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Multiresolution wavelet analysis for efficient analysis, compression and remote display of long-term physiological signals.

Increased inter-equipment connectivity coupled with advances in Web technology allows ever escalating amounts of physiological data to be produced, far too much to be displayed adequately on a single computer screen. The consequence is that large quantities of insignificant data will be transmitted and reviewed. This carries an increased risk of overlooking vitally important transients. This paper describes a technique to provide an integrated solution based on a single algorithm for the efficient analysis, compression and remote display of long-term physiological signals with infrequent short duration, yet vital events, to effect a reduction in data transmission and display cluttering and to facilitate reliable data interpretation. The algorithm analyses data at the server end and flags significant events. It produces a compressed version of the signal at a lower resolution that can be satisfactorily viewed in a single screen width. This reduced set of data is initially transmitted together with a set of 'flags' indicating where significant events occur. Subsequent transmissions need only involve transmission of flagged data segments of interest at the required resolution. Efficient processing and code protection with decomposition alone is novel. The fixed transmission length method ensures clutter-less display, irrespective of the data length. The flagging of annotated events in arterial oxygen saturation, electroencephalogram and electrocardiogram illustrates the generic property of the algorithm. Data reduction of 87% to 99% and improved displays are demonstrated.

Algorithms↗

From Halsted to prevention and beyond: advances in the management of breast cancer during the twentieth century.

This commentary evaluates progress made in the treatment of breast cancer during the twentieth century. Most of the period from 1900 to 1970 was governed by the 'non-science' of anecdotalism and classical inductivism and was marked by the absence of a scientific gestalt. In keeping with the Halstedian concept that breast cancer was a local disease that spread throughout the body by contiguous extension and could be cured by more expansive surgery, the disease was treated with radical surgery. In 1950, however, a new era of enlightenment began to emerge. The awareness that there was a scientific process in which hypotheses generated from laboratory and clinical investigation could be tested by means of randomised clinical trials was a seminal advance, as were findings from studies that laid the groundwork for the modern era of steroid hormone action, including identification of oestrogen receptors. Expanding knowledge regarding tumour cell kinetics, tumour heterogeneity, and technological advances related to mammography and radiation therapy were also to play a role in making possible the advances in therapy that were subsequently to occur. In the past 30 years, as a result of laboratory and clinical investigation, the Halstedian thesis of cancer surgery was displaced by an alternative hypothesis that was supported by findings from subsequent clinical trials. A new paradigm governed surgery for breast cancer, and lumpectomy followed by radiation therapy became accepted practice. A second paradigm that governed the use of adjuvant systemic therapy arose as a result of laboratory and clinical investigation. Treating patients who were free of identifiable metastatic disease with systemic adjuvant therapy because some of them might develop distant disease in the future was a revolutionary departure from prior treatment strategy and became a new exemplar. Not only did the chemotherapy favourably alter the outcome of breast cancer patients, but the anti-oestrogen tamoxifen benefited patients with all stages of the disease. Tamoxifen also reduced the incidence of contralateral breast cancer, as well as tumour in the ipsilateral breast following lumpectomy. The use of preoperative therapy was also found to enhance breast-conserving surgery in women with large tumours, although its value in other circumstances is still being defined. The observation that, as a result of tamoxifen administration, invasive and non-invasive breast cancers can be prevented in women who are at increased risk for such tumours, and the finding that pathological entities such as atypical hyperplasia, lobular carcinoma in situ (LCIS) and intraductal carcinoma (DCIS) can identify women who should be considered candidates for tamoxifen serve as a fitting capstone to the accomplishments of the twentieth century. Breast cancer prevention has now become a reality. Unfortunately, a variety of circumstances have arisen as the result of advances in the understanding and treatment of breast cancer over the last 30 years that threaten to nullify the progress that has been achieved. This distressing phenomenon may be reviewed as a 'paradox of accomplishment'. The numerous uncertainties, issues and questions that have arisen following the report of each advance in treatment, the surfeit of new information that has not yet been integrated into treatment strategies, the undesirable consequences of enhanced tumour detection, a reversion to Halstedianism and anecdotalism, and the uncertainty of therapeutic decision making resulting from the demonstration of small but statistically significant benefits, particularly in patients with good prognosis, need to be addressed. Inappropriate interpretation of those circumstances threatens to deny women with breast cancer and those at high risk for the disease the opportunity to benefit from treatments that have been proven to be of worth. Perhaps the most important accomplishment of the twentieth century relates to the change in the pro

Antineoplastic Agents, Hormonal↗

ATMTN: a telemammography network architecture.

One of the goals of the National Cancer Institute (NCI) to reach more than 80% of eligible women in mammography screening by the year 2000 yet remains as a challenge. In fact, a recent medical report reveals that while other types of cancer are experiencing negative growth, breast cancer has been the only one with a positive growth rate over the last few years. This is primarily due to the fact that 1) examination process is a complex and lengthy one and 2) it is not available to the majority of women who live in remote sites. Currently for mammography screening, women have to go to doctors or cancer centers/hospitals annually while high-risk patients may have to visit more often. One way to resolve these problems is by the use of advanced networking technologies and signal processing algorithms. On one hand, software modules can help detect, with high precision, true negatives (TN), while marking true positives (TP) for further investigation. Unavoidably, in this process some false negatives (FN) will be generated that are potentially life threatening; however, inclusion of the detection software improves the TP detection and, hence, reduces FNs drastically. Since TNs are the majority of examinations on a randomly selected population, this first step reduces the load on radiologists by a tremendous amount. On the other hand, high-speed networking equipment can accelerate the required clinic-lab connection and make detection, segmentation, and image enhancement algorithms readily available to the radiologists. This will bring the breast cancer care, caregiver, and the facilities to the patients and expand diagnostics and treatment to the remote sites. This research describes asynchronous transfer mode telemammography network (ATMTN) architecture for real-time, online screening, detection and diagnosis of breast cancer. ATMTN is a unique high-speed network integrated with automatic robust computer-assisted diagnosis-detection/digital signal processing (CAD/DSP) methods for mass detection, region of interest (ROI) compression algorithms using Digital Imaging and Communications in Medicine (DICOM) 3.0 medical image standard. While ATMTN has the advantage of higher penetration for cancer screening, it provides the diagnosis with higher efficiency, better accuracy and potentially lower cost. This paper presents the development of the infrastructure and algorithm design for ATMTN-based telemammography. The research goals involved: 1) networking stations for telemammography to demonstrate, evaluate, and validate technologies and methods for delivering mammography screening services via high-speed (155 MB/s) links, performing real-time network-transmitted, high-resolution mammograms for immediate diagnosis as a "second opinion" strategy; 2) development of object-oriented compression methods for storage, retrieval and transmission of mammograms; 3) inclusion and optimization of detection algorithms for identification of normal images in different resolutions to increase the speed and effectiveness of telemammography as a "second opinion" strategy; 4) resolving the compatibility issues between images from different equipment (DICOM standards); and 5) optimization of an integrated ATMTN with adaptive CAD/DSP methods that are robust for large image databases and input sources.

Algorithms↗

[My Kumamoto life of 19 years].

In this paper titled "My Kumamoto Life of 19 Years; The Travel for Times", the memorial lecture on my retirement from Kumamoto National University Corporation Integrated Medical and Pharmaceutical Sciences, Department of Biomedical Informatics (Chairman) is summarized. As they say "Time flies", time extends from seconds to years. The lecture includes a summary of my short term research and long term studies, such as age-dependant and gene-related changes in ageing over 5 or more years in the healthy elderly. Short-term study mostly involved of newly evaluated assay methods for important substances such as the second level in the cell life span in the variation of lipid metabolite of cardiovascular diseases based on atherosclerosis, Alzheimer disease, and their evaluation by homogeneous assay of HDL-C, LDL-C, enzymatic assay for choline relating metabolites, and lipoperoxide as the results of free radical reactions. The intermediate-term studies were mainly on the development of total laboratory automation (TLA) for the management of the laboratory of the university hospital. The hospital has various degrees of sophistication in its laboratory services. Technicians were allowed to transport specimens immediately by using an air-shooter system after drawing blood, from the emergency room to the central laboratory. Routine specimens could be measured within 30 min and the results could be automatically sent to the physician's office. It greatly minimized reporting errors, decreased the exposure to biohazards, reduced labor expense, improved operation efficiency, and shortened turnaround time. Moreover, for the outpatients and emergency laboratories, we constructed a robotic measuring system which was assembled into a sequential method for the analysis of chemistry, hematology and urinalysis specimens by using a polyarticular robot. The robot arm extends to a bar-coded tube, picking up and placing test tubes on a turn table of autoanalyzers for analysis without manpower. This is the first known effective unmanned procedure for assay in the world of laboratory medicine. Also, our research on pathological informatics was begun. Our laboratory had 7 themes; the study of the reference intervals in the elderly as one of strategy of standardization on laboratory data (Drs. Uji Y, Sugiuchi H), the study of the activation mechanism of ribosomal proteins by the functions of blood cells (Drs. Shibuya Y, Senba U), the evaluation of diagnostic methods in latent ailments by gene analysis (Dr. Ando Y), the evaluation of a highly sensitive method for disseminated intravascular coagulopathy (Okajima K), the study of the neogenesis of blood vessels by physical invasion (Uchiba M), the study of the deposition mechanism of amyloid proteins and evaluation of the diagnostic methods in the autonomic system(Drs. Ando Y, Nakamura M), and the study of the function of blood stem cells in blood transfusion services (Drs. Yamaguchi K, Yonemura M, Tsunemi M). Finally, my long term work also included research into the early diagnosis and prediction of latent ailments and the variation of serum proteins levels in the healthy aged. The conclusion was that the reference value of healthy populations and individuals (intra-personal) who had no combined ailments, in follow-up for 5 years, categorized by age, sex, and social conditions, gave a narrower range of variation than did large mixed populations (inter-personal), in laboratory tests and activity of daily living (ADL). Concerning the early diagnosis and prediction studies for the latent ailments in the aged, variations of serum protein levels in the healthy aged were classified into 3 types: serum proteins levels increased with advancing age (alphaAT, mainly acute phase reactant proteins), those that decreased with advancing age (albumin mainly transporting proteins) and proteins with no significant variation. The higher increase of the alpha1AT/beta2 III ratio in the healthy aged over 60 years old is suspected to create symptoms in the near future. The papers presented concerning ageing studies were presented at the APCCC Symposium (India, 2002) and the IFCC Symposium (Kyoto, 2002), and the TLA study was also presented at the Symposium of XX World Congress of Pathology and Laboratory Medicine (San Paulo Brazil 1999).

Clinical Laboratory Information Systems↗

American Society of Clinical Oncology policy statement: oversight of clinical research.

UNLABELLED: Well-publicized lapses in the review or implementation of clinical research studies have raised public questions about the integrity of the clinical research process. Public trust in the integrity of research is critical not only for funding and participation in clinical trials but also for confidence in the treatments that result from the trials. The questions raised by these unfortunate cases pose an important opportunity to reassess the clinical trials oversight system to ensure the integrity of clinical research and the safety of those who enroll in clinical trials. Since its inception, the American Society of Clinical Oncology (ASCO) has worked for the advancement of cancer treatments through clinical research and to help patients gain prompt access to scientifically excellent and ethically unimpeachable clinical trials. As an extension of its mission, ASCO is affirming with this policy statement the critical importance of a robust review and oversight system to ensure that clinical trials participants give fully informed consent and that their safety is a top priority. Ensuring the integrity of research cannot be stressed enough because of its seminal connection to the advancement of clinical cancer treatment. The overall goal of this policy is to enhance public trust in the cancer clinical trials process. To achieve this, the following elements are essential: 1. Ensure safety precautions for clinical trial participants and their fully informed consent. 2. Ensure the validity and integrity of scientific research. 3. Enhance the educational training of clinical scientists and research staff to ensure the highest standards of research conduct. 4. Promote accountability and responsibility among all those involved in clinical research (not just those serving on institutional review boards [IRBs], but also institutional officials, researchers, sponsors, and participants) and ensure support for an effective oversight process. 5. Enhance the professional and public understanding of clinical research oversight. 6. Enhance the efficiency and cost-effectiveness of the clinical research oversight system. This policy statement makes recommendations in several areas that serve as principles to support an improved system of oversight for clinical research. ASCO will work with all parties involved in the clinical research system to develop the steps necessary to implement these recommendations. Centralized Trial Review: A large percentage of oncology clinical trials are coordinated through the National Cancer Institute's (NCI) system of cooperative groups, which already incorporates centralized scientific review. As such, there is a tremendous opportunity to employ a centralized mechanism to provide ethical review by highly trained IRB members, allowing local IRBs to take advantage of the financial and time efficiencies that central review provides. Centralized review boards (CRBs) would also contribute consistency and efficiency to the process. Once successfully completed, the review would represent an approval to open the protocol at all of the institutions that have subscribed to the centralized review system. Local IRBs would be able to devote time usually spent on initial review to ongoing monitoring of the trial taking place at their institution. Considering the enormous size and complexity of the clinical research enterprise, ASCO envisions multiple CRBs, which could be distributed as regional review boards. Central review will use a single protocol and consent form, and monitor and evaluate adverse events (AEs) on a global basis, eliminating many of the time-consuming steps for the local IRB. Global monitoring and assessment of AEs has real potential to enhance trial participants' safety by giving local institutions more information on the overall trial and enabling them to devote more time to ongoing review of the trial onsite. Use of a CRB also has real potential to reduce the costs of clinical trial oversight by allowing local IRBs to eliminate the costs of initial review. These efficiencies will likely lead to institutions redirecting funds toward monitoring ongoing trials. Although a CRB has potential to improve the efficiency of the process, a CRB could also have tremendous ability to delay valuable trials. Checks and balances must be included in the newly devised system to ensure timely review and appeals of CRB actions. ASCO proposes the advent of a new pilot program for centralizing review of clinical trials. It requires clear engagement of all stakeholders in planning the experiment, clear articulation of the goals, and assurance of federal regulatory protection for institutions choosing to participate. If successful, this CRB pilot project could be expanded to include multi-institutional industry-sponsored research. Education and Training:Education and training are critical to the ultimate success of an improved oversight system. All members of the research team should receive comprehensive education on conducting scientifically and ethically valid clinical research. The curriculum should also include information on the prevailing local and federal regulations that pertain to the clinical trials process. IRB members should also receive ongoing education and training in the review of clinical research protocols. IRB training should pay particular attention to nonscientific members to give them the tools necessary to speak on behalf of research participants. ASCO should develop a curriculum that focuses on the proper conduct of human research and emphasize ethically sound clinical research in the context of its Annual Meeting. Informed Consent: Investigators and review boards have specific roles to play in ensuring the education of trial participants through the informed consent process, both when they are considering trial enrollment and as they participate in the trial. Review boards and investigators should focus primarily on the informed consent process, rather than the informed consent documents. Federal Oversight: The federal government has an important role to play in the oversight of clinical research. This role should be expanded to cover all research, not just that which is funded by the federal government or conducted with the oversight of the Food and Drug Administration (FDA). The Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) and the FDA should provide clear regulatory support and guidance for local institutions that choose to employ a CRB. In the case of the pilot CRB discussed in this policy statement, it should serve as the preferred option for the cancer cooperative group clinical trials. Ideally, the federal government should unify and streamline its regulations for the oversight of clinical research. Resources Supporting Clinical Research Infrastructure:An effective oversight process demands the highest quality scientific and ethical review and onsite monitoring of the safety of trial participants. This can only be accomplished by the involvement of an experienced IRB that receives funding, resources, and institutional support enabling it to fulfill its mandate. CONFLICT OF INTEREST: Critical to the integrity of research is the absence of bias in the process. ASCO strongly recommends the adoption of standards for the identification, management, and, where appropriate, elimination of conflicts of interests, whether they are actual, potential, or apparent.

Biomedical Research↗

Gamma knife radiosurgery as a primary treatment for prolactinomas.

OBJECT: The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. METHODS: Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6-72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. CONCLUSIONS: Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (> or = 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.

Humans↗