Robotic Systems in Operating Theaters: New Forms of Team-Machine Interaction in Health Care.

BACKGROUND: Health information systems have developed rapidly and considerably during the last decades, taking advantage of many new technologies. Robots used in operating theaters represent an exceptional example of this trend. Yet, the more these systems are designed to act autonomously and intelligently, the more complex and ethical questions arise about serious implications of how future hybrid clinical team-machine interactions ought to be envisioned, in situations where actions and their decision-making are continuously shared between humans and machines. OBJECTIVES: To discuss the many different viewpoints-from surgery, robotics, medical informatics, law, and ethics-that the challenges of novel team-machine interactions raise, together with potential consequences for health information systems, in particular on how to adequately consider what hybrid actions can be specified, and in which sense these do imply a sharing of autonomous decisions between (teams of) humans and machines, with robotic systems in operating theaters as an example. RESULTS: Team-machine interaction and hybrid action of humans and intelligent machines, as is now becoming feasible, will lead to fundamental changes in a wide range of applications, not only in the context of robotic systems in surgical operating theaters. Collaboration of surgical teams in operating theaters as well as the roles, competencies, and responsibilities of humans (health care professionals) and machines (robotic systems) need to be reconsidered. Hospital information systems will in future not only have humans as users, but also provide the ground for actions of intelligent machines. CONCLUSIONS: The expected significant changes in the relationship of humans and machines can only be appropriately analyzed and considered by inter- and multidisciplinary collaboration. Fundamentally new approaches are needed to construct the reasonable concepts surrounding hybrid action that will take into account the ascription of responsibility to the radically different types of human versus nonhuman intelligent agents involved.

Analysis of short-term efficacy as defined by RECIST and pathological response of neoadjuvant chemotherapy comprised paclitaxel and cisplatin followed by radical surgery in patients with locally advanced cervical cancer: A prospective observational study.

The purpose of this study is to investigate short-term efficacy as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) and pathological response of neoadjuvant chemotherapy (NACT) comprised of paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced cervical cancer (LACC).This is a prospective study involving 61 women with histologically confirmed LACC referred for NACT following radical surgery at Beijing Obstetrics and Gynecology Hospital between April 2013 and January 2015.The efficacy of NACT was evaluated by the RECIST. The total short-term efficacy of NACT was 91.8% (complete remission and partial remission). The cervical invasion ≤1/2 was 82.4% in the complete remission (CR) group, 46.2% in the partial remission (PR) group, and 20% in the stable disease (SD) group. The difference between groups was statistically significant (P = .012). The slides of all surgical specimens were reviewed and classified according to the Tumor Regression Grade (TRG). The good response was defined by good short-term efficacy (RECIST) and the difference between groups was statistically significant (P = .042). The route of administration of NACT is a factor predicting response to NACT. A significant higher response rate (P = .011) and lower chemotherapy-related adverse events (P < .05) were observed in the artery intervention (AI) group compared to those received NACT via intravenous (IV) route. All patients were followed-up to the last day of 2015 with the median follow-up time of 21.5 months for NACT. For the 61 patients referred for NACT in LACC, 2 patients had relapsed and 1 patient died from the disease.The study showed that the NACT comprised TP for LACC treatment had a significant local effect. It could reduce tumor myometrial invasion and regress tumor. The route of administrating NACT is a predicting factor to the NACT response; 2 cycles of NACT of AI treatment to LACC patients would obtain a desired response with low chemotherapy adverse events.

Effects of an Antagonistic Analog of Growth Hormone-Releasing Hormone on Endometriosis in a Mouse Model and In Vitro.

Endometriosis is a benign gynecologic disorder causing dysmenorrhea, pelvic pain, and subfertility. Receptors for the growth hormone-releasing hormone (GHRH) were found in endometriotic tissues. Antagonists of GHRH have been used to inhibit the growth of endometriotic endometrial stromal cells. In this study, the GHRH receptor splice variant (SV) 1 was detected in human endometrial tissue samples by Western blots and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The highest messenger RNA (mRNA) and protein levels of SV1 were found in eutopic endometrium from patients with endometriosis compared to ectopic endometriotic tissues and endometrium from normal patients. The highest expression for GHRH mRNA was found by qRT-PCR in ectopic endometriosis lesions. In an in vivo mouse model with human endometrial explants from patients with endometriosis, 10 µg MIA-602 per day resulted in significantly smaller human endometrial xenotransplants after 4 weeks compared to mice treated with vehicle. The endometrial tissues expressed SV1 before and after xenotransplantation. The proliferation of endometrial stromal cells as well as the endometriosis cell lines 12-Z and 49-Z was decreased by exposure to 1 µM MIA-602 after 72 hours. The protein levels of epithelial growth factor receptors in 12-Z and 49-Z cell lines were reduced 48 and 72 hours after the administration of 1 µM MIA-602. MIA-602 decreased the activation of the MAP-kinases ERK-1/2. Our study demonstrates the presence of SV1 receptor as a target for treatment with GHRH antagonist in endometriosis. Endometrial tissues respond to MIA-602 with inhibition of proliferation in vitro and in vivo. The use of MIA-602 could be an effective supplement to the treatment strategies in endometriosis.

L1 cell adhesion molecule as a potential therapeutic target in murine models of endometriosis using a monoclonal antibody approach.

BACKGROUND/AIMS: The neural cell adhesion molecule L1CAM is a transmembrane glycoprotein abnormally expressed in tumors and previously associated with cell proliferation, adhesion and invasion, as well as neurite outgrowth in endometriosis. Being an attractive target molecule for antibody-based therapy, the present study assessed the ability of the monoclonal anti-L1 antibody (anti-L1 mAb) to impair the development of endometriotic lesions in vivo and endometriosis-associated nerve fiber growth. METHODS AND RESULTS: Endometriosis was experimentally induced in sexually mature B6C3F1 (n=34) and CD-1 nude (n=21) mice by autologous and heterologous transplantation, respectively, of endometrial fragments into the peritoneal cavity. Transplantation was confirmed four weeks post-surgery by in vivo magnetic resonance imaging and laparotomy, respectively. Mice were then intraperitoneally injected with anti-L1 mAb or an IgG isotype control antibody twice weekly, over a period of four weeks. Upon treatment completion, mice were sacrificed and endometrial implants were excised, measured and fixed. Endometriosis was histologically confirmed and L1CAM was detected by immunohistochemistry. Endometriotic lesion size was significantly reduced in anti-L1-treated B6C3F1 and CD-1 nude mice compared to mice treated with control antibody (P<0.05). Accordingly, a decreased number of PCNA positive epithelial and stromal cells was detected in autologously and heterologously induced endometriotic lesions exposed to anti-L1 mAb treatment. Anti-L1-treated mice also presented a diminished number of intraperitoneal adhesions at implantation sites compared with controls. Furthermore, a double-blind counting of anti-neurofilament L stained nerves revealed significantly reduced nerve density within peritoneal lesions in anti-L1 treated B6C3F1 mice (P=0.0039). CONCLUSIONS: Local anti-L1 mAb treatment suppressed endometriosis growth in B6C3F1 and CD-1 nude mice and exerted a potent anti-neurogenic effect on induced endometriotic lesions in vivo. The findings of this preliminary study in mice provide a strong basis for further testing in in vivo models.

Phase II study of fulvestrant 250 mg/month in patients with recurrent or metastatic endometrial cancer: a study of the Arbeitsgemeinschaft Gynäkologische Onkologie.

OBJECTIVES: The aim of this study is to evaluate the activity and toxicity of fulvestrant, a pure estrogen receptor antagonist in patients with advanced or recurrent endometrial cancer, expressing estrogen and/or progesterone receptors (ER/PR). METHODS: Eligible patients with advanced or recurrent endometrial cancer not amenable to curative surgery and/or radiotherapy were treated with fulvestrant at a dose of 250 mg by IM injection every 4 weeks for at least 12 weeks. Therapy was continued until disease progression, death, intolerable side effects or end of study. Response was assessed in patients with at least one target lesion according to WHO-criteria. RESULTS: Thirty-five patients were enrolled in this study and received at least one injection of fulvestrant (intention to treat-population, ITT). Twenty six patients received the intended 3 injections of fulvestrant (per protocol population, PP). There was no complete response but 4 partial responses (11.4% ITT) and 8 stable diseases. The median time to progression was 2.3 months (ITT). Overall survival was 13.2 months (ITT). Treatment was well tolerated. CONCLUSIONS: Fulvestrant at a dose of 250 mg IM every 4 weeks has marginal activity and good tolerability in patients with ER and/or PR positive advanced or recurrent endometrial cancer. A loading dose strategy and the use of 500 mg/4 weeks might improve the efficacy of this treatment.

Incidence of testicular malignancies and correlation to risk factors in a TESE population of subfertile men.

INTRODUCTION: In recent years, researchers have postulated a decreasing fertility potential of males and a rising incidence of testicular malignancies. MATERIALS AND METHODS: In this retrospective observational diagnostic multicenter study, 302 patient files of subfertile men whose testes were biopsied for TESE procedure were analysed. All patients referred to reproductive medicine centres in Northern Germany and they were identified by the cycle data collected by the German IVF register. A total of 280 patients (436 cycles) treated for intracytoplasmatic sperm injection after TESE procedures were eligible to be analysed. RESULTS: Our findings: 13.0% overall paternity rate before TESE procedure, 45.9% smokers, maldescensus testis was found on occasion (12.9%), and mumps orchitis previously occurred to 10 patients (3.6%). The tumour incidence rate at the time of testicle biopsy was 1.81% (= 5 pts.). Two of these patients had an anamnesis for maldescensus testis and one patient acquired mumps orchitis in childhood. CONCLUSION: Our data even reflects that tumour patients express an interest in having children after completion of cancer treatment, presenting four patients who had testicular biopsies after a previous malignancy. Moreover, there is evidence suggesting that environmental factors are causative for the trends in occurrence of male reproductive health problems. Within our highly selected population, the testicular tumour incidence rate is 100-fold higher than in a standard population. Supposing that the incidence rate of testicular malignancies among infertile men continues to increase in comparison to the incidence rate of the general male population, one has to count on an incremental number of males suffering from subfertility and testicular tumours.

Bridge-1 is expressed in human breast carcinomas: silencing of Bridge-1 decreases Smad2, Smad3 and Smad4 expression in MCF-7 cells, a human breast cancer cell line.

PURPOSE: The aim of the study was to investigate the expression of Bridge-1 in human breast carcinomas, and to determine the in vitro regulation of Bridge-1 by activin A and the influence of Bridge-1 on activin A signaling in the human breast cancer cell line MCF-7. METHOD: Bridge-1 expression in human breast carcinomas was shown after staining paraffin slides with a specific antibody against Bridge-1. To gain insight into Bridge-1 function, immortalized, human breast cancer cells (MCF-7 cell line) were stimulated with activin A and the expression of Bridge-1 was analyzed by real-time PCR and Western blot. Next, Bridge-1 was downregulated via siRNA treatment in MCF-7 cells and the expression of Bridge-1, Smad2, 3 and 4 was investigated by real-time PCR and Western blot. RESULTS: Human breast carcinoma cells showed nuclear and cytoplasmic localization of Bridge-1. Activin A stimulation of the immortalized human breast adenocarcinoma cell line MCF-7 showed an increase in Bridge-1 expression by real-time PCR and Western blot. Downregulation of Bridge-1 by Bridge-1-siRNA resulted in a decreased expression of Smad2, 3 and 4 of up to 50% compared to the treatment with non-targeting siRNA. CONCLUSIONS: This study is the first to demonstrate the expression of Bridge-1 in human breast carcinomas. Bridge-1 expression is increased by activin A stimulation and itself seems to influence activin A signaling by affecting the expression of Smad2, 3 and 4.

Laparoscopic management of early primary omental pregnancy.

OBJECTIVE: To describe the successful laparoscopic management of an omental pregnancy. DESIGN: Case report. SETTING: University of Schleswig-Holstein, Campus Luebeck, Department of Gynecology and Obstetrics. PATIENT(S): A 25-year-old patient with an omental pregnancy. INTERVENTION(S): Laparoscopic partial omentectomy. MAIN OUTCOME MEASURE(S): Successful laparoscopic management of an omental pregnancy. RESULT(S): A 25-year-old woman reported having abdominal pain. Her urine pregnancy test was positive. She had been using an intrauterine copper device for a period of 2.5 years. Gynecologic examination revealed normal results, in the uterus and fallopian tubes especially, where no signs of pregnancy were found through clinical and sonographic examination. Because the patient had had increasing pain, a laparoscopy was performed. There was approximately 500 mL of dark blood found in the cul de sac. The uterus and fallopian tubes appeared normal and without any signs of pregnancy. However, there was a cavity detected in the omentum majus. A partial omentectomy then was performed laparoscopically. An omental pregnancy was confirmed by beta-hCG-positive trophoblast cells in the omentum majus. CONCLUSION(S): Omental pregnancy can be rather difficult to identify. If there is no evidence of tubal pregnancy, laparoscopy may help to confirm the diagnosis of omental pregnancy and simultaneously offer minimal invasive therapy.

Cell-specific enhancement of liposomal transfection by steroids in steroid receptor expressing cells.

The DNA transfer efficiency in liposomal versus viral transfection is very low, mainly due to an insufficient nuclear transport of the delivered DNA after its endocytotic uptake to the cell. Ligand activation of intracellular steroid receptors and their subsequent mobilization to the nucleus could result in a co-transport of DNA to the nucleus. The augmentation of nuclear transport of DNA after steroid addition might cause enhanced transfection efficiency. We used cell lines from gynecologic malignoma expressing steroid receptors, such as T47D and Mcf-7 breast cancer cell lines, as well as receptor-negative cell lines, such as Hec1A from endometrium carcinoma or the breast cancer cell line MDA-MB-231. The cells were transfected by the liposomal transfection agent Dotap with the gene for firefly-luciferase as a reporter gene and transfection efficiencies were determined in the luciferase assay. We compared the effect of the addition of cholesterol and steroids in different cell lines on the transfection efficiency. The addition of cholesterol to transfection agents led to an enhancement of the luciferase activity in all cell lines. Steroids enhanced the transfection efficiency only in receptor-positive cell lines. The transfection efficiencies of HEC-1A or MDA-MB-231 cells were not enhanced by steroids. A progesterone preincubation of receptor-positive T47D cells resulted in a decrease of progesterone receptors and afterwards the progesterone enhanced transfection was dramatically diminished. We presume that the transfection enhancement by steroids is dependent on increased nuclear import of the delivered DNA only in the presence of steroid receptors. Steroid enhancement of transfection is different from the benefit of cholesterol for transfection that acts on general cellular properties or the transfection complex as such. Liposomal transfection in combination with steroids might be useful for a cell-specific enhancement of gene transfer for example in gynecological malignoma where subgroups are expressing high levels of steroid receptors.

Cetrorelix in the treatment of female infertility and endometriosis.

The use of cetrorelix within ovarian-stimulation protocols demonstrates several advantages compared with gonadotropin-releasing hormone (GnRH) agonist-containing protocols, which include, for example, significantly less time for analogue treatment and a reduction in the amount of gonadotropins needed. Furthermore, fewer side effects can be expected. There is no difference regarding endometrium quality and hormone profiles, and the results of assisted reproduction cycles are comparable. Cetrorelix also seems to be useful in the treatment of endometriosis which, in most cases, is an estrogen-dependent disease. Furthermore, fewer side effects occur with this agent (e.g., postmenopausal symptoms) and no estradiol add-back is needed. In the future, new nonpeptic GnRH antagonists are expected to be available for oral administration. Although they are still under investigation, these agents have the potential to improve patients' comfort and compliance.

Is endometriosis associated with systemic subclinical inflammation?

Endometriosis is a pelvic inflammatory process with altered function of immune-related cells and increased number of activated macrophages in the peritoneal environment that secrete various local products, such as growth factors and cytokines. The elevation of cytokines and other factors in the peritoneal fluid is accompanied by the elevation of similar factors, such as CRP, SAA, TNF-alpha, MCP-1, IL-6, IL-8 and CCR1, in the peripheral blood of patients with endometriosis. CD44+ and CD14+ monocytes are significantly increased, while CD3+ T lymphocytes and CD20+ B lymphocytes show modest, but significant decrease in peripheral blood of women with endometriosis. This indicates that endometriosis could be viewed as a local disease with systemic subclinical manifestations. This review provides an overview of data on the changes of various factors in peripheral blood and their potential use as diagnostic tools in patients with endometriosis.

Assessment of luteinizing hormone level in the gonadotropin-releasing hormone antagonist protocol.

In the GnRH-antagonist multiple-dose protocol, the LH level retrieved from a single measurement during ovarian stimulation and concomitant GnRH-antagonist administration can vary according to [1] the time point of sampling with respect to the GnRH-antagonist injection and [2] episodic changes in circulating LH concentration due to the pulsatile release of LH from the pituitary gland. To exemplify the size of pharmacodynamic effect of a single 0.25-mg cetrorelix administration on LH concentration profile and pulsatility, we measured endogenous LH levels every 15 minutes from 8 hours before the first cetrorelix administration until 24 hours thereafter on ovarian stimulation day 6 and 7 in a single patient.

Application of novel tissue microarrays to investigate expression of tryptase, chymase and KIT protein in placental mast cells.

INTRODUCTION: Tissue microarrays comprise numerous small representative tissue samples from hundreds of different cases assembled on a single histologic slide, and therefore allow high throughput analysis of multiple specimens at the same time. Mast cells are paracrine cells found ubiquitously in connective tissue. Expression of the serine proteases tryptase and chymase, as well as KIT protein, the receptor for stem cell factor (SCF), has been demonstrated in mast cells. Because little is known about the role of mast cells in the placenta, we investigated the number and expression of chymase, tryptase, and KIT protein in placental mast cells using newly developed tissue microarrays. MATERIALS AND METHODS: Tissue microarrays were prepared from archival paraffin tissue blocks of 90 placentae, including 15 normal ones as a control group. Gestational age of the placentae ranged from 7 to 42 weeks. Sections of formalin-fixed paraffin-embedded material were prepared on chemically activated cover-slides. The slides were cut in 4-mm(2) squares containing representative areas, and transferred to a tissue microarray. Hematoxylin and eosin (H&E), chloroacetate esterase (CAE), toluidine blue, periodic acid--Schiff (PAS), and immunohistochemical staining were performed. The number of mast cells and expression of chymase, tryptase, and KIT protein were evaluated in each case. RESULTS: Mast cell numbers in placentae with inflammation/abortion exceeded that of normal placentae. Although statistically not significant, we furthermore observed an increase in chymase-positive mast cells in the group of placentae associated with fetal malformations/chromosomal aberrations compared with normal placentae. DISCUSSION: Novel tissue microarray technique has been introduced into placental research, and allows multiple placental tissue samples to be effectively analyzed simultaneously. This study indicated an increased number of chymase-positive mast cells in placentae with fetal malformation/chromosomal aberration. Activation of angiotensin II by chymase may play a role in fetal malformation. Moreover, it has been speculated that mast cells may only express chymase (MC(C)). Our findings denote the presence of placental MC(C). However, further studies are needed to elucidate more precisely the role of mast cell chymase in the placenta.

To agonize or antagonize in gonadotrophin stimulation cycles?

High hopes accompanied the release of gonadotrophin-releasing hormone (GnRH) antagonists onto the market at the end of the last millennium. Today, it must be admitted that not all of these hopes have been realized. According to large meta-analyses, treatment time for ovarian stimulation could be significantly shortened, and the incidence of severe ovarian hyperstimulation syndrome (OHSS) could also be reduced. However, the achieved clinical pregnancy rates seem not to be equivalent to those obtained after ovarian stimulation using GnRH agonists in the so-called long protocol. Very recent studies have demonstrated that oversuppression of LH after initiating GnRH antagonist administration seems not to be responsible for that observation. Moreover, supplementation with recombinant LH does not increase success rates. However, an analysis based on the data of the German IVF registry (DIR), scrutinizing more than 1800 cycles in so-called ideal patients (age < 35 years, first treatment cycle, pure tubal infertility, only classical IVF), did not demonstrate any differences in pregnancy rates between GnRH antagonists and GnRH agonists. These data seem to indicate that GnRH antagonists should be used as 'first choice treatment' in ovarian stimulation.

Additive effect of steroids and cholesterol on the liposomal transfection of the breast cancer cell line T-47D.

The efficiency of gene transfer is many times higher in viral than in liposomal transfection. One reason for this is an insufficient intracellular transport of the exogenous DNA into the nucleus in lipofection. Using liposomal transfection techniques for gene therapy is safer than viral approaches, so it would be of great importance to find solutions for their enhancement. We found a 4.51-fold increase in liposomal transfection of T-47D breast cancer cells by the addition of progesterone and a 2.81-fold increase by the addition of cholesterol. The transfection efficiency was measured as the activity of the delivered reporter gene luciferase. The addition of progesterone and cholesterol in combination led to a further enhancement of the transfection efficiency up to 13.72-fold. This additive effect could also be seen when we combined cholesterol with other steroids, but not by the combination of different steroids. All of these steroids alone had also the potential to increase liposomal transfection. Therefore we suggest that steroids and cholesterol enhance liposomal transfection by different mechanisms. Both substances have been shown to shift the exogenous DNA from the cytosol to the nucleus. Steroids normally act through intracellular steroid receptors, which migrate into the nucleus upon activation. The transfected DNA might be co-transported to the nucleus together with the migration of the activated steroid receptors. Even if cholesterol causes also an intracellular shift of DNA to the nucleus, its impact on the fluidity of cellular membranes or on the stability of lipoplexes in serum containing media could be mainly responsible for its effect. If the steroid enhanced liposomal transfection is dependent on the presence of steroid receptors, a specifically-enhanced gene delivery for a subgroup of gynecological tumours expressing high levels of steroid receptors could be possible.

Progesterone and estradiol enhance lipid mediated transfection of Sk-Br-3 mammalian cancer cells.

Cyclodextrin encapsulated beta-estradiol and progesterone were used for enhancement of gene delivery using the breast cancer cell line Sk-Br-3. A non-toxic concentration of cyclodextrin encapsulated sex steroids (50 microM) added to lipid or liposomal transfection led to a 12-fold increase of reporter gene expression (luciferase) with progesterone and an 8-fold increase with estradiol using Lipofectamine Plus mediated transfection. Using the lipid formulation Fugene-6 the results were a 5.5-fold and a 4.5-fold increase respectively. This enhancement could only be observed if the sex steroids were added to the cells before application of the DNA-Fugene complex supporting the evidence that intracellular processes are responsible for the activity of the steroids. The strong differences between progesterone and estradiol in modifying Lipofectamine Plus transfection in Sk-Br-3 cells may to be explained by differences in the distribution of these receptors in the cellular compartments. These results seem to add evidence on the possibility of using sex steroids to increase the efficiency of non-viral vectors for transfection, and may ultimately prove to be relevant to gene therapy in the treatment of breast cancer as well as other solid tumors.