[Palliative therapy concepts for pancreatic carcinoma]. / Palliative Konzepte beim Pankreaskarzinom.

The majority of patients with ductal pancreatic adenocarcinoma are already in a locally advanced or metastatic stage at the time of diagnosis and require palliative therapy. Interventional and operative measures are available for the restoration of biliary outflow in bile duct obstruction and the continuity of the upper intestinal lumen in duodenal or gastric outlet obstruction. In the presence of tumor-related pain, pain therapy according to the World Health Organization (WHO) scheme or a truncus coeliacus blockade, in cachexia a nutritional therapy and in thromboembolic events an anticoagulant therapy are used. An individualized palliative chemotherapy regimen should be selected for each patient, taking into account the patient's general condition and the side effects profile of the chemotherapeutic agents. Radiochemotherapy and local ablative therapies should currently only be used within the framework of studies. A palliative resection is not recommended according to current knowledge.

[Branch duct intraductal papillary mucinous neoplasm - contra resection]. / Intraduktale papillär-muzinöse Neoplasie des Seitengangs­ Kontra Resektion.

Due to improvements in imaging modalities the diagnosis of branch duct intraductal papillary mucinous neoplasms (BD-IPMN) has been significantly increased in recent years. A BD-IPMN is frequently diagnosed as an incidental finding in asymptomatic patients. The optimal management of BD-IPMN is the subject of controversial discussions. Numerous studies have shown that an individualized therapeutic strategy with a follow-up observation of most BD-IPMNs is feasible and safe, considering age, comorbidities and patient preference. An accurate evaluation of BD-IPMN with a detailed anamnesis, high-resolution imaging techniques and endoscopic ultrasound is necessary. Symptomatic patients as well as patients with so-called high-risk stigmata should undergo resection. Asymptomatic patients with so-called worrisome features can either undergo surveillance or surgical resection, taking age and comorbidities into account. For BD-IPMN patients without high-risk stigmata and worrisome features and showing no symptoms, surveillance of the pancreatic lesion is the preferred approach. The high prevalence of BD-IPMN, limitations in differential diagnostics, an overestimation of the risk of malignancy due to an overrepresentation of symptomatic and suspected BD-IPMN in resected cohorts, an overestimated role of BD-IPMN as precursor lesions for pancreatic carcinoma and evidence of the safety of follow-up surveillance, underline the enormous importance of surveillance. Based on this and considering the background of a notable mortality and morbidity of pancreatic surgery, aggressive management with prophylactic surgical resection is not justified for all BD-IPMN, in particular for low-risk lesions.

[R1 resection for pancreatic carcinoma]. / R1-Resektion beim Pankreaskarzinom.

BACKGROUND: Surgery is the only potentially curative therapeutic approach in patients with pancreatic ductal adenocarcinoma (PDAC); however, achieving a negative (R0) resection margin is not always possible. OBJECTIVE: The impact of R1 resection margins on survival rates and treatment options (surgical and multimodal) for intraoperatively and postoperatively identified R1 resection margins. RESULTS: For intraoperatively diagnosed R1 resection margins, a re-resection (e.g. pancreas, main bile duct, stomach, superior mesenteric and portal vein) can be performed to achieve R0 resection margins. Arterial resections and the resection of additional organs are occasionally technically feasible and can be performed in an individual approach. New neoadjuvant and adjuvant treatment strategies have increased the rate of resectable PDAC and have improved the outcome of patients with R0/R1 resected PDACs. CONCLUSION: An R0 resection is the primary goal of surgery in patients with PDAC as R1 resections are correlated with a poor outcome.

Nuclear osteopontin-c is a prognostic breast cancer marker.

BACKGROUND: Although Osteopontin has been known as a marker for cancer progression, the elevated production of this cytokine is not specific for cancer. We have identified the splice variant Osteopontin-c as being absent from healthy tissue but associated with about 75% of breast cancer cases. However, in previous studies of Osteopontin-c, follow-up information was not available. METHODS: Here we have analysed 671 patients, comprising a cohort of 291 paraffin blocks plus a population-based case-control study of 380 arrayed breast tumor tissues. RESULTS: We find that high staining intensity of nuclear Osteopontin-c is strongly associated with mortality in patients with early breast cancer. Cytosolic staining for exon 4, reflective of Osteopontin-a and -b also predicts poor outcome. By contrast, total Osteopontin does not correlate with prognosis. These diverse assessments of Osteopontin also do not correlate with each other, suggesting distinct expression patterns for the variant forms. Consistent with its role in tumor progression, not tumor initiation, Osteopontin-c is not correlated with proliferation markers (Ki-67, cyclin A, cyclin B, cyclin E and cyclin D), neither is it correlated with ER, PR or HER2. CONCLUSIONS: The addition of Osteopontin-c immunohistochemistry to standard pathology work-ups may have prognostic benefit in early breast cancer diagnosis.

Osteopontin is a marker for cancer aggressiveness and patient survival.

BACKGROUND: Only a fraction of molecular cancer markers identified in the scientific literature have found clinical use. Specifically, few predictors of invasiveness are established in diagnostics. Meta-analysis is a valuable tool for biomarker validation. Here, we evaluate Osteopontin as a marker for tumor aggressiveness (grade, stage, early progression) and patient survival. METHODS: Publications through 2008 with the keywords 'osteopontin AND cancer' were retrieved. Titles and abstracts were screened for studies presenting original data on human subjects. This left 228 publications for data extraction. We applied categorical data analysis for testing the relationship between Osteopontin and a clinical variable. RESULTS: Osteopontin ranks correlated with lower overall and disease-free/relapse-free survival in all tumors combined, as well as in lung cancer, breast cancer, prostate cancer, head and neck cancer, and liver cancer. Further, Osteopontin levels correlated with tumor grade and stage for all tumors combined and for several individual tumor types. Osteopontin levels were significantly associated with the early progression of eight cancers, independent in one, and inversely correlated in two. CONCLUSIONS: Osteopontin is significantly associated with survival in several forms of cancer. Osteopontin levels are also markers for stage, grade, and early tumor progression in multiple cancers, reflecting a common molecular underpinning for distinct clinical measures. Osteopontin has value as a clinical tumor progression marker.

An osteopontin splice variant induces anchorage independence in human breast cancer cells.

In malignant tumors, metastasis genes are typically deregulated by aberrant expression or splicing. Osteopontin is expressed at high levels by various cancers and contributes importantly to their invasive potential. In contrast, osteopontin derived from host cells induces cellular immunity and could bolster antitumor protection by cytotoxic T lymphocytes. Here we show that breast cancer cells express multiple splice variants of osteopontin. According to RT-PCR analysis of human breast tissue specimens, the splice variant osteopontin-c is a highly specific marker for transformed cells, which is not expressed in their surrounding normal tissue. The full-length form of osteopontin aggregates in the presence of physiologic amounts of calcium and, in this state, leads to enhanced cell adhesion. Ostensibly, this effect is inhibitory for tumor cell dissemination. The shortest splice variant, osteopontin-c, does not aggregate in the presence of calcium and enhances clone formation in soft agar. According to microarray analysis, osteopontin-c induces the expression of oxidoreductases, consistent with protection from anoikis during anchorage-independent growth. These studies define a third functional domain of osteopontin, beside the C-terminal CD44-binding site and the central integrin-binding site. They also provide evidence for a bifunctional character of osteopontin, with the soluble form supporting invasiveness and the aggregated form promoting adhesion.

Differential roles of osteopontin/Eta-1 in early and late lpr disease.

The cytokine osteopontin (Eta-1) leads to macrophage-dependent polyclonal B-cell activation and is induced early in autoimmune prone mice with the lpr mutation, suggesting a significant pathogenic role for this molecule. Indeed, C57BL/6-Fas(lpr/lpr) mice crossed with osteopontin(-/-) mice display delayed onset of polyclonal B-cell activation, as judged by serum immunoglobulin levels. In contrast, they are subject to normal onset, but late exacerbation of lymphoproliferation and evidence of kidney disease. These observations define two stages of Fas(lpr/lpr) disease with respect to osteopontin-dependent pathogenesis that should be taken into account in the design of therapeutic approaches to the clinical disease.

Costimulation by extracellular matrix proteins determines the response to TCR ligation.

Although ligation of the T-cell antigen receptor (TCR) is central to the responsiveness and antigen specificity of T-cells, it is insufficient to elicit a response. To determine whether the need for costimulation reflects inadequate strength of signal transduction through the TCR or an absolute block of signaling in the absence of a coligand, we studied T-cell activation under serum-free conditions eliminating costimulation by various extracellular matrix proteins which otherwise have an omnipresent and frequently overlooked effect. Engagement of the TCR leads to induction of Fas, but not to measurable IL-2 secretion or apoptosis. Those activation parameters are induced by costimulation through integrin alphaVbeta3. Furthermore, T-cell survival or elimination is determined by the type of ligand binding to this coreceptor with vitronectin, fibronectin, and fibrinogen efficiently inducing apoptosis and IL-2 production while osteopontin and entactin mediate IL-2 secretion comparably without causing programmed cell death. Consistent with the cytokine properties of these ligands, differential costimulation depends on their presentation in soluble rather than immobilized form. The determination of elimination versus survival of activated T-cells by coligation of beta3-integrins may have bearing on the fundamental postthymic mechanisms that shape the T-cell repertoire.

The metastasis gene osteopontin: a candidate target for cancer therapy.

Malignant tumors are characterized by dysregulated growth control, overcoming of replicative senescence, and metastasis formation. Current therapeutic regimens mostly exert their effects through inhibition of cell cycle progression, leaving two major components of transformation untouched. The cytokine osteopontin is essential for the dissemination of various cancers. Past research has implied several modes in which osteopontin and its main receptors on tumor cells can be suppressed. Osteopontin expression is inhibitable on the levels of gene transcription and the RNA message, and the osteopontin protein can be blocked with antibodies or synthetic peptides. The osteopontin receptor CD44 has been targeted by diverse therapeutic strategies, including cytotoxic and immunotherapeutic approaches. The receptor integrin alpha(V)beta(3) contributes not only to tumor cell dissemination, but also to angiogenesis and osteolysis in bone metastases. Small molecule inhibitors of this receptor are under study as drug candidates. Because receptors and cytokine ligands that mediate metastasis formation are sparsely expressed in the adult healthy organism and are more readily reached by pharmaceuticals than intracellular drug targets they may represent a particularly suitable focus for therapeutic intervention.

Stress response genes: the genes that make cancer metastasize.

Cancer is characterized by dysregulated growth control, overcoming of replicative senescence, and metastasis formation. The topology of cancer spread is mediated by a set of developmentally nonessential genes which are physiologically involved in stress responses, inflammation, wound healing, and neovascularization. The function of these gene products is extensively modified posttranscriptionally. In cancer, metastasis genes are dysregulated at the levels of expression or splicing. These genes constitute a unique group of cancer-related biomolecules.

Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity.

Cell-mediated (type-1) immunity is necessary for immune protection against most intracellular pathogens and, when excessive, can mediate organ-specific autoimmune destruction. Mice deficient in Eta-1 (also called osteopontin) gene expression have severely impaired type-1 immunity to viral infection [herpes simplex virus-type 1 (KOS strain)] and bacterial infection (Listeria monocytogenes) and do not develop sarcoid-type granulomas. Interleukin-12 (IL-12) and interferon-gamma production is diminished, and IL-10 production is increased. A phosphorylation-dependent interaction between the amino-terminal portion of Eta-1 and its integrin receptor stimulated IL-12 expression, whereas a phosphorylation-independent interaction with CD44 inhibited IL-10 expression. These findings identify Eta-1 as a key cytokine that sets the stage for efficient type-1 immune responses through differential regulation of macrophage IL-12 and IL-10 cytokine expression.

Molecular mechanisms of tumor dissemination in primary and metastatic brain cancers.

Cancer is characterized by dysregulated growth control, overcoming of replicative senescence, and metastasis formation. Tumor dissemination distinguishes malignant from benign neoplasms and is mediated by homing receptors, their ligands, and proteinases. The homing receptor CD44 is frequently expressed on primary brain tumors and brain metastases. Its engagement by osteopontin physiologically induces macrophage chemotaxis, a mechanism that may be utilized by metastatic brain tumors in the process of dissemination. In host defense, osteopontin and its receptors, CD44 and integrin alpha(V)beta(3), play key roles in mediating delayed type hypersensitivity responses by activating macrophages to induce Th1 cytokines while inhibiting Th2 cytokines. Other metastasis associated gene products similarly contribute to host defenses. Hence, cancer spread is regulated by a set of developmentally non-essential genes which physiologically mediate stress responses, inflammation, wound healing, and neovascularization. Function of the relevant gene products is extensively modified post-transcriptionally and their dysregulation in cancer occurs on the levels of expression and splicing. Consistent patterns of organ preference by malignancies of particular tissue origin suggest a necessary connection between loss of growth control and senescence genes and expression of genes mediating the dissemination of tumor cells.

Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death.

Misselected CD8 cells that express T cell receptors (TCRs) that do not recognize class I major histocompatibility complex (MHC) protein can emerge from thymic selection. A postthymic quality control mechanism that purges these cells from the repertoire is defined here. The failure of mature CD8 cells to simultaneously engage their TCR and CD8 coreceptor triggers an activation process that begins with inhibition of CD8 gene expression through remethylation and concludes with up-regulation of surface Fas and Fas ligand and cellular apoptosis. Thus, inhibition of a death signal through continued TCR-CD8 coengagement of MHC molecules is a key checkpoint for the continued survival of correctly selected T cells. Molecular defects that prevent delivery of the death signal to mistakenly selected T cells underlie the expansion of double-negative T cells, which is the cellular signature of a subset of systemic autoimmune diseases.

Final common pathways in neurodegenerative diseases: regulatory role of the glutathione cycle.

Attempts to unify diverse mechanisms of neurotoxicity have led to the concept of final common pathways which characterize frequently occurring cellular responses to disruption of homeostasis. The clinical presentation and common patho-biochemistry of reactive oxygen intermediates of Guam's disease have suggested that such pathways may be operative in three major neurodegenerative disorders: Alzheimer's dementia, amyotrophic lateral sclerosis and Parkinson's disease. A candidate-signaling pathway in this regard is characterized by the cascade arachidonic acid/HPETE/*OH/cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB. This sequence may lead to apoptosis as well as long-term potentiation and memory and constitutes a biochemical correlate to excitotoxicity. The predominant control of *OH release from HPETE, a checkpoint in this pathway, is exerted by the glutathione cycle, a central biochemical process that is also intimately associated with the synthesis of the neurotransmitters glutamate and GABA and is connected to energy metabolism. Modifications in the activity of the glutathione cycle may provide treatment options.

Activation of T cells by superantigen: cytokine production but not apoptosis depends on MEK-1 activity.

Engagement of the TCR may result in proliferation and cytokine release or programmed cell death. These two outcomes may be the consequence of distinct T cell receptor-coupled signal transduction pathways or may reflect quantitative differences in signaling strength via a single pathway. Here we show that genetic inhibition of MAP kinase kinase (MEK) by a dominant negative mutant or through chemical inhibition by PD98059 inhibits IL-2 secretion but not programmed cell death after TCR ligation by superantigen. This supports the hypothesis that T cell cytokine release and apoptosis result from signaling through distinct pathways and implies that the molecular signaling mechanisms regulating apoptosis of mature T cells and negative selection of thymocytes may be similar.

A novel Bcl-x isoform connected to the T cell receptor regulates apoptosis in T cells.

We define a novel Bcl-x isoform, Bcl-x gamma, that is generated by alternative splicing and characterized by a unique 47 amino acid C-terminus. Bcl-x gamma is expressed primarily in thymocytes, where it may depend on an interaction between the TCR and host MHC products, and in mature T cells, where its expression is associated with ligation of the T cell receptor. Overexpression of Bcl-x gamma in T cells inhibits activation-induced apoptosis; inhibition of Bcl-x gamma, after stable expression of Bcl-x gamma antisense cDNA, enhances activation-induced apoptosis. In contrast to other Bcl-x isoforms, cells that fail to express Bcl-x gamma after CD3 ligation undergo programmed cell death, while activated T cells that express Bcl-x gamma are spared. Identification of Bcl-x gamma helps provide a molecular explanation of T cell activation and death after antigen engagement.

Quality of care, process, and outcomes in elderly patients with pneumonia.

CONTEXT: Pneumonia is a frequent cause of hospitalization and death among elderly patients, but the relationships between processes of care for pneumonia and outcomes are uncertain, making quality improvement a challenge. OBJECTIVES: To assess quality of care for Medicare patients hospitalized with pneumonia and to determine whether process of care performance is associated with lower 30-day mortality. DESIGN: Multicenter retrospective cohort study with medical record review. SETTING: A total of 3555 acute care hospitals throughout the United States. PATIENTS: A total of 14069 patients at least 65 years old hospitalized with pneumonia. MAIN OUTCOME MEASURES: Four processes of care: time from hospital arrival to initial antibiotic administration; blood culture collection before initial hospital antibiotics; blood culture collection within 24 hours of hospital arrival; and oxygenation assessment within 24 hours of hospital arrival. Associations between processes of care and 30-day mortality were determined with logistic regression analysis. RESULTS: National estimates of process-of-care performance were antibiotic administration within 8 hours of hospital arrival, 75.5% (95% confidence interval [CI], 73.1-77.9); blood cultures before antibiotics, 57.3% (95% CI, 54.5-60.1); initial blood culture collection, 68.7% (95% CI, 66.2-71.2); and initial oxygenation assessment, 89.3% (95% CI, 87.5-90.9). Lower 30-day mortality was associated with antibiotic administration within 8 hours of hospital arrival (odds ratio [OR], 0.85; 95% CI, 0.75-0.96) and blood culture collection within 24 hours of arrival (OR, 0.90; 95% CI, 0.81-1.00). State and territory performance estimates varied from 49.0% to 89.7% for antibiotics given within 8 hours and from 45.6% to 82.6% for blood cultures drawn within 24 hours. CONCLUSIONS: Administering antibiotics within 8 hours of hospital arrival and collecting blood cultures within 24 hours were associated with improved survival. The fact that states varied widely in the performance of these measures suggests that opportunities exist to improve hospital care of elderly patients with pneumonia.

Measurement of apoptosis in heterogenous cell populations.

The increasing interest in programmed cell death has created the need to measure apoptosis in complex cell systems. We have combined the use of fluorescent antibodies with the Hoechst 33342/propidium iodide system in order to quantitate programmed cell death in fractions of heterogenous cell populations. Here we describe the analysis of T-cell apoptosis after ligation of the T-cell antigen receptor by superantigen in vitro and ex vivo. This technique can separate cells according to seven parameters, fluorescence caused by FITC, PE, allophycocyanin, incorporation of Hoechst 33342, PI, forward scatter, and side scatter, and it allows determination of elevated Hoechst 33342 uptake in less than 10% of the cell population.

Interaction between CD44 and osteopontin as a potential basis for metastasis formation.

Malignant growth has been associated with oncogene activation, telomerase activity, and expression of CD44 splice variants on the cell surface. Though dysregulation of growth control due to expression of oncogene products is fairly well understood, the mechanism of CD44-mediated homing and colony formation in specific tissues has remained cryptic. We have identified the cytokine osteopontin as a ligand for CD44. Osteopontin binds to naturally expressed and stably transfected CD44 in a manner that is specific, dose-dependent, inhibitable by anti-CD44 antibodies, insensitive to competition by Gly-Arg-Gly-Asp-Ser, and sensitive to competition by hyaluronate. The receptor-ligand interaction mediates chemotaxis or attachment, depending on presentation of osteopontin in soluble or immobilized form. In contrast, binding of CD44 to hyaluronate mediates aggregation or attachment but not chemotaxis. We found that two events occurring in malignancy-secretion of osteopontin and expression of CD44v-are linked in such a way that they may cause migration of tumor cells to specific sites of metastasis formation.