A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin.

Human skin contains a population of memory T cells that supports tissue homeostasis and provides protective immunity. The study of human memory T cells is often restricted to in vitro studies and to human PBMC serving as primary cell source. Because the tissue environment impacts the phenotype and function of memory T cells, it is crucial to study these cells within their tissue. Here we utilized immunodeficient NOD-scid IL2rγnull (NSG) mice that carried in vivo-generated engineered human skin (ES). ES was generated from human keratinocytes and fibroblasts and was initially devoid of skin-resident immune cells. Upon adoptive transfer of human PBMC, this reductionist system allowed us to study human T cell recruitment from a circulating pool of T cells into non-inflamed human skin in vivo. Circulating human memory T cells preferentially infiltrated ES and showed diverse functional profiles of T cells found in fresh human skin. The chemokine and cytokine microenvironment of ES closely resembled that of non-inflamed human skin. Upon entering the ES T cells assumed a resident memory T cell-like phenotype in the absence of infection, and a proportion of these cutaneous T cells can be locally activated upon injection of monocyte derived dendritic cells (moDCs) that presented Candida albicans. Interestingly, we found that CD69+ memory T cells produced higher levels of effector cytokines in response to Candida albicans, compared to CD69- T cells. Overall, this model has broad utility in many areas of human skin immunology research, including the study of immune-mediated skin diseases.

Toxicity and cosmetic outcome after hypofractionated whole breast irradiation and boost-IOERT in early stage breast cancer (HIOB): First results of a prospective multicenter trial (NCT01343459).

BACKGROUND AND PURPOSE: To assess the role of intraoperative radiation with electrons (IOERT) as tumor bed boost followed by hypofractionated whole breast irradiation (HWBI) after breast conserving surgery (BCS) of patients with low to intermediate risk breast cancer focusing on acute/late toxicity and cosmetic outcome. MATERIAL AND METHODS: In 2011, a prospective multicenter trial (NCT01343459) was started. Treatment consisted of BCS, IOERT (11.1 Gy) and HWBI (40.5 Gy in 15 fractions). In a single-arm design, 5-year IBR-rates are benchmarked by a sequential ratio test (SQRT) against best published evidences in 3 age groups (35-40 y, 41-50 y, >50 y). Acute/late toxicity and cosmesis were evaluated by validated scorings systems. RESULTS: Of 627 eligible patients, 44 were excluded, leaving 583 to analyze. After a median follow-up (FUP) of 45 months (range 0-74), for acute effects CTCAE-score 0/1 was noted in 91% (end of HWBI) and 92% (4 weeks later), respectively. Late toxicity Grading 0/1 (mean values, ranges) by LENT-SOMA criteria were observed in 92.7% (89-97.3) at 4/5 months, rising to 96.5% (91-100) at 6 years post HWBI. Baseline cosmesis after wound healing prior to HWBI was scored as excellent/good in 86% of cases by subjective (patient) and in 74% by objective (doctor) assessment with no impairment thereafter. CONCLUSIONS: Acute and late treatment tolerance of a combined Boost-IOERT/HWBI regimen is excellent in short/mid-term assessment. Postoperative cosmetic appearance is not impaired after 3 years FUP.

Prepectoral direct-to-implant breast reconstruction with complete ADM or synthetic mesh coverage - 36-Months follow-up in 200 reconstructed breasts.

BACKGROUND: Prepectoral implant placement is an innovative option for breast reconstruction, due to multiple advantages over subpectoral implant placement. The adoption of various ADMs and meshes supports the utilization of the prepectoral technique. METHODS: 200 breasts were reconstructed with prepectoral implant placement after nipple-sparing mastectomy in a one-stage direct-to-implant procedure. The implants were completely covered and fixed with porcine ADMs (Strattice™ or Artia™), or with synthetic meshes (TIGR®). The pectoralis major muscle was not detached at all and kept intact entirely. RESULTS: Minor complications included minimal nipple necrosis without further intervention and complete healing in 14 breasts (7.0%). Major complications comprised implant loss due to skin necrosis and wound infection in 7 breasts (3.5%), and hematoma with revision surgery in 8 breasts (4.0%). At a mean follow-up of 36 months cosmetic results were excellent and good in 180 breasts (90.0%), sufficient in 13 breasts (6.5%) and insufficient in 7 breasts (3.5%). Breast animation deformity and implant displacement could not be observed, while implant rotation was documented in 5 breasts (2.5%). Capsular contractures grade III or IV could not be observed neither in patients with previous radiotherapy nor in patients with radiotherapy to the reconstructed breast. CONCLUSIONS: The single-stage direct-to-implant prepectoral implant placement after NSM with complete coverage of the implant with ADM or synthetic mesh represents a novel and feasible technique for breast reconstruction. This technique provides an alternative to the subpectoral implant placement with excellent cosmetic results avoiding the disadvantages of the subpectoral implant placement.

Age-related distribution of basal serum AMH level in women of reproductive age and a presumably healthy cohort.

In this study, day 1 to 4 serum anti-Müllerian hormone (AMH) level was analyzed in 2,741 patients attending our department for reproductive medicine or reproductive surgery, including a subgroup of 1,105 women who attended an assisted reproductive technology program because of a male factor as a presumably healthy subgroup. Day 1 to 4 serum AMH levels showed an age-dependent distribution and there is a wide range of AMH in each year of age analyzed, showing that even young women are at a risk of reduced ovarian reserve.

Anti muellerian hormone serum levels in women with endometriosis: a case-control study.

OBJECTIVE: To compare the anti muellerian hormone (AMH) serum levels in women with and without endometriosis. DESIGN: A case-control study SETTING: Women's General Hospital, Linz, Austria. PATIENT(S): Our study included a total of 909 patients undergoing in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) treatment or consulting our specific endometriosis unit. After proofing the exclusion criteria, 153 of these patients with endometriosis (study group) were matched with 306 patients undergoing IVF/ICSI treatment because of a male factor (control group). INTERVENTIONS: None. MAIN OUTCOME MEASURES: AMH serum level. RESULTS: Mean AMH serum level was significantly lower in the study than in the control group (2.75 + or - 2.0 ng/ml vs. 3.46 + or - 2.30 ng/ml, p < 0.001). In women with mild endometriosis (rAFS I-II), the mean AMH level was almost equal to the control group (3.28 + or - 1.93 ng/ml vs. 3.44 + or - 2.06 ng/ml; p = 0.61). A significant difference in mean AMH serum level was found between women with severe endometriosis (rAFS III-IV) and the control group (2.38 + or - 1.83 ng/ml vs. 3.58 + or - 2.46 ng/ml; p < 0.0001). CONCLUSION: Lower AMH serum levels and an association with the severity were found in women with endometriosis. Physicians have to be aware of this fact. Because of the expected lower response on a controlled ovarian hyperstimulation (COH), AMH serum level should be measured to optimise the dose of gonadotropin treatment previous to a COH, especially in women with severe endometriosis.

Cryopreserved blastocysts have a lower implantation but an equal live birth rate as compared to fresh blastocysts of the same quality - a case-control study.

The purpose of this case-control study was to compare implantation, pregnancy, and live birth rate of cryopreserved embryos with that of fresh embryos. A total of 1,488 assisted reproductive technology (ART) trials including 188 cryopreserved embryo replacement trials were reviewed. After proofing the exclusion criteria, 112 patients undergoing a cryopreserved embryo replacement (study group) were matched with 112 patients undergoing a fresh embryo transfer (control group). Matching was done for age of patients, number, and quality of embryos (Day 5 embryos). Data concerning maternal characteristics, survival rate of warming procedure, implantation, pregnancy, ongoing pregnancy, and live birth rates were collected. A lower implantation rate was found for cryopreserved embryo replacement compared to transferring fresh embryos. Live birth rate was found to be equal in both groups.

Risk in twin pregnancies after the use of assisted reproductive techniques.

OBJECTIVE: To analyze whether there is an increased perinatal risk for twin pregnancies after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). STUDY DESIGN: The medical files of 216 twin pregnancies (group 1) conceived through IVF/ICSI and 377 spontaneously conceived twin pregnancies (group 2) were assessed retrospectively. Data on gestational age at delivery, mode of delivery, birth weight, neonatal intensive care unit admission, duration of hospitalization, perinatal mortality and malformations were recorded. Statistical analysis was made by the chi2 test. Differences of the means of parametric data were analyzed using the Mann-Whitney test. RESULTS: The frequency of cesarean section was higher in group 1. Mean gestational age, frequency of preterm birth, birth weight, and frequency of low birth weight and very low birth weight were similar in both groups. The frequency of small-for-gestational-age (SGA) infants was significantly higher in group 1. Perinatal outcome, rate of malformations and neonatal mortality rate were similar in the 2 groups. CONCLUSION: We found an increased risk of SGA infants in IVF/ICSI twin pregnancies as compared to spontaneously conceived twin pregnancies.

Birth weight is lower for survivors of the vanishing twin syndrome: a case-control study.

OBJECTIVE: To compare the outcome of singleton pregnancies originating from a twin gestation with singleton pregnancies originating from a single gestation. DESIGN: Case-control study. SETTING: Women's general hospital in Austria. PATIENT(S): A total of 794 singleton deliveries after IVF/intracytoplasmic sperm injection, including 46 survivors of vanishing twin syndrome (study group) and 92 matched singletons (control group). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Data concerning duration of gestation, mode of delivery, birth weight, neonatal intensive care unit admission, duration of hospitalization, perinatal mortality. RESULT(S): Of all singletons born, 5.8% originated from a twin gestation. Mean (+/- SD) birth weight was significantly higher in the control group (2876.3 +/- 600.5 g vs. 3249.6 +/- 624.5 g). The frequency of low birth weight (26.1% vs. 12.0%) and being small for gestational age (32.6% vs. 16.3%) was significantly lower in the control group. No differences were observed in terms of duration of gestation. CONCLUSION(S): A higher risk for lower birth weight and being small for gestational age for survivors of the vanishing twin syndrome was found. Such pregnancies need to be carefully monitored, and parents must be informed about the associated risks when transferring more than one embryo.

Central quadrantectomy with resection of the nipple-areola complex compared with mastectomy in patients with retroareolar breast cancer.

Appropriate surgery in women with retroareolar breast cancer should allow resection of the cancer with wide free margins and an acceptable cosmetic result. The aim of this study was to compare breast conservation surgery (BCS) to mastectomy for treatment of retroareolar breast cancer. In a prospective nonrandomized study, 69 women with retroareolar breast cancers underwent either central quadrantectomy (n=33) with complete removal of the nipple-areola complex or mastectomy (n=36). Two of 33 (6%) patients scheduled for BCS had a secondary mastectomy and immediate reconstruction due to involved margins. After a median follow-up of 42 month (range 17-99 months) in the BCS group and 43 months (range 16-118 months) in the mastectomy group local and regional recurrences as well as systemic disease were comparable between both groups. The postoperative cosmetic result after BCS as evaluated by the patients was rated as excellent in 80% and good in 20% with no poor result. BCS followed by radiation therapy is a feasible alternative to mastectomy in patients with retroareolar breast cancer.