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Cladribine (2-chlorodeoxyadenosine) is a nucleoside analog with specific antilymphocytic activity that has been used in patients with a variety of lymphoid malignancies and autoimmune diseases. Primary sclerosing cholangitis (PSC) is a chronic hepatic autoimmune disorder of unknown etiology, thought to be mediated by biliary autoreactive cytotoxic lymphocytes. Because cladribine is an effective antilymphocytic drug, it may have potential disease-modifying activity in patients with PSC. We studied four patients with stages I and II PSC in an open-label pilot trial of 6 months' duration and 2 years' follow-up. Drugs were administered at 0.1 mg/kg/d subcutaneously for 5 days per monthly cycle for a total of 3 cycles. Patients evaluation included monthly liver panel test, cell count and lymphocytes subset, symptom severity score, posttreatment liver biopsy, and endoscopic retrograde cholangiopancreatography at 6 months and 2 years. All patients had a significant decrease in peripheral total lymphocyte (1,629 +/- 462 to 426 +/- 57; p < 0.01) and CD4 cell count (782 +/- 200 to 144 +/- 21; p < 0.05) with consequent decrease of CD4:CD8 ratio (3.82 +/- 1.96 to 1.84 +/- 0.69; p = 0.09). This was associated with a quantifiable decrease in the hepatic inflammatory infiltrate on liver biopsy. No significant changes were found in symptom scores, liver panel tests, or cholangiograms. The drug was well-tolerated and two of four patients reported remission of their inflammatory bowel disease symptoms. Cladribine decreases the hepatic lymphocytic inflammatory infiltrate in early-stage PSC, which did not translate into any short-term symptomatic, biochemical, or radiologic improvements. Further studies with long-term follow-up are needed to assess if this anti-inflammatory effect can modify the progression of disease.

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Although extensive tissue remodeling occurs during the various phases of aortic dissection, the underlying proteinases remain to be identified. Matrix metalloproteinase-9 (MMP-9) and components of the fibrinolytic system have been implicated in numerous tissue remodeling events and were therefore analyzed in surgical specimens of acute (n = 9), subacute (n = 4), and chronic (n = 7) aortic dissection by in situ hybridization. In the acute phase, intense plasminogen activator inhibitor 1 (PAI-1) gene expression was apparent in areas interfacing the dissecting hematoma, but no tissue-type PA (t-PA), urokinase-type PA (u-PA), or MMP-9 mRNAs were detected. Although PAI-1 mRNA was still present in the subacute phase, t-PA, u-PA, and MMP-9 mRNAs were now obvious, with PA gene expression co-localizing with areas of PAI-1 gene expression. In the chronic phase, PAI-1 mRNA was demonstrated around erythrocyte extravasations and surrounding bands of medial degeneration. However, there was little expression of PAs in these areas, and no MMP-9 was detected. Thus, fibrinolytic genes and MMP-9 are differentially expressed during the progression of aortic dissections. The kinetics of expression are consistent with acute fibrinolytic shutdown in response to the initial injury, a secondary subacute phase with active proteolysis, and finally, a chronic hypofibrinolytic state. Extensive neovascularization in the chronic phase may further reduce the physical stability of the dissected wall.

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Although the liver is the major source of the adhesive glycoprotein vitronectin (Vn) in vivo, we recently demonstrated low levels of extrahepatic Vn transcription. In this report, in situ hybridization was employed to identify the Vn-producing cells at these extrahepatic sites. In the central nervous system (CNS), high levels of Vn transcripts were prominent in arachnoid cells and in cells frequently present in the vicinity of brain capillaries. Significant amounts of Vn mRNA were also detected in selected peripheral organs. In the myocardium, the signal was localized to cells in the endomysium and subepicardial fat. Additionally, the pulmonary alveolar walls contained Vn-positive cells. The parenchyma of the kidney and spleen were negative. Moreover, larger blood vessels and adjacent cells in the CNS and peripheral organs were devoid of the Vn transcript. Unexpectedly, the rate of Vn gene expression in subsets of cells present in the CNS was similar to that of hepatocytes. These results suggest that the low level of Vn gene expression detected by quantitative PCR may reflect relatively high levels of synthesis by a small subset of cells, and raise the possibility that tissue Vn may, in part, be derived from local biosynthesis rather than from plasma.

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Expansion of atherosclerotic abdominal aortic aneurysm (AAA) has been attributed to remodeling of the extracellular matrix by active proteolysis. We used in situ hybridization to analyze the expression of fibrinolytic genes in aneurysm wall from eight AAA patients. All specimens exhibited specific areas of inflammatory infiltrates with macrophage-like cells expressing urokinase-type plasminogen activator (u-PA) and tissue-type PA (t-PA) mRNA. Type 1 PA inhibitor (PAI-1) mRNA was expressed at the base of the necrotic atheroma of all specimens and also within some of the inflammatory infiltrates where it frequently colocalized in regions containing u-PA and t-PA mRNA expressing cells. However, in these areas, the cellular distribution of the transcripts for t-PA and u-PA extended far beyond the areas of PAI-1 expression. These observations suggest a local ongoing proteolytic process, one which is only partially counteracted by the more restricted expression of PAI-1 mRNA. An abundance of capillaries was also obvious in all inflammatory infiltrates and may reflect local angiogenesis in response to active pericellular fibrinolysis. The increased fibrinolytic capacity in AAA wall may promote angiogenesis and contribute to local proteolytic degradation of the aortic wall leading to physical weakening and active expansion of the aneurysm.

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Decreased fibrinolytic capacity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. To investigate the potential role of this inhibitor in atherosclerosis, we examined the expression of PAI-1 mRNA in segments of 11 severely diseased and 5 relatively normal human arteries obtained from 16 different patients undergoing reconstructive surgery for aortic occlusive or aneurysmal disease. Densitometric scanning of RNA (Northern) blot autoradiograms revealed significantly increased levels of PAI-1 mRNA in severely atherosclerotic vessels (mean densitometric value, 1.7 +/- 0.28 SEM) compared with normal or mildly affected arteries (mean densitometric value, 0.63 +/- 0.09 SEM; P less than 0.05). In most instances, the level of PAI-1 mRNA was correlated with the degree of atherosclerosis. Analysis of adjacent tissue sections from the same patients by in situ hybridization demonstrated an abundance of PAI-1 mRNA-positive cells within the thickened intima of atherosclerotic arteries, mainly around the base of the plaque. PAI-1 mRNA could also be detected in cells scattered within the necrotic material and in endothelial cells of adventitial vessels. In contrast to these results, PAI-1 mRNA was visualized primarily within luminal endothelial cells of normal-appearing aortic tissue. Our data provide initial evidence for the increased expression of PAI-1 mRNA in severely atherosclerotic human arteries and suggest a role for PAI-1 in the progression of human atherosclerotic disease.

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Histological analysis remains the primary method of distinguishing between small cell (SCLC) and non-small cell lung cancer (NSCLC). This distinction has significant impact therapeutically because of their relative difference in chemoresponsiveness (J.D. Minna et al., Principles and Practice of Oncology, pp. 396-474, 1981). Yet for at least 10% of lung tumors, pathologists will disagree upon the classification (A.R. Feinstein et al., Am. Rev. Respir. Dis., 101: 671-684, 1970). Furthermore, current neuroendocrine markers lack specificity for SCLC although the presence of these markers may help predict chemosensitivity (S.L. Graziano et al., J. Clin. Oncol., 7: 1375-1376, 1989; S.B. Baylin, J. Clin. Oncol., 7: 1375-1376, 1989; C.L. Berger et al., J. Clin. Endocrinol. Metab., 53: 422-429, 1981; A.F. Gazdar et al., Cancer Res., 45: 2924-2930, 1985). In vitro growth characteristics may more accurately reflect biological properties of aggressiveness and susceptibility to chemotherapy. In this study, 3-dimensional gel-histoculture was used to retrospectively distinguish between NSCLC and SCLC. Tumor explants from 78 patients with NSCLC and 13 patients with SCLC were grown in gel-supported histocultures with an overall success rate of 92%. These 2 tumor types were distinguishable by their 3-dimensional in vitro tissue architecture. In addition, proliferation rates were measured by histological autoradiography after 4-day incorporation of [3H]dThd. The percentage of cells labeled in the most proliferatively active regions of the autoradiograms was termed the growth fraction index (A.F. Gazdar et al., Cancer Res., 45: 2924-2930, 1985; R.A. Vescio et al., Proc. Natl. Acad. Sci. U.S.A., 84: 5029-5033, 1987; R.M. Hoffman et al., Proc. Natl. Acad. Sci. U.S.A., 86: 2013-2017, 1989). The mean growth fraction index for pure small cell lung cancer was 79 +/- 10%, differing markedly from that of 35 +/- 19% for mixed small cell/large cell tumors, adenocarcinoma (38 +/- 16%), large cell undifferentiated carcinoma (40 +/- 18%), and squamous cell carcinoma (33 +/- 15%) (P less than 0.001 in each case). We therefore conclude that 3-dimensional gel-histoculture is a useful means of distinguishing pure SCLC from NSCLC, which may improve treatment decision making.

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There is a need for individualization of all aspects of cancer therapy. Because of significant heterogeneity within a tumor class, there is a need to develop an in vitro test to accurately gauge tumor aggressiveness. Such a measurement would greatly aid treatment decision making. Current methodologies such as flow cytometry, which lacks unambiguous interpretation of cell-proliferative data, and determination of the thymidine-labeling index, which measures nucleotide uptake in a nonphysiological state, have not reproducibly attained this goal. We have developed an in vitro native-state three-dimensional gel-supported histoculture system that allows the growth of all human solid tumor types for relatively long time periods. The native-state system was used to identify the percent of cells capable of incorporating [3H]thymidine over a 4-day period, which we term the growth fraction index (GFI). We have compared the ability of cancer tissue to proliferate in native-state culture to the stage and histological grade of four major types of human carcinomas: breast, ovarian, colon, and lung. Eighty percent of tumor explants could be evaluated, even when sent from across the country. We have determined that the GFI correlates with tumor stage and grade for breast and ovarian carcinoma. In colon carcinoma, there is a trend toward higher GFIs in tumors of more advanced stage and grade. In non-small cell lung carcinomas, GFI, stage, and grade do not correlate. These results suggest the applicability of gel-supported three-dimensional native-state histoculture for prognostic purposes in patients with breast and ovarian cancers and demonstrate the clinical relevance of the native-state histoculture system.

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Eight patients with basal cell carcinomas were treated with recombinant alpha-2 interferon. Each patient had a biopsy-proved basal cell carcinoma of the nodular or superficial type that was injected intralesionally three times a week for 3 weeks (9 total injections) with 1.5 X 10(6) IU (0.15 ml) of alpha-2 interferon per injection (total dose, 13.5 X 10(6) IU). Excisional biopsy 2 months after completion of therapy revealed no evidence of basal cell carcinoma in any patient. Minimal side effects were observed. In these eight patients alpha-2 interferon was therefore an effective and safe modality of treatment. The encouraging results of this pilot study suggest that additional evaluation of interferon in the treatment of basal cell carcinoma is warranted.

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Two cases of lethal carcinoid neoplasia that involved unusual polypoid intraperitoneal metastases rather than the usual flat, sclerotic foci are reported. This type of intraperitoneal polypoid carcinomatosis should alert both the surgeon and pathologist to the possibility of carcinoid neoplasia.

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A 61-year-old man with a history of cerebral reticulum cell sarcoma-microglioma (histiocytic lymphoma) in remission was initially seen with uveitis and exudative retinal detachment. Pars plana vitreous biopsy established the diagnosis by cytologic findings and allowed the immunofluorescent demonstration of a monoclonal immunoglobulin within the vitreous cells. Direct immunofluorescent microscopy of the vitreous infiltrate may prove to be of benefit in the workup of patients with uveitis in whom malignant lymphoma must be excluded.

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The clinical and radiological features of idiopathic aneurysmal dilatation of the ileum in 3 adult patients are described. This uncommon lesion presents as an aperistaltic saccular segment in direct continuity with the normal ileal lumen. On barium examination of the small bowel, however, it may closely resemble and be mistaken for a Meckel's diverticulum. Previous reports about this entity manifesting in the pediatric age group are reviewed.

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A case of fibro-inflammatory thickening of the mesosigmoid simulating pelvic carcinomatosis on barium enema and ultrasound examination is presented. Histologic features of this case and cases of retractile mesenteritis and mesenteric panniculitis are discussed.

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Primary carcinomas of the breast were studied in age-matched populations of Southwestern American Indian, Spanish American, and Anglo women from an area served by the New Mexico Tumor Registry. Histologic tumor type, nuclear grade, and stromal inflammatory response were compared among these three groups. Indian women presented with less favorable tumor stage at diagnosis. Histologic tumor types were similar with the the exception that lobular carcinoma was less frequent among Indian and Spanish American than among Anglo women. Carcinomas from Indian patients showed less differentiated nuclei than those from the other groups.

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A review of the population-based New Mexico Tumor Registry data identified 446 patients with nonsimultaneous multiple primary cancers, excluding non-melanoma skin cancers and carcinomas in situ of the uterine cervix. Expected numbers of cases were established by observing the person-years of exposure to the risk of developing a second or subsequent primary cancer and then applying the appropriate locally determined age-, sex-, ethnic-, and site-specific cancer incidence rates. The relative risk (observed/expected) of developing a second primary cancer was elevated for "Anglo" and Spanish American cancer patients in comparison with the risk of developing a first primary cancer in persons who have never had one. Only six cases of nonsimultaneous multiple primary cancer were observed (6.39 expected) in the region's American Indian population. There were differences in site-site associations among the three ethnic groups, but in many categories there were too few cases for analysis.

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