Activity of Pembrolizumab in Recurrent Cervical Cancer: Case Series and Review of Published Data.

OBJECTIVES: Recent data support the use of pembrolizumab in cervical cancer. The aim of this study was to investigate pembrolizumab in heavily pretreated patients with recurrent cervical cancer. METHODS: Data from consecutive patients treated with pembrolizumab at a single academic institution were assessed. Programmed cell death ligand 1 (PD-L1) status and microsatellite instability were assessed from tumor samples. Irrespective of PD-L1 expression status, pembrolizumab was administered at fixed dose of 200 mg intravenously every 3 weeks. Treatment response was evaluated by computed tomography, using iRECIST (2017) criteria. Descriptive statistics were performed. Results from previous publications were summarized. RESULTS: In total, 11 heavily pretreated patients with recurrent cervical cancer received pembrolizumab. Of these, 2 (18%) patients showed partial response and 2 (18%) patients showed disease stabilization on computed tomography, resulting in a clinical benefit rate of 36%. These 4 patients are still on treatment and durable antitumor activity of up to 52 weeks was observed. Treatment was generally well tolerated with 1 patient showing dose-limiting toxicity. Median overall survival was 26 (3-53) weeks, and a 6-month overall survival rate of 65% was observed. Of the 5 patients with high PD-L1 expression, 3 showed response to treatment. CONCLUSIONS: Pembrolizumab shows promising activity in heavily pretreated patients with recurrent cervical cancer in a real-life clinical setting. Treatment was generally well tolerated, and adverse effects were manageable. Growing evidence supports the use of pembrolizumab in this group of patients.

High-level ERBB2 gene amplification is associated with a particularly short time-to-metastasis, but results in a high rate of complete response once trastuzumab-based therapy is offered in the metastatic setting.

Despite patient selection based on ERBB2 overexpression, not all patients benefit from trastuzumab therapy. We have investigated whether a ERBB2 gene dosage effect might provoke increased biological aggressiveness and altered trastuzumab sensitivity. Absolute ERBB2 copy numbers ("CN") and ERBB2/centromer 17 ratios ("R") were measured by FISH analysis in tumors of 127 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer. CN and R were both significantly associated with shorter time to first metastasis (TTM) (CN: OR: 1.099, 95% CI: 1.042-1.159; R: OR: 1.211, 95% CI: 1.080-1.357) and longer PFS (CN: OR: 0.917, 95% CI: 0.867-0.969; R: OR: 0.840, 95% CI: 0.743-0.949) in a continuous variable Cox's regression model. Tumors with ERBB2/centromer 17 ratios of <2.2 had a significantly shorter TTM (p = 0.002) and significantly longer PFS (p = 0.003) than tumors with low-level (R: 2.2-6) and high-level amplification (R: >6). Interestingly, when ERBB2 copy numbers were analyzed, a significantly shorter TTM (p = 0.001) and longer PFS (p = 0.026) were observed in the group with high-level amplified CN (CN: >13), while no difference was observed between non- and low-level amplified CN. R, but not CN, was an independent predictor of complete (CR; OR: 1.685; 95% CI: 1.122-2.532) and partial (PR; OR: 1.704; 95% CI: 1.136-2.556) response in logistic regression analysis. CR (p = 0.016) rates were significantly higher in the high-level amplification group (R > 6), but no difference existed in response rates between non- and low-level amplified tumors in Chi-square tests. High-level ERBB2 amplification is associated with shorter TTM, but improved response to trastuzumab in metastatic breast cancer.

Initially localized synovial sarcoma in adults: a retrospective single-center analysis of 26 patients registered at the Department of Oncology, University of Vienna between 2004 and 2013.

BACKGROUND: Synovial sarcoma is a rare subgroup of all soft-tissue sarcomas. The aim of this retrospective single-center analysis was to investigate the outcome of patients with initially localized disease. PATIENTS AND METHODS: Twenty-six patients were enrolled in this retrospective single-center analysis. Baseline characteristics, treatment and outcome were evaluated. RESULTS: In 13 patients (50%), the tumor was located in the lower extremity and in 4 patients (15%) in the upper extremity. Surgical resection was done in all but 2 patients (92%). Re-resection was done in 7 patients (27%). Fourteen patients (54%) received adjuvant chemotherapy. After a median follow-up of 23.3 months (range: 2.6-150.3), median disease-free survival was not reached at the time of analysis. Eight patients (31%) relapsed after initial therapy. Surgery was done in 2 patients, amputation in 1 patient, palliative chemotherapy was administered in 3 and radiation therapy in 2 patients. Median overall survival (OS) for all patients was not reached at the time of analysis. The estimated 5-year OS rate was 62%. CONCLUSION: Patients with initially localized synovial sarcoma who were included in this retrospective single-center analysis have an estimated 5-year OS rate of 62%.

Distinctive outcome in patients with non-uterine and uterine leiomyosarcoma.

BACKGROUND: Leiomyosarcomas represent the largest subtype of soft tissue sarcomas. Two subgroups can be distinguished, non-uterine (NULMS) and uterine leiomyosarcomas (ULMS). The aim of this retrospective study was to evaluate differences in clinical features and outcome between these two subgroups. METHODS: Outcome and clinical-pathological parameters between 50 patients with NULMS and 45 patients with ULMS were assessed, and compared between both groups. Univariate and multivariable survival analyses were performed. RESULTS: Patients with ULMS presented with larger tumors when compared to patients with NULMS (p < 0.001). More patients with ULMS initially presented with metastatic disease (67% vs. 36%, p = 0.007). Most common metastatic site was lung for both subtypes (28% and 38%). Five-year overall survival (OS) rates of 82.6% and 41.2% and median OS times of 92.6 (range: 79.7-105.4) and 50.4 (range: 34.8-66.0) months were observed in patients with NULMS and ULMS, respectively (p = 0.006). In multivariate analysis, initial metastatic disease remained an independent prognostic factor in terms of OS (p < 0.0001). CONCLUSION: At time of diagnosis ULMS were larger and more often metastasized. Therefore patients with ULMS showed unfavorable outcome when compared to NULMS. Later diagnosis might be caused by differences in symptoms and clinical presentation or a more aggressive biological tumor behavior.

HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer.

Trastuzumab is effective in the treatment of HER2/neu over-expressing breast cancer, but not all patients benefit from it. In vitro data suggest a role for HER3 in the initiation of signaling activity involving the AKT­mTOR pathway leading to trastuzumab insensitivity. We sought to investigate the potential of HER3 alone and in the context of p95HER2 (p95), a trastuzumab resistance marker, as biomarkers of trastuzumab escape. Using the VeraTag® assay platform, we developed a dual antibody proximity-based assay for the precise quantitation of HER3 total protein (H3T) from formalin-fixed paraffin-embedded (FFPE) breast tumors. We then measured H3T in 89 patients with metastatic breast cancer treated with trastuzumab-based therapy, and correlated the results with progression-free survival and overall survival using Kaplan­Meier and decision tree analyses that also included HER2 total (H2T) and p95 expression levels. Within the sub-population of patients that over-expressed HER2, high levels of HER3 and/or p95 protein expression were significantly associated with poor clinical outcomes on trastuzumab-based therapy. Based on quantitative H3T, p95, and H2T measurements, multiple subtypes of HER2-positive breast cancer were identified that differ in their outcome following trastuzumab therapy. These data suggest that HER3 and p95 are informative biomarkers of clinical outcomes on trastuzumab therapy, and that multiple subtypes of HER2-positive breast cancer may be defined by quantitative measurements of H3T, p95, and H2T.

Trabectedin in patients with metastatic soft tissue sarcoma: a retrospective single center analysis.

The aim of this study was to retrospectively evaluate the efficacy and safety of trabectedin treatment in patients with metastatic soft tissue sarcoma (STS) in the routine clinical setting. Further, the type and frequency of systemic treatments before commencing treatment with trabectedin and after its discontinuation, as well as the frequency of pulmonary metastasectomies, were analyzed. The current analysis includes retrospective data from consecutive STS patients treated with trabectedin at the Department of Medicine I, Division of Oncology, Medical University of Vienna, between January 2008 and December 2012. Patients were analyzed for median progression-free survival, overall survival (OS), and therapy-related toxicity. Data of 60 STS patients were included in the present analysis. In total, 198 cycles of trabectedin were administered, whereas the median number of cycles administered per patient was two (range 1-25). The median progression-free survival was 2.2 months and the median OS (mOS) was 11.8 months. mOS calculated from the first time point of detection of metastatic disease was 35.8 months. The 18 patients (30%) who underwent pulmonary metastasectomy had an mOS of 50.2 months. Further, trabectedin had a manageable toxicity profile comparable to data reported in previous phase II trials. Our findings support the use of trabectedin as an active and feasible therapeutic option among advanced, metastatic, and refractory STS patients. The good safety profile and lack of cumulative toxicity allow prolonged administration in highly pretreated patients. As visible from the present data, a considerable percentage of patients with advanced/metastatic STS benefit from sequential lines of drug therapy as well as pulmonary metastasectomy.

Coupled pre-mRNA and mRNA dynamics unveil operational strategies underlying transcriptional responses to stimuli.

Transcriptional responses to extracellular stimuli involve tuning the rates of transcript production and degradation. Here, we show that the time-dependent profiles of these rates can be inferred from simultaneous measurements of precursor mRNA (pre-mRNA) and mature mRNA profiles. Transcriptome-wide measurements demonstrate that genes with similar mRNA profiles often exhibit marked differences in the amplitude and onset of their production rate. The latter is characterized by a large dynamic range, with a group of genes exhibiting an unexpectedly strong transient production overshoot, thereby accelerating their induction and, when combined with time-dependent degradation, shaping transient responses with precise timing and amplitude.

Long-term Survival After Salvage Surgery for a Giant Primary Rib Osteosarcoma.

A 29-year-old woman with a primary rib osteosarcoma declined treatment and was readmitted 20 months later in life-threatening condition caused by major local tumor progression with severe mediastinal shifting, and without distant metastases. She underwent extended tumor resection with palliative intent and recovered well after a prolonged course with post-pneumonectomy empyema. Further treatment was declined, and she presented again 4.5 years later with local chest wall recurrence that was completely resected. Currently, 7 years after diagnosis, the patient is free from disease. In this rare case, salvage surgery was associated with an unexpected favorable long-term outcome.

Inflammation-Based Scores as a Common Tool for Prognostic Assessment in Heart Failure or Cancer.

Background: Inflammation-based scores are widely tested in cancer and have been evaluated in cardiovascular diseases including heart failure. Objectives: We investigated the impact of established inflammation-based scores on disease severity and survival in patients with stable heart failure with reduced ejection fraction (HFrEF) paralleling results to an intra-institutional cohort of treatment naïve cancer patients. Methods: HFrEF and cancer patients were prospectively enrolled. The neutrophil-to-lymphocyte-ratio (NLR), the monocyte-to-lymphocyte-ratio (MLR), the platelet-to-lymphocyte-ratio (PLR), and the prognostic nutritional index (PNI) at index day were calculated. Association of scores with disease severity and impact on overall survival was determined. Interaction analysis was performed for the different populations. Results: Between 2011 and 2017, a total of 818 patients (443 HFrEF and 375 cancer patients) were enrolled. In HFrEF, there was a strong association between all scores and disease severity reflected by NT-proBNP and NYHA class (p ≤ 0.001 for all). In oncologic patients, association with tumor stage was significant for the PNI only (p = 0.035). In both disease entities, all scores were associated with all-cause mortality (p ≤ 0.014 for all scores). Kaplan-Meier analysis confirmed the discriminatory power of all scores in the HFrEF and the oncologic study population, respectively (log-rank p ≤ 0.026 for all scores). A significant interaction with disease (HFrEF vs. cancer) was observed for PNI (p interaction = 0.013) or PLR (p interaction = 0.005), respectively, with higher increase in risk per inflammatory score increment for HFrEF. Conclusion: In crude models, the inflammatory scores NLR, MLR, PLR, and PNI are associated with severity of disease in HFrEF and with survival in HFrEF similarly to cancer patients. For PNI and PLR, the association with increase in risk per increment was even stronger in HFrEF than in malignant disease.

Intensity dependent estimation of noise in microarrays improves detection of differentially expressed genes.

BACKGROUND: In many microarray experiments, analysis is severely hindered by a major difficulty: the small number of samples for which expression data has been measured. When one searches for differentially expressed genes, the small number of samples gives rise to an inaccurate estimation of the experimental noise. This, in turn, leads to loss of statistical power. RESULTS: We show that the measurement noise of genes with similar expression levels (intensity) is identically and independently distributed, and that this (intensity dependent) distribution is approximately normal. Our method can be easily adapted and used to test whether these statement hold for data from any particular microarray experiment. We propose a method that provides an accurate estimation of the intensity-dependent variance of the noise distribution, and demonstrate that using this estimation we can detect differential expression with much better statistical power than that of standard t-test, and can compare the noise levels of different experiments and platforms. CONCLUSIONS: When the number of samples is small, the simple method we propose improves significantly the statistical power in identifying differentially expressed genes.

Open-wedge osteotomy using an internal plate fixator in patients with medial-compartment gonarthritis and varus malalignment: 3-year results with regard to preoperative arthroscopic and radiographic findings.

PURPOSE: Our purpose was to evaluate the 3-year clinical results of patients with medial-compartment osteoarthritis of the knee and varus malalignment who underwent open-wedge high tibial osteotomy (HTO) with an internal plate fixator (TomoFix; Synthes, Solothurn, Switzerland). Clinical results are correlated with arthroscopic and radiographic findings at the time of surgery. METHODS: This study included 69 patients with a minimum follow-up of 36 months who underwent open-wedge HTO for medial-compartment osteoarthritis of the knee. Knee function was assessed before surgery and at 6, 12, 24, and 36 months after HTO by use of subjective International Knee Documentation Committee and Lysholm scores. Arthroscopic findings before HTO and radiographic assessment of the metaphyseal deformity of the proximal tibia (tibial bone varus angle) were correlated with clinical outcome. RESULTS: A significant continuous increase in International Knee Documentation Committee score from 47.25 ± 18.71 points before surgery to 72.72 ± 17.15 points at 36 months after HTO was found (P < .001). Grade of cartilage damage of the medial compartment and partial-thickness defects of the lateral compartment did not significantly influence clinical outcome (P > .05 at all time points). The tibial bone varus angle was correlated significantly with greater improvement and better clinical outcome after HTO (P < .01). The overall complication rate of 8.6% was mostly related to surgical causes; nevertheless, a high proportion of patients reported discomfort related to the implant at some point during the follow-up period (40.6%). CONCLUSIONS: Open-wedge osteotomy by use of the TomoFix system leads to reliable 3-year results. Results do not depend on the severity of medial cartilage defects, whereas partial-thickness defects of the lateral compartment seem to be well tolerated. The prognostic relevance of patellofemoral cartilage defects remains unclear. Local irritation of the implant was observed in a significant number of patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Standardized cartilage biopsies from the intercondylar notch for autologous chondrocyte implantation (ACI).

Autologous chondrocyte implantation (ACI) is an established therapy for the treatment of cartilage defects across the knee joint. Even though different techniques for initial biopsy have been described, the exact location, depth, and volume of the biopsy are chosen individually by the treating surgeon. This study evaluated 252 consecutive cartilage biopsies taken from the intercondylar notch with a standardized hollow cylinder system for the isolation and in vitro cultivation of human chondrocytes assigned to ACI. All biopsies were assessed for weight of total cartilage obtained, cartilage biopsy weight per cylinder, biopsy cylinder quality, and initial cell count after digestive cellular isolation as well as cell vitality. Parameters were correlated with individual patient parameters. Mean patient age was 35.1 years (median 35.9; range 14.7-56.4). Adequate amounts of cartilage assigned to chondrocyte in vitro cultivation could be harvested in all cases. The mean overall biopsy weight averaged 75.5 mg (SD +/- 44.9) and could be identified as main factor for initial cell number (mean 1.05E+05; SD +/- 7.44E+04). No correlation was found between the initial cell count and patient age (correlation coefficient r = 0.005) or grade of joint degeneration (r = 0.040). Concerning cell viability, a total of 4.4% (SD + 3.0) of the chondrocytes harvested were apoptotic. Cartilage biopsies from the intercondylar notch using a standardized hollow cylinder system provides a reliable, safe, and successful method to obtain articular cartilage for further in vitro cultivation of articular chondrocytes to achieve autologous chondrocyte transplantation.

Presence of subchondral bone marrow edema at the time of treatment represents a negative prognostic factor for early outcome after autologous chondrocyte implantation.

INTRODUCTION: Since introduction of autologous chondrocyte implantation (ACI), various factors have been described that influence the clinical outcome. The present paper investigates the influence of bone marrow edema at time of treatment on clinical function before and in the early clinical course after ACI. METHODS: 67 patients treated with ACI for cartilage defects of the knee joint were included. Presence of subchondral bone marrow edema was graded as absent (1), mild (2), moderate (3) or severe (4) using magnetic resonance (MR) imaging before surgery. All patients were assessed in terms of clinical function before surgery and 6 as well as 12 months after ACI using IKDC and Lysholm scores. Presence of subchondral edema was correlated with functional outcome. RESULTS: In 18 patients edema on initial MRI was graded as "absent", while 17 patients had grade 2 edema, 19 patients had grade 3 edema and 13 patients had grade 4 edema. IKDC score increased significantly from 49.8 points (SD +/- 14.9) to 72.3 points (SD +/- 17.5) at 12 months (p < 0.01). At all time points investigated, patients of group "4" showed inferior results to all other groups (p < 0.05). In addition, in patients without any edema, better clinical function was detected compared to all other groups before surgery (p < 0.05) and compared to group 3 at 6 months following ACI (p < 0.05). CONCLUSIONS: Presence of severe subchondral bone marrow edema seems to correlate with knee function in patients with cartilage defects and may be a reliable prognostic factor for the early clinical course after ACI.

Lymphoepithelial Carcinoma of Larynx and Hypopharynx: A Rare Clinicopathological Entity.

(1) Background: Lymphoepithelial carcinoma of the hypopharynx and larynx is a rare tumor with fewer than 50 cases in the published literature. We present a literature review to discuss the clinical findings, viral or genetic associations, diagnostic challenges, histopathological findings and therapeutic aspects of the disease. (2) Methods: A comprehensive literature review was performed through MEDLINE/PubMed from 1968 to 2018. We identified 21 studies comprising 46 patients. Data on all the clinicopathological features, diagnostic modalities, treatment options and viral or genetic etiology were extracted and analyzed using SPSS. (3) Results: The mean age of presentation was 64 years (range 40-82 years) and mostly involved males. The supraglottis and pyriform sinus were the most commonly involved sub-sites, with surgery as the preferred treatment modality. The presence of the Epstein-Barr virus possibly directs a viral etiology. The incidence of cervical and distant metastasis was 54% and 21%, respectively. The median survival time was 30 months. (4) Conclusions: Lymphoepithelial carcinoma of the hypopharynx is an aggressive tumor with a strong predilection for regional and distant metastasis. Surgery, in combination with adjuvant therapy, provides promising results. Immunohistochemistry helps in differentiating LEC from other pathologies.

Incomplete surgical resection of ductal carcinomas in situ results in activation of ERBB2 in residual breast cancer cells.

ERBB2 amplification and consecutive overexpression is a predictor for poor prognosis in breast cancer patients. In addition, incomplete resection of ERBB2-overexpressing tumors leads to increased proliferation of residual breast cancer cells. While the local release of cytokines is thought to be responsible for the malignant behavior of remaining tumor tissue, the exact mechanism is still unknown. We have analyzed epidermal growth factor receptor (EGFR), activated (p)EGFR, and activated (p)ERBB2 protein expression in ERBB2-overexpressing and in non-ERBB2-overexpressing tumors from patients who underwent breast surgery and consecutive re-excision for involved margins, and compared expression levels by immunohistochemistry. While overall ERBB2 protein expression in the initial and the re-excised sample were comparable, we observed an increase in pERBB2 in ductal carcinomas in situ in both, ERBB2-overexpressing (16/21 vs 24/24; P=0.018, chi(2) test) and non-ERBB2-overexpressing tumors (3/28 vs 5/12; P=0.025, chi(2) test). pERBB2 was not increased in invasive tumors, regardless on whether the samples had been taken from a ERBB2-overexpressing (9/25 vs 6/17; P=0.261, chi(2) test) or a non-ERBB2-overexpressing tumor (1/27 vs 0/8; P=0.581, chi(2) test). EGFR expression was only detected in 1/47 ERBB2-overexpressing primary tumors and 2/48 non-ERBB2-overexpressing tumors, and was undetectable in re-excised specimen. Taken together, we have demonstrated an increase in ERBB2 receptor activation in incompletely resected preinvasive breast cancer. We hypothesize that receptor phosphorylation is caused by growth factor stimulation in response to intraoperative tissue damage, and perioperative inhibition of specific cytokines could become a promising therapeutic strategy.

Predicting the efficacy of trastuzumab-based therapy in breast cancer: current standards and future strategies.

Breast cancer is the most common female malignancy in many industrialized countries. Approximately one fourth of all women diagnosed with early breast cancer present with tumors that are characterized by erbB2 amplification. While the associated Her-2/neu receptor overexpression results in a high risk of relapse and poor prognosis, these tumors also represent a target for a selective monoclonal antibody therapy with trastuzumab (Herceptin). The combination of trastuzumab with chemotherapy has led to a considerable reduction of recurrences and to a significant reduction in breast cancer mortality both in the adjuvant and metastatic setting. Unfortunately, despite Her-2/neu overexpression, not all patients equally benefit from trastuzumab treatment, and almost all women with metastatic breast cancer eventually progress during antibody therapy. Moreover, trastuzumab is burdened with cardiotoxicity, thus increasing the risk of symptomatic congestive heart failure. In addition, the marginal costs for a 1 year therapy of trastuzumab-based therapy, which is currently considered to be the most effective treatment regimen in the adjuvant setting, may amount for up to US$ 40.000. Testing for erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH), respectively, and staining for Her-2/neu receptor overexpression by immunohistochemistry (IHC) represent the current standard for determining patient eligibility for trastuzumab-based therapy. However, while the negative predictive value of these assays for predicting the absence of benefit from trastuzumab-based therapy is sufficiently high, their positive predictive value remains insufficient, i.e. only a proportion of patients selected by these tests substantially benefit from trastuzumab-containing regimen. Accordingly, over the last years a number of biomarkers have been evaluated in their potential to predict response to trastuzumab-based therapies. These include markers auf activation of Her-2/neu (e.g., tyrosine phosphorylated Her-2/neu in tissue and cleaved Her-2/neu extracellular domain in serum) and its dimerization partners (e.g., EGFR), respectively, but also components of Her-2/neu-induced downstream signaling pathways that are crucial for the growth inhibitory effects of trastuzumab (e.g., PTEN and PI3K). Other parameters, such as topoisomerase-II alpha and c-myc co-amplifications, have also been identified as potentially useful predictors of response to trastuzumab-based chemotherapy regimen. While the benefit of these predictive biomarkers in the metastatic setting is currently explored, their usefulness in the adjuvant setting is still largely unknown. It is, however, undisputable that, within the group of Her-2/neu overexpressing tumors, further response predictors are needed in order to minimize trastuzumab-associated side effects, and to reduce the considerable societal costs that are associated with trastuzumab-based treatment regimen.

In vivo quantification of intraarticular cytokines in knees during natural and surgically induced cartilage repair.

BACKGROUND AIMS: Cartilage defects are considered to be an initial event in the progress of osteoarthritis. Reliable data about in vivo regulation of cytokines in natural and surgically induced cartilage repair are still missing. METHODS: Knee lavage fluids of 47 patients were collected prospectively between August 2006 and September 2007. Five patients without cartilage lesions served as a control group. In 42 patients the cartilage defects were treated by microfracturing (19) or autologous chondrocyte implantation (ACI) (23). Total protein content and concentrations of aggrecan, basic fibroblast growth factor (bFGF), Insulin-like growth factor and interleukin (IL)-1beta were determined. Clinical status was evaluated using the Lysholm score. RESULTS: High-level expression in all knees was found for aggrecan, low-level constitutive expression for bFGF and IGF-I, while concentrations of IL-1beta in the control group remained below detection levels. The concentration of IGF-I in the knees with cartilage lesions was significantly higher (P<0.05) than in the control group. bFGF concentrations depended on cartilage lesion size; levels in the knees of patients undergoing ACI (6.1 cm(2)), were significantly higher compared with the control group (P<0.05) and the group of patients undergoing microfracturing (3.4 cm(2), P<0.001). Levels of aggrecan did not change after surgical cartilage repair, whereas concentrations of bFGF, IL-1beta and IGF-I significantly increased (P<0.01). Levels of IL-1beta significantly correlated with systemic C-reactive protein (CRP). The Lysholm score showed a medium significant negative correlation with IGF-I levels. CONCLUSIONS: Aggrecan is constitutively expressed in knee joints. bFGF and IGF-I seem to play a pivotal role in natural and surgical cartilage repair. Operative intervention is additionally associated with IL-1beta-related inflammation-like reactions.

Signet Ring Cell Carcinoma of the Lung: A Diagnostic Pitfall in Pregnancy.

Lung cancer during pregnancy represents a rare disease. In this case report, we present a patient at advanced and metastasized stage of signet ring cell carcinoma who presented in the 22nd week of gestation.

Autologous chondrocyte implantation for the treatment of retropatellar cartilage defects: clinical results referred to defect localisation.

INTRODUCTION: Although autologous chondrocyte implantation (ACI) has become well established for the treatment of full-thickness cartilage defects of the knee joint, nevertheless clinical results of retropatellar lesions are still inferior compared to those of defects located on femoral condyles. We report the clinical results obtained in 70 patients treated with ACI for full-thickness defects of the patella, with special reference to defect location and size, age, body mass index and sports activity. METHODS: At a follow-up of 38.4 months (range 14-64, follow-up rate 83.3%), patients' subjective functional knee scores (IKDC, Lysholm) were analysed, as were the results of objective examination (according to ICRS). RESULTS: Mean patient age at the time of surgery was 34.3 years (+/-10.1). The mean Lysholm score at the time of follow-up was 73.0 (+/-22.4) and the subjective IKDC score was 61.6 (+/-21.5); normal and nearly normal clinical results according to the objective criteria of the International Cartilage Research Society (ICRS) were achieved in 67.1% of the patients, while abnormal results were achieved in 20.0% of the patients and severely abnormal results, in 12.9%. While different surgical techniques did not seem to have any significant influence on the treatment results, both defect size and defect location within the patella were found to be significantly associated with clinical outcome. The corollaries to this are that larger cartilage lesions of the patella are associated with an inferior outcome (p = 0.007) and that cartilage defects located on the lateral patellar facet are correlated with a better clinical outcome than those located on the medial facet or those involving both facets (p = 0.017). CONCLUSION: This study demonstrates that within a group of patients treated with ACI for retropatellar cartilage lesion there are significant differences in clinical outcome, which are important and should be taken into account of when a decision has to be made on whether or not ACI is indicated.

Coordinated Pulses of mRNA and of Protein Translation or Degradation Produce EGF-Induced Protein Bursts.

Protein responses to extracellular cues are governed by gene transcription, mRNA degradation and translation, and protein degradation. In order to understand how these time-dependent processes cooperate to generate dynamic responses, we analyzed the response of human mammary cells to the epidermal growth factor (EGF). Integrating time-dependent transcript and protein data into a mathematical model, we inferred for several proteins their pre-and post-stimulus translation and degradation coefficients and found that they exhibit complex, time-dependent variation. Specifically, we identified strategies of protein production and degradation acting in concert to generate rapid, transient protein bursts in response to EGF. Remarkably, for some proteins, for which the response necessitates rapidly decreased abundance, cells exhibit a transient increase in the corresponding degradation coefficient. Our model and analysis allow inference of the kinetics of mRNA translation and protein degradation, without perturbing cells, and open a way to understanding the fundamental processes governing time-dependent protein abundance profiles.