Assessment and comparison of prognostic classification schemes for survival data.

Prognostic classification schemes have often been used in medical applications, but rarely subjected to a rigorous examination of their adequacy. For survival data, the statistical methodology to assess such schemes consists mainly of a range of ad hoc approaches, and there is an alarming lack of commonly accepted standards in this field. We review these methods and develop measures of inaccuracy which may be calculated in a validation study in order to assess the usefulness of estimated patient-specific survival probabilities associated with a prognostic classification scheme. These measures are meaningful even when the estimated probabilities are misspecified, and asymptotically they are not affected by random censorship. In addition, they can be used to derive R(2)-type measures of explained residual variation. A breast cancer study will serve for illustration throughout the paper.     

Antimetastatic action of the prostacyclin analogue cicaprost in experimental mammary tumors

Summary In breast cancer, the survival rate strongly depends on the number of lymph nodes involved. A drug with a specific inhibitory activity on lymph node and organ metastases would therefore be a candidate for adjuvant therapy after surgery. Prostacyclin and its stable analogues have been shown to interfere with certain steps of the metastatic cascade and to inhibit the number of lung colonies after i.v.-inoculation of various tumor cell lines. Our data reveal that cicaprost, a metabolically stable and orally active analogue of prostacyclin, has pronounced antimetastatic effects in a series of spontaneously metastasizing rodent tumors. In the SMT 2a and 13762 MTLn3 mammary carcinomas of the rat, cicaprost given daily from the day of tumor implantation strongly inhibits the number of lung metastases as well as lymph node weights without exerting an effect on the primary tumor. Even starting treatment when palpable primary tumors are present gives a pronounced antimetastatic activity. To demonstrate that cicaprost has an effect on metastases already settled in the respective organ, treatment was started after surgical removal of the primary tumor. In the SMT 2a tumor, a strong inhibition of the number of metastases was shown. Interestingly, a perioperative treatment schedule was also effective in both models used. As primary tumor growth in vivo or proliferation in vitro remained unchanged by cicaprost, its mode of action seems to be related to one or more mechanisms of the metastatic process. In tumor cell lines expressing a functional prostacyclin receptor, stimulated tumor cell migration is inhibited and changes of differentiation status are obvious. In conclusion, cicaprost strongly inhibits lymph node and organ metastases of spontaneously metastasizing rodent mammary tumors with a mode of action different from cytostatic or antihormonal drugs.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

Hip sonography--how reliable? Sector scanning versus linear scanning? Dynamic versus static examination?

In Europe, the use of ultrasonography has become a routine procedure for the detection of hip dislocations and dysplasias; clinical and historical data alone are not fully reliable. Under the right conditions, ultrasonographic examination of the hip can reliably detect hip joints in need of treatment. Furthermore, results are reproducible without the use of roentgenograms; thus the danger of "overtreatment" can be avoided. The use of sector scanners for examinations of hip joints leads to distortions in the geometry of the picture. As a result, the use of linear transducer is presently indispensable. Thanks to a reference level, static examinations of the hip joint provide us with the possibility of measuring and comparing individual hip joints. With dynamic examinations, we can quantify the data and assess hip stability. In fact, the static and dynamic approaches do not exclude but, rather, complement each other. The ultrasonographic method must be learned from experts. Given the above-mentioned conditions, all developmental abnormalities of the hip can be diagnosed in the first six weeks of life, and healthy hip joints can be clearly distinguished from those requiring follow-up examination. Based on observations on 8530 cases, hip joints of infants at least 4.5 months of age can be successfully treated in a conservative manner. Femoral head necroses have disappeared altogether and the need for later surgery has decreased dramatically.     

Thymic Function and Output of Recent Thymic Emigrant T Cells During Intracranial Glioma Progression

One of the hallmarks of patients with glioblastoma multiforme (GBM) is profound lymphopenia mostly confined to the T cell lineage. A deficiency in the production of naïve T cells from the thymus could contribute to the lymphopenia seen in GBM patients. In this study we asked whether thymic function and the production of recent thymic emigrant (RTE) T cells from the thymus was influenced by intracranial (i.c.) glioma progression. We found significant thymic involution in animals with progressive i.c. gliomas. Involuted thymi from animals with progressive i.c. T9.F gliomas showed dramatic losses of CD4⁺CD8⁺ (DP) thymocytes. Microscopic analysis complemented those findings by demonstrating a reversal of the typical cortico-medullary structure. Significant increases in apoptosis accompanied the rapid loss of viable thymocytes, which was prevented in part by adrenalectomy, suggesting a dominant role for endogenous glucocorticoids. This thymic involution was also associated with a significant decrease in peripheral RTE T cells, reflecting the diminished thymic function. Finally, we found that CD8⁺ RTE T cells were enriched in progressively growing T9 gliomas, which points to an immunological role for RTE's in anti-glioma immunity. Our findings may shed light on the significance of thymic function for anti-glioma immunity and the response to immunotherapeutic treatment paradigms.     

Validating the EQ-5D with time trade off for the German population

The aim of this survey study was to derive the societal values of the general public for the EuroQol EQ-5D. Using the same protocol as previously used in the United Kingdom, we compared the German values with the British. In face-to-face interviews a sample of 339 individuals in northern Germany valued 15 different health states from a sample of 36 states. Values were derived using the York MVH protocol for time trade-off (TTO) and a visual analogue scale (VAS). Values for all 243 health states of the EQ-5D were estimated by a regression model. The VAS values revealed close a resemblance to the British VAS results. German TTO values were higher than the British. This was especially the case for the worse health states. The results suggest that the TTO values are more related to national variables than values derived by VAS. The use of the TTO values of this investigation makes it possible to anticipate these cultural differences in studies carried out in Germany.     

Lazarillo expression reveals a subset of neurons contributing to the primary axon scaffold of the embryonic brain of the grasshopper Schistocerca gregaria

The authors studied the contribution of seven clusters of Lazarillo-expressing cells to the primary axon scaffold of the brain in the grasshopper Schistocerca gregaria from 26% to 43% of embryogenesis. Each cluster, which was numbered according to when Lazarillo expression first appeared, was uniquely identifiable on the basis of its stereotypic position in the brain and the number of Lazarillo-expressing cells it contained. At no time during embryogenesis was Lazarillo expression found in brain neuroblasts: It was found only in progeny. For ease of analysis, axogenesis was followed in a cell cluster that contained only a single Lazarillo-expressing cell (the lateral cell) in the dorsal median domain of the brain midline. Bromodeoxyuridine incorporation revealed the presence of only a single midline precursor cell in this region during embryogenesis. Intracellular injection of Lucifer yellow into the lateral cell at various ages showed that there was no dye coupling to the midline precursor or to the nearby term-1-expressing primary commissure pioneers. The lateral cell is not related lineally to these cells and most likely differentiates directly from the neuroectoderm of the brain midline. Lazarillo expression appears at the onset of axogenesis as the lateral cell projects an axon laterally toward the next Lazarillo-expressing cell cluster. The cells of this target cluster direct axons into separate brain regions, thereby establishing an orthogonally organized scaffold that the lateral cell axon follows as it navigates away from the brain midline. The primary axon scaffold of the brain results from a stepwise interlinking of discrete brain regions, as exemplified by axons from neighboring Lazarillo-expressing cell clusters.     

Desflurane induces only minor Ca2+ release from the sarcoplasmic reticulum of mammalian skeletal muscle

BACKGROUND: Desflurane is a weaker trigger of malignant hyperthermia than is halothane. There are very few data of the pathophysiologic background of this observation. Therefore, the authors' aim was to investigate the direct effect of desflurane on calcium release in skinned skeletal muscle fibers. METHODS: For the measurements, single saponin-skinned muscle fiber preparations of BALB/c mice were used. For Ca2+ release experiments, liquid desflurane at 0.6 and 3.5 mm was applied to weakly calcium-buffered solutions with no added Ca2+. Desflurane was diluted in strongly Ca2+-buffered solutions, with [Ca2+] between 3.0 and 24.9 micrometer for [Ca2+]-force relations. Force transients were transformed into Ca2+ transients based on the individual [Ca2+]-force relations. As controls, 30 mm caffeine and equimolar sevoflurane were investigated in the same muscle fibers. RESULTS: At 3.5 mm, desflurane induced peak force transients of 8 +/- 4% (mean +/- SD) of maximal Ca2+-activated force (Tmax). These peak values were significantly smaller than those in the presence of 3.5 mm sevoflurane (24 +/- 10% of Tmax, P < 0.05), and 4 or 5 times smaller than previously reported Ca2+-release-induced force transients by equimolar halothane. Calculated peak Ca2+ transients derived from force transients and induced by 3.5 and 0.6 mm desflurane were significantly smaller than those induced by 30 mm caffeine. The [Ca2+]-force relation was shifted by desflurane, resulting in a Ca2+-sensitizing effect. The maximal Ca2+-activated force was significantly increased by 0.6 mm desflurane in comparison with the control, with no added substance (P 相似文献   

Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility.

PURPOSE: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of alpha6beta4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors. EXPERIMENTAL DESIGN: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility. RESULTS: The majority of pancreatic and colorectal tumors expressed the alpha2, alpha3, alpha6, beta1, and beta4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of alpha6beta4 and CO-029 was restricted to tumor cells, whereas alpha1, alpha2, alpha3, alpha6, beta1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and beta1 expression was observed at comparably high levels in healthy pancreatic tissue. alpha3beta1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas alpha6beta4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with beta4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration. CONCLUSION: alpha6beta4 is selectively up-regulated in pancreatic and colorectal cancer. The association of alpha6beta4 with CD151 and CO-029 correlates with increased tumor cell motility.