > 0.85, with savings of 18,500 per low-risk patient attributable to the test. The cost-effectiveness of forgoing CTX is very high as HR_CTX(LR) approaches one. Conversely, comparing to a "no-CTX" strategy (e.g., patients who initially refuse CTX) without the test, the test is very cost-effective at all ages in the target group if high-risk patients are willing to undergo CTX: ICER (test vs. no-CTX) < 6,000 at age 55 and even better at younger ages, remaining < 25,000 up to age 75. The main determinants of cost utility are age and residual CTX benefit in low-uPA/PAI-1 patients. The uPA/PAI-1 test is cost-effective in the target group compared to either an "all-CTX" or a "no-CTX" scenario. This model thus lends health economic support to current guideline recommendations that uPA/PAI-1 testing is beneficial for BC patients with no lymph node involvement.

AAGL Practice Report: Practice Guidelines for the Management of Hysteroscopic Distending Media: (Replaces Hysteroscopic Fluid Monitoring Guidelines. J Am Assoc Gynecol Laparosc. 2000;7:167-168.).

The objective of this guideline is to provide clinicians with evidence-based information about commonly used and available hysteroscopic distending media to guide them in their performance of both diagnostic and operative hysteroscopy. While necessary for the performance of hysteroscopy and hysteroscopically-directed procedures, distending media, if absorbed systemically in sufficient amounts, can have associated adverse events, including life-threatening complications. Consequently, understanding the physical properties and the potential risks associated with the use of the various distending media is critical for the safe performance of hysteroscopic procedures. This report was developed under the direction of the Practice Committee of the AAGL as a service to their members and other practicing clinicians.

Relevance of health economics in breast cancer treatment: integration of economics in the management of breast cancer at the clinic level.

Since the introduction of the diagnosis-related groups (DRG) system with cost-related and entity-specific flat-rate reimbursements for all in-patients in 2004 in Germany, economics have become an important focus in medical care, including breast centers. Since then, physicians and hospitals have had to gradually take on more and more financial responsibilities for their medical care to avoid losses for their institutions. Due to financial limitations of resources, most medical services have to be adjusted to correlating revenues, which results in the development of a variety of active measures to understand, steer, and optimize costs, resources and related processes for breast cancer treatment. In this review, the challenging task to implement microeconomic management at the clinic level for breast cancer treatment is analyzed from breast cancer-specific publications. The newly developed economic management perspective is identified for different stakeholders in the healthcare system, and successful microeconomic projects and future aspects are described.

A pragmatic guide on how physicians can take over financial control of their clinical practice.

Control of clinical cost is becoming increasingly important in health care worldwide. Physicians should accept the limitation of resources and take responsibility to improve their clinical cost-reimbursement ratio. To achieve this, they will need basic education in clinic management to control and adjust costs and reimbursement, without impacting professional quality of care. Rational use of diagnostics and therapy should be implemented and frequently verified. Physicians are the only professionals that are able to integrate economics with health care. This is in the best interest of patients and will improve a physician's position, influence, and professional freedom levels within our hospitals.

Comparison of actual hospital costs versus DRG revenues for in-patient treatment of febrile neutropenia during adjuvant anthracycline plus/minus taxane-based chemotherapy for primary breast cancer.

BACKGROUND: In flat-rate reimbursement systems, the hospital's own costs should not exceed its revenues. In a cohort of primary breast cancer (pBC) patients, costs and reimbursement for febrile neutropenia (FN) were compared to verify cost coverage. METHODS: A prospective, observational study in pBC patients receiving adjuvant anthracycline ± taxane-based chemotherapy calculated the costs per in-patient FN episode. The correlating revenues were retrospectively analyzed from diagnosis-related group (DRG) invoices. The actual costs of the therapies were compared to the individual DRG revenues, and the results are presented from the provider's perspective. RESULTS: In 50 patients, n = 11 patients were treated for FN as in-patients. The hospital's overall treatment costs were € 18,288, on average (Ø) € 1663 per case (range € 1139-2344); the overall DRG revenues were € 23,593, Ø € 2145 per case (range € 1266-2660). In n = 8 cases, the DRGs were cost covering, and in n = 3 cases, a loss was observed, but overall resulting in a gain of Ø € 482 per case and thus being cost covering for the provider. Inadequate DRG coding (n = 4/11; 36.4%) resulted in a preventable loss of Ø € 1069/case. CONCLUSIONS: The costs of FN treatment vary substantially and DRG reimbursements do not necessarily reflect the provider's costs. Surprisingly, the in-patient treatment of FN here is overall more than cost covering if adequately coded. The main reasons are asymmetrical costs for this FN low-risk pBC group. These results emphasize the importance of correct medical coding to avoid potential losses.

Financial Quality Control of In-Patient Chemotherapy in Germany: Are Additional Payments Cost-Covering for Pharmaco-Oncological Expenses?

SUMMARY: BACKGROUND: Cost-covering in-patient care is increasingly important for hospital providers in Germany, especially with regard to expensive oncological pharmaceuticals. Additional payments (Zusatzentgelte; ZE) on top of flat rate diagnose-related group (DRG) reimbursement can be claimed by hospitals for in-patient use of selected medications. To verify cost coverage of in-patient chemotherapies, the costs of medication were compared to their revenues. METHOD: From January to June 2010, a retrospective cost-revenue study was performed at a German obstetrics/gynecology university clinic. The hospital's pharmacy list of inpatient oncological therapies for breast and gynecological cancer was checked for accuracy and compared with the documented ZEs and the costs and revenues for each oncological application. RESULTS: N = 45 in-patient oncological therapies were identified in n = 18 patients, as well as n = 7 bisphosphonate applications; n = 11 ZEs were documented. Costs for oncological medication were € 33,752. The corresponding ZE revenues amounted to only € 13,980, resulting in a loss of € 19,772. All in-patient oncological therapies performed were not cost-covering. Data discrepancy, incorrect documentation and cost attribution, and process aborts were identified. CONCLUSIONS: Routine financial quality control at the medicine-pharmacy administration interface is implemented, with monthly comparison of costs and revenues, as well as admission status. Non-cost-covering therapies for in-patients should be converted to out-patient therapies. Necessary adjustments of clinic processes are made according to these results, to avoid future losses.

Management of febrile neutropenia--a German prospective hospital cost analysis in lymphoproliferative disorders, non-small cell lung cancer, and primary breast cancer.

BACKGROUND: Febrile neutropenia/leukopenia (FN/FL) is the most frequent dose-limiting toxicity of myelosuppressive chemotherapy, but German data on economic consequences are limited. PATIENTS AND METHODS: A prospective, multicentre, longitudinal, observational study was carried out to evaluate the occurrence of FN/FL and its impact on health resource utilization and costs in non-small cell lung cancer (NSCLC), lymphoproliferative disorder (LPD), and primary breast cancer (PBC) patients. Costs are presented from a hospital perspective. RESULTS: A total of 325 consecutive patients (47% LPD, 37% NSCLC, 16% PBC; 46% women; 38% age = 65 years) with 68 FN/FL episodes were evaluated. FN/FL occurred in 22% of the LPD patients, 8% of the NSCLC patients, and 27% of the PBC patients. 55 FN/FL episodes were associated with at least 1 hospital stay (LPD n = 34, NSCLC n = 10, PBC n = 11). Mean (median) cost per FN/FL episode requiring hospital care amounted to € 3,950 (€ 2,355) and varied between € 4,808 (€ 3,056) for LPD, € 3,627 (€ 2,255) for NSCLC, and € 1,827 (€ 1,969) for PBC patients. 12 FN/FL episodes (LPD n = 9, NSCLC n = 3) accounted for 60% of the total expenses. Main cost drivers were hospitalization and drugs (60 and 19% of the total costs). CONCLUSIONS: FN/FL treatment has economic relevance for hospitals. Costs vary between tumour types, being significantly higher for LPD compared to PBC patients. The impact of clinical characteristics on asymmetrically distributed costs needs further evaluation.

Underfinancing of 90.3% for implant costs of prostheses and expanders in DRG revenues for uni- and bilateral mastectomy with immediate breast reconstruction.

BACKGROUND: From the clinic's point of view economic patient care requires comparison and adjustment of costs to revenues. To verify cost coverage for implants in mastectomy with immediate breast reconstruction, a comprehensive cost-reimbursement analysis was performed. METHODS: Retrospective analysis of the German diagnosis-related group (G-DRG) revenues for implants from the DRG Browser 2007/2009HA and comparison with actual costs for implants in 2009 from the annual clinic report and the database of the controlling department. Calculation of the relative cost coverage for implants in unilateral (DRG J06Z) and bilateral mastectomy (DRG J16Z). RESULTS: In 2009, n = 98 J06Z and n = 18 J16Z were performed. DRG-calculated expenses for implants were € 69.65 for J06Z and € 123.07 for J16Z, i.e. a total of € 9,040.96. Actual costs for all implants were € 121,645.60, mean € 699.11 (€ 404.94-1,171.44). Attributable implant costs for 100% immediate breast reconstruction rate were € 93,679.28. Thus, implants are not cost covering by -90.3% (-82.8 to -94.7%). Subsidies for implants from the clinic's budget range from € 335.29 to € 2,219.81 per case. CONCLUSIONS: Immediate breast reconstruction with implants after mastectomy is - even 6 years after introduction of the DRGs - not adequately calculated to be cost covering since the actual implant costs exceed the calculated revenues by far. At present, these implants are subsidized by the clinic at, on average, 90.3%. If economic patient care is mandatory, a maximum of only 1 in 10 patients with mastectomy can be offered immediate breast reconstruction with implants in Germany.

Novel markers of mesenchymal stem cells defined by genome-wide gene expression analysis of stromal cells from different sources.

Mesenchymal stem cells (MSC) represent a mixture of different cell types, of which only a minority is therapeutically relevant. Surface markers specifically identifying non-differentiated MSC from their differentiated progeny have not been described in sufficient detail. We here compare the gene expression profile of the in vivo bone-forming bone marrow-derived MSC (BM-MSC) with non-bone-forming umbilical vein stromal cells (UVSC) and other non-MSC. Clustering analysis shows that UVSC are a lineage homogeneous cell population, clearly distinct from MSC, other mesenchymal lineages and hematopoietic cells. We find that 89 transcripts of membrane-associated proteins are represented more in cultured BM-MSC than in UVSC. These include previously identified molecules, but also novel markers like NOTCH3, JAG1, and ITGA11. We show that the latter three molecules are also expressed on fibroblast colony-forming units (CFU-F). Both NOTCH3 and ITGA11, but not JAG1, further enrich for CFU-F when combined with CD146, a known marker of cells with MSC activity in vivo. Differentiation studies show that NOTCH3+ and CD146+ NOTCH3+ cells sorted from cultured BM-MSC are capable of adipogenic and osteogenic progeny, while ITGA11-expressing cells mainly show an osteogenic differentiation profile with limited adipogenic differentiation. Our observations may facilitate the study of lineage relationships in MSC as well as facilitate the development of more homogeneous cell populations for mesenchymal cell therapy.