Molecular aspects of bladder cancer III. Prognostic markers of bladder cancer

The current pathological and clinical parameters provide important prognostic information, yet still have limited ability to predict the true malignant potential of most bladder tumors. In the last years, investigation of the basic mechanisms involved in carcinogenesis and tumor progression by molecular biology has provided a host of markers which are of potential diagnostic or prognostic value for bladder carcinoma. These markers may serve as tools for early and accurate prediction of tumor recurrence, progression and development of metastases and for prediction of response to therapy. The precise prediction of tumor biological behavior would facilitate treatment selection for patients who may benefit from radical surgical treatment or adjuvant therapy. We provide a current, comprehensive review of the literature on bladder tumor markers with a special emphasis on their prognostic potential. The literature suggests that currently no single marker is able to accurately predict the clinical course of bladder tumors and thus would serve as a reliable prognosticator. A combination of prognostic markers could predict which superficial tumors need an aggressive form of therapy and which invasive tumors require adjuvant therapy. Altogether, the most promising markers are, at this point, Ki-67 and p53 expression as well as matrixmetalloproteinase complex and angiogenesis.     

Pain treatment tomorrow

In the last few years global understanding of pain has improved due to current molecular biological studies. The identification of a large number of different proteins is an essential part of future therapies, since they, as enzymes, receptors or ion channels, are specific relays in the nociceptive system and therefore have key functions in pharmacotherapeutic therapy. Nature itself supplies a variety of substances which are of therapeutic value, some of which are already in scientific trial. In contrast, even today not all available pain therapy measures are in use in Germany, at least not in all areas. Especially the treatment of children is not state of the art. Thus a further increase of chronic pain patients is to be expected in the future. This development has to be stopped, not only for ethical reasons, but also to prove the economical value of adequate pain therapy. Qualified treatment of acute pain within well defined limits can help to avoid chronification and further costs. This will be the decisive argument with which to mobilize the necessary funds for the development of the pain treatment of the future.     

PINP as a biological response marker during teriparatide treatment for osteoporosis

Postmenopausal women with severe osteoporosis may require treatment with the bone anabolic drug teriparatide. While changes in bone mineral density (BMD) are one measure of response, BMD changes often require a minimum of one year to observe measureable changes. Biochemical markers of bone turnover change within 1 to 3 months of initiating osteoporosis therapy. Monitoring with a marker such as procollagen type I N propeptide (PINP), an osteoblast-derived protein, during teriparatide treatment may provide clinically useful information for managing patients with osteoporosis. Clinical trials have shown consistent increases in PINP within 3 months of initiating teriparatide, increases that are significantly greater than placebo and significantly different from baseline. Increases in PINP concentrations during teriparatide treatment correlate well with increases in skeletal activity assessed by radioisotope bone scans and quantitative bone histomorphometry parameters. Individuals treated with teriparatide in clinical trials usually experienced an increase in PINP > 10 mcg/L from baseline, while those given placebo usually did not. In the clinical setting, patients experiencing a significant increase in PINP > 10 mcg/L after initiating teriparatide therapy may receive an earlier confirmation of anabolic effect, while those who do not may be assessed for adherence, proper injection technique, or undetected secondary conditions that might mitigate an anabolic response. PINP monitoring may provide information supplemental to BMD monitoring and be a useful aid in managing patients receiving anabolic osteoporosis treatment in the same way that biochemical markers of bone resorption are useful in monitoring antiresorptive therapy. This review examines PINP as a biological response marker during teriparatide treatment for osteoporosis.     

Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.     

Bone turnover markers: understanding their value in clinical trials and clinical practice

While bone mineral density (BMD) by dual-energy X-ray absorptiometry is the primary method of determining fracture risk, assessing bone turnover may add valuable information for the management of patients with low bone mass. Bone turnover markers (BTMs) are used in clinical trials where they can provide essential information on the biological efficacy of osteoporosis treatments. In such population-based studies, BTMs can predict fracture risk independent of BMD. When combined with BMD, they improve the fracture risk estimate above and beyond BMD alone in postmenopausal osteoporotic women. Since changes in bone turnover after the initiation of therapy with bone resorption inhibitors occur much more rapidly than changes in BMD, treatment efficacy could, in theory, be determined within weeks of using BTMs. However, such predictive value is limited by the large biological variability of these biochemical markers, even though newer automated methods have reduced their analytical variability. Consequently, widespread adoption as a means of predicting treatment efficacy in fracture prevention for individual patients cannot yet be recommended. BTMs may be useful for monitoring adherence to antiresorptive therapy and may aid in identifying patients for whom antiresorptive therapy is most appropriate. Thus, although BTMs are currently confined to clinical research applications, further improvement in assay precision may extend their diagnostic value in clinical settings.     

An update on traumatic brain injuries

Severe traumatic brain injury (TBI) represents a major cause of neurological mortality and morbidity throughout the world. Several challenges have been faced in the conduct of clinical research in TBI in past decades, including inclusion of a broad heterogeneity of injuries, difficulties with standardization and consistency of complex medical management, and lack of sophisticated outcomes measures to sufficiently detect differences in outcomes. Consequently, evidence-based guidelines for targeted therapeutic approaches remain for the most part at the level of Class II or III evidence. Harnessing the power of computing is paramount to our understanding of different prognostic groups in order to devise treatments of the future. Multimodality bedside monitoring of various physiological parameters and events can be deployed in the intensive care unit (ICU) but better data repositories and analytics are required. Recent developments in neuroimaging and definition of potential genetic and biological markers in TBI are also aiding in the sub-categorization of patients into finer diagnostic and prognostic groups. Using mathematical prediction models incorporating the plethora of data gathered, future research will provide means of tailoring therapies to individuals based upon best evidence in populations similar to them, and according to their own biological and physiological situation.     

The International Bladder Cancer Bank: proposal for a new study concept

At present, results of marker studies are often inconsistent and sometimes contradictory. Recognized problems include multiple different methods of performing the assays, different subsets of patients and different endpoints, leading to incompatible datasets. Although there has been discussion of establishing general methodological principles and guidelines (analogous to those for clinical trials) for design, conduct, analysis, and reporting of marker studies, these have not been widely implemented. There are no well-recognized prototypes or examples that the urologic researcher can use to model future marker studies. We will discuss our plans to establish a multi-institutional bladder cancer data base and virtual tumor bank as a resource for participating institutions to evaluate the biological and prognostic significance of potential markers for bladder cancer. Samples will be identified and stored at each participating institution and will be available for analysis. A standard, minimal set of patient and pathologic information will be collected. The use of common software, as part of this proposal will facilitate the data transfer of updated patient information to a central database. All contributing centers will have access to summarized information, also to simplify the process of finding collaborating partners. Prospectively collected, consistent datasets with available long-term follow-up, should provide information sooner than with a conventional prospective study. Furthermore, the quality of these data and samples may be superior to that of retrospectively collected data and samples. The proposed International Bladder Cancer Bank of specimens and data will be an effective tool during all phases of marker development.     

Diagnosis and monitoring of renal osteodystrophy

A variety of biochemical investigations and radiological techniques are available to assist in the diagnosis and monitoring of renal osteodystrophy. Measurement of serum parathyroid hormone remains the single most useful biochemical test in predicting bone histology in an individual patient. Newer biochemical markers of bone turnover are unlikely to supplant this in everyday practice, but may provide useful supplementary information in the future. The present review discusses the role of radiological investigation, including bone densitometry and quantitative ultrasound. Bone biopsy remains the 'gold standard' investigation. Its invasive nature and the need for specialized processing and interpretation limits its use in clinical practice, although it still has a role particularly in the investigation of low turnover states. Also, as molecular biological techniques are increasingly being used, the evaluation of biopsy specimens will in the future provide new insights into the disordered bone cell function that occurs in renal osteodystrophy.     

Antiphospholipid syndrome: why and how should we make the diagnosis?

Antiphospholipid syndrome (APLS) is characterized by recurrent thrombosis and/or pregnancy loss associated with persistently elevated levels of autoantibodies to phospholipids or plasma proteins. APLS occurs both as a primary disease and as a condition secondary to lupus and other autoimmune diseases. Awareness of the polymorphic presentations of APLS is vital given the risk of life-threatening thrombosis associated with this condition. Anticoagulant therapy is effective in preventing recurrent thrombosis. New biological markers have been developed, including autoantibodies to beta-2-glycoprotein 1 (anti-beta2GP1), phosphatidylethanolamine (PE), and annexin-V. These autoantibodies are not listed in the new diagnostic criteria set (Sapporo, 1999) because their usefulness needs to be validated and their detection standardized. Nevertheless, they may be helpful as part of a biological evaluation strategy for APLS. Progress can be expected in the near future, particularly regarding prediction of thrombosis. Although no marker predicts thrombosis with complete certainty, persistent high titers of the IgG variants of one or more antiphospholipid antibodies (particularly circulating anticoagulant and anti-beta2GP1) indicate a high risk of thrombosis. Evaluation of other thrombogenic factors such as inherited thrombophilia is probably useful in patients with APLS. Improvements in our ability to predict the risk of thrombosis may lead to novel strategies for prevention and treatment. New drugs such as complement factor (C3) inhibitors are being developed.     

代谢组学对肌骨衰减疾病的研究进展

代谢性疾病肌肉减少症（sarcopenia，SP）、骨质疏松症（osteoporosis，OP）和肌少-骨质疏松症（osteosarcopenia, OS）严重威胁着中老年人的身心健康。肌骨衰减疾病的特点是骨密度或肌肉质量、功能的病理性丢失，这将导致患者发生骨折、残疾甚至死亡等不良后果。虽然目前对肌骨病变的研究有一定成果，但对低分子量代谢物进行综合、系统的分析，可有效补充基因、转录和蛋白质信息的不足，为系统生物研究提供更多信息。代谢物的动态变化也使得筛选肌骨衰减疾病的潜在标志物或作用靶点成为可能，进而为肌骨衰减疾病的管理提供新策略和新思路。本文基于代谢组学对肌骨衰减疾病的临床诊断、病理机制以及预防治疗的研究进展作一综述。     

SABR in oligometastatic breast cancer: Current status and future directions

Oligometastatic breast cancer (OMBC) is a heterogeneous disease with intrinsic biological diversity. It is increasingly accepted in clinical practice that patients with OMBC could be treated with the expectation of long-term disease remission. Local ablative treatments, such as radiotherapy or surgery have a role in this setting. At present, patients that may benefit are characterised by low tumour burden, long disease-free interval and the capacity to completely ablate all sites of disease. In the future, biological or genomic classifiers may help predict which patients may benefit the most from local ablative treatments. This review provides an overview of the proposed classifications of oligometastatic disease and outlines the standard systemic treatment options of endocrine therapy, chemotherapy, and immunotherapy. The evidence for localized treatment with stereotactic ablative body radiotherapy (SABR) is presented. We discuss current active trials in oligometastatic cancer and discuss potential future directions for the use of SABR in the treatment of OMBC.     

Prognostic factors in superficial bladder cancer

Summary A large body of evidence suggests that intravescial prophylaxis using vacilus Calmette-Guérin can favorably alter the natural history of superficial bladder cancer. The search for prognostic factors impacting the clinical alternative between conservative and radical treatment has been the subject of numerous efforts and remains a major objective in improving the carcinological results and the quality of life patients with superficial bladder cancer. In this regard, information is available on three levels: clinicopathological parameters, quantitative analysis, and biological markers. Recent advances in as well as the limitations and pitfalls of the use of three kinds of information in prognostication are reviewed. The proper use of prognostic factors will modify our attitude toward superficial bladder cancer in the near future.     

Molecular diagnostics of prostate cancer

Although a number of studies have identified molecular markers for prostate cancer, their clinical utility remains mainly unclear. Markers, which allow improved determination of the biological aggressiveness of individual prostate cancers, may help to optimize therapeutic management of this heterogeneous tumor type. Here, a subset of molecular markers, which are intensively discussed in the literature or which are supposed to gain clinical utility in the future, are described in more detail. For a better survey, the markers are divided into (a) susceptibility markers, (b) malignancy markers, and (c) aggressiveness markers. The number of markers described as well as the inconsistency across studies in assessing their clinical utility reflect the heterogeneity of prostate cancer also on a genetic level so that it is unlikely that a single marker will gain clinical relevance. Future research must include systematic analysis of the clinical utility of not only single markers but rather of marker profiles in appropriate studies.     

Breaking the adherence barriers: Strategies to improve treatment adherence in dialysis patients

Nonadherence to therapy (dietary/fluid restrictions, medications, and dialysis treatment), is common in patients with end-stage kidney disease (ESKD) undergoing dialysis. It is associated with a higher risk of mortality and adverse outcomes. Clinical trials evaluating adherence improvement interventions have largely addressed patient-related factors by employing educational/cognitive, counselling/behavioral, psychological strategies, or combinations thereof. A major barrier to progress in addressing ESKD-related adherence is the difficulty in comparing these trials due to the highly diverse nature of interventions and adherence outcomes. Surrogate outcomes like changes in inter-dialysis weight gain or phosphate levels are frequently used without adjusting for confounders, with the potential for biased efficacy estimates. A majority of trials reported improvement in some adherence measures, but some of the same studies showed no improvement in other adherence markers, questioning the validity of outcome measurement. Among the interventions, cognitive/behavioral strategies, combination strategies, and individually delivered interventions may have some advantages. Relapse of nonadherence, which is common on follow-up, should be managed to sustain long-term adherence. Technology-based interventions hold great future potential for addressing ESKD nonadherence. Streamlining intervention strategies and standardizing outcome measures in future clinical trials will provide reliable guidance to manage nonadherence effectively, which may improve clinical outcomes in dialysis patients.     

Anatomic changes after endovascular grafting for aneurysmal disease.

Long-term follow-up of controlled clinical trials of endovascular grafting for aortic aneurysms will provide data on the safety and efficacy of this new treatment to reduce morbidity and mortality compared with standard treatment. It will be several years before this information will be available, and careful analysis of surrogate markers for clinical success has value for predicting long-term outcome. One essential surrogate marker is aortic aneurysm diameter, which has traditionally been the most important variable in calculating rupture risk, and multiple studies have shown that aneurysms shrink after complete endovascular exclusion. Furthermore, measurements of aortic neck size and aortic length has shown interesting patterns that may affect the durability of endovascular repair and, thus, may suggest potential strategies for the design of future devices.     

Hemodialyzer Performance: Biological Indices

Abstract: In the last decade there has been a rapid increase in the number of biological indices that could potentially be used as measures of hemodialyzer or membrane biocompatibility. Consequently, it has become more challenging for all of those involved in renal replacement therapy to evaluate the relative merits of one membrane versus another when faced with their ever increasing variety of parameters. This review attempts to summarize the current array of biological parameters described in the literature as indices of biocompatibility and provide a critique of their utility. Emphasis is placed on measures of activation of the plasma cascade systems, complement, coagulation, and kinin as primary indices of biocompatibility. Additional information on neutrophil, monocyte, platelet, lymphocyte and natural killer (NK.) cell effects may provide further insight into blood-membrane mediated interactions although many of these may parallel plasma cascade systems activation. The importance of good statistical design and analysis is emphasized to ensure meaningful interpretation of any study     

Review of psychosocial stress and asthma: an integrated biopsychosocial approach

Environmental stressors may impact asthma morbidity through neuroimmunological mechanisms which are adversely impacted and/or buffered y social networks, social support, and psychological functioning. In addition, life stress may impact on health beliefs and behaviours that may affect asthma management. Whereas earlier psychosomatic models have supported a role for psychological stress in contributing to variable asthma morbidity among those with existing disease, a growing appreciation of the interactions between behavioural, neural, endocrine, and immune processes suggest a role for these psychosocial factors in the genesis of asthma as well. While a causal link between stress and asthma has not bee established, this review provides a framework in which we can begin to see links between these systems that might provide new insights to guide future explorations. The complexity of these interactions underscore the need for a multidisciplinary approach which combines the idea that the origin of asthma is purely psychogenic in nature with the antithetical consideration that the biological aspects are all important. These distinctions are artificial, and future research that synthesizes biological, psychological, sociocultural, and family parameters is urgently needed to further our understanding of the rising burden of asthma.     

Clinical, biochemical and imaging methods of assessing osteoarthritis and clinical trials with agents claiming 'chondromodulating' activity

This paper reviews, in a first part, methods used for the clinical assessment of osteoarthritis (OA) with special reference, in a second part, to trials of drugs claimed to be chondromodulating agents. The agents examined include glycosaminoglycan-peptide complex (GP-C, Rumalon) and glycosaminoglycan-polysulfate (GAGPS, Arteparon), which both showed some beneficial clinical response. However, their effect on cartilage still remains controversial. The development of a functional hip and knee OA index in clinical assessment and the role of imaging methods and biochemical markers are discussed. In future clinical trials only validated OA indices such as the Lequesne or WOMAC index and the newly established ILAR guidelines for classifying and testing drugs in OA will be accepted for registration purposes. Imaging methods including magnetic resonance imaging (MRI) offer the capacity to provide more precise information concerning cartilage destruction in OA joints. In addition, the biochemical assessment of proteoglycan fragments, bone sialoprotein (BSP), cartilage oligometric matrix protein (COMP) and the balance between stromelysin and its inhibitor (TIMP) in synovial fluid would appear to offer potential applications for the determination of joint tissue damage in the early and later stages of OA. However, these biochemical markers have yet to be validated. It is clear that in the 1990s, for a drug to be designated as disease modifying in OA, it will require a more rigorous evaluation than was hitherto required.     

Detection of small pancreatic cancers: Diagnostic potential of tumor markers, oncogenes, and tumor-suppressor genes

The development of the monoclonal antibody technique has made it possible to use various tumor markers, such as CA 19-9, to detect pancreatic cancer. Although it has been reported that these markers are not sensitive or specific enough to detect small pancreatic cancers, nearly 70% of small pancreatic cancers (<4.0 cm) release pancreatic-cancer associated antigens. In addition, the use of serum tumor markers and ultrasound (US) as screening tools in the outpatient clinic is very effective in detecting pancreatic cancer, including small pancreatic cancers. Recently, observations of carcinogenesis in the pancreas in humans and in experimental models have suggested several cellular pathways for carcinoma of the pancreas. There is increasing evidence that pancreatic cancer results from an accumulation of dominant and recessive mutations in oncogenes and tumor-suppressor genes. Identification of the mutations that occur in pancreatic cancer may provide important information concerning the early stage of this disease. Although there are currently no methods of detecting the premalignant stages of pancreatic cancer, the study of genetic markers may play a central role in the development of techniques for the early detection of pancreatic cancer in the future. (For more detailed information on genetic changes in pancreatic cancer, see: PG Terhune and DS Longnecker,Do Oncogene and Tumor Suppressor Gene Abnormalities Vary with Type of Carcinoma of the Pancreas? J Hep Bil Pancr Surg (1995) 2:1–7.)     

Biological Reactors As Renal Substitutes

It is the goal of research on renal substitutes to develop systems that may be more physiologic in that they provide continuous purification, provide selective adaptive transport mechanisms, are suitable for in situ use and aid other physiologic processes. In an effort to meet these goals, the concept of using specific strains of microorganisms (biological reactors) was studied. Batch reactor studies, carried out in uitro with normal urine in an aerobic environment, were done to assess the mass transfer characteristics of select strains of microorganisms, based upon the removal of nitrogenous metabolites. Appreciable quantities of these metabolites (urea, creatinine and uric acid) were removed. Studies indicated that mixed strains of microorganisms are required and that interdependence among the, different strains exists. For certain solutes, such as creatinine, there was a temperature dependence. While further work is required, these background studies stimulate further research into the possibility of applying nature's own mechanisms for the treatment of renal failure. Whether as viable species or as carriers of enzymes, biological reactors may be useful in combination with other present technologies and in the design of future treatment modalities.