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Multiple primary malignancies in association with soft tissue sarcomas.

BACKGROUND: Modern cancer treatment has increased the survival of patients with various malignancies substantially. One of the late sequelae of successful treatment is the development of a second malignant tumor. However, in many cases of second primary tumors, exposure to chemotherapy or radiation therapy is not evident, and it should be postulated that the putative mechanism for the development of the second tumor is different. In the current series, the association between soft tissue sarcoma (STS) in adults and the development of other primary malignancies was studied. METHODS: A retrospective search of the data files of 610 patients with STS or bone sarcomas who were treated at the study institution between January 1995 and December 1999 was performed. All files regarding patients with STS who developed a second malignant tumor were retrieved for analysis. RESULTS: Of 375 patients with STS, 28 (7.5%) developed other malignant neoplasms either before or after the diagnosis of STS. STS as the first tumor occurred in 14 patients (ages 16-72 years). Only three patients were treated with chemotherapy for their sarcoma. Radiation therapy was administered to five patients as an adjuvant to surgery for the first tumor. The second tumor types mainly included STS and renal cell carcinoma. The time interval between the diagnosis of the STS and the second malignancy was 0 (for synchronous tumors) to 21 years. Three patients developed a third primary tumor within 3 years after the diagnosis of the second tumor. The median overall survival was > 78 months. Fourteen patients (ages 35-87 years) had a first primary tumor other than STS (mainly breast carcinoma and genitourinary malignancies). The second tumors (mainly STS) appeared within 0 (for synchronous tumors) to 27 years. The median overall survival for the 14 patients in this group from the time of diagnosis of the first tumor was > 102 months. CONCLUSIONS: The phenomenon of two or three primary neoplasms developing in patients in whom one of the tumors was STS occurs at a rate of 7.5%, a significantly higher rate than that reported for the occurrence of STS among the general cancer population (1%). The majority of cases occur incidentally. The clinical implication includes the need to search for an occult second primary tumor in patients with STS as an integral part of their follow-up. This is especially true in patients with primary malignant fibrous histiocytoma who demonstrate a risk for developing a renal cell carcinoma.

Adolescent↗

Tracheoesophageal fistula, gastrointestinal abnormalities, hypospadias, and prenatal growth deficiency.

We studied 2 sibs, born to consanguineous parents, who presented with an MCA pattern which includes low birthweight, tracheoesophageal fistula, duodenal atresia, extrahepatic biliary atresia, hypoplastic pancreas, and hypospadias. This constellation of congenital anomalies appears to be a previously unreported autosomal recessive syndrome. A computerized search of the data files of the Spanish Collaborative Study of Congenital Malformations (ECEMC) identified 3 other unrelated infants with intestinal atresias, hypospadias, and low birth weight. These cases may represent a milder expression of the same syndrome.

Abnormalities, Multiple↗

Segmentation anomalies of the vertebras and ribs: a developmental field defect: epidemiologic evidence.

Opitz has defined developmental field defects (DFD) as "any dysmorphogenetically reactive unit of the developing organism that leads to final structure." We have incorporated in our coding system specific codes to identify individual DFDs in each child, irrespective of the cause or type of the MCA pattern (i.e., chromosomal, mendelian, environmental, or unknown). Using this approach, we can analyze the group of defects included in the expression of each DFD as a discrete unit. To confirm our hypothesis that vertebral and rib anomalies constitute a DFD, we have studied all of our cases with segmentation anomalies of the spine and ribs, including hemivertebrae, fused or absent vertebrae, and "crab-like" thorax, all of which fall into the loosely defined groups of spondylothoracic dysplasia, costovertebral dysplasia, Jarcho-Levin syndrome, and others. The study was performed using the 18,743 malformed children from the ECEMC data files, 110 of them having vertebral/rib anomalies.

Abnormalities, Multiple↗

Climate and the evolution of brachycephalization.

Significant associations of cranial shape for 82 ethnic groups and seven climate variables are described. Variation among current populations is partially attributed to cold adaptation throughout the Pleistocene. Application of data files tabulated by the authors is described for a number of problems. Temporal distribution of 115 specimens indicates a geometric trend (CI = 76.7-1.96 log time X 10(3) ). Cranial indices are summarized within alternative taxonomic models and between climatic ecotypes. Evidence supports the hypothesis of cold adaptation among "Classic" Neandertals. Limitations of the thermodynamic model are discussed. It is probable that a decrease of the cranial index occurs from the Middle to Upper Paleolithic. During the Holocene, the index increases under all climatic conditions.

Adaptation, Biological↗

Computational and noncomputational clinical information processing by computer.

Computers have been used in their computational as well as noncomputational modes for the scientific study of the clinical decision making. As computational tools, computers serve as storage devices for hospital file data so that these data can be analyzed statistically for a large variety of epidemiological and diagnostic purposes. As noncomputational devices, computers are functioning as knowledgable medical teachers that interface with students who can query the system. In this mode, computers are sometimes used as consultants to clinicians who need information on technical topics. Noncomputational computers are also used to simulate the inferences of clinicians. Byproducts of these simulations are computer programs that become formal statements or theories of the decision processes under investigation.

Computer-Assisted Instruction↗

Excessive violence and psychotic symptomatology among homicide offenders with schizophrenia.

BACKGROUND: It is not currently known how psychotic symptoms are associated with the nature of violence among homicide offenders with schizophrenia, or, more specifically, whether different psychotic symptoms are differentially linked with excessive violence. AIM: To identify factors associated with the use of excessive violence among homicide offenders with schizophrenia. METHODS: Forensic psychiatric examination statements and Criminal Index File data of 125 consecutive Finnish homicide offenders with a diagnosis of schizophrenia were analysed. RESULTS: Nearly one-third of the cases in this sample involved extreme violence, including features such as sadism, mutilation, sexual components or multiple stabbings. Excessive violence was a feature of acts when the offender was not the sole perpetrator or when there was a previous homicidal history. Positive psychotic symptoms, including delusions, were not associated with the use of excessive violence. CONCLUSIONS: These results highlight the importance of variables other than clinical state when examining qualitative aspects of homicidal acts, such as the degree and nature of violence, by offenders with schizophrenia. Further study is needed with a more specific focus on the qualities of the violence among different subgroups of offenders, but inclusive of those with psychosis.

Adolescent↗

Educational interventions to improve practice of nonspecialty physicians who are identified in need by peer review.

This article reports on the peer review process of the College of Physicians and Surgeons of Ontario, the licensing and regulatory authority, and the effect of educational interventions on physicians identified to be in need. Since 1980, the college has assessed more than 175 random and targeted nonspecialist physicians each year. A structured remediation process has been employed for those in need. Extensive data files have been maintained by the college. A majority of physicians identified as needing improvement improved and maintained their improved performance. The simple structured interventions employed by the college demonstrate an educational intervention that produces practice improvement.

Age Factors↗

Three-dimensional motility cycle in leukocytes.

A 3-dimensional dynamic image analyzing system (3D-DIAS) has been developed in which a translocating cell is optically sectioned in the z-axis within a 2 sec period; the perimeter of the cell in each section is digitized into the 3D-DIAS data file, and the digitized perimeters are wrapped in order to reconstruct the cell image in three dimensions. Using 3D-DIAS, we have obtained the first dynamic 3-dimensional description of human polymorphonuclear leukocytes (PMN) translocating on a glass surface. A general behavior cycle has emerged which includes two phases. In the first, an ellipsoidal PMN with significant z-axis extends anteriorly and descends to the substratum. When the ventral surface of the anterior end contacts the substratum, there is rapid anterior expansion, which correlates with velocity peaks. In the second phase, the elongate PMN stops translocating along the substratum, the anterior end lifts off of the substratum, sometimes to heights greater than the length of the PMN at the substratum, and finally the PMN retracts into an ellipsoidal morphology still capable of random protrusions. During this second phase, which correlates with velocity troughs, turning usually occurs. The degree of turning is restricted by the continuous integrity of the posterior uropod. The period of the behavior cycle varies from roughly 0.5 to 2 min between PMNs, but is relatively constant within each individual PMN.

Cell Movement↗

Hematopoietic stem cell transplantation among patients with leukemia of all ages in Texas.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective but expensive medical procedure to which some ethnic minorities, the elderly, and those without insurance have been shown to have limited access. The purpose of the current study was to determine whether socioeconomic factors were associated with HSCT usage rates in patients with leukemia. METHODS: The authors identified 6574 patients with acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, or other leukemias from the 1999 Texas Hospital Inpatient Discharge Public Use Data File. Of these patients, 1604 received an autologous or allogeneic HSCT. The authors assessed patients' ethnicity, payer status, age, gender, and comorbid medical conditions. Logistic regression was used to control for patient characteristics and to evaluate associations among payer status, ethnicity, and HSCT use. P < or = 0.05 indicated statistical significance. RESULTS: Patients who self-paid had the highest rate of HSCT use in all age groups (32%; P < or = 0.01) and in the adult group (36%; P = 0.11). Elderly patients with Medicare had a low rate of HSCT use (17%; P = 0.13). Logistic regression showed no statistically significant associations between payer status or ethnicity and HSCT use. However, elderly women were significantly less likely to undergo HSCT than elderly men (odds ratio, 0.34; P < or = 0.01). CONCLUSIONS: The lack of statistically significant differences in HSCT use among adult patients with leukemia was surprising because previous studies had shown differences in HSCT by ethnicity and insurance.

Adolescent↗

Programming for the DNA analysis of FCM data on an IBM microcomputer.

The analysis of data generated on a flow cytometer (FCM) is often performed on a computer obtained especially for dedicated use with the flow cytometer. This computer component can be expensive and also presents the FCM user with the added burden of mastering specialized programming language or of accepting the secret analytical processes of protected proprietary program routines. We believe that the evolution of more accurate and efficient FCM analyses that have the power to consider complex signal distributions can be assisted by the availability of analysis programs written in languages common to many users. DNA analysis routines written for a relatively inexpensive microcomputer (IBM PC/XT) in Basic and Pascal are described here. The routines can automatically process multiple FCM data files and can provide high-resolution graphic hardcopy. A foreground/background utilization is also described that allows the computer to be available for other uses in the laboratory.

Animals↗

Spectral analysis of flow cytometric data: design of a special-purpose low-pass digital filter.

Spectral decomposition of flow cytometric datafiles of arbitrary dimension reveal information of both the signal and the noise components that constitute the histograms. This spectral information is used to construct a low-pass digital filter, which removes the high-frequency noise from the actual data. It is shown that this procedure guarantees non-trivial smoothing of the flow cytometric data in accordance with the local experimental situation. As a consequence optimal reconstruction of the signal is possible, which facilitates unambiguous interpretation of the data files and mathematical estimation of the statistical parameters.

Flow Cytometry↗

Slide-based cytometry and predictive medicine: the 8th Leipziger workshop and the 1st international workshop on slide-based cytometry.

Slide-based cytometry (SBC) and related techniques offer unique tools to perform complex diagnostic procedures at very early disease stages. Multicolor or polychromatic analysis of cells by SBC is of special importance, not only as a cytomics technology platform, but for patients with low blood volume such as neonates. The exact knowledge of the location of each cell on the slide allows the specimen to be restained and subsequently reanalyzed. These separate measurements can be fused to one data file (merging), increasing the information obtained per cell. Relocalization and optical evaluation of the cells, a typical feature of SBC, can be of integral importance for cytometric analysis. Predictive medicine is aimed at the detection of changes in the patient's state prior to the manifestation of deterioration or improvement. Such instances are concerned with multiorgan failure in sepsis or noninfectious posttraumatic shock in intensive care patients, or the pretherapeutic identification of high risk patients in cancer cytostatic therapy. Early anti-infectious or anti-shock therapy, as well as curative chemotherapy in combination with stem cell transplantation, may provide better survival chances for the patient as well as concomitant cost containment. Predictive medicine-guided, individualized, early reduction or cessation of therapy may lower or abrogate potential therapeutic side effects (individualized medicine). With the 8th Leipziger Workshop and the 1st International Workshop on Slide-Based Cytometry, cytomics technologies moved to more practical applications in the clinics and the clinical laboratory. This development will be continued in 2004, at the upcoming Leipziger Workshop and the International Workshop on Slide-Based Cytometry.

Cytodiagnosis↗

Regenerative and predictive medicine of cardiovascular disease: the 9th Leipziger Workshop and the 2nd International Workshop on slide based cytometry.

Slide-based cytometry (SBC) and related techniques offer unique tools to perform complex immunophenotyping, thereby enabling diagnostic procedures at very early disease stages. Multicolor or polychromatic analysis of cells by SBC is of special importance, not only as a cytomics technology platform but also for patients with low blood volume such as neonates. The exact knowledge of the location of each cell on the slide allows restaining and subsequent reanalysis of the specimen. These separate measurements of the same specimen can be fused to one data file (merging), thus increasing the information obtained per cell. Relocalization and optical evaluation of the cells, a feature typical of SBC, can be of integral importance for cytometric analysis. Due to this feature, artifacts can be excluded and morphology of measured cells can be documented. Predictive medicine aims at the detection of changes in patient's state before the manifestation of the disease or its complications. Such instances concern multiorgan failure in sepsis or noninfectious posttraumatic shock in intensive care patients or the pretherapeutic identification of high-risk patients undergoing cancer cytostatic therapy. Early anti-infectious or antishock therapy and curative chemotherapy in combination with stem cell transplantation may provide better chances of patients' survival at concomitant cost containment. Predictive medicine that guides early individualized decrease or cessation of therapy may lower or abrogate potential therapeutic side effects (individualized medicine). Regenerative medicine concerns patients who have diseased and injured organs and may be treated with transplanted organs. However, there is a severe shortage of donor organs that is worsening yearly given the aging population. Regenerative medicine and tissue engineering apply the principles of cell transplantation, material science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. Neovascularization is promoted by bone marrow-derived endothelial progenitor cells that lead to the formation of entirely new vessels into ischemic tissue. With this knowledge, many therapeutical borders can be skipped. Diseases formerly uncontrolled can be corrected with stem cells to provide causal healing with regeneration processes. The 9th Leipziger Workshop combined with the 2nd International Workshop on SBC aimed to offer new methods in image cytometry and SBC for solutions in clinical research. It moved toward practical applications in clinics and the clinical laboratory. This development will be continued in 2005 at the upcoming Leipziger Workshop and the 3rd International Workshop on SBC.

Cardiovascular Diseases↗

Polychromatic (eight-color) slide-based cytometry for the phenotyping of leukocyte, NK, and NKT subsets.

BACKGROUND: Natural killer (NK) and NK T (NKT) cells are important in innate immune defense. Their unequivocal identification requires at least four antigens. Based on the expression of additional antigens, they can be further divided into functional subsets. For more accurate immunophenotyping and to describe multiple expression patterns of leukocyte subsets, an increased number of measurable colors is necessary. To take advantage of the technologic features offered by slide-based cytometry, repeated analysis was combined with sequential optical-filter changing. METHODS: Human peripheral blood leukocytes from healthy adult volunteers were labeled with antibodies by direct or indirect staining. Tandem dyes of Cy7 (phycoerythrin [PE]-/allophycocyanin [APC]-Cy7), Cy5.5 (PE-/APC-Cy5.5), and PE-Cy5 and the fluorochromes fluorescein isothiocyanate (FITC), PE, and APC were tested alone and in combinations. Optical filters of the laser scanning cytometer were 555 DRLP/BP 530/30 nm for photomultiplier tube (PMT) 1/FITC, 605 DRLP/BP 580/30 nm for PMT 2/PE, 740 DCXR/BP 670/20 nm for PMT 3/Cy5/APC, and BP 810/90 nm for PMT 4/Cy7. Filter PMT 3 was replaced for detection of PE/Cy5.5 and APC/Cy5.5 by 740 LP/BP 710/20 nm and the sample was remeasured. Both data files were merged into one to combine the different information on a single-cell basis. The combination of eight antibodies against CD3, CD4, CD8, CD14, CD16, CD19, CD45, and CD56 was used to characterize NK and NKT cells and their subsets. RESULTS: In this way Cy5.5 is measurable at 488-nm and 633-nm excitation. Further, with the two different filters it is possible to distinguish Cy5 from Cy5.5 in the same detection channel (PMT 3). With this method we identified NK and NKT cells, subsets of NK (CD3-16+56+, CD3-16+56-, CD3-16-56+) and NKT (CD3+16+56+, CD3+16-56+) and their CD4+8-, CD4-8+, CD4-8- and CD4+8+ subsets. CONCLUSION: With our adaptations it is possible to discriminate tandem conjugates of Cy5, Cy5.5, and Cy7 for eight-color immunophenotyping. Using this method, novel rare subsets of NK and NKT cells that are CD4/CD8 double positive are reported for the first time.

CD3 Complex↗

A single-fluor approach to DNA sequence determination using high performance capillary electrophoresis.

The Tabor and Richardson strategy for enzymatic chain termination sequencing of DNA using relative peak intensity has been adapted to high performance capillary gel electrophoresis with laser induced fluorescence detection. This approach to DNA sequencing involves the use of only a single fluor and results in significant reduction in the time required to determine a DNA sequence without the use of highly complicated and expensive instrumentation. We present a modification of the Tabor and Richardson approach employing two reactions, each containing complementary mixtures of only three ddNTP's in the concentration ratio 4:2:1. The DNA sequence is determined by relative peak height and by assigning the missing ddNTP to "gaps" between the peaks. The use of only three terminators/reaction simplifies the software task of differentiating between the termination types and makes more efficient use of the available dynamic range. Both complementary mixes generate complete sequence information and the two data files are combined in order to make a more confident sequence call. This process helps to eliminate errors caused by occasional non-uniform incorporation of ddNTP's or false terminations and also alleviates some of the difficulty associated with reading through compressed regions of the electropherogram.

Base Sequence↗

A computer model for time-based simulation of electrophoresis systems with freely defined initial and boundary conditions.

A PC-based program has been developed that allows the user to perform one-dimensional computer simulations of electrophoresis systems with freely definable initial- and boundary conditions. The program can handle n constituents with n pK-values and calculates constituent concentrations and derived parameters as a function of time. Results are displayed graphically on screen and are stored as data files for graphical hard-copy processing.

Computer Simulation↗

The cost-effectiveness of breast cancer screening.

The costs and effects of different invitation schedules of breast cancer screening are compared. The effect estimates are based on trials from the USA, Sweden and the Netherlands. The cost estimates use registration data, file studies and organization charts. The calculations were performed with the MISCAN computer simulation package, which is developed especially for the evaluation of mass screening programmes. Screening women of 50-70 years at 2-yearly intervals is a relatively cost-effective schedule. In a real population, it will reduce breast cancer mortality by 12%. Screening of women under 50 is probably far less cost-effective. Screening induces a considerable shift towards breast-conserving therapy. Although a 12% mortality reduction may seem low, in absolute numbers this represents more than the total mortality from, e.g., cervical cancer. Moreover, cost per death prevented or per life-year saved is much lower than for most other medical interventions for which cost-effectiveness ratios are known, screening for cervical cancer included.

Aged↗

The risk of cancer at all sites following gastric operation for benign disease. A cohort study of 4,224 patients.

This report represents the results of a historical cohort analysis of 3,360 males and 864 females who had a gastric resection or gastroenterostomy for benign disease between 1990 and 1969. Within the period 1970 to 1988 the cohort was cross-checked with the data files at the Cancer Registry of Norway to identify the patients in whom cancer had been diagnosed. When analyzed according to cancer sites, increased risk was recorded for the oropharynx, stomach, colon, pancreas, liver, biliary tract, larynx, lungs, urinary bladder and non--melanomatous cancers of the skin in males. In females, increased risk was only observed for the oropharynx, but was close to a statistically significant level also for cancer of the stomach. A lower number of tumors of the central nervous system than expected was observed in both males and females. The increased risk of cancer of the lungs, larynx and urinary bladder in males can be regarded as evidence of the high prevalence of smokers in the cohort. We suggest that the increased risk of cancer of digestive organs is mainly related to life-style factors, particularly tobacco-specific nitrosamines whose effect is enhanced by surgical sequelae.

Cohort Studies↗