Comparative characterization of experimental and calculated lipophilicity and anti-tumour activity of isochromanone derivatives.

Compound lipophilicity connected to ADME(T)(a) has great importance in drug development and it has to be evaluated by the generally used drug developmental process. In addition to the importance of lipophilicity in ADMET, recently it has been reported that lipophilicity of small molecules correlates with their antiproliferative activity because of certain specific hydrophobic and lipophilic interactions. Due to the complexity of ADME(T) parameters an efficient and fast method is needed to characterize the many promising candidate lead molecules as a preselection in order not to be rejected from the latter phase of drug development. In the present paper we provide an overview of the importance of lipophilicity of drug candidates for biological action and for ADME(T) and describe a novel approach for drug-likeness characterization of a molecular library using correlation study between lipophilicity and biological activity. Lipophilicity and molecular characteristics have been measured, predicted and optimized for a diverse library from which the best members have been selected to describe their biological, chemical and drug-likeness properties. Molecules were selected from the family of alpha,beta-unsaturated ketones and thorough HPLC characterization for lipophilicity and morphological, antiproliferative and flow cytometric studies were carried out on them. Based on the results 17 member isochromanone library including E and Z geometric isomers were selected for further characterization. In this focused library linear correlation has been found between the calculated and measured lipophilicity and significant parabolic correlation was found between the antiproliferative effect and lipophilicity. Using our efficient and fast method, from a diverse library, we identified an outstandingly effective inhibitor of A431 tumour cell growth via a PARP(a) cleavage dependent apoptosis. In summary the optimized HPLC analyses of lipophilicity combined with the cell-culture assay, introduced above, resulted in the determination of an optimal lipophilicity range. This optimized lipophilicity range should be used in designing novel antiproliferative compounds.

Clinical assessment of the cancer diagnostic value of prostatic zinc: a comprehensive needle-biopsy study.

BACKGROUND: The correlation between Zinc concentration in the prostate's peripheral zone to the onset or presence of malignant process needs to be evaluated in detail. METHODS: Zinc concentration was measured in approximately 1-4 mm3 segments of fresh needle-biopsy cores, with X-ray fluorescence, and correlated with the histological findings of these tissue segments. RESULTS: Local Zinc concentration is correlated with the presence of cancer (PCa); the higher the Gleason score the greater the Local Zinc depletion. The Zinc value averaged over the entire extracted tissue is specific only to Gleason score 8-9 PCa. The results refer to patients avoiding Zinc-rich supplements since those show elevated prostatic Zinc concentration in identified cancer tissue. A computer simulation analysis of randomly located 0.03-3.3 cm3 lesions, with particular Gleason score and the measured Local Zinc concentration, revealed a potential diagnostic approach definitely superior to PSA, with sensitivity to the tumor grade and with excellent detection capability for Gleason score >6. Further clinical studies have been designed, both on full prostates after radical prostatectomy as well as on biopsy cores at higher resolution, to establish the accuracy of the method for Gleason score = 6. CONCLUSIONS: The PCa diagnostic potential of Local Zinc concentration is confirmed and there is indication that the amount of Zinc depletion could be used as a measure of the Gleason score of the tumor. Local Zinc concentration mapping has the potential to improve patient selection for biopsy, biopsy site selection and local therapy (e.g., Cryotherapy, Brachytherapy) site selection.

L1 cell adhesion molecule (L1CAM) as a pathogenetic factor in endometriosis.

BACKGROUND: Endometriosis is a benign and progressive disease with a high prevalence. Women with endometriosis, especially with atypical endometriosis, have a higher probability for developing ovarian cancer compared with women without endometriosis. The L1 cell adhesion molecule (L1CAM) is over expressed in ovarian and endometrial carcinomas and is associated with a bad prognosis. Here, we have analysed L1CAM expression in endometriosis. METHODS AND RESULTS: In our study with the samples from 79 patients with, and 37 patients without, endometriosis, we found that endometriosis cell lines and short-term cultures of endometrium from women with endometriosis expressed L1CAM at the mRNA and protein level. Quantitative RT-PCR analysis showed that L1CAM was expressed at significantly higher level in the epithelial compartment from patients with endometriosis compared with healthy controls (P = 0.0126). By immunohistochemical staining, 15 of 31 ovarian endometriotic lesions (48%) were shown to have L1CAM-positive staining. Of these 15 L1CAM-positive samples, 13 were atypical endometriotic lesions. Soluble L1 present in the conditioned medium of epithelial endometrium cultures from women with endometriosis was able to stimulate neurite outgrowth as measured in a chicken ganglion assay. CONCLUSIONS: We propose that L1CAM could promote endometriosis development by increasing enervation and aggravation. L1CAM expression is higher in atypical endometriosis compared with normal endometriosis.

Very late antigen-1 in psoriasis: an immunohistochemical study.

BACKGROUND: Currently, psoriasis is thought to be an inflammatory response to an antigenic stimulation, in which angiogenesis plays a fundamental role. Very late antigen-1 (VLA-1) is a beta(1) integrin collagen receptor that is up-regulated in many angiogenic processes. Data on its role in psoriasis are sparse. OBJECTIVE: In a prospective study, we evaluated the staining of VLA-1 in lesional skin from patients with psoriasis and atopic dermatitis. MATERIAL AND METHODS: Frozen sections from skin biopsies of patients with chronic plaque-type psoriasis (n = 18) and chronic atopic dermatitis (n = 7) were stained with a monoclonal antibody to VLA-1. The number of blood vessels stained with VLA-1 and the staining intensity were evaluated. These were correlated with the histologic features. RESULTS: The absolute number of blood vessels was found to be similar in the atopic and psoriatic samples. However, the number of vessels stained with anti-VLA-1, as well as the staining intensity, was shown to be significantly higher in the psoriasis group (P < 0.05). Differences between psoriatic lesions showing typical histological features of psoriasis and those showing features that overlap with dermatitis were found as well. CONCLUSIONS: Expression of VLA-1 was found significantly higher in lesional dermal blood vessels of psoriatic patients compared with atopic patients. These findings suggest a possible role for VLA-1 in the pathological angiogenesis of psoriasis. It may be an additional tool for establishing the diagnosis of psoriasis and provide a basis for new strategies in the treatment of psoriasis.

The role of L1-CAM immunohistochemial staining in the diagnosis of abdominal-pelvic cancer of uncertain primary site in women.

OBJECTIVE: The L1 adhesion molecule (L1-CAM,CD171) is over expressed in ovarian and endometrial carcinomas and other tumors derived from the Mullerian tract. Here we evaluated whether L1-CAM could serve as a novel tumor marker for the diagnosis of metastatic abdominal-pelvic cancers of uncertain origin in women. PATIENTS AND METHODS: During a 6-year period we investigated 28 patients with metastatic abdominal or pelvic cancer with uncertain primary-origin. In all these cases a thorough clinical, surgical, pathologic and immunohistochemistry evaluation was performed and correlated to the L1-CAM expression as determined by immunohistochemical staining. RESULTS: In 20 patients where the differential diagnosis was primary ovarian or endometrial cancer and primary or recurrent colon cancer, L1 immunohistochemistry staining allowed or supported the correct diagnosis. In four cases L1 staining allowed the correct diagnosis between breast and ovarian cancer. In two cases vaginal metastases of unknown origin were positive to L1 immunohistochemistry staining implying their mullerian origin and one case each of inguinal lymph node metastases and abdominal wall cancer that were positive for L1-CAM, allowed the correct diagnosis of primary ovarian cancer. In a whole, L1-CAM was of crucial role of delinating the final diagnosis in 17 of the 28 cases described. CONCLUSIONS: L1-CAM, a new tumor marker, was found to be specific for metastatic cancer originating from mullerian origin. Its incorporation into the conventional immunohistochemistry analysis in cases of cancer of unknown primary in women, allows a correct diagnosis and subsequent treatment in the majority of cases with abdominal-pelvic carcinomatosis.

A community-based cohort of 201 consecutive patients with primary Sjögren's syndrome in Israel: Ashkenazi patients compared with those of Sephardic descent.

OBJECTIVE: To determine the spectrum and prevalence of the varied manifestations, associated conditions and laboratory abnormalities of patients with primary Sjögren's syndrome in Israel and compare them between individuals of Sephardic and Ashkenazi descent and with data from the literature. METHODS: A retrospective study of a cohort of 201 consecutive patients diagnosed and followed at a single academic medical center. All cases were diagnosed using stringent criteria according to the American European Concensus Group including a labial minor salivary gland biopsy in all cases. RESULTS: Patients' mean age was 57 years and 84% were women. Overall, more than 98% of patients had sicca symptoms of dry eyes and mouth. About 35% of the cohort had hematological manifestations--primarily immune cytopenias, protein immunoelectrophoresis abnormalities and lymphoma. About 20% had associated neurological conditions (not only peripheral but often central nervous system) and 15% had pulmonary involvement. In addition, thyroid disease, liver disease, vascular or cutaneous manifestations, synovitis, ocular and renal disease could be found. In fact, the presenting manifestation was extraglandular or an abnormal test result in 39% of the patients. CONCLUSION: No significant differences were found in glandular or extraglandular manifestations or laboratory test results between Ashkenazi and Sephardic patients, despite their genetic differences. A negative history of sicca symptoms effectively rules out primary Sjögren's syndrome in this cohort. These symptoms may not be volunteered by patients and the large variety of extraglandular involvement patterns and associated conditions observed may dominate the patient's presentation, and mandate physicians' awareness and a high index of suspicion for a timely diagnosis.

Prostatic Zn determination for prostate cancer diagnosis.

We present our studies of prostatic Zn concentration measurements, carried out in the light of a novel prostate cancer (CAP) diagnosis method proposed by us. The method is based on in vivo prostatic Zn mapping by XRF trans-rectal probe. We report on the extensive clinical studies, intended to assess the validity of the novel proposed diagnostic method. Zn content was measured in vitro in needle-biopsy samples from several hundreds of patients, and was correlated with histological findings and other patient parameters. For this purpose, a technique of absolute Zn content determination in approximately 1mm(3) fresh tissue samples by XRF was developed. The experimental details and the main clinical-evaluation results are presented. We further outline the suggested design of the XRF trans-rectal probe for an efficient in vivo detection and mapping of the Zn fluorescence radiation from the prostate through the rectal wall. Laboratory phantom studies, a preliminary design concept and its expected performance are also reported.

Dermatomyositis following the diagnosis of ovarian cancer.

We present a case history of a woman who developed dermatomyositis following the diagnosis of stage IV ovarian cancer. Dermatomyositis is a rare paraneoplastic syndrome that usually precedes the diagnosis of ovarian cancer by several months or years. Ours is the fifth reported case of dermatomyositis after an established diagnosis of ovarian cancer in the literature.

Prostatic zinc and prostate specific antigen: an experimental evaluation of their combined diagnostic value.

PURPOSE: In cancer affected prostate cells lose the ability to concentrate zinc, resulting in a substantial decrease in Zn in the prostate. We investigated the possibility of using prostatic zinc combined with prostate specific antigen (PSA) as a novel tool for the reliable diagnosis of prostate cancer. MATERIALS AND METHODS: Using the x-ray fluorescence method the Zn concentration was determined in vitro in prostate samples extracted by surgery from 28 patients. Clinical records included age, serum PSA, sextant prostate needle biopsy, previous medical therapy, surgical procedure and histological findings. RESULTS: A new relationship was found between Zn in prostate tissue and PSA in blood, which allows improved separation between prostate cancer and benign prostate hyperplasia, and might have a significant impact on the reliable diagnosis of prostate cancer. CONCLUSIONS: Zn concentration is not uniform even in the same anatomical region of the prostate, so that a number of measurements at various locations are required for a diagnostic procedure. The most interesting finding in this study is the relationship between Zn concentration and PSA. A combination of these parameters represents a significant improvement on the diagnostic value of each of them separately and provides a powerful tool for more accurate diagnosis. Although the method may be applied in vitro on biopsy samples, our study underlines the importance of developing a facility for in vivo Zn determination in the prostate.

A simple technique for minor salivary gland biopsy appropriate for use by rheumatologists in an outpatient setting.

Minor salivary gland biopsy is a potentially simple procedure with high diagnostic value used primarily in the diagnosis of Sjögren's syndrome. We summarise our experience performing a simplified biopsy procedure, which is modified to allow its use by rheumatologists and other non-surgical physicians in an outpatient setting.

Lymphoid elements and apoptosis-related proteins (Fas, Fas ligand, p53 and bcl-2) in lichen sclerosus and carcinoma of the vulva.

We studied some of the morphological and immunohistochemical parameters of lichen sclerosus (LS) and carcinomas of the vulva in order to verify some characteristics in LS related to neoplasm transformation. Parameters such as proliferating index, rate of proliferation of lymphoid elements into a tumor and types of such elements were studied. In parallel, the number of cells positive to apoptosis-related proteins such as Fas, Fas ligand, p53 and bcl-2 were evaluated. Biopsy material from patients with different vulvar disorders--22 samples with LS and 23 samples with vulvar squamous cell carcinoma (VSCC)--was studied by the methods of morphometry and immunohistochemistry. In LS, the number of T cells is a few times higher than those of B cells. Among the T cells, the number of killers is significantly higher than the number of helpers. Carcinomas, especially those with lymphoid depletion, are characterized by a further significant increase in some parameters such as the rate of lymphoid proliferation and the number of T helpers and killers. The progression in to tumorigenesis was accompanied with a significant increase in the number of Fas+ and FasL+ lymphocytes. In tumor epithelial cells the proliferative index increased in carcinomas with lymphoid depletion. The number of p53+ epithelial cells increased whereas the number of bcl-2+ cells showed a distinct tendency to decrease with progression in to tumorigenesis. Development of a tumor is manifested in deep changes in relationships between different lymphoid components. Only two lymphoid markers are significantly different in VSCC compared to LS: the number of T killers and macrophages. The other parameters studied (rate of proliferative activity, the total number of T cells and T helpers, B cells, IL-2-connective cells) already showed high expression in LS as the first signs of transformation of this inflammation into neoplasia.

Expression of apoptosis and apoptosis-related proteins in microvessels of human ovarian epithelial tumors.

We performed an immunohistochemical analysis of apoptosis and the expression of apoptosis-related proteins (ARP) such as Fas and Fas ligand (FasL), bcl-2 and p53 in human ovarian epithelial tumors. Fas and FasL were abundant in endothelial cells of microvessels, and were observed, at times, in the myocytes of small arteries and veins, in parietal or in obstructive thrombi and fibroblasts. Apoptosis was also noticed in the endothelial cells of capillaries and sinuses. The expression of bcl-2 or p53 was rare. We found that the progression of tumor development was accompanied by considerable changes in the microvessels of ovarian tumors. These changes are probably related to the effect of ARP that are expressed by tumor epithelial cells, lymphocytes and macrophages. We suggest that the ARP are released as a result of necrosis of these cells and are taken up by cells of microvessels and by the cellular remnants of blood clots. The effect of tumors on the microvasculature can be regarded as an angiopathy that results in necrosis and hemorrhage within the tumoral tissue and enhances the progression of the malignancy.

Macrophage-recognized molecules of apoptotic cells are expressed at higher levels in AKR lymphoma of aged as compared to young mice.

While a direct relation between aging and tumorigenesis is well established, a slower tumor progression rate was reported in old as compared to young cancer patients. The mechanisms responsible for the less aggressive behavior of tumors in the aged, are largely unknown. We have recently shown an increase in apoptotic cell death in tumors derived from aged as compared to young animals in the AKR lymphoma. This was shown by DNA flow cytometry and by the ladder type DNA fragmentation in agarose gel electrophoresis. Analysis of the expression of genes involved in apoptosis in tumors derived from young and old animals showed a lower bcl-2 expression in those from the aged. The Fas antigen, on the contrary, displayed higher expression levels on lymphoma cells derived from old than on those from young mice. Apoptotic cells are recognized and phagocytosed mainly by macrophages. One molecular property of apoptotic cells which is recognized by macrophages is a loss in cell surface sialic acid concomitantly uncovering galactose residues. While comparing the "eat me status" phenotype of the tumor cells derived from young and aged animals, by the use of lectins recognizing sialic acid and galactose residues, FACS analysis showed a decrease in cell surface sialic acid and a gain in galactose residues in aged as compared to young mice. Moreover, Western blot analysis showed that a 130 Kda sialylated membrane glycoprotein was expressed at a lower level in tumors from the old as compared to young mice. Our results, at both the cellular and molecular levels, particularly with regard to molecules recognized by macrophages, indicate that increased apoptotic cell death in tumors from old as compared to those from young animals constitutes, as we have previously suggested, one of the mechanisms of the age-related decrease in tumor progression rate.

Apoptosis and apoptosis-related proteins (Fas, Fas ligand, bcl-2, p53) in macrophages of human ovarian epithelial tumors.

Apoptosis and the apoptosis-related proteins (ARP) (Fas, Fas ligand (FasL), bcl-2 and p53) were analyzed in macrophages of different human ovarian epithelial tumors. Few macrophages were found in ovaries of women without oncologic disorders. In ovarian benign cysts, macrophagic density reached 4.9+/-1.2 per 50,000 microm2, most were present in lymphoid-macrophagic infiltrates of the sub-epithelial stroma (3.7+/-0.5% of the area of a slide), and 23.4% were Fas and FasL positive. In borderline tumors, the expanse of lymphoid infiltrates increased to 15.6% of the area of a slide, and the number of macrophages increased 2.4-fold compared to benign cysts. Of the macrophages, 83-88% expressed Fas and FasL, few had bcl-2 and CD25 receptors, and isolated ones were apoptotic. In carcinomas with high lymphoid-macrophagic infiltration, the infiltrate occupied 17.5% of the slide and macrophages amounted to 12.1+/-1.5/50,000 microm2. Many macrophages were in regions of grouping apoptosis of tumor epithelial cells and significantly fewer expressed Fas, FasL and bcl-2. Macrophages destroyed by apoptosis accounted for 4.6%. In carcinomas with low lymphoid-macrophageal infiltration, the area of the last was 5.1% of the slide. There were 8.6+/-0.8 macrophages/50,000 microm2, mainly at the margins of zones of necrosis and of tumor cells' grouping apoptosis. Extensive macrophagic infiltration into tumor parenchyma is one way by which the host immune system destroys tumors. Fas and FasL appear in macrophages of benign cysts, but in borderline tumors and in carcinomas with low infiltration their concentration increases sharply, to 79.8% and 96.6%, respectively. In 4.5% of these cells, apoptosis of macrophages was seen. The findings suggest that macrophages participate in the transfer of ARP to tumor epithelial cells, thereby inducing their apoptosis, but undergoing the simultaneous apoptosis.

Apoptosis and apoptosis-related proteins (Fas, Fas ligand, Blc-2, p53) in lymphoid elements of human ovarian tumors.

Different types of lymphocytes have different roles in tumor suppression. Thus, their expression of apoptosis-related proteins (ARP - Fas and Fas ligand, bcl-2, p53) in lymphocytes and their apoptosis were analyzed immunohistochemically in ovarian tumors of different grades. Ovaries without oncologic disorders had few lymphocytes, mainly T cells, and no ARP. Benign cysts presented features of weak immune reaction: small lymphoid infiltration and few lymphocytes. The ARP were present in 13.7% to 23.5% of the lymphocytes, and apoptosis was rare. In borderline tumors, expansion of lymphoid infiltrates and increased density of lymphocytes resulted in a tenfold rise in total lymphocytes, reflecting intensification of the immune response. Most lymphocytes were T cells (92%) predominated by CD8+ cells that were in direct contact with tumor epithelial cells. ARP species were found in 47% to 65% of the lymphocytes, and apoptosis in 2.2%. In carcinomas with ligh lymphoid infiltration, lymphocytes were 2.5 times more abundant, and the apoptotic index as well as the number of CD20+ and CD25+ lymphocytes rose sharply, whereas bcl-2 positive lymphocytes decreased to 8% of their number in borderline tumors. In carcinomas with low lymphoid infiltration, the total lymphocyte count decreased eightfold compared to carcinomas with high lymphoid infiltration, reflecting the deep subcompensation of the lymphoid system. Few p53-positive lymphocytes were found in the carcinomas. In conclusion, we found a positive correlation between apoptosis and the numbers of CD4+ or CD8+ lymphocytes in epithelial ovarian tumors. This correlation could reflect the antitumor activity of T cells. However, the high expression of ARP studied by immune cells at the vicinity of the tumor ARP reveals the lymphoid vulnerability to apoptosis, resulting in devastation of the lymphoid tissue, and consequently in tumor progression.

Apoptosis and apoptosis-related proteins in the epithelium of human ovarian tumors: immunohistochemical and morphometric studies.

BACKGROUND: The origin of malignant ovarian tumors is the subject of considerable controversy, which may be resolved by elucidation of molecular mechanisms of tumorigenesis. Therefore we have undertaken the study of apoptosis in these tumors. METHODS: Apoptosis and the expression of its related proteins, Fas, Fas ligand (FasL), bcl-2 and p53, in epithelial cells of human ovarian tumors of different histological grades, were determined immunohistochemically and morphometrically. RESULTS: Apoptosis-related proteins were absent from ovarian epithelia of patients afflicted with non-cancerous diseases. In ovarian tumors, the distribution of individual proteins varied, and depended on the grade and type of tumor. Fas and FasL were highly expressed in all tumors, while epithelial cells expressing bcl-2 were abundant in benign tumors, but their numbers significantly dwindled with the progression of malignancy. Cells expressing p53 were found in borderline tumors, and their numbers increased with malignancy, inverse of bcl-2 expression. Apoptotic tumor cells were scarce in borderline tumors and abundant in carcinomas. Grouping apoptosis was found in approximately 60% of the carcinomas. CONCLUSIONS: The initial development of ovarian tumors is accompanied by high epithelial expression of Fas, FasL and bcl-2 proteins, while apoptosis and p53 proteins are detected only at later stages of tumorigenesis.

Biological behavior and cell properties of new AKR lymphoma malignancy variants.

The AKR lymphoma-leukemia is a T lymphocyte neoplasm, most suitable as a model for human T cell malignancies. We have been interested in the process of tumor progression in the AKR lymphoma system. In the present study, two newly isolated variants, the TAU-42 and TAU-44, were characterized with respect to their biological behavior, by comparing them to a previously studied low-malignancy variant, the TAU-39. While the TAU-44 variant formed large s.c. local tumors, the TAU-42 variant formed only small growths or none at all. The TAU-42 lymphoma was found to have the highest malignant potential: it displayed very marked dissemination to spleen, lymph nodes, liver and lungs. The TAU-44 variant had an intermediate degree of metastatic potential but presented a predilection for spread to lymph nodes and spleen and was sometimes found to metastasize to peculiar organs, such as heart and pancreas. Cells derived from the different lymphoma variants varied in their immunophenotype: the highly malignant variant cells expressed more CD4 antigen than the low-malignancy one. The opposite was observed with regard to CD8. The variant cells also differed in their migrating capacity, the more malignant one exhibiting a higher motile activity. Studies on the tumor progression model of AKR lymphoma might contribute to the elucidation of the features determining the aggressiveness of T lymphocytic malignancies.

The prognostic application of cytokeratin typing of nonsmall cell lung carcinoma. A retrospective study.

BACKGROUND: In a previous study, the authors used a variety of anticytokeratin monoclonal antibodies to show that a large proportion of lung tumors cytologically diagnosed as squamous cell carcinoma contain cells expressing simple epithelial cytokeratins, suggesting that these tumors have their origin in adenocarcinoma. These findings raised the possibility that cytokeratin (CK) typing might have a diagnostic capacity not attainable by standard histopathology. The aim of the current study was to assess the value of CK typing for this purpose by determining the correlation between the diagnosis of lung tumors based on CK typing and the survival rate of the patients. METHODS: Paraffin embedded tissue sections of 66 nonsmall cell lung carcinoma (NSCLC) specimens were examined. These included 18 adenocarcinomas, 32 squamous cell carcinomas, and 16 undifferentiated carcinomas, all diagnosed surgically and histopathologically, and further classified as either Stage I or II. CK typing was performed using the streptavidin-biotin-peroxidase method, employing the following anti-CK monoclonal antibodies: Ks.B.17 (which reacts with CK 18), A3-3 (which reacts with CK 13), and E5-9 (which reacts with CK 10). RESULTS: Comparison between the 5-year survival rates (5 ysr) of patients with different NSCLC indicated that all types of Stage II tumors had a much poorer prognosis than Stage I tumors. Differences found in the 5 ysr among patients with different types of Stage I tumors were not statistically significant (adenocarcinomas, 33% 5 ysr; squamous cell carcinomas, 59% 5 ysr; undifferentiated carcinomas, 36% 5 ysr; all diagnosed by conventional histopathology). Similarly, no significant differences were noted in 5 ysr between patients with tumors stained positively or negatively with monoclonal antibodies A3-3 or E5-9 (anti-CK 13 and anti-CK 10, respectively). In contrast, highly significant differences (P = 0.002) were found in the 5 ysr between patients with Stage I tumors positively or negatively stained with monoclonal antibody Ks.B.17 (23% vs. 75% 5 ysr, respectively) regardless of the histologic types of tumors. Especially informative was a combination of immunohistochemical and histologic diagnoses, with best survival rates (87% 5 ysr) in Ks.B.17 negative tumors histologically diagnosed as Stage I squamous cell carcinomas and worst survival rates (14% 5 ysr) in Ks.B.17 positive tumors diagnosed as adenocarcinomas. CONCLUSIONS: The current study showed that CK 18 typing of lung tumors can provide a more accurate diagnosis and therefore facilitate the planning of more suitable therapeutic approaches.

Absence of p53 mutations in malignant mesotheliomas.

Mutations in the p53 gene are the most common genetic alterations found in human malignancies. In this study, a search was done for mutations in the conserved regions of the p53 gene in malignant mesotheliomas. Thirteen malignant mesotheliomas collected over the preceding 12 yr and maintained in paraffin blocks were examined by polymerase chain reaction (PCR) followed by both single-strand conformation polymorphism (SSCP) and denaturing gradient-gel electrophoresis (DGGE). Direct sequence analysis was performed in cases suspected for mutations. No mutations in exons 5 to 8 of the p53 gene were detected. Our results suggest that malignant transformation of human mesothelioma cells does not require inactivation of p53 by point mutations in the conserved regions of the gene.

Surgical management of innominate giant cell tumor.

The surgical outcome for innominate giant cell tumors was reviewed in 7 patients; 6 (86%) were female patients and 1 (14%) was a male patient. The patients had an average age of 28.7 years (range, 16-42 years) and an average followup of 4.6 years (range, 2.0-7.3 years). Three tumors were in the ischiopubic region, 3 were acetabular, and 1 was iliosacral. The tumors ranged in size from 5 cm x 6 cm to 17 cm x 18 cm. All margins were intralesional. Reconstruction in 3 cases used osteoarticular acetabular allografts. The local recurrence rate was 3 of 7 (43%). Ischiopubic tumors accounted for all recurrences. Vascular invasion was seen in all patients who had a recurrence and only 1 patient without a recurrence. Patients with recurrences underwent subsequent resections and radiation therapy, and remain disease free at an average followup of 3.0 years (range, 0.8-4.2 years) after recurrence. There were no malignant, metastatic, or multicentric recurrences, and no patient died of disease or complications. Innominate giant cell tumor occurs most often in women and is associated with a high risk for local recurrence. Wide margins usually are not possible; intralesional margins are accepted in cases of limited accessibility or potential functional compromise.