Detachable shape-memory sewing ring for heart valves

The novel sewing ring concept consists of a detachable ring snap connection between valve housing or stent and suture cuff. The suture cuff itself is a memory metal ring of nickel-titanium (NiTi) that is embedded within a textile fabric torus. After a special training program the ring can assume two geometric shapes when alternately cooled and heated. Due to this physical property, the sewing ring can be safely fixed within a groove of the housing or stent by changing between room and physiological temperature. This allows the surgeon first to implant the sewing ring followed by arbitrary positioning and final fixation of the valve by the shape-memory effect. Additional advantages are an increased stiffening of the valve base for minimizing potential leaflet dysfunction, and reduced time and risk of implantation, particularly when a reoperation is necessary.     

Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients.

PURPOSE: To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays. RESULTS: The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation. CONCLUSION: We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.     

Three-dimensional power Doppler sonography of the (sub)endometrium and angiogenic cytokine concentrations

The aim of this study was to determine the correlation between three-dimensional power Doppler sonography (3D-PDS) of the (sub)endometrium and concentrations of angiogenic cytokines in patients attending an IVF programme. A total of 42 patients was included in a prospective, non-randomized clinical study. 3D-PDS of the (sub)endometrium was performed on the day of oocyte aspiration, with and without contrast agent. Quantitative assessment included the following 3D Doppler parameters: vascularization index, flow intensity, and vascularization flow index. On the same day, concentrations of oestradiol (serum only), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF) 1, IGF-binding protein 3 (IGFBP-3) and leptin were determined in the serum and in the follicular fluid. All 3D-PDS indices were significantly higher with contrast enhancement (P < 0.05). Follicular fluid concentrations of VEGF and IGFBP-3, as well as serum concentrations of leptin, showed significant P-values when correlated with (sub)endometrial Doppler indices. A weak linear dependency appeared between flow intensity and VEGF and leptin. Furthermore, weak dependencies were apparent between 3D Doppler parameters and high follicular fluid concentrations of VEGF and IGFBP-3. It is concluded that there is only little evidence for an association between (sub)endometrial Doppler indices as assessed by 3D-PDS and concentrations of angiogenic cytokines.     

Early experience with the ARTISENTIAL® articulated instruments in laparoscopic low anterior resection with TME

Techniques in Coloproctology - The notion of articulation in surgery has been largely synonymous with robotics. The ARTISENTIAL® instruments aim at bringing advanced articulation to...     

Construction and in vivo evaluation of a dual layered collagenous scaffold with a radial pore structure for repair of the diaphragm

In each organ the extracellular matrix has a specific architecture and composition, adapted to the functional needs of that organ. As cells are known to respond to matrix organization, biomaterials that take into account the specific architecture of the tissues to be regenerated may have an advantage in regenerative medicine. In this study we focussed on the diaphragm, an organ essential for breathing, and consisting of radial oriented skeletal muscle fibres diverging from a central tendon plate. To mimic this structure dual layered collagenous scaffolds were constructed with a radial pore orientation, prepared by inward out freezing, and reinforced by a layer of compressed collagen. Similar scaffolds with a random round pore structure were taken as controls. Scaffolds were first mildly crosslinked by formaldehyde vapour fixation for initial stabilization (13% and 17% crosslinking for the radial and control scaffolds, respectively), and further crosslinked using aqueous 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (38% and 37% crosslinking, respectively). Scaffolds were implanted into a surgically created diaphragm defect in rats and explanted after 12 weeks. Macroscopically, integration of the radial scaffolds with the surrounding diaphragm was better compared with the controls. Cells had infiltrated further into the centre of the scaffolds (P = 0.029) and there was a tendency of blood vessels to migrate deeper into the radial scaffolds (P = 0.057, compared with controls). Elongated cells (SMA-positive) were aligned with the radial structures. In conclusion, collagenous scaffolds with a stable radial pore structure can be constructed which facilitate cellular in-growth and alignment in vivo.     

Click-Evoked Otoacoustic Emissions in Children and Adolescents with Gender Identity Disorder

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds that are produced by the inner ear in response to click-stimuli. CEOAEs generally have a higher amplitude in women compared to men and neonates already show a similar sex difference in CEOAEs. Weaker responses in males are proposed to originate from elevated levels of testosterone during perinatal sexual differentiation. Therefore, CEOAEs may be used as a retrospective indicator of someone’s perinatal androgen environment. Individuals diagnosed with Gender Identity Disorder (GID), according to DSM-IV-TR, are characterized by a strong identification with the other gender and discomfort about their natal sex. Although the etiology of GID is far from established, it is hypothesized that atypical levels of sex steroids during a critical period of sexual differentiation of the brain might play a role. In the present study, we compared CEOAEs in treatment-naïve children and adolescents with early-onset GID (24 natal boys, 23 natal girls) and control subjects (65 boys, 62 girls). We replicated the sex difference in CEOAE response amplitude in the control group. This sex difference, however, was not present in the GID groups. Boys with GID showed stronger, more female-typical CEOAEs whereas girls with GID did not differ in emission strength compared to control girls. Based on the assumption that CEOAE amplitude can be seen as an index of relative androgen exposure, our results provide some evidence for the idea that boys with GID may have been exposed to lower amounts of androgen during early development in comparison to control boys.     

Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.