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Purpose: Acetabular defect reconstruction can be a complex and challenging surgical procedure, with stable long-term fixation of the implants remaining the ultimate goal. The purpose of this study was (1) to evaluate the radiological and clinical outcome of complex acetabular reconstruction surgery with the use of modular tantalum TM augments in combination with cemented revision cups; (2) to investigate blood tantalum concentrations in these patients; and (3) to report complications and mechanisms of failure related to this procedure at mid-term follow-up (mean 4.5 years). Methods: We retrospectively reviewed 29 patients (29 hips) with severe acetabular bone loss (Paprosky type III A) reconstructed using a modular tantalum TM augment in combination with a cemented cup. We evaluated the implant survival and the radiological and clinical outcomes after a mean follow-up of 4.5 years (SD 2.2; range 8.4 – 2.1 years) using patient reported outcome scores (PROMs). Blood samples were analysed regarding tantalum concentration and compared with a control group. Results: The cumulative survival rate at 4.5 years with the endpoint "revision of the acetabular component for any reason" was 96.2% (95% Confidence Interval 75.7–99.5). The PROMs improved significantly up to the latest follow-up, and radiographic data showed only one patient with signs of initial implant migration with a broken screw and a change of the position of the augment and the cup. Mean blood tantalum concentrations were significantly higher in the study group (0.16 µg/L) compared to the control group (0.002 µg/L) (P < 0.001). Conclusions: This study has demonstrated good mid-term (mean 4.5 years) clinical and radiological outcomes of modular tantalum TM augments in combination with a cemented cup for the reconstruction of major acetabular defects. Mean blood tantalum concentrations were increased in patients with stable tantalum implants compared to healthy controls. [ABSTRACT FROM AUTHOR]

Introduction: The radiographic evaluation of novel cementless anatomic polyethylene (PE) glenoid components featuring a titanium-coated back is still unclear. This study explores potential radiolucent lines (RLL) between the radiopaque titanium layer and sclerotic convex reamed bone in an intermodal comparison analysis with computed tomography (CT) scans. Materials and methods: Eight RM pressfit vitamys glenoids (Mathys®) were implanted into cadaveric scapulae. In the CT scans, glenoids were quantified by evaluating ideal complete bony support (NO GAP) and gap between bone and titanium coating (GAP). X-rays were in perfect 0-degree projection and tilted in ± 10° and ± 20° mediolateral (ml) and craniocaudal (cc) directions. Radiographs evaluated were graded as NO RLL, RLL (gap > 1 mm) or DL (double line, gap < 1 mm) in an intermodal comparison of CT and X-ray findings. Results: The inter-rater (Cohen's = 0.643) and intra-rater reliability (Cohen's = 0.714) were good. The overall evaluation showed a significant agreement between (NO) RLL on X-ray and (NO) GAP on CT (p < 0.001). The − 10-degree ml projection showed good agreement between CT and X-ray (Cohen's = 0.628). Adequate agreement was shown at 0 degrees (Cohen's = 0.386), + 10 degrees ml (Cohen's = 0.338), and + 20 degrees cc (Cohen's = 0.327). Compared to the scenario DL = NO RLL, the true a.p. view showed better sensitivity when the DL is classified as RLL. Conversely, the true a.p. view demonstrated both better specificity and significant agreement between the X-ray and CT findings in scenario when DL = No RLL. Conclusion: Standard true a. p. projections are reliable in ruling out gaps when no RLL or DL is visible and the detection of RLL shows high intermodal agreement. Varying agreement across tilting angles emphasizes the importance of a comprehensive approach in evaluating bone support and CT is indispensable for a scientifically reliable assessment. Level of evidence: Level III Treatment Study. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the role of leg alignment on long‐term clinical outcome after matrix‐associated autologous chondrocyte implantation (M‐ACI) and to define an individualized target range to optimize clinical outcome. Methods: The present study examined patients who underwent M‐ACI of the femoral condyle. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) were used to assess the results. Clinical outcomes were related to Patient Acceptable Symptomatic State (PASS). For intra‐ and interobserver reliability of mechanical tibiofemoral angle, mechanical medial proximal tibial angle and mechanical lateral distal femoral angle, we calculated intraclass correlation coefficients using a two‐way mixed model with absolute agreement. A regression model and receiver‐operating characteristics curve were used to identify an individual range of alignment where a favourable clinical outcome could be expected in the long term. Results: Additional osteotomy was performed in 50% of patients with similar clinical outcomes as physiologically aligned patients (p > 0.05). The curve‐fitting regression model identified a target range of −2.5° valgus to 4.5° varus for ideal postoperative alignment (R2 = 0.12, p = 0.01). Patients within this range were more likely to achieve PASS (70% vs. 27%, p = 0.001). In medially treated defects, a refined range of −2.5° valgus to 4° varus alignment was found (R2 = 0.15, p = 0.01). These patients were more likely to achieve PASS (67% vs. 30%, p = 0.01) and showed favourable postoperative KOOS and MOCART scores (p = 0.02). Patients with lateral defects were more likely to achieve PASS within a range of −2° valgus and 0.5° varus (90% vs. 45%, p = 0.03) and showed favourable postoperative KOOS and MOCART scores (p = not significant). Conclusions: An individual range of leg alignment—whether achieved by osteotomy or physiologic alignment—should be respected in M‐ACI treatment. A neutral to slightly undercorrected alignment favours the postoperative outcome after M‐ACI. When planning surgery for patients with focal cartilage defects of the femoral condyle, these ranges should be recognized as critical factors. Level of Evidence: Level III. [ABSTRACT FROM AUTHOR]

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Abstract Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple‐negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their ‘basal‐like’ transcriptional profiles. We therefore hypothesized that targeting TNBC cells on a systems level by exploiting the transcriptional cell state might be a viable strategy to find novel therapies for this highly aggressive disease. We performed a large‐scale chemical genetic screen and identified a group of compounds related to the drug PKC412 (midostaurin). PKC412 induced apoptosis in a subset of TNBC cells enriched for the basal‐like subtype and inhibited tumor growth in vivo. We employed a multi‐omics approach and computational modeling to address the mechanism of action and identified spleen tyrosine kinase (SYK) as a novel and unexpected target in TNBC. Quantitative phosphoproteomics revealed that SYK inhibition abrogates signaling to STAT3, explaining the selectivity for basal‐like breast cancer cells. This non‐oncogene addiction suggests that chemical SYK inhibition may be beneficial for a specific subset of TNBC patients and demonstrates that targeting cell states could be a viable strategy to discover novel treatment strategies.

The testis produces gametes through spermatogenesis and evolves rapidly at both the morphological and molecular level in mammals1–6, probably owing to the evolutionary pressure on males to be reproductively successful7. However, the molecular evolution of individual spermatogenic cell types across mammals remains largely uncharacterized. Here we report evolutionary analyses of single-nucleus transcriptome data for testes from 11 species that cover the three main mammalian lineages (eutherians, marsupials and monotremes) and birds (the evolutionary outgroup), and include seven primates. We find that the rapid evolution of the testis was driven by accelerated fixation rates of gene expression changes, amino acid substitutions and new genes in late spermatogenic stages, probably facilitated by reduced pleiotropic constraints, haploid selection and transcriptionally permissive chromatin. We identify temporal expression changes of individual genes across species and conserved expression programs controlling ancestral spermatogenic processes. Genes predominantly expressed in spermatogonia (germ cells fuelling spermatogenesis) and Sertoli (somatic support) cells accumulated on X chromosomes during evolution, presumably owing to male-beneficial selective forces. Further work identified transcriptomal differences between X- and Y-bearing spermatids and uncovered that meiotic sex-chromosome inactivation (MSCI) also occurs in monotremes and hence is common to mammalian sex-chromosome systems. Thus, the mechanism of meiotic silencing of unsynapsed chromatin, which underlies MSCI, is an ancestral mammalian feature. Our study illuminates the molecular evolution of spermatogenesis and associated selective forces, and provides a resource for investigating the biology of the testis across mammals.Evolutionary analyses of single-nucleus transcriptome data for testes from 11 species are reported, illuminating the molecular evolution of spermatogenesis and associated forces, and providing a resource for investigating the testis across mammals. [ABSTRACT FROM AUTHOR]

Copyright of Der Unfallchirurg is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We explore the effect of connectivity and topology on the dynamical behaviour of Reservoir Computers. At present, considerable effort is taken to design and hand-craft physical reservoir computers. Both structure and physical complexity are often pivotal to task performance, however, assessing their overall importance is challenging. Using a recently developed framework, we evaluate and compare the dynamical freedom (referring to quality) of neural network structures, as an analogy for physical systems. The results quantify how structure affects the behavioural range of networks. It demonstrates how high quality reached by more complex structures is often also achievable in simpler structures with greater network size. Alternatively, quality is often improved in smaller networks by adding greater connection complexity. This work demonstrates the benefits of using dynamical behaviour to assess the quality of computing substrates, rather than evaluation through benchmark tasks that often provide a narrow and biased insight into the computing quality of physical systems. [ABSTRACT FROM AUTHOR]

The first in vitro tests for developmental toxicity made use of rodent cells. Newer teratology tests, e.g. developed during the ESNATS project, use human cells and measure mechanistic endpoints (such as transcriptome changes). However, the toxicological implications of mechanistic parameters are hard to judge, without functional/morphological endpoints. To address this issue, we developed a new version of the human stem cell-based test STOP-tox(UKN). For this purpose, the capacity of the cells to self-organize to neural rosettes was assessed as functional endpoint: pluripotent stem cells were allowed to differentiate into neuroepithelial cells for 6 days in the presence or absence of toxicants. Then, both transcriptome changes were measured (standard STOP-tox(UKN)) and cells were allowed to form rosettes. After optimization of staining methods, an imaging algorithm for rosette quantification was implemented and used for an automated rosette formation assay (RoFA). Neural tube toxicants (like valproic acid), which are known to disturb human development at stages when rosette-forming cells are present, were used as positive controls. Established toxicants led to distinctly different tissue organization and differentiation stages. RoFA outcome and transcript changes largely correlated concerning (1) the concentration-dependence, (2) the time dependence, and (3) the set of positive hits identified amongst 24 potential toxicants. Using such comparative data, a prediction model for the RoFA was developed. The comparative analysis was also used to identify gene dysregulations that are particularly predictive for disturbed rosette formation. This 'RoFA predictor gene set' may be used for a simplified and less costly setup of the STOP-tox(UKN) assay. [ABSTRACT FROM AUTHOR]

Engineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000 mg/m2 of body surface on day 1 of 21-day cycles) as single agent, while in two other arms L19IL2 (22.5 million international units of IL2 equivalents) was added, based on two different schedules of administration. In total, 69 patients with stage IV melanoma were enrolled (24 in the dacarbazine arm, 23 and 22 in the other combination arms, respectively) and 67 received treatment. Analyses of efficacy results show a statistically significant benefit in terms of overall response rate and median progression-free survival for patients receiving L19IL2 in combination with DTIC, compared to DTIC as single agent. In light of these results, further clinical investigations with L19IL2 (alone or in combination with other agents) are warranted. [ABSTRACT FROM AUTHOR]

Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored, little is known about effects of minor, possibly pleiotropic, genome changes. We addressed this question for the human dopaminergic neuronal precursor cell line LUHMES by comparing two subpopulations (SP) maintained either at the American-Type-Culture-Collection (ATCC) or by the original provider (UKN). Drastic differences in susceptibility towards the specific dopaminergic toxicant 1-methyl-4-phenylpyridinium (MPP+) were observed. Whole-genome sequencing was performed to identify underlying genetic differences. While both SP had normal chromosome structures, they displayed about 70 differences on the level of amino acid changing events. Some of these differences were confirmed biochemically, but none offered a direct explanation for the altered toxicant sensitivity pattern. As second approach, markers known to be relevant for the intended use of the cells were specifically tested. The "ATCC" cells rapidly down-regulated the dopamine-transporter and tyrosine-hydroxylase after differentiation, while "UKN" cells maintained functional levels. As the respective genes were not altered themselves, we conclude that polygenic complex upstream changes can have drastic effects on biochemical features and toxicological responses of relatively similar SP of cells. [ABSTRACT FROM AUTHOR]

Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer. [ABSTRACT FROM AUTHOR]

Genotoxic chemotherapy is the most common cancer treatment strategy. However, its untargeted generic DNA-damaging nature and associated systemic cytotoxicity greatly limit its therapeutic applications. Here, we used a haploid genetic screen in human cells to discover an absolute dependency of the clinically evaluated anticancer compound YM155 on solute carrier family member 35 F2 (SLC35F2), an uncharacterized member of the solute carrier protein family that is highly expressed in a variety of human cancers. YM155 generated DNA damage through intercalation, which was contingent on the expression of SLC35F2 and its drug-importing activity. SLC35F2 expression and YM155 sensitivity correlated across a panel of cancer cell lines, and targeted genome editing verified SLC35F2 as the main determinant of YM155-mediated DNA damage toxicity in vitro and in vivo. These findings suggest a new route to targeted DNA damage by exploiting tumor and patient-specific import of YM155. [ABSTRACT FROM AUTHOR]

Background: α(v) integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α(v)-integrin monoclonal antibody.Methods: In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1:1:1:1 to 1000 mg m(-2) dacarbazine+placebo (n=32), 1000 mg m(-2) dacarbazine+10 mg kg(-1) intetumumab (n=32), 10 mg kg(-1) intetumumab (n=33), or 5 mg kg(-1) intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics.Results: No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg(-1) intetumumab, and 5 mg kg(-1) intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab-dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1-2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22-30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16-73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred.Conclusion: With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma. [ABSTRACT FROM AUTHOR]

Purpose: There are no biological markers available to predict outcome in melanoma patients treated with adjuvant interferon-alpha (IFN-α). The clinical activity of IFN-α is thought to be mediated not only by anti-proliferative effects, but also by induction and modulation of secondary cytokines. We examined serum cytokine levels in IFN-α-treated patients to find potential biological markers for response or toxicity. Patients and methods: In a prospective randomized trial, 66 stages II and III melanoma patients underwent an induction treatment of 10 MU IFN α2b s.c. 5×/week, followed by either 5 MU or 10 MU IFN α2b s.c. 3×/week for a total of 2 years. Serial measurements of serum IL-1β, IL-2, sIL-2R, IL-6, IL-10, TNF-α and β-2 microglobulin (B2M) were taken. Two factorial analysis of repeated measurements (ANOVA) as well as univariate and multivariate analyses was used to identify prognostic factors for relapse and toxicity. Results: TNF-α levels correlated with toxicity. In patients with relapse, significantly lower levels of TNF-α were detected at baseline and throughout therapy compared with patients without relapse. B2M and sIL-2R showed a significant increase throughout the therapy phase. At baseline, the combination of TNF-α, B2M and sIL-2R revealed a positive predictive value for relapse of 82.9% in the multivariate analyses. Conclusion: Low TNF-α levels are negatively associated with relapse-free survival. Conversely, high TNF-α levels are correlated with toxicity but seem to be beneficial to patients with regard to relapse-free survival. B2M and sIL-2R are biological markers of adjuvant IFN-α2b treatment. [ABSTRACT FROM AUTHOR]

There are situations where exact identification and localisation of sentinel lymph nodes (SLNs) are very difficult using lymphoscintigraphy, a hand-held gamma probe and vital dye, either a priori or a posteriori. We developed a new method using a simultaneous injection of two lymphotropic agents for exact topographical tomographic localisation and biopsy of draining SLNs. The purpose of this prospective pilot study was to investigate the feasibility and efficacy of this method ensemble. Fourteen patients with different tumour entities were enrolled. A mixture of 99mTc-nanocolloid and a dissolved superparamagnetic iron oxide was injected interstitially. Dynamic, sequential static lymphoscintigraphy and SPECT served as pathfinders. MR imaging was performed 2 h after injection. SPECT, contrast MRI and, if necessary, CT scan data sets were fused and evaluated with special regard to the topographical location of SLNs. The day after injection, nine patients underwent SLN biopsy and, in the presence of SLN metastasis, an elective lymph node dissection. Twenty-five SLNs were localised in the 14 patients examined. A 100% fusion correlation was achieved in all patients. The anatomical sites of SLNs detected during surgery showed 100% agreement with those localised on the multimodal fusion images. SLNs could be excised in 11/14 patients, six of whom had nodal metastasis. Our novel approach of multimodal fusion imaging for targeted SLN management in primary tumours with lymphatic drainage to anatomically difficult regions enables SLN biopsy even in patients with lymphatic drainage to obscure regions. Currently, we are testing its validity in larger patient groups and other tumour entities. [ABSTRACT FROM AUTHOR]

Purpose: Merkel cell carcinoma (MCC) is the most aggressive of the cutaneous malignancies, showing a propensity to spread to regional lymph nodes (LNs). The aim of this prospective study was to examine the feasibility and clinical impact of sentinel lymph node biopsy (SLNB) in this cutaneous malignancy. Methods: The study population comprised 23 patients with stage I MCC (median age 70 years, range 50-85 years). Lymphoscintigraphic mapping with 99mTc-nanocolloid was performed in all patients. Sentinel lymph nodes (SLNs) were identified, excised and analysed in serial sections by conventional histopathology and cytokeratin-20 immunohistochemistry. Results: Metastatic disease was determined in the SLNs of 11 patients (47.8%). Elective lymph node dissection (ELND) was performed in eight of these 11 patients, four of whom had additional positive LNs. During follow-up (median 36.1 months, range 3-79 months), seven of the 23 patients (30%) relapsed: four had a local recurrence and three, in-transit metastases. Recurrence developed in two SLN-negative patients with local LN metastases and in one SLN-positive patient with distant metastases. This patient died, representing the only tumour-related death in our sample. Median survival was 49.1 and 35.5 months for SLN-negative and SLN-positive patients, respectively. This difference was not statistically significant (p = 0.3452). Conclusion: SLNB allows for exact nodal staging in patients with MCC. Whether additional ELND is of further benefit remains unclear. [ABSTRACT FROM AUTHOR]

Brain metastases are a common complication in patients suffering from metastatic malignant melanoma. We analyzed efficacy and toxicity of the alkylating agent temozolomide with excellent CNS penetration and known activity in brain metastasis in 35 patients with unresectable melanoma brain metastases. Patients received 200mg/m2 temozolomide on days 1 to 5 every 28days as first or second-line therapy. This therapy regimen was combined with radiotherapy of the brain metastases in 22/35 patients. Grade III and IV toxicity was observed in 8/35 patients (leukopenia, granulocytopenia, thrombocytopenia, anemia, nausea and obstipation). Complete remission was observed in 1/34, partial remission in 2/34 and stable disease in 9/34 patients. In 5/34 a mixed response was assessed, 17/34 had disease progression and in one patient tumor response was not evaluable. The median progression free time was 5 (08)months for all patients, the median survival time for all patients from start of therapy was 8 (028)months, 9 (228)months in patients with concurrent stereotactic radiotherapy and 7 (317)months in patients with concurrent whole brain radiotherapy. Our results demonstrate that temozolomide can be combined with radiotherapy for the treatment of brain metastases in malignant melanoma, and that this combination may prolong survival in this patient group. [ABSTRACT FROM AUTHOR]

Hybrid cells generated by fusing allogenic-presenting cells, such as dendritic cells, with tumor cells are a new tool in cancer immunotherapy which are designed to enhance the immunogenicity of antigenic tumors by presenting the whole spectrum of tumor-associated antigens, by providing the co-stimulatory molecules required for T-cell activation, and by the expression of allogenic MHC molecules for recruitment and activation of T-cell help. This approach has been successfully tested in animal models as well as in clinical phaseI/II trials with various tumors. Besides clinical repsonses, induction of tumor-specific cytolytic T-cells were observed. The electrofusion protocol described here has the advantage of high fusion efficiency, high hybrid-cell viability, as well as high reproducibility, and can be used for various tumor cell types after minor adjustments are made to the instrument settings in order to process large numbers of dendritic cells with consistent efficiencies. [ABSTRACT FROM AUTHOR]

Antibodies such as HMB-45 and anti-S100 protein have been widely used as markers of malignant melanoma despite evidence that HMB-45 has a sensitivity of only 67–93% and S100 is nonspecific for melanoma. Using a subtractive immunization protocol in a mouse model of human melanoma, we have generated several monoclonal antibodies with putative specificity for melanoma. After initial screenings, the antibody SM5-1 was chosen because of its intriguing reactivity with melanocytic tumors in both frozen and paraffin sections. The immunohistochemical staining of SM5-1 was studied in paraffin-embedded specimens of 401 melanomas (n = 401; 250 primary melanomas, 151 metastases), melanocytic nevi of the skin (n = 16), nonmelanocytic neoplasms (n = 84). The results were compared with HMB-45 and anti-S100 staining. All antibodies reacted with nevi and 97–99% with primary melanomas. Whereas both SM5-1 and anti-S100 stained 96% (146/151) of melanoma metastases, HMB-45 correctly identified only 83% (126/151). All HMB-45-negative metastases were positive for SM5-1. Whereas neither SM5-1 nor HMB-45 stained any of 84 specimens from 40 different nonmelanocytic neoplasms, anti-S100 was positive in 21/84 (25%). While the staining pattern of SM5-1 was mostly homogeneous, small tumor areas in some metastases remained unstained. Staining with SM5-1 was also observed in perivascular dendritic cells, in plasma cells, some myofibroblasts and the secretion of eccrine sweat glands. Nonactivated epidermal melanocytes, keratinocytes, endothelial cells, smooth muscle cells and peripheral nerves were all negative for SM5-1. These results suggest that SM5-1 is highly specific, as well as sensitive, for melanocytic lesions and is useful in the immunohistochemical evaluation of melanoma. [ABSTRACT FROM AUTHOR]

Reports of spontaneous regressions of metastases and the demonstration of tumor-reactive cytotoxic T lymphocytes indicate the importance of the host's immune system in controlling the devastating course of metastatic renal cell carcinoma. Recent research indicates that immunization with hybrids of tumor and antigen presenting cells results in protective immunity and rejection of established tumors in various rodent models. Here, we present a hybrid cell vaccination study of 17 patients. Using electrofusion techniques, we generated hybrids of autologous tumor and allogeneic dendritic cells that presented antigens expressed by the tumor in concert with the co-stimulating capabilities of dendritic cells. After vaccination, and with a mean follow-up time of 13 months, four patients completely rejected all metastatic tumor lesions, one presented a ‘mixed response’, and two had a tumor mass reduction of greater 50%. We also demonstrate induction of HLA-A2-restricted cytotoxic T cells reactive with the Muc1 tumor-associated antigen and recruitment of CD8+ lymphocytes into tumor challenge sites. Our data indicate that hybrid cell vaccination is a safe and effective therapy for renal cell carcinoma and may provide a broadly applicable strategy for other malignancies with unknown antigens. [ABSTRACT FROM AUTHOR]

Reservoir Computing is a computing model ideal for performing computation on varied physical substrates. However, these physical reservoirs can be difficult to scale up. We propose joining various reservoirs together as an approach to solving this problem, simulating physical reservoirs with Echo State Networks (ESNs). We investigate various methods of combining ESNs to form larger reservoirs, including a method that we dub Restricted ESNs. We provide a notation for describing Restricted ESNs, and use it to benchmark a standard ESN against restricted ones. We investigate two methods to keep the weight matrix density consistent when comparing a Restricted ESN to a standard one, which we call overall consistency and patch consistency. We benchmark restricted ESNs on NARMA10 and the sunspot prediction benchmark, and find that restricted ESNs perform similarly to standard ones. We present some application scenarios in which restricted ESNs may offer advantages over standard ESNs. We then test restricted ESNs on a version of the multi-timescale Multiple Superimposed Sines tasks, in order to establish a baseline performance that can be improved upon in further work. We conclude that we can scale up reservoir performance by linking small homogeneous subreservoirs together without significant loss in performance over a single large reservoir, justifying future work on using heterogeneous subreservoirs for greater flexibility. [ABSTRACT FROM AUTHOR]

Interleukin-7 (IL-7) is thought to be a growth factor for cutaneous T-cell lymphoma (CTCL) since it has been shown that IL-7 transgenic mice develop a cutaneous disorder characterized by enhanced T-cell proliferation with progression to malignancy and that in vitro growth of Sézary cell lines is IL-7 dependent. However, no direct in vivo evidence exists for the involvement of IL-7 in the pathogenesis of CTCL. Therefore, we examined IL-7 mRNA expression in skin biopsies from patients with mycosis fungoides (MF) ( n = 20) and pleomorphic T-cell lymphoma ( n = 5). By semiquantitative RT-PCR, IL-7 mRNA was not detectable in any of the CTCL samples, or in normal human skin ( n = 8) or in skin from patients with psoriasis ( n = 7) or atopic dermatitis ( n = 5). In contrast, IL-7 mRNA was detected in a biopsy from a kidney allograft transplant, in normal keratinocytes under various culture conditions and in several cell lines. Interestingly, using a highly sensitive nested PCR, IL-7 mRNA was detectable in all specimens tested, but there was no indication of IL-7 overexpression in MF when analysing lesions of patch, plaque or tumour stages. In contrast, increasing CD3 expression was found, which was most likely a consequence of the enhanced density of malignant T cells in advanced tumour stages. In summary, by the use of semiquantitative RT-PCR we were not able to detect IL-7 overexpression in MF or pleomorphic T-cell lymphoma. This indicates that IL-7 is probably not an autocrine growth factor in these CTCLs. [ABSTRACT FROM AUTHOR]

The skin reaction to radiation is regularly monitored in order to detect enhanced radiosensitivity of the patient, unexpected interactions (e.g. with drugs) or any inadvertent overdosage. It is important to distinguish secondary disease from radiation reaction to provide adequate treatment and to avoid unnecessary discontinuation of radiotherapy. A case of bullous eruption or blisters during radiotherapy of the breast is presented. Differential diagnoses bullous pemphigoid, pemphigus vulgaris, and bullous impetigo are discussed and treatment described. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions Level of Evidence The purpose of this study was to evaluate long‐term survival, patient‐reported outcomes (PROs) and radiographic results of matrix‐associated autologous chondrocyte implantation (M‐ACI) in adolescents with immature cartilage and compare them to adult controls.A retrospective matched‐pair analysis was performed comparing the PRO after M‐ACI for focal cartilage defect of the knee in cartilaginous immature adolescents to mature adults. Groups were matched for sex, body mass index, defect site and size, symptom duration and the number of previous knee surgeries. Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART 2.0) scores were assessed at least 60 months postoperatively. Patient acceptable symptomatic state (PASS) and clinical response rate in KOOS and KOOS subscores were calculated.A total of 54 patients were matched. At a mean of 96 months (65–144 months), no surgical complications, graft hypertrophy or reoperations were noted in the cohorts studied. Adolescents showed superior PROs at the final follow‐up (76.9 ± 14.1 vs. 66.4 ± 15.0, p = 0.03) and were significantly more likely to achieve PASS (74.1% vs. 55.6%; p = 0.02) compared to the adult cohort. The KOOS subscale analysis showed long‐term benefits for adolescents in terms of symptom improvement, pain reduction, activities of daily living, sports and quality of life (p < 0.05). None of the patients in the adolescent group showed graft hypertrophy on magnet resonance imaging or signs of osteoarthritis on radiographs at long‐term follow‐ups.M‐ACI is an effective treatment for chondral defects of the knee in patients with immature cartilage with low revision rates and high patient satisfaction over the long term. Adolescents showed comparable clinical and radiographic results in the short and medium term, with slightly more favourable, clinically relevant functional results in adolescents in the long term. M‐ACI can be safely used in adolescents, and consideration should be given to expanding the indication to include these patients.Level III. [ABSTRACT FROM AUTHOR]