Detection and tracking of cracks based on thermoelastic stress analysis.

Thermoelastic stress analysis using arrays of small, low-cost detectors has the potential to be used in structural health monitoring. However, evaluation of the collected data is challenging using traditional methods, due to the lower resolution of these sensors, and the complex loading conditions experienced. An alternative method has been developed, using image decomposition to generate feature vectors which characterize the uncalibrated map of the magnitude of the thermoelastic effect. Thermal data have been collected using a state-of-the-art photovoltaic effect detector and lower cost, lower thermal resolution microbolometer detectors, during crack propagation induced by both constant amplitude and frequency loading, and by idealized flight cycles. The Euclidean distance calculated between the feature vectors of the initial and current state can be used to indicate the presence of damage. Cracks of the order of 1 mm in length can be detected and tracked, with an increase in the rate of change of the Euclidean distance indicating the onset of critical crack propagation. The differential feature vector method therefore represents a substantial advance in technology for monitoring the initiation and propagation of cracks in structures, both in structural testing and in-service using low-cost sensors.

An open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer.

BACKGROUND: Sunitinib monotherapy in pretreated patients with advanced gastric cancer (AGC) was investigated. Preplanned analyses of tumour biomarkers on treatment outcome were performed. PATIENTS AND METHODS: Patients received sunitinib 50mg/day for 4 weeks with 2 weeks rest until disease progression or unacceptable toxicity. The primary end-point was objective response rate (ORR). Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Fifty-two patients were enrolled and treated (safety population, SP). In the intention to treat population (n=51); the ORR was 3.9%, median PFS was 1.28 months [95% CI, 1.18-1.90], median OS was 5.81 months [95% CI, 3.48-12.32], the estimated one-year survival rate was 23.7% [95%CI: 12.8-36.5]. In subgroup analyses, tumour VEGF-C expression compared with no expression was associated with significantly shorter median PFS (1.23 versus 2.86 months, logrank p=0.0119) but there was no difference in tumour control rate (p=0.142). In the SP, serious adverse events occurred in 26 patients, leading to 13 deaths, all sunitinib unrelated. Thirty-eight patients died from progressive disease, nine died <60 days after treatment start. CONCLUSION: Sunitinib monotherapy was associated with limited tumour response and good/moderate tolerability in this setting.

Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy.

BACKGROUND: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. METHODS: Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. RESULTS: Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P<0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P<0.01) and a reduction of 91% in the hazard of death (P<0.05). CONCLUSION: Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment.

CD40-activated B cells can be generated in high number and purity in cancer patients: analysis of immunogenicity and homing potential.

Cellular adjuvants such as dendritic cells (DC) are in the focus of tumour immunotherapy. In DC-vaccine trials, induction of tumour antigen-specific immunity is observed frequently and well-documented clinical responses have been reported. However, the overall response rate is less than 3%, therefore alternative strategies are being investigated. CD40-activated B cells (CD40-B) have been characterized previously as an interesting alternative because they present antigen efficiently and can be expanded by several logs from small amounts of peripheral blood. To determine the central technical challenges of cell-based vaccines we performed a single-patient analysis of 502 patients from DC-based tumour vaccine trials and identified at least three factors contributing to their limited efficiency: (1) lack of cell numbers; (2) lack of documented purity thus high contamination of bystander cells; and (3) lack of quality control and thus heterogeneous or unknown expression of important surface molecules such as major histocompatibility complex (MHC) and chemokine receptors. Based on these findings we re-evaluated the CD40-B approach in cancer patients. Here, we show that proliferation of B cells from cancer patients is equivalent to that observed in healthy donors. Purity is always > 90% after 2 weeks and remains stable for several weeks. They have comparable antigen-presenting capability determined phenotypically and by allogeneic mixed lymphocyte reaction. Expression of CCR7 and CD62L was detected in all samples and B cells migrated towards the relevant homing chemokines. Taken together, CD40-B cells from cancer patients can be expanded in virtually unlimited numbers at high purity and full function concerning antigen-presentation and migratory properties.

Comparison of MR-thermography and planning calculations in phantoms.

A systematic comparison of three-dimensional MR (magnetic resonance) thermography and planning calculations in phantoms for the hyperthermia (HT) SIGMA-Eye applicator. We performed 2 x 6 experiments in a homogeneous cylindrical and a heterogeneous elliptical phantom by adjusting 82 different patterns with different phase control inside an MR tomograph (Siemens Magnetom Symphony, 1.5 Tesla). For MR thermography, we employed the proton resonance frequency shift method with a drift correction based on silicon tubes. For the planning calculations, we used the finite-difference time-domain (FDTD) method and, in addition, modeled the antennas and the transforming network. We generated regions according to a segmentation of bones and tissue, and used an interpolation technique with a subgrid of 0.5 cm size at the interfaces. A Gauss-Newton solver has been developed to adapt phases and amplitudes. A qualitative agreement between the planning program and measurements was obtained, including a correct prediction of hot spot locations. The final deviation between planning and measurement is in the range of 2-3 W/kg, i.e., below 10%. Additional HT phase and amplitude adaptation, as well as position correction of the phantom in the SIGMA-Eye, further improve the results. HT phase corrections in the range of 30-40 degrees and HT amplitude corrections of +/- 20-30% are required for the best agreement. The deviation /MR-FDTD/, and the HT phase/amplitude corrections depend on the type of phantom, certain channel groups, pattern steering, and the positioning error. Appropriate agreement between three-dimensional specific absorption rate distributions measured by MR-thermography and planning calculations is achieved, if the correct position and adapted feed point parameters are considered. As long as feed-point parameters are uncertain (i.e., cannot be directly measured during therapy), a prospective planning will remain difficult. However, we can use the information of MR thermography to better predict the patterns in the future even without the knowledge of feed-point parameters.

[Functional outcome after corrective osteotomy of the distal radius]. / Funktionelle Ergebnisse nach Radiuskorrekturosteotomie.

BACKGROUND: Malunited fractures of the distal radius frequently show disabling and painful reductions in active range of motion (AROM) of the wrist and forearm with reduced grip strength. Shortening and three-dimensional torsion of the distal radius occur with relative ulnar lengthening. Corrective osteotomy of the distal radius is indicated in these conditions. METHODS: We examined 24 of 30 patients after corrective osteotomy with respect to AROM, grip strength, DASH, and pain perception (visual analogue scale). The mean age of the population was 49 years (18-69 years), and the mean follow-up period was 22 months (6-63 months). RESULTS: Preoperative extension/flexion was 65 degrees , postoperative 92 degrees (p<0.05). Forearm rotation improved from 129 degrees preoperative to 160 degrees postoperative (p<0.01). The DASH score could be reduced from 40 (n=9) to 18 (n=24). Grip strength increased from 17 kg to 27 kg postoperative (p<0.01). Radioulnar inclination increased from 15 degrees preoperative to 24 degrees postoperative (p<0.05). Relative ulnar lengthening could be minimized from 4.3 mm to 0.7 mm (p<0.05). CONCLUSION: Data show that reconstruction of the distal radius improves grip strength and range of motion significantly with simultaneous reduction of pain perception and DASH scores.

Artificial sweeteners--do they bear a carcinogenic risk?

Artificial sweeteners are added to a wide variety of food, drinks, drugs and hygiene products. Since their introduction, the mass media have reported about potential cancer risks, which has contributed to undermine the public's sense of security. It can be assumed that every citizen of Western countries uses artificial sweeteners, knowingly or not. A cancer-inducing activity of one of these substances would mean a health risk to an entire population. We performed several PubMed searches of the National Library of Medicine for articles in English about artificial sweeteners. These articles included 'first generation' sweeteners such as saccharin, cyclamate and aspartame, as well as 'new generation' sweeteners such as acesulfame-K, sucralose, alitame and neotame. Epidemiological studies in humans did not find the bladder cancer-inducing effects of saccharin and cyclamate that had been reported from animal studies in rats. Despite some rather unscientific assumptions, there is no evidence that aspartame is carcinogenic. Case-control studies showed an elevated relative risk of 1.3 for heavy artificial sweetener use (no specific substances specified) of >1.7 g/day. For new generation sweeteners, it is too early to establish any epidemiological evidence about possible carcinogenic risks. As many artificial sweeteners are combined in today's products, the carcinogenic risk of a single substance is difficult to assess. However, according to the current literature, the possible risk of artificial sweeteners to induce cancer seems to be negligible.

[The medical dissertation--no definitive model. Results of a survey about obtaining a doctorate contradict frequently stated opinions]. / Die medizinische Dissertation--kein Auslaufmodell. Ergebnisse einer Befragung von Promovierenden stehen im Widerspruch zu oft geäusserten Meinungen.

BACKGROUND AND OBJECTIVE: The relevance of medical dissertations is controversial in Germany. The "Wissenschaftsrat" (Science Council) of Germany even made the radical proposal of abolishing medical dissertations, in their present form, in the recently published "Guidelines on writing a thesis". METHODS: Using a questionnaire with 22 items all students submitting their dissertations within one year at the Medical School in Hannover were asked to participate in a survey about the dissertation, supervision, time spent on it and publishing the results. The answers were evaluated statistically by explorative data analysis. RESULTS: A total of 232 questionnaires were evaluated, which is equivalent to a response rate of 87% (47% were women). A majority of 69% had prepared their thesis in a clinical institution. The supervision during various phases of the dissertation was graded as good. Altogether 90% thought that it had been personally worth-while. In 57% of cases the data of the dissertation had already been published and in 39 % of these cases the author of the dissertation was listed as first author of the publication. CONCLUSIONS: In agreement with former studies in German universities an overwhelming majority of 90% of respondents graded dissertations as a significant part of their medical studies, although requiring much additional time. They would recommend such a research phase to younger students as highly valuable. These results are in contrast to many repeatedly made statements.

[Hodgkin's lymphoma in nuclear medicine: diagnostic and therapeutic aspects]. / Nuklearmedizinische Aspekte in der Diagnostik und Therapie des Hodgkin-Lymphoms.

Today, diagnostic and therapeutic strategies of Hodgkin lymphoma (HL) with positron emission tomography and radioimmunotherapy include state-of-the-art nuclear medicine which require the cooperation between oncology and nuclear medicine. The benefit of FDG-PET in HL patients with residual tumor masses consists of its high negative predictive value in the therapy control of the disease. The concept of waitful watching in patients with PET-negative residual masses after BEACOPP-chemotherapy will be evaluated in a large multicenter trial of the GHSG (German Hodgkin Study Group). Radioimmunotherapy has been performed in patients with CD20-positive Non-Hodgkin lymphoma for 10 years with promising results. HL is also an excellent target for immunotherapy due to the expression of antigens such as CD25 and CD30. Thus, a new radioimmunoconstruct consisting of the murine anti-CD30 antibody Ki-4 labeled with iodine-131 was developed for patients with relapsed or refractory HL.

Carcinogen-specific mutation pattern in the p53 tumour suppressor gene in UV radiation-induced basal cell carcinoma.

OBJECTIVES: Basal cell carcinoma (BCC) is mainly caused by high and long-term UV radiation. UV radiation causes DNA damage in various genes. Mutations of the p53 tumour suppressor gene have been identified in a wide variety of human cancers. The aim of the study was to analyse specific p53 mutations in BCCs in workers exposed to high and long-term UV radiation. METHODS: The mutation pattern of the p53 tumour suppressor gene was analysed in tissue from 12 patients with UV-related BCC. All patients had a suspected occupational disease notified within the period 1995-1999. As a control, 20 BCC skin samples removed from areas definitively unexposed to sunlight were analysed. The specific mutations were determined by direct sequencing of codon 4 to 9 of the p53 gene in carcinomatous and adjacent non-neoplastic tissue after microdissection. Immunohistochemical analysis was performed to detect p53 protein. RESULTS: p53 mutations were detected in 7/12 cases (58%). Point mutations were found in six cases (50%). In one case a deletion of 24 base pairs was observed. The most frequent mutations we found were CC-->TT base-pair changes in four and C-->T mutations in two cases. Within the control group specific p53 mutations were found in 11 cases (55%) without any C-->T predominance. No case showed CC-->TT mutations. CONCLUSIONS: Mutations of the p53 tumour suppressor gene in UV-associated BCC are frequent events. A predominance of C-->T mutations and tandem CC-->TT base-pair changes were observed in the sunlight-exposed cases only supporting the idea of site-directed mutagenesis by UV radiation in human BCC.

Whole-body positron emission tomography using 18F-fluorodeoxyglucose for initial staging of patients with Hodgkin's disease.

An accurate initial staging of patients with Hodgkin's disease (HD) is important for the evaluation of clinical stage and risk factors, which are crucial for the choice of an appropriate treatment. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful for detecting active tumor tissue in patients with lymphoproliferative diseases and may contribute to conventional staging methods in patients with HD. Twenty-two patients who presented with newly diagnosed HD underwent conventional staging methods including computed tomography (CT) as well as FDG PET. Lesions apparent in FDG PET and CT were correlated to each other. Seventy-seven lesions were observed either in PET or CT or in both. In 48 (62%) lesions PET and CT were both positive. In 20 (26%) sites, PET was positive and CT negative. Of 22 patients (18%) 4 were upstaged due to these positive PET findings, and as a result one patient received a different therapeutic regimen. PET failed to detect nine (12%) CT-positive sites in six patients. Statistically, these data are reflected by a sensitivity for PET and CT of 88% and 74%, respectively. Specificity of both imaging modalities was 100%. PET can contribute valuable information as an additional staging examination and led to an upstaging in some patients with primary HD. However, PET should not be used as the only imaging modality as it failed to detect CT-positive, active tumor regions in some cases.

Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease.

Residual mediastinal masses are frequently observed in patients with Hodgkin disease (HD) after completed therapy, and the discrimination between active tumor tissue and fibrotic residues remains a clinical challenge. We studied the diagnostic value of metabolic imaging by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in detecting active mediastinal disease and predicting relapse. Twenty-eight HD patients with a residual mediastinal mass of at least 2 cm after initial therapy or after salvage chemotherapy were prospectively assigned to 29 examinations with FDG PET and were evaluated as 29 "subjects." Patients were monitored for at least 1 year after examination and observed for signs of relapse. Median follow-up was 28 months (range, 16 to 68 months). A PET-negative mediastinal tumor was observed in 19 subjects, of whom 16 stayed in remission and 3 relapsed. Progression or relapse occurred in 6 of 10 subjects with a positive PET, whereas 4 subjects remained in remission. The negative predictive value (negative PET result and remission) at 1 year was 95%, and the positive predictive value (positive PET result and relapse) was 60%. The disease-free survival for PET-negative and PET-positive patients at 1 year was 95% and 40%, respectively. The difference was statistically significant. A negative FDG PET indicates that an HD patient with a residual mediastinal mass is unlikely to relapse before 1 year, if ever. On the other hand, a positive PET result indicates a significantly higher risk of relapse and demands further diagnostic procedures and a closer follow-up.

[Factitious disorders. Hematologic, neurologic and dermatologic symptoms in a physician with factitious disorder]. / Artifizielle Störungen. Hämatologische, neurologische und dermatologische Symptome bei einer Arztin mit artifizieller Störung.

HISTORY AND FINDINGS: A 38-year-old female physician was admitted with the suspected diagnosis of a myelodysplastic syndrome. The self-reported history was inconsistent and incoherent. On physical examination neurological and dermatological disorders could be found. EXAMINATIONS: A bone marrow puncture revealed a toxicity-induced bone marrow damage. Extensive examinations to evaluate the neurological symptoms did not show any pathological findings. A toxicological screening identified opioids, benzodiazepines and promethazine. TREATMENT AND COURSE: Because of the inconsistent history and the contradictory results of our clinical tests, we asked in other hospitals for past admissions and were thus able to have insight into a hospital career that grasped numerous different admission diagnoses. All presented symptoms, especially the bone marrow damage, were self-induced by the patient. CONCLUSIONS: For the first time in this patient's history, a factitious disorder was diagnosed after a hospital career of almost 10 years. In this publication, the case is thoroughly presented. Additionally, the current literature is reviewed with latest recommendations for therapeutic strategies about this poorly understood disorder.

High prevalence of K-ras-2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride.

OBJECTIVES: Vinyl chloride (VC) and its metabolites are human carcinogens associated with liver angiosarcomas (LAS) and also with hepatocellular carcinomas (HCCs). In VC associated LAS mutations of the K-ras-2 gene have been reported, however, no data about the prevalence of such mutations in VC-associated HCCs are available. The aim of the study was to evaluate possible specific K-ras-2 oncogene mutations in the case of HCCs due to VC. METHODS: The presence of K-ras-2 mutations was analysed in tissue from 12 patients with VC-associated HCCs. All patients had known long-term exposure to VC (average exposure amount: 9,942 ppm-years). Twenty patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n= 8) served as a control group. The specific mutations were determined by direct sequencing of codons 12 and 13 of the K-ras-2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. Immunohistochemical analysis was performed to detect p21ras protein. RESULTS: K-ras-2 mutations were found in five of 12 (42%) examined HCCs and in three cases of adjacent non-neoplastic liver tissue (25%). There were three guanine to adenine (G --> A) point mutations in the tumour tissue. All three mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Within the control group, K-ras-2 mutations were found in three of 20 (15%) examined HCCs. CONCLUSIONS: Mutations of the K-ras-2 gene in hepatocellular carcinomas associated with VC exposure are frequent events. We observed a K-ras-2 mutation pattern characteristic of chloroethylene oxide, one of the carcinogenic metabolites of VC analysed in animal models. Our results suggest that VC had direct toxic effects not only on endothelial cells but also on hepatocytes, as it was previously only described in animal models.

p16INK4A-alterations in primary angiosarcoma of the liver.

BACKGROUND/AIMS: Alterations in the p16 (CDKN2/MTS-1/INK4A) gene have been implicated in the tumorigenesis of different human cancers. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of p16INK4a gene inactivation in malignant epithelial tumors. This study was performed to determine whether alterations of p16 are involved in the development of angiosarcoma of the liver. METHODS: The status of p16 was evaluated in 17 angiosarcomas of the liver by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. The results obtained were correlated with histopathological variables and with patient survival. RESULTS: Hypermethylation of the 5' CpG island of the p16 gene was found in 12 out of 17 (71%) angiosarcomas examined. Homozygous deletion at the p16 region was present in one case (6%), and loss of heterozygosity was present in two cases (12%). We failed to detect p16 gene missense mutations. The status of p16 correlated with neither histopathological factors nor with the prognosis of the patients with angiosarcomas. CONCLUSIONS: These data suggest that inactivation of the p16 gene is a frequent event in angiosarcomas of the liver. The most common somatic alteration is promotor methylation of the p16 gene. We failed to establish p16 as independent prognostic factors in these tumors.

Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride.

Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K- ras -2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K- ras -2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K- ras -2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K- ras -2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K- ras -2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G --> A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5' CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K- ras -2 mutations, 5 specimens also showed methylated p16. Within the control group, K- ras -2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K- ras -2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K- ras -2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K- ras -2 mutations play an important role in the pathogenesis of VC-associated HCC.

[Artificial sweeteners--are they potentially carcinogenic?]. / Künstliche Süssstoffe--Haben sie ein kanzerogenes Potential?

BACKGROUND: Artificial sweeteners have rapidly evolved over the last 20 years and are added to a broad variety of food, drinks, drugs, and hygiene products. Since their introduction, especially mass media have reported about potential cancer risks, which has attributed to undermine the people's sense of security. It can be assumed that every citizen of the western countries is using artificial sweeteners--knowingly or not. A cancer-inducing activity of one of these substances would mean a health risk to an entire population. STUDIES: This article gives an overview about the most important publications dealing with the cancerogenic potential of artificial sweeteners.