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Lung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivo spheroids obtained from the patient’s liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.

Background: Germany has seen rapid development in the digitization of medicine in recent years. Especially, the CO­VID-19 pandemic has dramatically accelerated this process. Nevertheless, it is accompanied by legal innovations that promote the application of digital tools as well as create respective remuneration options. Ultimately, this continued implementation of digital innovations and telemedicine approaches will lead to the improvement of care and the more efficient provision of medical services. Summary: The article primarily describes the development and current status of digitization using 2 key examples of telemedicine and digital innovations – video consultation and digital health applications. Starting with the liberalization of remote treatment options, video consultation gained many users, especially during the COVID pandemic. The introduction of digital health applications with the possibility of reimbursement by the statutory health insurance funds has put Germany in a leading position in international comparison in this respect. Key Messages: Digitization in healthcare offers enormous opportunities both to professionals working in the healthcare sector and to patients. However, in order to successfully use digital tools in practice, the legal, organizational, and financial framework must be clarified. All medical professionals are well advised to further qualify themselves in this area in order to keep pace with developments.

Deutschland hat im Vergleich zu anderen Industrienationen noch einen grosen Nachholbedarf bei der Digitalisierung des Gesundheitswesens. Aktuell ist viel Bewegung in diesem Bereich zu sehen, v.a. bei der Liberalisierung der ausschlieslichen Fernbehandlung. Weitere Beispiele sind die Fernuberwachung von Herzinsuffizienzpatienten, telemedizinische Neurokonsile und das digitale Rezept. Viele Fragen der konkreten Umsetzung sind noch ungeklart, viele Angste ob der Datensicherheit und der Verdrangung von Tatigkeitsfeldern bestehen. Daher ist eine unabhangige, wissenschaftliche Begleitung der weiteren Entwicklung notwendig. Um nicht – wie bislang – in Deutschland eine Verhinderungsdiskussion zur digitalen Gesundheit zu fuhren, sondern eine inhaltsgetriebene, offene Nutzenanalyse zu gewahrleisten, bedarf es der Objektivierung durch neutrale Kompetenzzentren.

Peritrochantare Schmerzen sind eine haufige Beschwerde in der orthopadischen Praxis. Die haufigsten Diagnosen sind myofasziale Schmerzsyndrome, Bursitis trochanterica, Tendinosen und Rupturen der Mm. glutaeus medius et minimus sowie die Coxa saltans externa. Ferner spielen Nervenkompressionssyndrome wie das Piriformissyndrom eine wichtige Rolle. Im vorliegenden Beitrag werden die wesentlichen diagnostischen und therapeutischen Verfahren bei peritrochantaren Schmerzsyndromen zusammengefasst. Mit einer subtilen klinischen Untersuchung, welche durch gezielte bildgebende Verfahren und diagnostische Infiltrationen erganzt wird, kann in den meisten Fallen eine Differenzierung der zugrunde liegenden Entitaten erreicht werden. Nach Diagnosestellung kann eine gezielte und meist zunachst konservative Therapie folgen, mit Erfolgsraten von mehr als 90 %. Bei Beschwerdepersistenz oder Sehnenruptur lassen sich Schmerz und Funktion mittels endoskopischer und offener Operationsverfahren in den meisten Fallen deutlich verbessern.

Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. Two mechanisms are known to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called alternative lengthening of telomeres (ALT). Whereas 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. Telomerase inhibitors are already investigated in clinical trials, although the regulation as well as potential coexistence and redundancy of both telomere maintenance mechanisms during distinct steps of carcinogenesis are poorly understood. Herein, we demonstrate that telomerase activity and ALT alternate in a cell cycle dependent fashion in human esophageal epithelial cells, and can coexist in a genetically defined model of oral-esophageal squamous carcinogenesis. Moreover, we show that immortalized premalignant cells as well as cancer cells are able to switch from telomerase activation to ALT upon inhibition of telomerase. This indicates that cancer cells treated with telomerase inhibitors can use alternative and adaptive ways to maintain their telomeres and thereby escape telomere-based therapeutic strategies.

Purpose of the research The purposes of this paper are to describe the methods used and the knowledge gained during a pilot study that evaluated the effects of a self-management intervention for cancer pain, as well as the adaptations that were made for a larger clinical trial. Methods and sample In a randomized controlled trial, the adapted German version of the PRO-SELF © Plus Pain Control Program (PCP), a 10-week intervention to support self-management of pain in adult oncology outpatients and their family caregivers, was compared to attention control. Primary endpoints were average and worst pain measured at 6, 10, 14, and 22 weeks after enrollment. Key results A total of 39 patients (19 intervention, 20 control) were recruited over 18 months. During the study, inclusion criteria were expanded. Furthermore, the structured timing of the intervention visits was too static for a dynamic symptom like cancer pain. The intervention was expanded to include symptoms that severely impacted pain self-management including chemotherapy-induced nausea and vomiting. Conclusions Apart from the provision of information and skills building, coaching cancer patients across a complex treatment is an important function of an intervention to support pain self-management. The pilot study proved to be highly useful in order to adapt planned study procedures, to balance burden and benefit for participants, and to customize the intervention to patients' needs and abilities in order to enhance feasibility and effectiveness. Findings from this pilot study will be fully integrated in a larger randomized controlled trial. Clinical trial registration number: NCT00920504.

Intensive wissenschaftliche Bemuhungen haben in den letzten 20 Jahren zu einem verbesserten Verstandnis der Biologie von Tumorzellen gefuhrt. So fuhren genetische und epigenetische Veranderungen in Tumorzellen zu Alterationen in Signalwegen, die wichtige zellulare Prozesse wie Proliferation und Uberleben steuern. Durch die Einfuhrung zielgerichteter Substanzen ist ein unmittelbarer Eingriff in veranderte Signalwege und Stoffwechselprozesse der Tumorzelle moglich geworden; dies wird heute bei zahlreichen Tumorarten therapeutisch genutzt. Der Tyrosinkinaseinhibitor Imatinib wurde als erste zielgerichtete Substanz zunachst 2001 zur Therapie der chronisch-myeloischen Leukamie und spater zur Therapie der gastrointestinalen Stromatumoren zugelassen. Imatinib gehort zur Klasse der „Small Molecules“, die gezielt die Aktivitat von zelleigenen Proteinen beeinflussen und so das Wachstum der Tumorzelle bremsen. Zusatzlich wurden in den vergangenen Jahren monoklonale Antikorper zum klinischen Gebrauch zugelassen, die gegen Wachstumsfaktorrezeptoren der Tumorzellen gerichtet sind oder die Neubildung von Blutgefasen im Tumor verhindern. Zielgerichtete Substanzen werden heute erfolgreich zur Therapie von hamatologischen und soliden Tumoren eingesetzt. Dieser Artikel gibt einen Uberblick uber den klinischen Einsatz zielgerichteter Therapien in gastrointestinalen Tumoren und fasst die derzeit vorliegenden Studienergebnisse zusammen.

Patients with UICC stage II colorectal cancer (CRC) have a risk of approximately 20% to develop disease recurrence after tumour resection. The presence and significance of micrometastases for locoregional recurrence in these patients lacking histopathological lymph node involvement on routine stained HE sections is undefined. Oestrogen receptor (ER) promoter methylation has earlier been identified in CRC. Therefore, we evaluated the methylation status of the ER promoter in lymph nodes from 49 patients with CRC UICC stage I and II as a molecular marker of micrometastases and predictor of local recurrence. DNA from 574 paraffin-embedded lymph nodes was isolated and treated with bisulphite. For the detection of methylated ER promoter sequences, quantitative real-time methylation-specific PCR was used. Of the 49 patients tested, 15 (31%) had ER methylation-positive lymph nodes. Thirteen of those (86%) remained disease free and two (14%) developed local recurrence. In the resected lymph nodes of 34 of the 49 patients (69%), no ER promoter methylation could be detected and none of these patients experienced a local relapse. The methylation status of the ER promoter in lymph nodes of UICC stage I and II CRC patients may be a useful marker for the identification of patients at a high risk for local recurrence.

From 1972 through 1976 90 patients with idiopathic scoliosis underwent posterior spine fusion using Harrington instrumentation. Follow up was 10 years or more with an average of 12 years. The most frequent and most serious complications occurred in adults with scoliotic deformities of more than 90 degrees. Vital capacity of adults improved more than 20 percent. In young patients with low grade scoliotic spines a better immediate postoperative correction was achieved. There was also a higher loss of correction later on in this group. Thus in the long term follow up there was no correlation between magnitude of the preoperative curve and postoperative correction.

From 1972 through 1976 40 patients with congenital scoliosis, scoliosis in neurofibromatosis and scoliosis following poliomyelitis underwent posterior spine fusion using Harrington instrumentation. Follow up was 10 years or more with an average of 12 years. 63 percent of all patients showed a curve of more than 90 degrees before operation. The different types of scolioses revealed characteristical results according to their etiology during long time follow up. Concerning long time reduction of curve the best results were obtained in patients following poliomyelitis. Patients with congenital and neurofibromatous scoliosis showed loss of correction 2 and 5 years postoperatively.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Little is known about its molecular pathogenesis and the relevance of DNA methylation for disease initiation and progression. Nevertheless, promoter methylation of some genes has been implicated as potential marker for HCC. Thirty-four HCC, 34 matching non-malignant, cirrhotic livers and 16 normal livers were analyzed for the methylation status of the genes p16INK4a, GSTP1, MGMT, DAP-K and APC by quantitative methylation-specific PCR. DNA promoter methylation frequencies in HCC and matching non-malignant cirrhotic liver, respectively, were as follows: p16INK4a (76% vs. 24%), GSTP1 (53% vs. 32%), MGMT (6 vs. 12%), DAP-K (68 vs. 100%) and APC (100 vs. 100%). GSTP1 and/or p16INK4a promoter methylation was observed in 88% of the HCC samples. In normal liver tissue, the p16INK4a, GSTP1 and MGMT promoter were not methylated. DAP-K was methylated in 31% and APC even in 100% of normal liver samples. Quantitative levels of methylated promoter DNA of all genes were significantly different in the various tissue types except for MGMT. Our results suggest that promoter methylation of tumor-associated genes is a common event in hepatocarcinogenesis. Significantly, higher levels and frequencies of promoter methylation in HCC were found for p16INK4a and GSTP1 compared to non-malignant cirrhotic liver. This indicates that these epigenetic events may serve as a good marker for HCC. These data also demonstrate the importance of the quantification of methylated promoter DNA within a given sample and the use of normal tissue as controls. Quantitative analyses of methylated GSTP1 and p16INK4a promoter may serve as a powerful molecular marker in detecting HCC in biopsies. © 2008 Wiley-Liss, Inc.

Serum carbohydrate antigen 19-9 (CA 19-9) has been identified as biochemical marker for biliary tract cancer (BTC). The purpose of this study was to evaluate its value as a treatment response marker and its value as a prognostic parameter in patients with unresectable BTC. We analyzed 70 patients with BTC treated with chemotherapy. CA 19-9 levels before and after two treatment courses were analyzed with respect to their effect on treatment response. Patients were categorized into two subgroups according to biliary stenting: patients without endoscopic intervention or biliary drainage (non-stent subgroup) and patients with endoluminal stenting (stent subgroup). Pretreatment CA 19-9 levels were prognostic with respect to overall survival for the entire study population. Patients with CA 19-9 levels above the median of 300 units/mL had a nearly 3-fold risk for early death (hazard ratio, 2.92; 95% confidence interval, 1.51-5.64; adjusted P = 0.002) as compared with patients with CA 19-9 levels ≤300 units/mL. An association between CA 19-9 and therapeutic response was observed in the non-stent subgroup (P = 0.001) only. Furthermore, the decrease of CA 19-9 levels after treatment was predictive for improved survival in the non-stent subgroup (adjusted P = 0.018) but not in the stent subgroup. Our results indicate that pretreatment CA 19-9 levels and CA 19-9 decrease after chemotherapy are of prognostic relevance in patients with BTC. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2097–100)

Telomerase activity is observed in approximately 90% of human cancer including esophageal squamous cell cancer. Normal somatic cells do not display telomerase activity on a regular basis. The major mechanism to regulate telomerase activity in human cells is the transcriptional control of the catalytic subunit, the human reverse transcriptase gene hTERT. However, the manner in which telomerase activity is regulated during malignant transformation and whether this regulation is influenced by single genetic alterations important in this process are not well understood. In this study we investigated the transcriptional regulation and activity of human telomerase in a cellular model representing important known genetic alterations observed in esophageal cancer. We characterized the respective cells with regard to their telomere biology and telomerase expression, transcriptional regulation using promoter--as well as electrophoretic mobility shift assay--analyses and their promoter methylation status. We could demonstrate that telomerase expression and subsequent activity are differentially regulated in the progression from normal esophageal epithelial cells to genetically defined esophageal cells harboring a specific genetic alteration frequently found in esophageal cancer and compared those changes with esophageal cancer cells. Whereas primary esophageal cells are mainly regulated by Sp1, in cells harboring a genetic alteration as cyclin D1 overexpression other transcription factors like E2F and c-myc as well as promoter methylation influence hTERT transcription. This model demonstrates that the transcriptional regulation of telomerase is influenced by a given genetic alteration important in esophageal cancer, and therefore provides new insight in telomerase regulation during carcinogenesis.

Squamous cancers of the oral cavity and esophagus are common worldwide. A number of environmental factors as well as genetic alterations have been identified. However, the specific combination of genetic events and their interplay with environmental carcinogens are largely un-known. Furthermore, no good animal model existed to study the molecular changes important in the induction and progression of the disease. Here we summarize the efforts made to establish a mouse model of oral-esophageal carcinogenesis. Cyclin D1 overexpressing(L2D1+) mice were generated using an EBV promoter to specifically target the oral cavity and the esophageal squamous epithelium. Besides analyzing different environmental factors, such as nitrosamines and zinc deficiency, cyclin D1 transgenic mice were crossbred with p53-deficient mice. While L2D1+ mice exhibited a phenotype of dysplasia, different combinations of mice result-ed in invasive oral-esophageal cancer. This mouse model provides a well-defined and reproducible model of oral-esophageal cancer that should be useful for testing chemopreventive, diagnostic, and therapeutic strategies.

In den westlichen Industriestaaten sterben weiterhin nahezu 90% aller Patienten mit Ösophaguskarzinom an ihrer Tumorerkrankung. Hauptursache ist die späte Diagnosestellung mit Vorliegen eines fortgeschrittenen Tumors mit Lymphknotenmetastasen. Die Häufigkeit des Adenokarzinoms nimmt im Verhältnis zum Plattenepithelkarzinom in letzter Zeit zu. Die chirurgische Resektion wird weiterhin als Standardtherapie des Ösophaguskarzinoms angesehen. Die Prognose von Patienten mit lokalisierten Tumoren ist streng stadienabhängig. Eine Chemo-, Strahlen- oder kombinierte Radiochemotherapie ist bei frühen Tumoren (Tis-T1 N0-N1 M0) vor oder nach chirurgischer Resektion des Tumors nicht indiziert. Mit dem Stadium T2 steigt die Häufigkeit regionaler und entfernter Lymphknotenmetastasen auf über 60% und damit sinkt die Prognose der Patienten nach der Operation deutlich, obwohl bei diesen Tumoren (T2-T3 N0-N1 M0) häufig eine R0-Resektion gelingt. Nach derzeitiger Datenlage kann bei diesem Patientenkollektiv keine klare Empfehlung für eine alleinige Operation, die Durchführung einer neoadjuvanten Chemo- oder Radiochemotherapie ausgesprochen werden. Weiterhin scheint es eine Gruppe von Patienten zu geben, die nach einem Ansprechen auf eine Radiochemotherapie nicht mehr von einer weiteren Operation profitieren. Patienten mit lokal fortgeschrittenen Tumoren (T3-4 N0-1 M0) stellen Hochrisikopatienten dar, bei denen die alleinige Operation nicht als Standard definiert werden kann. Die Planung der Therapie bei diesen Patienten sollte interdisziplinär erfolgen, da die wirksamste Art der Vorbehandlung bislang nicht eindeutig definiert ist und nach Durchführung einer neoadjuvanten Radiochemotherapie trotz verbesserter lokaler Tumorkontrolle die Mehrzahl der Patienten an Fernmetastasen stirbt. Demzufolge sollten multimodale Therapiekonzepte nur im Rahmen von klinischen Studien durchgeführt werden. Patienten mit metastasiertem Ösophaguskarzinom leben nach Diagnosestellung in der Regel weniger als sechs Monate. Die palliativen Behandlungsmassnahmen müssen deshalb symptomorientiert sein. Die Sicherung der Ernährung steht dabei häufig im Vordergrund.

Zf9/CPBP/KLF6 is a widely expressed member of the Krüppel-like family of transcriptional factors which regulates gene expression in hepatic stellate cells. Because of its ubiquitous expression including in the esophagus, we have explored its function in the esophageal squamous epithelium, a model system to study cellular proliferation and differentiation. Reverse transcription-PCR (RT-PCR) and Western blot analyses revealed that Zf9 was highly expressed in human esophageal squamous cancer cell lines. Additionally, Zf9 localizes to the esophageal squamous epithelium by immunohistochemistry. Using transient transfection, Zf9 transactivates the human keratin 4 (K4) promoter reporter gene construct in a subset of the esophageal cancer cell lines through indirect mechanisms. Co-transfection of Zf9 and GKLF/KLF4, which is also a member of the Krüppel-like factors and expressed in the esophageal squamous epithelium, leads to coactivation in an additive fashion. Furthermore, we demonstrate that there is a physical interaction between GKLF and Zf9, a novel finding for Krüppel-like family members.

The ets family of transcription factors comprises many members which contribute to diverse cellular functions that vary depending upon the cell- and tissue-type context. Recently, different groups have identified a novel member of the ets family that is epithelial-specific. Variably called ESE-1, ERT, jen, ESX, this gene is designated currently as ELF3. In order to understand transcriptional regulatory mechanisms mediated by ELF3, we investigated its effect on the human keratin 4 gene promoter based upon the role of keratin 4 in early differentiation of the esophageal squamous epithelium. Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter. Furthermore, serial deletion constructs of the keratin 4 promoter continued to be suppressed by ELF3, a phenomenon that was only partially rescued by ELF3 ets domain mutants, but completely abrogated by deletion of the ELF3 pointed domain. These results suggest that ELF3 may have dual functions in the transcriptional regulation of genes involved in squamous epithelial differentiation. One of these functions may not be exclusively mediated through DNA binding in the context of transcriptional suppression of the keratin 4 promoter.

Background In vitro cell culture models can provide unique insights into squamous epithelial proliferation, differentiation, and neoplastic transformation. Cultures of human esophageal keratinocytes could be advantageous for the study of these processes. Methods Normal human esophageal keratinocytes were cultivated on 3T3 fibroblast feeder layers in vitro and expanded through four serial subcultivations. Confluent tertiary cultures were analyzed by morphological and immunohistochemical techniques to define their basic properties. The ability to transiently transfect cultured esophageal epithelium was tested using a Rous sarcoma virus-luciferase reporter gene by the calcium phosphate and lipofection methods. Results Postconfluent cultures displayed a predominantly basal cell phenotype with limited stratification, widespread expression of keratins 5 and 14, and production of attachment specialization proteins such as alpha6beta4 integrin and collagen VII. Terminal differentiation markers (involucrin and transglutaminase) were prematurely expressed. The cells expressed growth factors important in proliferation and differentiation, such as transforming growth factor-beta and interleukin-1beta. Tertiary cultures were successfully transiently transfected with a Rous sarcoma virus-luciferase reporter gene construct. Conclusion Normal human esophageal cells can be serially passaged through extended numbers of cell generations and transfected by standard methods. This in vitro system may be useful in the study of fundamental cellular processes governing proliferation and differentiation in the esophageal epithelium.

The stratified squamous epithelium comprises actively proliferating basal cells that undergo a program of differentiation accompanied by morphological, biochemical, and genetic changes. The transcriptional regulatory signals and the genes that orchestrate this switch from proliferation to differentiation can be studied through the keratin gene family. Given the localization of keratin 4 (K4) to the early differentiated suprabasal compartment and having previously demonstrated that targeted disruption of this gene in murine embryonic stem cells results in impairment of the normal differentiation program in esophageal and corneal epithelial cells, we studied the transcriptional regulation of the human K4 promoter. A panel of K4 promoter deletions were found in transient transfection assays to be predominantly active in esophageal and corneal cell lines. A critical cis-regulatory element resides between -163 and -140 bp and contains an inverted CACACCT motif. A site-directed mutated version of this motif within the K4 promoter renders it inactive, whereas the wild-type version is active in a heterologous promoter system. It specifically binds esophageal-specific zinc-dependent transcriptional factors. Our studies demonstrate that regulation of the human K4 promoter is in part mediated through tissue-specific transcriptional factors.

Restrictions ordered by the U.S. Food and Drug Administration on the use of silicone gel-filled breast implants, as well as patient and surgeon dissatisfaction with the aesthetic results sometimes attained with saline solution-filled implants, have prompted new interest in developing alternative implant filler materials, including triglycerides. Soybean oil-filled breast implants are now in various stages of testing and use in the United States, Europe, and Canada. This article reports on experience with Trilucent® breast implants (prefilled with soybean oil) by one plastic surgeon in Sweden. A total of 96 patients (191 implants) underwent primary augmentation or replacement augmentation mammaplasty between October 1995 and June 1997. Data have been analyzed for all 96 patients with a mean follow-up period of 15 months and for 67 patients (133 implants) with a mean follow-up of 18 months. The significant findings of the study include the absence of systemic reactions or unusual local complications, the low incidence (2.3%) of symptomatic capsular contracture (grades III and IV) among the 67 patients at the 18-month postoperative time point, and high patient satisfaction with the aesthetic results. The mammographic radiolucency of soybean oil-filled implants was also demonstrated. At the 18-month follow-up point, the only negative observations were the presence of skin wrinkling in 3% of the breasts and implant palpability in 46% of the breasts. These findings are in general agreement with preliminary data from the European clinical trials of Trilucent® breast implants.

We addressed the question whether the in vitro interaction of two Epstein-Barr virus (EBV)-genome-positive B cell lines (EB-3 and HilB-γ) with either Mycoplasma pneumoniae or M. hominis , with the «AIDS-related» mycoplasma species ( M. fermentans , M. fermentans subsp. incognitus , M. penetrans , M. genitalium ) or with mycoplasma species known to be mere commensals of the respiratory tract ( M. orale and M. salivarium ) would result in expression of mRNAs for IL-2, IL-2R, IL-4 and IL-6 as determined by reverse transcriptase (RT)-PCR after 4 and 24 h of cocultivation. The pattern of cytokine gene expression observed depended on (i) the origin of the transformed cell line, (ii) the pathogenicity of the Mycoplasma species, and (iii) the length of cocultivation. The EBV-immortalized lymphoblastoid cell line HilB-γ showed mRNA expression for IL-2, IL-2-receptor, IL-4 and IL-6 peaking 24 h after stimulation with M. pneumoniae and all AIDS-related mycoplasma species tested. The Burkitt lymphoma cell line EB-3 showed a distinct and isolated strong II-2/IL-2 R-mRNA expression within 4 h after contact with the pathogenic and all of the AIDS related mycoplasma species. In neither EBV-containing cell line cytokine was gene expression detectable after stimulation with the commensal mycoplasma species, M. orale and M. salivarium , indicating species differences in the ability of mycoplasmas to interact with and stimulate B-cell lines. Our data suggest that some mcyoplasma species may act as immunomodulatory cofactors by eliciting inappropriate cytokine gene expression in B cells latently infected with EBV. Therefore, this cultivation model may prove useful in evaluating the pathogenetic potential of novel isolated mycoplasma species.

The Kruppel-like family of transcription factors comprises genes that appear to have tissue-restricted functions. Expression of gut-enriched Kruppel-like factor (GKLF) may be important in the switch from proliferation to differentiation in the squamous epithelium. We sought to determine transcriptionally mediated effects of GKLF on two promoters active in the esophageal squamous epithelium, namely the Epstein-Barr virus ED-L2 and human keratin 4 promoters. Both promoters contain a CACCC-like motif previously shown to bind GKLF. To determine whether GKLF regulates genes containing this element, we first demonstrated expression and then cloned the full-length human GKLF from an esophageal squamous carcinoma cell line. In a transient transfection system, GKLF increased the activity of both promoters >25-fold, localized to regions containing the CACCC-like element. Recombinant GKLF specifically binds the CACCC-like motif in both promoters. GKLF epitope-tagged protein leads to the formation of two proteins of 65 and 34 kDa. The chromatographically purified 65-kDa protein binds the CACCC-like element from both Epstein-Barr virus ED-L2 and keratin 4 promoters, which is not attenuated by the 34-kDa protein. In summary, GKLF is expressed in esophageal squamous epithelial cells and transcriptionally activates two esophageal epithelial promoters important at the transition toward differentiation.

Bovine seminal ribonuclease (RNase) binds, melts, and (in the case of RNA) catalyzes the hydrolysis of double-stranded nucleic acid 30-fold better under physiological conditions than its pancreatic homologue, the well-known RNase A. Reported here are site-directed mutagenesis experiments that identify the sequence determinants of this enhanced catalytic activity. These experiments have been guided in part by experimental reconstructions of ancestral RNases from extinct organisms that were intermediates in the evolution of the RNase superfamily. It is shown that the enhanced interactions between bovine seminal RNase and double-stranded nucleic acid do not arise from the increased number of basic residues carried by the seminal enzyme. Rather, a combination of a dimeric structure and the introduction of two glycine residues at positions 38 and 111 on the periphery of the active site confers the full catalytic activity of bovine seminal RNase against duplex RNA. A structural model is presented to explain these data, the use of evolutionary reconstructions to guide protein engineering experiments is discussed, and a new variant of RNase A, A(Q28L K31C S32C D38G E111G), which contains all of the elements identified in these experiments as being important for duplex activity, is prepared. This is the most powerful catalyst within this subfamily yet observed, some 46-fold more active against duplex RNA than RNase A.

Greater trochanteric pain is one of the common complaints in orthopedics. Frequent diagnoses include myofascial pain, trochanteric bursitis, tendinosis and rupture of the gluteus medius and minimus tendon, and external snapping hip. Furthermore, nerve entrapment like the piriformis syndrome must be considered in the differential diagnosis. This article summarizes essential diagnostic and therapeutic steps in greater trochanteric pain syndrome. Careful clinical evaluation, complemented with specific imaging studies and diagnostic infiltrations allows determination of the underlying pathology in most cases. Thereafter, specific nonsurgical treatment is indicated, with success rates of more than 90 %. Resistant cases and tendon ruptures may require surgical intervention, which can provide significant pain relief and functional improvement in most cases.

AIM: To investigate the expression and clinical relevance of inhibitor of differentiation (ID) proteins in biliary tract cancer. METHODS: ID protein expression was analyzed in 129 samples from patients with advanced biliary tract cancer (BTC) (45 extrahepatic, 50 intrahepatic, and 34 gallbladder cancers), compared to normal controls and correlated with clinical an pathological parameters. RESULTS: ID1-3 proteins are frequently overexpressed in all BTC subtypes analyzed. No correlation between increased ID protein expression and tumor grading, tumor subtype or treatment response was detected. Survival was influenced primary tumor localization (extrahepatic vs intrahepatic and gall bladder cancer, OS 1.5 years vs 0.9 years vs 0.7 years, P = 0.002), by stage at diagnosis (OS 2.7 years in stage I vs 0.6 years in stage IV, P < 0.001), resection status and response to systemic chemotherapy. In a multivariate model, ID protein expression did not correlate with clinical prognosis. Nevertheless, there was a trend of shorter OS in patients with loss of cytoplasmic ID4 protein expression (P = 0.076). CONCLUSION: ID protein expression is frequently deregulated in BTC but does not influence clinical prognosis. Their usefulness as prognostic biomarkers in BTC is very limited.

The stereospecificity of acrylonitrile polymerization initiated by organometallic compounds of alkali and alkaline earth metals was investigated. The triad tacticities of the polymers obtained was analyzed by 13 C NMR and the molecularweights and their distributions were measured by size exclusion chromatography. A decisive influence of temperature on acrylonitrile polymerization initiated by dialkylmagnesium (di-n-hexyl- and di-n-butylmagnesium) in mesitylene was found. Products polymerized at temperatures above 100 °C contain high molecular weight fractions with predominantly isotactic configuration (isotactic triad content 50-55%). The stereospecificity of polymerization was observed only in a medium which is a non-solvent for the product. All the other investigated metalorganics do not initiate a stereospecific polymerization on these conditions. In order to elucidate the stereospecific polymerization mechanism we examined NMR data by model calculations. The triad tacticity of some predominant isotactic polyacrylonitrile samples is described by the enantiomorphic sites (e.m.s.) model. This means that the propagation takes place at enantiomeric catalyst sites which determine the configuration of the incoming monomer unit. Summarizing the experimental observations and the interpretation of the polymer structure, a model of the active centers involving associated dialkylmagnesium structures is proposed.

Chondrosarcoma is the third most frequent primary malignant tumor of bone, constituting up to 16% of the malignant osseous neoplasms. Up to date several genetic alterations and markers were described concerning the pathogenesis and the progression of the chondrosarcoma, which represents actually a heterogeneous group of different types including conventional intramedullary, clear cell, myxoid, mesenchymal, and dedifferentiated chondrosarcoma. The pathologic appearance varies, however, in general they grow with a lobulated pattern. Histologically the hyaline cartilage demonstrates high water content and typically enchondral ossification is apparent. Imaging reflect this while radiographic findings suggest the diagnosis when the typical "ring-and-arc" chondroid matrix mineralization, endosteal scalloping and soft-tissue extension were apparent. The CT is used for detecting the mineralization of the matrix, especially when it is subtle or when the lesion is located in complex areas. MRT is the method of choice to detect the high water content of these lesions with a high signal intensity with T2-weighting and its bone marrow extend. Surgical resection is the primary and preferred treatment modality for most individuals with localized disease. In selected cases of the Grad I conventional chondrosarcoma curettage should be discussed. Systemic chemotherapy may be considered in variant forms such as mesenchymal or dedifferentiated chondrosarcomas. In knowledge of the "many faces" of the primary chondrosarcoma individualized patient assessment and optimal clinical management is possible.

This paper reports findings from a randomized controlled pilot study evaluating the PRO-SELF Plus Pain Control Program, a U.S.-developed cancer pain self-management intervention, regarding feasibility and effect sizes in a German patient sample.Thirty-nine German oncology outpatients were randomized to intervention (n = 19) and control (n = 20) groups. The intervention group received the PRO-SELF Plus Pain Control Program in 6 visits and 4 phone calls a 10-week period. The control group received standard education and care. The intervention employed three key strategies: information provision, skills building, and nurse coaching. Primary outcomes were changes in average and worst pain intensity. Secondary outcomes included changes in pain-related knowledge, opioid intake, and self-efficacy. Data were collected at enrollment, then at 6, 10, 14, and 22 weeks.The group-by-time effect showed a statistically significant increase in knowledge (week 10: p = 0.04; week 22: p0.01). Despite slight reductions in average and worst pain, no statistically significant changes were found for pain, opioid intake, or self-efficacy.This study is the first to evaluate and demonstrate the feasibility of a U.S.-developed cancer pain self-management intervention in a German patient population. Pain self-management related knowledge improved significantly and effect sizes for pain reduction were determined. Findings from this pilot RCT provide the basis for planning a larger RCT.NCT00920504.

The impact of chemotherapy (CTx) on morbidity after liver resection for colorectal metastases (CRC-LM) has been increasingly investigated during recent years. Biologic agents like bevacizumab (BEV) or cetuximab (CET) are now added as “targeted therapy” (TT), also in neoadjuvant settings. Initial series could demonstrate the safety of those regimens in liver resection but data are still scarce. We evaluated the impact of CTx with BEV or CET (CTx + TT) on perioperative morbidity and mortality. Two hundred thirty-seven patients who underwent liver resections for CRC-LM after chemotherapy before surgery since 1999 were included. One hundred eighty-five patients (78%) had preoperative CTx regimen without biologic agents (fluoropyrimidine-, oxaliplatin-, or irinotecan-based) and 52 (22%) had CTx + TT (39 BEV, 11 CET, 2 CET/BEV). After preoperative CTx + TT, a time interval of at least 4–6 weeks and a residual liver volume of >35% before surgery were required. Hemihepatectomy or more was performed in about half of the patients. The median amount of intraoperatively transfused blood was 0 ml in both groups (p = 0.34). Overall mortality was 1.7% and slightly elevated in patients with CTx + TT (3.8% vs. 1.1%, p = 0.17). Any complication occurred in (CTx + TT vs. CTx) 52% and 46%, respectively (p = 0.47). The rates of liver failure (9.6% vs. 9.7%, p = 0.98), infectious complications such as wound infection (19% vs. 16%, p = 0.62) and abdominal abscess (8% vs. 6.5%, p = 0.71), as well as the rate of relaparotomies (11.5% vs. 7.0%, p = 0.29) showed no significant differences between the groups with TT or without. In multivariate analyses, neither type nor duration of CTx nor the time interval between CTx and surgery showed any influence on complication rates. Our data confirm the safety of targeted therapy before liver resection for CRC-LM. This effect may in part be due to our treatment policy (time interval to resection and residual liver volume) after intensive preoperative CTx.

Context Cancer pain continues to be extensively undertreated, despite established guidelines. Although the efficacy of interventions that support patients' self-management of cancer pain has been demonstrated in several studies, the most effective components of these interventions remain unknown. Objectives The purpose of this review of experimental and quasi-experimental studies was to systematically describe the structure and content components, as well as the efficacy of various components, of interventions designed to improve patients' self-management of cancer pain. Methods A systematic review of the literature was done that supplemented the 2009 meta-analysis of Bennett et al. Intervention components were categorized using content analysis. The intervention components were compared based on their calculated largest effect sizes (ESs) within each study (i.e., Hedges G u for between-group differences in pain intensity scores). Results Based on 34 publications (i.e., 24 interventions), seven structure and 16 content components were identified. In 11 studies with statistically significant ESs, the largest ES within each study ranged from −1.87 to −0.44, which represented clinically meaningful effects. No single component was found to have a discernable influence on ES. Conclusion This analysis provides researchers and clinicians with a detailed overview of the various structural and content components, as well as various combinations that were tested in intervention studies to improve cancer pain management. However, because of a variety of limitations, the most efficacious intervention components or combination of components remain to be determined in future studies.

Telomerase plays an important role during immortalization and malignant transformation as crucial steps in the development of human cancer. In a cellular model of oral-esophageal carcinogenesis, recapitulating the human disease, immortalization occurred independent of the activation of telomerase but through the recombination-based alternative lengthening of telomeres (ALT). In this stepwise model, additional overexpression of EGFR led to in vitro transformation and activation of telomerase with homogeneous telomere elongation in already immortalized oral squamous epithelial cells (OKF6-D1_dnp53). More interestingly, EGFR overexpression activated the PI3K/AKT pathway. This strongly suggested a role for telomerase in tumor progression in addition to just elongating telomeres and inferring an immortalized state. Therefore, we sought to identify the regulatory mechanisms involved in this activation of telomerase and in vitro transformation induced by EGFR. In the present study we demonstrate that telomerase expression and activity are induced through both direct phosphorylation of hTERT by phospho-AKT as well as PI3K-dependent transcriptional regulation involving Hif1-alpha as a key transcription factor. Furthermore, EGFR overexpression enhanced cell cycle progression and proliferation via phosphorylation and translocation of p21. Whereas immortalization was induced by ALT, in vitro transformation was associated with telomerase activation, supporting an additional role for telomerase in tumor progression besides elongating telomeres.

Background Aurora kinases and loss of p53 function are implicated in the carcinogenesis of aneuploid esophageal cancers. Their association with occurrence of multipolar mitoses in the two main histotypes of aneuploid esophageal squamous cell carcinoma (ESCC) and Barrett's adenocarcinoma (BAC) remains unclear. Here, we investigated the occurrence of multipolar mitoses, Aurora-A/-B gene copy numbers and expression/activation as well as p53 alterations in aneuploid ESCC and BAC cancer cell lines. Results A control esophageal epithelial cell line (EPC-hTERT) had normal Aurora-A and -B gene copy numbers and expression, was p53 wild type and displayed bipolar mitoses. In contrast, both ESCC (OE21, Kyse-410) and BAC (OE33, OE19) cell lines were aneuploid and displayed elevated gene copy numbers of Aurora-A (chromosome 20 polysomy: OE21, OE33, OE19; gene amplification: Kyse-410) and Aurora-B (chromosome 17 polysomy: OE21, Kyse-410). Aurora-B gene copy numbers were not elevated in OE19 and OE33 cells despite chromosome 17 polysomy. Aurora-A expression and activity (Aurora-A/phosphoT288) was not directly linked to gene copy numbers and was highest in Kyse-410 and OE33 cells. Aurora-B expression and activity (Aurora-B/phosphoT232) was higher in OE21 and Kyse-410 than in OE33 and OE19 cells. The mitotic index was highest in OE21, followed by OE33 > OE19 > Kyse-410 and EPC-hTERT cells. Multipolar mitoses occurred with high frequency in OE33 (13.8 ± 4.2%), followed by OE21 (7.7 ± 5.0%) and Kyse-410 (6.3 ± 2.0%) cells. Single multipolar mitoses occurred in OE19 (1.0 ± 1.0%) cells. Distinct p53 mutations and p53 protein expression patterns were found in all esophageal cancer cell lines, but complete functional p53 inactivation occurred in OE21 and OE33 only. Conclusions High Aurora-A expression alone is not associated with overt multipolar mitoses in aneuploid ESCC and BAC cancer cells, as specifically shown here for OE21 and OE33 cells, respectively. Additional p53 loss of function mutations are necessary for this to occur, at least for invasive esophageal cancer cells. Further assessment of Aurora kinases and p53 interactions in cells or tissue specimens derived from non-invasive dysplasia (ESCC) or intestinal metaplasia (BAC) are necessary to disclose a potential causative role of Aurora kinases and p53 for development of aneuploid, invasive esophageal cancers.

The adherence-mediating sites of the 153 kDa adhesin of Mycoplasma genitalium (MgPa-protein) were characterized at the amino acid sequence level using six monoclonal anti-MgPa antibodies which showed adherence-inhibiting activity. For characterization of the regions to which antibody bound, three segments of the adhesin (N-terminal region, a D1-domain located approximately in the middle of the molecule and a D2-domain located near to the C-terminus) were synthesized as overlapping octapeptides. These regions were chosen in analogy to the three domains of Mycoplasma pneumoniae that are involved in the adhesion process. Whereas two monoclonal antibodies (mAb 5B11 and mAb 6F3) bound exclusively to an epitope in the N-region, mAb 3B7 and mAb 6A2 reacted with two distinct epitopes of the D2-domain only. Binding to short synthetic peptides of different regions was analysed for mAb 3A12 (N-region and D1-region) and mAb 2B6 (N-region and D2-region). Close proximity of the N-region and the D2-region in the native MgPa-protein of M. genitalium was indicated in a competitive ELISA test, using freshly harvested M. genitalium cells. Epitope mapping and competition experiments with monoclonal anti-MgPa antibodies revealed interesting differences in the adherence-mediating sites of MgPa and the adhesin (P1-protein) of M. pneumoniae. Whereas a three-dimensional arrangement of protein loops is suggested for both native adhesins, the MgPa-protein and the P1-protein adherence-mediating epitopes are located in non-homologous regions of these two related proteins. Thus, the two mycoplasma species appear adapted to different host epithelial cells, i.e. to those of the human urogenital tract as the main binding site for M. genitalium and to those of the respiratory tract as the binding site for M. pneumoniae.