Creation of a CT Image Library for the Lung Screening Study of the National Lung Screening Trial.

The CT Image Library (CTIL) of the Lung Screening Study (LSS) network of the National Lung Screening Trial (NLST) consists of up to three annual screens using CT imaging from each of 17,308 participants with a significant history of smoking but no evidence of cancer at trial enrollment (Fall 2002-Spring 2004). Screens performed at numerous medical centers associated with 10 LSS-NLST screening centers are deidentified of protected health information and delivered to the CTIL via DVD, external hard disk, or Internet/Virtual Private Network transmission. The collection will be completed in late 2006. The CTIL is of potential interest to clinical researchers and software developers of nodule detection algorithms. Its attractiveness lies in its very specific, well-defined patient population, scanned via a common CT protocol, and in its collection of evenly spaced serial screens. In this work, we describe the technical details of the CTIL collection process from screening center retrieval through library storage.

[The feasibility of the razor-blade shave technique in the diagnosis and treatment of benign and malignant skin lesions on the face]. / Een huidschaaftechniek voor diagnostiek en behandeling van benigne en maligne huidtumoren in het aangezicht.

The razor-blade shave technique uses a slightly-curved classic razor blade to shave and remove the exophytic part of a skin lesion and part of the intradermal structure down to the stratum papillare. It can then be sent for pathology investigations. This treatment is curative for many benign skin conditions. The cosmetic result ofthe razor-blade technique is superior to that of surgical excision. The razor-blade technique is useful as a biopsy instrument in the diagnosis of skin rumours of unknown nature, especially in keratoacanthomas. The technique is very easy and cheap. However, if the skin lesion is a suspected malignant melanoma, traditional surgical excision should be performed. The shave technique is not suitable for malignant skin tumours.

The craniofacial anomalies archive at St. Louis Children's Hospital: 20 years of craniofacial imaging experience.

This article describes how the Craniofacial Imaging Laboratory at the Cleft Palate and Craniofacial Deformities Institute, St. Louis Children's Hospital, Washington University Medical Center, has developed an electronic archive for the storage of computed tomography image digital data that is independent of scanner hardware and independent of units of storage media (i.e., floppy disks and optical disks). The archive represents one of the largest repositories of high-quality computed tomography data of children with craniofacial deformities in the world. Archiving reconstructed image data is essential for comparative imaging, surgical simulation, quantitative analysis, and use with solid model fabrication (e.g., stereolithography). One tertiary craniofacial center's experience in the establishment and maintenance of such an archive through three generations of storage technology is reported. The current archive is housed on an external 35-GB hard drive attached to a Windows-based desktop server. Data in the archive were categorized by specific demographics into groups of patients, number of scans, and diagnoses. The Craniofacial Imaging Laboratory archive currently contains computed tomography image digital data for 1827 individual scans. The earliest scan was done in 1980; the most recently stored scan for the purposes of this report occurred in May of 2000. The average number of scans archived per complete year was 94, with a range of 59 to 138. Of the 1827 total scans, 74 percent could be classified into specific diagnostic categories. The majority of the archive (55 percent) is composed of the following five diagnoses: sagittal synostosis (17 percent), unilateral coronal synostosis (11 percent), hemifacial microsomia (10 percent), plagiocephaly without synostosis (10 percent), and metopic synostosis (7 percent). Storage of computed tomography image data in a digital archive currently allows for continuous upgrading of image display and analysis and facilitates longitudinal and cross-sectional studies, both intramural and extramural. Internet access for clinical and research purposes is feasible, but contingent on protection of patient confidentiality. The future of digital imaging regarding craniofacial computed tomography scan storage and processing is also discussed.

A new in vivo model for testing cartilage grafts and biomaterials: the 'rabbit pinna punch-hole' model.

In this study an animal model was developed for evaluation of the feasibility of cartilage grafts. In the cartilage of the external ear of the rabbit multiple holes, 6 mm in diameter, were punched, leaving the adherent skin intact. Different experimental groups were evaluated. First, the punch-hole model was validated under various conditions to study spontaneous or perichondrial initiated regeneration of the cartilage defect. When both cartilage and perichondrium was excised no spontaneous repair of the cartilage defect was observed. When perichondrium is present, variable patch-like closure of the punch hole was found. As 'golden standard' a punched out piece of cartilage was reimplanted directly. This condition showed adequate closure of the punch hole, however, no perfect integration of graft and surrounding cartilage was observed. Secondly, to evaluate the 'punch-hole model' a biomaterial, trabecular demineralized bovine bone matrix (DBM), was implanted and tested as a scaffold for tissue engineering techniques in vivo and in vitro. Direct implantation of DBM did not lead to any cartilage formation to close the defect. In vivo engineered cartilage, generated by enveloping DBM in perichondrium for 3 weeks, could adequately close the punch hole. When DBM was seeded with isolated chondrocytes in vitro before implantation in the defect, a highly fragmented graft, with some islets of viable cells was seen. To promote an efficient and reliable evaluation of cartilage grafts a semi-quantitative grading system was developed. Items such as quality, quantity and integrity of the cartilage graft were included in a histomorphological grading system to provide information about the properties of a specific cartilage graft. To validate the grading system, all conditions were scored by two independent observers. An excellent reliability (R = 0.96) was seen between the observers. In summary, the rabbit pinna punch-hole model is a reliable and efficient method for first evaluation of cartilage grafts. The results can be easily analyzed using a semi-quantitative grading system.

The role of trabecular demineralized bone in combination with perichondrium in the generation of cartilage grafts.

The use of a composite graft of bovine trabecular demineralized bone matrix (DBM) and perichondrium has been found a reliable method for in vivo generation of cartilage. In the present study, the mechanism whereby this commercially available matrix increases cartilage formation was investigated. First, the time course of cartilage formation in vivo, in the combined implant of perichondrium and DBM in the rabbit ear was studied, with special focus on tissue reactions to DBM. DBM was colonized by macrophages from day 3 post-operatively, reaching a maximum after 2 weeks. Only a minimal number of neutrophils was found. After 3 weeks the DBM appeared to be resorbed. In the first week the DBM was invaded with chondroblasts, and chondrogenesis occurred between the first and second week of implantation. After 3 weeks, the initially formed islets of cartilage had fused. Next, the chondrogenic capacity of DBM itself was investigated by implantation of DBM without perichondrium. This never resulted in cartilage formation. Immunohistochemistry showed only a faint staining of the DBM for growth factors. This indicates a minimal chondrogenic effect of DBM alone and the requirement of perichondrium as cell provider. In order to define the conditions which cause chondrogenesis in composites of perichondrium and DBM, a series of in vitro culture experiments was performed in which the in vivo situation was mimicked step by step. The basic condition was perichondrium cultured in medium with 10% FCS. In this condition, cartilage formation was variable. Because in the in vivo situation both DBM and macrophages can release growth factors, the effect of IGF1, TGFbeta2 or OP1 added to the culture medium was tested. Neither the incidence nor the amount of cartilage formation was stimulated by addition of growth factors. Perichondrium wrapped around DBM in vitro gave cartilage formation in the perichondrium but the incidence and amount were not significantly stimulated compared to cultures of perichondrium without DBM. However, cartilage-like cells were found in the DBM suggesting an effect of DBM on perichondrium-derived cells. Finally, macrophages and/or blood were added to the composite DBM-perichondrium to mimic the in vivo situation as close as possible. However, no effect of this treatment was found. In conclusion, this study indicates that DBM itself has few chondrogenic qualities but functions merely as a spacer for cell ingrowth. The fast resorption of DBM by macrophages in vivo seems of importance for the cartilage forming process, but in vitro the presence of macrophages (in combination with blood) could not enhance chondrogenesis.

Efficacy of perichondrium and a trabecular demineralized bone matrix for generating cartilage.

A pedicled auricular perichondrial flap wrapped around trabecular demineralized bovine bone matrix can generate an autologous cartilage graft. In earlier experimental studies, it was demonstrated that this graft could be used for nasal and cricoid reconstruction. It was assumed that the vascularization of the perichondrial flap was obligatory, but it was never proven that the flap should be pedicled. Moreover, for clinical use, the dimensions of the auricle would set restrictions to the size of the graft generated. Therefore, the possibility to generate cartilage with a composite graft of a free perichondrial flap wrapped around demineralized bovine bone matrix, by using young New Zealand White rabbits, was studied. This composite graft was implanted at poorly (subcutaneously in the abdominal wall; n = 12), fairly (subcutaneously in the pinna; n = 12), and well-vascularized sites (quadriceps muscle; n = 12). As a control, trabecular demineralized bovine bone matrix was implanted without perichondrial cover. Half of these grafts (n = 6) were harvested after 3 weeks, and the remaining grafts (n = 6) after 6 weeks of implantation. In histologic sections of these grafts, the incidence of cartilage formation was scored. Furthermore, the amount of newly formed cartilage was calculated by computerized histomorphometry. Trabecular demineralized bovine bone matrix without perichondrial cover demonstrated early resorption; no cartilage or bone was formed. In demineralized bovine bone matrix wrapped in perichondrium, early cartilage formed after 3 weeks at well- and fairly vascularized sites. No cartilage could be detected in grafts placed at a poorly vascularized site after 3 weeks; minimal cartilage formed after 6 weeks. In summary, the highest incidence of cartilage formed when trabecular demineralized bovine bone matrix was wrapped either in a pedicled auricular perichondrial flap or in a free perichondrial flap, which was placed at a well-vascularized site. Second, a significantly higher percentage of the total area of the graft was cartilaginized at well-vascularized sites after 3 weeks. The newly generated cartilage contained collagen type II and proteoglycans with hyaluronic acid binding regions, whereas collagen type I was absent, indicating the presence of hyaline cartilage. This study demonstrates that new cartilage suitable for a graft can be generated by free perichondrial flaps, provided that the site of implantation is well vascularized. Consequently, the size of such a graft is no longer limited to the dimensions of the auricle.

Wound healing of cartilage structures in the head and neck region.

This study was performed to determine the various processes involved in the behaviour of hyaline cartilage during the wound healing period after trauma or surgery of vulnerable structures like the nasal septal cartilage and the cricoid. The results of different procedures (perpendicular and parallel to the cartilage surface) in young and young-adult animals were analyzed: septal incision at different locations (young-old), cricoid split (young-old), suturing cartilage, closing defects with autologous cartilage (young), biomaterials (young) and newly engineered cartilage in 4- and 24-week-old rabbits (series of ten animals). Cartilage of the young rabbit and child have similar hyaline cartilage with a varying distribution in thickness. Thinner areas are more susceptible to malformations. Incisions through younger cartilage give rise to some new cartilage formation covered by a new layer of perichondrium: through older, differentiated cartilage the incision causes superficial but permanent necrosis. Edges of cut cartilage mostly do heal by formation of fibrous junctions. This forms a weak spot, sensitive to deviations. The same fate goes for the healing between the autologous graft and the surrounding pre-existent cartilage. Trauma parallel to the surface, leads to inconsistent quantity of neocartilage. With ageing the wound healing and regenerative capacities decrease. In general, biomaterials are less accepted by the surrounding tissues and would impede further growth. Only newly engineered, and thus less differentiated (younger) cartilage of hyaline nature, appeared to be well accepted at the interface with the edges of a cartilage defect. There are indications that the release of growth factors might play a role in cartilage wound healing. In the child as well as the adult, wound healing of hyaline cartilage structures is incomplete, and surgery remains 'experimental' surgery. The clinical implications of gradual loss of the regenerative capacity of hyaline cartilage should be further investigated.

The immediate effects of local trauma on the shape of the cricoid cartilage.

Injury-induced abnormal development of the cricoid ring has been demonstrated in previous growth studies. In this study we focused on the immediate effects of various types of lesions to the cricoid, eliminating the influence of inserting muscles. In isolated, vital cricoids (cricoid explants) the anterior arch was split, creating a small gap between the cut ends. Previous injury to the internal surface of the cricoid ring resulted in a three to four fold increase of the diameter of the gap, actually widening the interrupted cricoid. On the contrary, injuring the external surface of the cricoid cartilage prior to anterior cricoid split, leads to an overlap of the cut edges, and a narrowing of the ring. These injury-specific changes in shape of the cricoid ring are ascribed to the release of interlocked stresses, present in the cartilage. It is suggested that the demonstrated methods to change the shape of the cricoid ring in a predictable way, are relevant for the treatment of patients with cricoid malformation.

Induction in vivo of cartilage grafts for craniofacial reconstruction.

In the craniofacial region, defects of cartilage structures are preferably reconstructed with autologous cartilage. Donor-site morbidity related to the creation of a new defect elsewhere, and a lack of growth potential of the graft--mandatory in children--have stimulated investigators to find other ways to generate new "extra" cartilage. Several biomaterials have been tested as a matrix for the ingrowth of (peri)chondroblasts in experimental animals. In young (growing) rabbits we have developed a process of heterotopic cartilage induction with the use of a demineralized (bovine) bone matrix which is enfolded in a pedicled flap of ear perichondrium for at least three weeks. During this period the demineralized matrix is colonized by macrophages and polymorphonuclear cells which start a process of complete biodegradation of the material. Simultaneously, the collagen matrix is invaded by mesenchymal cells, originating from the perichondrium and differentiating into chondroblasts and later, into chondrocytes forming the intercellular substance. The developing, very young cartilage could be demonstrated as collagen type II, thus, hyaline cartilage. When applied with its adherent perichondrium as a graft, it merges easily with the more matured host cartilage and even appears to be capable of further growth. Therefore, it seems suitable for the reconstruction of a cartilaginous defect in growing cartilaginous structures like the nasal septum or the larynx.

Detection of the binaural interaction component in the auditory brainstem response.

In humans, the binaural interaction at the brainstem level has been studied for over 15 years. The binaural interaction component (BIC) is obtained by subtracting the summed auditory brainstem response (ABR) in the monaural stimulus mode from the ABR obtained in the binaural stimulus mode. By nature of this subtraction process, the signal-to-noise ratio of the difference waveform is poor, requiring an objective detection criterion to decide whether a significant BIC is present. In this study, the effectiveness of two analysis methods was compared. The first method is the "3 SD' method, which is based on a signal-to-noise evaluation. The second method is a template matching method, in which templates are derived from normal hearing subjects' responses and individual responses are cross-correlated with these templates. The templates were allowed to shift over a range of -0.8 to 0.8 ms in search of the maximum correlation coefficient. Thirty-nine subjects with normal hearing and five patients with a unilateral profound hearing loss participated in the study. ABRs were obtained with rarefaction and condensation clicks at a rate of 15/s and a level of 70 dB nHL. Latencies of the ABR waves I, III and V for all normal hearing subjects and for the normal ear of the patients were within the normal range. The efficiencies of both methods, defined as the number of normal hearing adults with a significant BIC plus the number of patients without a significant BIC divided by the total number of subjects, were determined. The results show that the "3 SD' method is superior to the template matching method: the efficiencies were 95% and 70% respectively, when responses to rarefaction and condensation clicks were taken together. With the "3 SD' method, a significant BIC is demonstrated in almost all normal hearing subjects (97%). However, the "3 SD' method also falsely indicated a significant BIC in one patient. These results suggest that the BIC may have clinical value in studying binaural interaction in humans.

Attenuation correction in cardiac SPECT without a transmission measurement.

UNLABELLED: The accuracy of SPECT cardiac perfusion imaging is impaired by artifacts induced by nonuniform gamma-ray attenuation. This study proposes a method to estimate attenuation in the chest of patients without the additional hardware and expense of transmission imaging. METHODS: After the standard 201Tl or 99mTc-sestamibi delayed images were obtained, 99mTc macroaggregated albumin (MAA) was injected and dual-energy SPECT acquisition was performed with windows centered at 140 keV and 94 keV. Lung contours were obtained by thresholding the on-peak (140 keV) reconstructions. Outer body contours were defined from images produced by reconstruction of the lower energy scatter window obtained simultaneously at the time of the lung (MAA) imaging. Following assignment of standard attenuation values to the lung and nonlung (soft tissue) regions attenuation correction was achieved by means of a modified iterative Chang algorithm. The results were quantitatively evaluated by imaging of a cardiac phantom filled with uniform activity placed in a chest phantom. Sensitivity to the choice of lung and soft tissue attenuation values, the choice of the threshold used for lung segmentation, and errors in registration of the attenuation map were assessed. RESULTS: Application of this technique in a chest phantom and in patients imaged with both 201Tl and 99mTc-sestamibi resulted in improvement in artifactually decreased inferior wall activity without adversely affecting the other walls. The results were relatively insensitive to choice of values for lung and soft-tissue attenuation, lung thresholding, and small (< or = 1.3 cm) registration errors. CONCLUSION: This simple method corrects for nonuniform attenuation in males; studies are underway to adapt the method to determine breast contour in females and to determine the value of the method in clinical practice.

The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the efficacy of gonadotropin-releasing hormone agonists (GnRH-a) used in ovulation induction for in vitro fertilization and embryo transfer (IVF-ET) and gamete intrafallopian transfer (GIFT). DESIGN: Meta-analysis of 10 trials comparing treatment cycle outcomes after GnRH-a (n = 914) with other ovulation induction protocols (n = 722) and 7 trials comparing outcomes after short flare-up (n = 368) with longer suppression (n = 476) GnRH-a protocols. MAIN OUTCOME MEASURES: The outcome of primary interest was clinical pregnancy rate (PR) per treatment cycle commenced. Data describing the amount of gonadotropin used, cycle cancellation rate, clinical pregnancy per ET, and multiple pregnancy and abortion rates were also analyzed. RESULTS: Clinical PR per cycle commenced was significantly improved after GnRH-a use for IVF (common odds ratio [OR] 1.80, 95% confidence interval [CI] 1.33 to 2.44) and GIFT (common OR 2.37, 95% CI 1.24 to 4.51). Clinical PR per embryo transfer was also significantly improved with GnRH-a use (common OR 1.40, 95% CI 1.01 to 1.95). Cycle cancellation was decreased (common OR 0.33, 95% CI 0.25 to 0.44), whereas spontaneous abortion rate was similar with and without GnRH-a use. Cycle cancellation and PRs after short flare-up and longer suppression protocols were similar between groups. CONCLUSIONS: This meta-analysis supports the routine use of GnRH-a for IVF and GIFT. Further research is needed, however, to assess the potential for increased rates of multiple pregnancy and ovarian hyperstimulation syndrome, which may be associated with this treatment.

Induction of chemiluminescence during interaction of tumoricidal effector cell populations and tumor cells is dependent on the presence of mycoplasma.

A variety of host cells, such as activated macrophages, natural killer (NK) cells, and polymorphonuclear leukocytes (PMNL), are cytotoxic for an array of non-antibody-coated tumor cells. Because such effector cells appear to use oxygen-dependent mechanisms to effect tumor cell destruction in certain systems, the possibility of an involvement of toxic oxygen species has been considered. To investigate whether interaction of effector cells with neoplastic cells induces the generation of reactive oxygen species, resting and activated rat macrophages and rat spleen cells (as a source of NK activity) were exposed to viable tumor cells of varied origin, and chemiluminescence was monitored. This sensitive indicator of reactive oxygen generation was stimulated only when tumor cells or culture supernatants were contaminated with mycoplasma. Mycoplasma-free tumor cells and culture supernatants were in no case able to trigger chemiluminescence in any of these effector cell populations. On the other hand, tumor targets were equally susceptible to killing by effector cells irrespective of whether mycoplasma were present. The data suggest that generation of chemiluminescence during interaction of natural cytotoxic cells and neoplastic cells is an artifact and that reactive oxygen species do not function as an effector mechanism in antibody-independent natural killing effected by activated macrophages and NK cells.

Antibody-free target cells stimulate chemiluminescence in polymorphonuclear leukocytes: an artifact due to mycoplasma contamination.

The generation of toxic oxygen species represents a significant mechanism in the killing of microorganisms and antibody-coated cells by phagocytic cells. We have investigated the possibility that antibody-free target cells stimulate reactive oxygen generation in polymorphonuclear leukocytes (PMNL) using the measurement of luminol-dependent chemiluminescence (CL). It was found that the induction of CL consistently correlated with a mycoplasma contamination of the target cells. Free mycoplasma organisms of two species found frequently as contaminants in cell culture also stimulated CL. Upon artificial infection with mycoplasma, cultured cells acquired the capacity to evoke CL generation in PMNL. Our experiments strongly suggest that the induction of reactive oxygen generation by antibody-free target cells is an artifact due to mycoplasma contamination of the target cell cultures.

Cathepsin B-like proteinase as a marker for metastatic tumor cell variants.

Serial transplantation of a spontaneous BDX rat tumor, classified as an anaplastic sarcoma, gives rise to two variants; a rapidly growing nonmetastatic line (AS) and a slowly growing, invasive, and highly metastatic variant (ASML). The availability of two cell lines of the same origin but with markedly differing metastatic potential offers an ideal model for the identification of the cellular properties involved in invasive and/or metastatic behavior. The present work focuses on the pattern of various proteinases in the two tumor cell variants. The findings disclosed one major consistent difference which relates to a cathepsin B-like cysteine proteinase. The metastatic ASML variant manifests exceedingly high intracellular cathepsin B-like activity; in the nonmetastatic AS variant, the activity of this proteinase is significantly lower. Other proteinases, in particular elastase-like, chymotrypsin-like, collagenase-like enzymes and plasminogen activator, showed low, essentially comparable activity patterns. Thus, cathepsin B-like proteinase is a marker enzyme of the metastatic ASML tumor cell variant.

Suppression of natural tumor resistance by tumor promoters.

The findings of the present and other studies (4,7) show that TPA and other tumor-promoting esters suppress various in vitro manifestations of natural cell-mediated tumor resistance: (a) prevention of enhancement of macrophage cytocidal activity; (b) suppression of cytocidal capacity by activated macrophages; and (c) suppression of cytolytic activity of NK cells. Moreover, they abrogate host tumor resistance in vivo. These suppressive effects of tumor promoters on natural antitumor effector systems may constitute a fundamental mechanism in carcinogenesis.

An improved method for the isolation of eosinophilic leukocytes from normal human blood.

A relatively short and simple method for the isolation of the eosinophils from normal human blood is reported. With a recovery of about 45-55%, cell preparations, showing a degree of purity of 90-98%, are obtained. The isolated cells are morphologically intact and viable, as assessed by the trypan blue exclusion test and by active phagocytosis.