Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience.

BACKGROUND: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. RESULTS: A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. CONCLUSIONS: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.

Towards mobile gaze-directed beamforming: a novel neuro-technology for hearing loss.

Contemporary hearing aids are markedlylimited in their most important role: improving speech perception in dynamic "cocktail party" environments with multiple, competing talkers. Here we describe an open-source, mobile assistive hearing platform entitled "Cochlearity" which uses eye gaze to guide an acoustic beamformer, so a listener will hear best wherever they look. Cochlearity runs on Android and its eight-channel microphone array can be worn comfortably on the head, e.g. mounted on eyeglasses. In this preliminary report, we examine the efficacy of both a static (delay-and-sum) and an adaptive (MVDR) beamformer in the task of separating an "attended" voice from an "unattended" voice in a two-talker scenario. We show that the different beamformers have the potential to complement each other to improve target speech SNR (signal to noise ratio), across the range of speech power, with tolerably low latency.

Evaluation of the Metasin assay for intraoperative assessment of sentinel lymph node metastases in breast cancer.

AIMS: Sentinel lymph node (SLN) biopsy is the preferred surgical technique for staging the axilla in clinically node-negative breast cancer. Accurate intraoperative staging allows for the immediate performance of an axillary clearance in node-positive patients. We assessed the Metasin assay for the intraoperative analysis of SLNs in a prospective evaluation of 250 consecutive patients undergoing intraoperative SLN analysis at the Breast Unit, University Hospital, Southampton, UK. METHODS: Metasin uses a quantitative reverse transcription PCR to detect two markers of metastasis: cytokeratin 19 (CK19) an epithelial marker and mammaglobin (MGB) a breast specific marker. Metasin results were compared with the results from routine paraffin block histopathology. RESULTS: Metasin was robust, with a failure rate of <1%, and demonstrated excellent accuracy and reproducibility. The average turnaround time for the Metasin assay was 42 min, the largest variable being the number of nodes assayed. A total of 533 SLNs were evaluated with 75 patients testing positive for MGB and/or CK19. Based on the analysis of individual SLNs, the overall concordance between Metasin and histology was 92.3% (sensitivity 88.7%, specificity 92.9%). When adjusted for tissue allocation bias, the concordance was 93.8% (sensitivity 89.8%, specificity 94.6%). In this evaluation, 57/250 patients (23%) proceeded to axillary clearance based on Metasin results and were considered spared a second operative procedure. CONCLUSIONS: Metasin has proven to be an accurate, reproducible and reliable laboratory test. The analysis time is acceptable for intraoperative use, and in comparison to routine histology demonstrates acceptable concordance, sensitivity and specificity.

The expression of transforming growth factor type beta in fetal and adult rabbit skin wounds.

Transforming growth factor, subtype beta (TGF-beta) exists in several isoforms and is known to have important roles in adult wound healing by promoting collagen and extracellular matrix component deposition. It is also believed that TGF-beta influences normal developmental processes during embryo-genesis. Immunolocalization of two isoforms, TGF-beta 1 and TGF-beta 2, in healing fetal and adult rabbit skin wounds shows distinctly different forms of expression of these molecules. TGF-beta 1 and TGF-beta 2 are both expressed within the developing fetal dermis, but no differential upregulation in the area of the healing wound is noted. In contrast, the expression of TGF-beta 1 and TGF-beta 2 is increased in adult wounds by day 7 after wounding, within macrophages that are abundant by this time. High levels of TGF-beta 1 and TGF-beta 2 within adult wounds might indicate that the relative paucity and differential distribution of these factors in fetal wounds are important in the production of scar in adults and the absence of scar in the fetus. Further, these patterns of expression suggest fundamental differences between fetal and adult tissues in accomplishing wound repair.

The regulation of collagen in fetal skin wounds: mRNA localization and analysis.

The deposition of collagen in fetal skin wounds has been shown in several animal models. The authors used a radiolabeled RNA antisense probe, complementary to the mRNA for the alpha-1 chain of human procollagen type I, to assess regulation of this collagen species in fetal and adult rabbit wounds. Dorsal skin wounds were placed on fetal and maternal animals at the beginning of the third trimester, and were harvested 3, 5, and 7 days later. In situ RNA/RNA hybridization was performed on suitable specimens, and morphometric analysis was carried out with a computerized LECO image analyzer. Fetal wounds exhibited an inflow of mesenchymal cells that produced collagen type I at levels higher than the surrounding tissue; this activity was highest on days 3 and 5 after wounding. Adult wounds had increased fibroblast presence by day 7, producing collagen type I at levels higher than those of adjacent unwounded tissue. Morphometric analysis of the signal produced by in situ hybridization and of the number of cells producing the signal in a given field showed that fetal wounds appear to produce collagen type I by an increase in the number of cells in the area of the wound--not by induction of the gene for procollagen type I. In contrast, adult wounds had both fibroblast migration and induction of procollagen type I mRNA synthesis. These findings imply multilevel regulation of collagen production in the adult and posttranslational regulation in the fetus.

A novel approach for inhibiting growth factor signalling in murine tooth development. Inhibition of FGF's.

Growth factors belonging to the FGF and TGF-beta families, together with other secreted factors such as Sonic hedgehog, have been shown to be spatially and temporally regulated during tooth development. Providing evidence of the functions of these molecules has, however, proved difficult. We have developed a novel strategy for investigating the role of secreted molecules in tooth development using soluble forms of membrane bound receptors to sequester ligands. Chimeric fusion proteins of receptor extracellular domains were cloned into the eukaryotic expression vector pIG-1 and transfected into COS cells. Fusion proteins secreted by the COS cells were purified using Protein A Sepharose. A soluble form of the FGF receptor FGF-1IIIc, which preferentially binds FGF-2 and FGF-4, was produced using this technique and added to mouse mandible cultures. Addition of the soluble receptors to E13 cultures resulted in down-regulation of Sonic hedgehog expression in molar enamel knots, consistent with inhibition of FGF-4 signalling.