Human Cord Blood B Cells Differ from the Adult Counterpart by Conserved Ig Repertoires and Accelerated Response Dynamics.

Neonatal and infant immune responses are characterized by a limited capability to generate protective Ab titers and memory B cells as seen in adults. Multiple studies support an immature or even impaired character of umbilical cord blood (UCB) B cells themselves. In this study, we provide a comprehensive molecular and functional comparison of B cell subsets from UCB and adult peripheral blood. Most UCB B cells have a mature, naive B cell phenotype as seen in adults. The UCB Ig repertoire is highly variable but interindividually conserved, as BCR clonotypes are frequently shared between neonates. Furthermore, UCB B cells show a distinct transcriptional program that confers accelerated responsiveness to stimulation and facilitated IgA class switching. Stimulation drives extensive differentiation into Ab-secreting cells, presumably limiting memory B cell formation. Humanized mice suggest that the distinctness of UCB versus adult B cells is already reflected by the developmental program of hematopoietic precursors, arguing for a layered B-1/B-2 lineage system as in mice, albeit our findings suggest only partial comparability to murine B-1 cells. Our study shows that UCB B cells are not immature or impaired but differ from their adult mature counterpart in a conserved BCR repertoire, efficient IgA class switching, and accelerated, likely transient response dynamics.

Single-center study for robotic-assisted laparoscopic sacropexies: a one-fits-all strategy for pelvic organ prolapse?

PURPOSE: Sarcopenia has been established as the "gold standard" for the treatment of pelvic organ prolapse (POP). Minimal invasive laparoscopy can help to reduce the risks of open access surgery. We compare the surgical results and outcomes of robotic-assisted sacropexies. METHODS: In this monocentric retrospective study we enrolled 49 patients operated on symptomatic POP. Patients were divided into two groups according to the type of robotic-assisted sacropexy: patients with a history of hysterectomy received robotic-assisted sacrocolpopexy (RSCP; n = 19), while patients with subtotal hysterectomy received robotic-assisted cervicosacropexy (RCSP; n = 30). Failure was defined as recurrence of the disease with a need for reoperation. Validated questionnaires (the Pelvic Floor Distress Inventory-20 (PFDI-20) and Pelvic Floor Impact Questionnaire-7 (PFIQ-7)), were used for evaluation of patients quality of life postoperatively. RESULTS: The comparison between RCSP versus RSCP showed that the latter is related to slightly but not significantly increased recurrence rates and a higher impact of POP symptoms on quality of life in long-term follow-up (p = 0.04). Perioperative data showed similar complication rates in both RSP types but shorter postoperative time of bladder catheterization in the case of RCSP (p = 0.008). CONCLUSIONS: The monocentric long-term data confirm that RSP is a safe and effective method of surgical POP treatment, regardless of the site of the anatomical compartment. In comparison to RSCP, RCSP is associated with a lower impact of POP symptoms on patients' quality of life with a tendency to slightly lower rates of POP recurrence.

Zinc distribution within breast cancer tissue of different intrinsic subtypes.

PURPOSE: To show feasibility of laser ablation inductively coupled mass spectrometry (LA-ICPMS) for analysis of zinc content and concentration in breast cancer tissue and to correlate this with validated prognostic and predictive markers, i.e. histological grading and expression of steroid receptors (estrogen receptor, ER; progesterone receptor, PR) and human epidermal growth-factor receptor 2 (Her2). METHODS: 28 samples of human invasive ductal breast cancer tissue were subclassified into groups of four different intrinsic subtypes according to the expression of ER, PR and Her2 by immunohistological staining and then analyzed for zinc content and distribution by LA-ICPMS applying a calibration technique based on spiked polyacrylamide gels. A correlation of zinc concentration with histological grading and molecular subtypes was analyzed. RESULTS: Consistent with results of a pilot-study LA-ICPMS was feasible to show zinc accumulation in cancerous tissue, even more adjacent healthy stroma was with proportional increase of zinc. Zinc levels were most elevated in triple-positive (TPBC) and in triple-negative (TNB) breast cancers. CONCLUSION: LA-ICPMS was feasible to confirm a connection between zinc and grade of malignancy; furthermore, focusing on a correlation of zinc and intrinsic breast cancer subtypes, LA-ICPMS depicted an upwards trend of zinc for "high-risk-cancers" with highest levels in Her2-positive and in triple-negative (TNBC) disease. The currently uncommon alliance of clinicians and analytical chemists in basic research is most promising to exploit the full potential of diagnostic accuracy in the efforts to solve the enigma of breast cancer initiation and course of disease.

The Society of European Robotic Gynaecological Surgery (SERGS) Pilot Curriculum for robot assisted gynecological surgery.

PURPOSE: To set forth experiences in the context of the SERGS Pilot Curriculum-the first standardized educational program for robotic use in gynecological surgery-in terms of feasibility, effectiveness and potential for certification. METHODS: The Society of European Robotic Gynecological Surgery (SERGS) outlined a Pilot Curriculum for standardized education in robot-assisted laparoscopic gynecological surgery. Its feasibility and acceptance were checked in the form of a fellowship pilot program conducted at four European Centers of Excellence for robot-assisted surgery. Results and conclusions derived from this pilot program are presented. RESULTS: The SERGS Pilot Curriculum defines criteria for a standardized training and assessment of performance, boosts the learning curve of the candidate and increases contentment at work. Regarding face validity, it proves valuable as finally all candidates could perform the outlined procedure safely and efficiently without supervision. CONCLUSION: Due to the immense increase of robotic procedures in gynecology standardized training curricula are indispensable. This seems highly necessary to ensure patients' safety and surgical outcome. The SERGS Pilot Curriculum sets standards for a stepwise theoretical and practical training in gynecological robotic procedures. It seems feasible as instrument for accreditation as gynecologic robotic surgeon. Though as a general applicable guideline for systematic training in robot-assisted surgery, a definite curriculum should have a more definite timeline and implementation of a structured assessment of performance.

Intraoperative navigation in robotically assisted compartmental surgery of uterine cancer by visualisation of embryologically derived lymphatic networks with indocyanine-green (ICG).

BACKGROUND AND OBJECTIVES: To evaluate feasibility of intraoperative visualization of embryologically defined organ compartments and their drainage by ICG in uterine cancer. METHODS: Total of 2.5 mg of ICG have been injected into cervix or corpus in uterine cancer patients immediately prior to surgery. Green fluorescence was intermittently detected during robotically assisted laparoscopic surgery (Firefly System®, Intuitve Surgical Inc.). Total of 36 patients with uterine cancer without macroscopically suspicious nodes were evaluated with respect to their compartmental lymphatic network, collecting lymphatic vessels, and the connection to the postponed lymph basins. RESULTS: Müllerian (sub) compartment and transport of lymph fluid along the lymphatic collectors and connecting vessels to the postponed lymph basins could be visualized invariably in all patients. Cervix drained along the ligamentous and caudal part of vascular mesometria, whereas midcorporal and fundal drainage occurred along the upper part of vascular mesometria and along the mesonephric pathway along the ovarian vessels. CONCLUSIONS: Visualization of lymphatic network and downstream flow of lymphatic fluid to the postponed lymph basins by ICG is feasible; it can be used to navigate along compartment boarders for education, intraoperative orientation, and quality control. It seems to confirm the compartmental order of pelvic organ systems and postponed lymph basins. J. Surg. Oncol. 2016;113:554-559. © 2016 Wiley Periodicals, Inc.

Cyclic volatile methylsiloxanes in human blood as markers for ruptured silicone gel-filled breast implants.

The replacement of medical-grade silicone with industrial-grade silicone material in some silicone gel-filled breast implants (SBI) manufactured by Poly Implant Prothèse and Rofil Medical Nederland B.V., reported in 2010, which resulted in a higher rupture tendency of these SBI, demonstrates the need for non-invasive, sensitive monitoring and screening methods. Therefore a sensitive method based on large volume injection-gas chromatography coupled to mass spectrometry (LVI-GC/MS) was developed to determine octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclo-hexasiloxane (D6) in blood samples from women with intact (n = 13) and ruptured SBI (n = 11). With dichloromethane extraction, sample cooling during preparation, and analysis extraction efficiencies up to 100 % and limits of detection of 0.03-0.05 ng D4-D6/g blood were achieved. Blood samples from women with SBI were investigated. In contrast to women with intact SBI, in blood from women with ruptured SBI higher D4 and D6 concentrations up to 0.57 ng D4/g blood and 0.16 ng D6/g blood were detected. With concentrations above 0.18 D4 ng/blood and 0.10 ng D6/g blood as significant criteria for ruptured SBI, this developed analytical preoperative diagnostic method shows a significant increase of the recognition rate. Finally a higher precision (error rate 17%) than the commonly used clinical diagnostic method, mamma sonography (error rate 46%), was achieved.

Cancer field surgery in endometrial cancer: peritoneal mesometrial resection and targeted compartmental lymphadenectomy for locoregional control.

OBJECTIVE: Peritoneal mesometrial resection (PMMR) plus targeted compartmental lymphadenectomy (TCL) aims at removal of the locoregional cancer field in endometrial cancer (EC). Optimal locoregional control without adjuvant radiotherapy and acceptable surgical morbidity should be achieved concomitantly sparing systematic lymphadenectomy (LNE) for most of the patients. METHODS: We evaluated data from 132 patients treated for EC. Out of these, between January 2017 and June 2020 we performed robotic PMMR and TCL on 51 women. We present the first data of feasibility and safety of the procedure as well as preliminary oncological results. RESULTS: The 51 patients treated with robotic PMMR and TCL showed comparable morbidity to classic laparoscopic hysterectomy or PMMR without LNE. One intraoperative complication occurred. Postoperative complications grade 3 and higher occurred in 2 cases (3.9%). One of these (85 years old) experienced grade 5 following pulmonary embolism with lysis therapy. Fifteen patients (29.4%) could be spared complete LNE. The rate of adjuvant radiotherapy was 3.9% in our collective (n=2), compared to 39.2% of patients (n=20) eligible for irradiation according to international guidelines. In a mean follow-up time of 15 months (0-41), no locoregional recurrences were observed, although three patients showed distant relapse. CONCLUSIONS: Our data suggest that robotic PMMR and pelvic TCL can be performed regardless of BMI and comorbidities without a relevant increase in surgical morbidity. Moreover, despite a relevant reduction of adjuvant radiotherapy, first follow-up data hint at a favorable locoregional recurrence rate in the reported cohort.

Evaluation of carcinoembryonic antigen-related cell adhesion molecule 1 blood serum levels in women at high risk for preeclampsia.

PROBLEM: The aim of this study was to evaluate the sCEACAM1 concentrations in serum from patients in the first trimester who have a high risk for developing PE during pregnancy. METHOD OF THE STUDY: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) levels were determined with ELISA. The patients (n = 109) were divided into two groups: patients who have a high risk of developing PE early-onset and a control group. Patients who have a high risk of developing PE were then divided into two subgroups depending on PE development in third trimester of pregnancy: PE in third trimester versus no PE in third trimester. RESULTS: sCEACAM1 concentrations in patients who were screened as having a high risk for developing PE were significantly higher than in healthy pregnant women in the first trimester (p = .03). The highest sCEACAM1 concentration was found in the high-risk group with PE development compared to the control group (p = .004). CONCLUSION: Elevated sCEACAM1 blood serum levels in women with PE suggest that there is immune dysregulation in early pregnancy, which may be helpful in PE prediction and therapy.

Surgical anatomy of the ligamentous mesometrium and robotically assisted ICG-guided resection in cervical cancer.

The ligamentous mesometrium is a 3-dimensional structure consisting of a rectouterine/-vaginal part with attachment to the anterior lateral mesorectum and a sacrouterine part surrounding the mesorectum attached to the pelvic fascia and the mesorectum dorsolaterally. The lymphatic network draining the posterior cervix connected caudally ventrally to the deep venous lymph network of the vascular mesometrium is running at the lateral surface of the sacrouterine part and dorsomedially of the inferior hypogastric plexus; it drains to the deep internal iliac, prespinal and preischiadic nodes.

Technique of ICG-guided Targeted Compartmental Pelvic Lymphadenectomy (TCL) combined with Pelvic Peritoneal Mesometrial Resection (PMMR) for locoregional control of endometrial cancer - A proposal.

•PMMR is a compartment based radical hysterectomy in endometrial cancer.•Pelvic PMMR may be combined with ICG guided Targeted Compartmental Lymphadenectomy (TCL).•Video of Pelvic PMMR and TCL technique may be basis for a prospective study.

Aortic utero-ovarian sentinel nodes and left infrarenal aortic lymph node dissection by ICG supported navigation.

•Visualization of paraaortic sentinel compartments in endometrial cancer•Nerve sparing dissection of left paraaortic infrarenal lymph compartment•Educational video may be basis for standardization of paraaortic sentinel node dissection.

Early ovarian cancer surgery with indocyanine-green-guided targeted compartmental lymphadenectomy (TCL, pelvic part).

OBJECTIVE: Para-aortic indocyanine-green (ICG)-guided targeted compartmental lymphadenectomy is feasible in early ovarian cancer; systematic pelvic and para-aortic lymphadenectomy could potentially be avoided if thoroughly investigated sentinel nodes could predict whether residual nodes will be involved or free of disease. In contrast to advanced ovarian cancer, where the therapeutic potential of lymphadenectomy will soon be clarified by the results of the Arbeitsgemeinschaft Gynäkologische Onkologie lymphadenectomy in ovarian neoplasms (AGO LION) trial, systematic lymphadenectomy seems to be mandatory for diagnostic and also therapeutic purposes in early ovarian cancer. Sentinel node biopsy or resection of the regional lymphatic network may reduce morbidity compared to systematic lymphadenectomy as shown already for other entities. Apart from the ovarian mesonephric pathway, a second Müllerian uterine pathway exists for lymphatic drainage of the ovary. Lymphatic valves apparently do not exist at this level of the utero-ovarian network since injection of radioactivity into the ovarian ligaments also labelled pelvic nodes. METHODS: We applied ICG using 4×0.5 mL of a 1.66 mg/mL ICG solution for transcervical injection into the fundal and midcorporal myometrium at each side [10] instead of injection into the infundibulopelvic ligament, since the utero-ovarian drainage was intact. RESULTS: In this case a 1.8 cm cancer of the right ovary was removed in continuity with its draining lymphatic vessels and at least the first 2 sentinel nodes in each channel "en bloc" as shown in this video for the pelvic part, consistent with the loco-regional ontogenetic approach. CONCLUSION: This could potentially avoid most of systematic lymphadenectomies in early ovarian cancer.

Surgical treatment of early ovarian cancer with compartmental resection of regional lymphatic network and indocyanine-green-guided targeted compartmental lymphadenectomy (TCL, paraaortic part).

OBJECTIVE: Whether pelvic and para-aortic lymphadenectomy is of therapeutic benefit in advanced ovarian cancer will remain unclear until the publication of the Arbeitsgemeinschaft Gynäkologische Onkologie lymphadenectomy in ovarian neoplasms (AGO LION) trial. In early ovarian cancer, however, lymphadenectomy seems mandatory for diagnostic and also therapeutic reasons. METHODS: Complete systematic lymphadenectomy is accompanied by morbidity which may be reduced by sentinel node biopsy already established for several solid tumors. In ovarian cancer there are 2 main pathways in lymphatic drainage: along the ovarian vessels to the para-aortic nodes and the uterine vessels to the iliac lymph compartments. Following injection of radioactive dye into the ovarian ligaments this could be confirmed suggesting that there is bidirectional flow at this level of the ovarian and uterine lymphatic pathways. Indocyanine-green-guided (ICG) injection to the uterine corpus seems to be equally effective in labelling the "uterine Müllerian" and the "ovarian mesonephric" lymphatic drainage of the ovary. RESULTS: This technique was applied and will be outlined in the video showing the procedure with respect to the para-aortic lymphatic drainage. Isolated sentinel node biopsy and tumor excision will not resect the organ compartment together with its super-ordinated draining lymphatic system at risk. CONCLUSION: Thus, the authors suggest to remove the malignancy together with its draining lymphatic vessels and at least the first 2 sentinel nodes in each channel en bloc; we propose to analyze this procedure consistent with the ontogenetic approach with respect to diagnostic accuracy and loco-regional control. This could potentially avoid most of systematic lymphadenectomies in early ovarian cancer.

Left paraaortic, inframesenteric lymphadenectomy preserving the superior hypogastric plexus supported by indocyanine green (ICG) labeling of the lymphatic compartment in cervical cancer.

Superior hypogastric plexus (SHG) contains mainly sympathetic and most probably also postganglionic parasympathetic fibers. Thus, surgical damage of SHG may cause autonomic pelvic organ dysfunction (Kraima et al., 2015). As already shown for rectal cancer, preservation of the autonomic nerves is facilitated by robotic surgery and may avoid sexual dysfunctions and voiding disorders (Kim et al., 2015). In this educational video, we demonstrate left lower paraaortic lymph node dissection preserving the SHG using ICG fluorescence to label the lymphatic compartment. Prior to total mesometrial resection (TMMR) with therapeutic lymphadenectomy for cervical cancer (Höckel et al., 2009, Kimmig et al., 2013) 4 × 0.5 ml of a 1.66 mg/ml Indocyanine green solution (ICG Pulsion®, PMS SE, Feldkirchen, Germany) was injected into the uterine cervix at all four quadrants, 0.5 cm in depth (Kimmig et al., 2016). The lymphatic network of the downstream common iliac and inferior paraaortic lymph compartments of the uterine cervix is visualized (ICG fluorescence) including the individual connecting vessels between the different compartments. As can be demonstrated, the medial upper common iliac (subaortic) compartment drains preferentially into the anterior (mesenteric) compartment, whereas lateral common iliac lymphatic vessels mainly drain to the posterior (lumbar) paraaortic compartment. The autonomic nerve fibers of the SHP may easily be identified and preserved due to the excellent image resolution and the discrimination from fluorescent lymphatic structures. The video shows the preparation of left lower paraaortic nodes in cervical cancer following ICG labeling using a da Vinci Xi system®. This technique seems not only advantageous for preserving SHP, but even more highly educational to learn surgical anatomy for trainees.

Distant metastasis detected by routine staging in breast cancer patients participating in the national German screening programme: consequences for clinical practice.

PURPOSE: To determine frequency of routine radiological staging of breast cancer patients diagnosed in a German Breast Cancer Screening Center from 2007 to 2014, the incidence and consequences of distant metastases detected and the resulting implications for clinical routine. METHODS: Records of 896 patients with primary breast cancer diagnosed in the Screening Centre and treated in five participating hospitals were analyzed retrospectively. Evaluation included frequency and type of staging procedures and results with respect to distant metastasis and their consequences on clinical management. RESULTS: 894/896 Patients (99.8 %) received staging for distant metastases by bone scintigraphy, chest X-ray and liver sonography and/or CT/MRT diagnostics. Distant metastasis was suggested In 6/894 patients but excluded in 3 by further diagnostics or clinical course. Thus, 3 (0.3 %) were clinically verified to have metastatic disease in bone (n = 2; both pT2) or in bone and lung (n = 1; cT4, cN3). CONCLUSION: Due to the low incidence of verified metastatic disease, the high false positive rate of staging procedures and the unfavorable cost/benefit ratio routine radiological staging should be completely omitted in asymptomatic breast cancer patients diagnosed in a breast cancer screening programme.

Zinc distribution within breast cancer tissue: A possible marker for histological grading?

PURPOSE: Focusing on the trace metal zinc as a potential biomarker for breast cancer, the literature describes bulk zinc concentrations in breast cancer tissue to be higher than in normal tissue. From a histopathological point of view, cancer cells are intermingled with normal cells of the stroma within breast cancer tissues; therefore, bulk analysis cannot reflect this situation adequately. To address this problem, analysis of zinc distribution in histological sections is the method of choice. METHODS: In the present study, nine samples of invasive ductal and lobular breast carcinoma of histological grade 1-3 were investigated, clearly differentiating between cancer and stroma areas. Zinc concentrations were determined by laser ablation inductively coupled plasma mass spectrometry applying a calibration technique based on spiked polyacrylamide gels. RESULTS: Direct comparison between hematoxylin- and eosin-stained tissues and zinc contour plots revealed that zinc is enriched in cancer tissue containing tumor cells in contrast to normal stroma. Moreover, zinc concentration in carcinomatous tissues directly correlates with the histological malignancy grade. CONCLUSIONS: Differentiation between carcinomatous tissue and stroma by determination of zinc content and the correlation of zinc concentration with the histological malignancy grade not only provides a key feature for clinical decision making for cancer therapy but also suggests the trace metal zinc as a potential biomarker for breast cancer.