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Nodular fasciitis is an uncommon lesion that is also designated as a pseudosarcomatous, self-limiting reactive process. We describe a 40-year-old woman with a nodular fasciitis that was detected by computed tomography (CT), positron emission tomography (PET) with 18F-fluorodeoxyglucose (18-FDG), and histology while she was being examined for upper abdominal pain.

DX-8951f or exatecan mesylate ((1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10-13(9H,15H)-dione methanesulfonate dihydrate), is a new water-soluble derivative of camptothecin. We determined the activity of DX-8951f in experimental human colon cancer and ovarian cancer, being tumor types sensitive to camptothecins. With the use of the MTT assay, DX-8951f was more potent than SN-38 in four out of five human colon cancer cell lines and three out of four human ovarian cancer cell lines (P<0.05). DX-8951f was considerably more potent than topotecan in all cell lines tested (P<0.05). Prolonged exposure to DX-8951f resulted in a greater increase in inhibition of cell proliferation as compared to that obtained with SN-38 or topotecan (P<0.05). Overexpression of Pgp, MRP1, and LRP did not affect the in vitro activity of DX-8951f. DX-8951f administered daily x 5 or weekly x 2 resulted in growth inhibition <50% in two human colon cancer xenografts grown s.c. in nude mice. In three human ovarian cancer xenografts, however, >50% growth inhibition was observed at both schedules. In the OVCAR-3 human ovarian cancer model, DX-8951f showed considerably greater activity than topotecan (P<0.01). DX-8951f combined with cisplatin or paclitaxel did not indicate the presence of a pharmacological interaction. In OVCAR-3 xenografts the combination was clearly more effective than DX-8951f alone, as the number of complete remissions increased substantially. In conclusion, this study shows that DX-8951f is highly potent in vitro and highly effective in experimental human ovarian cancer in vivo. Prolonged exposure to DX-8951f in vitro greatly increased the antiproliferative effects, which may be a rationale for testing a continuous infusion schedule in the clinic. Addition of cisplatin or paclitaxel improved the in vivo antitumor effects of DX-8951f.

DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor=9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor =34), SN-38 (resistance factor =47), mitoxantrone (resistance factor =59) and doxorubicin (resistance factor =2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRP1, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells. In vivo experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.

The novel camptothecin derivative BNP1350 (7-[2-trimethylsilyl)ethyl]-20(S)-camptothecin), also known as Karenitecin, has been developed for superior oral bioavailability and increased lactone stability. In our study, we describe the antiproliferative effects of BNP1350, SN-38 and topotecan in 4 human ovarian cancer cell lines. BNP1350 was found to be slightly more potent than SN-38 (p<0.01) and was considerably more potent than topotecan (p<0.01). We extended these studies to well-established human ovarian cancer xenografts in which we compared the growth inhibition induced by BNP1350 with that of topotecan given in equitoxic schedules. The growth inhibition in all 3 xenografts induced by BNP1350 was > or =75%, which was significantly better than that resulting from topotecan (p<0.05). We then selected BNP1350-resistant variants of the A2780 human ovarian cancer cell line, 2780K4 (resistance factor: 41) and 2780K32 (resistance factor: 90), to analyze possible resistance mechanisms. These variants exhibited cross-resistance against all camptothecins tested. In comparison with 2780K4 cells, 2780K32 cells were relatively more resistant against SN-38, topotecan, DX-8951f and BNP1350. In addition, 2780K32 cells were highly cross-resistant against mitoxantrone. In both 2780K4 and 2780K32, the amount of topoisomerase I was not changed but the catalytic activity was reduced. Furthermore, 2780K32 cells clearly overexpressed the breast cancer resistance protein (BCRP), as demonstrated for both the gene and the protein. In contrast to topotecan, BNP1350 proved not to be a good substrate for BCRP. Overall, we conclude that BNP1350 offers advantages over topotecan expressed by high efficacy in experimental human ovarian cancer and poor affinity for BCRP., (Copyright 2002 Wiley-Liss, Inc.)

BNP1350, 7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, is a novel semi-synthetic, highly lipophilic, silicon-containing camptothecin and an inhibitor of topoisomerase I. It has been supercomputer engineered for superior oral bioavailability, superior lactone stability, broad anti-tumor activity, increased potency and insensitivity to Pgp/MRP/LRP drug resistance. We determined the efficacy of BNP1350 in experimental human colon cancer and compared its anti-tumor effects with those of CPT-11/SN-38. We also determined a possible influence of Pgp, MRP and LRP on the efficacy of BNP1350. The in vitro anti-proliferative capacity of the compounds using various exposure times was assessed in five colon cancer cell lines and indicated that BNP1350 was similarly effective or slightly more potent than SN-38. Four cell lines of other origin with sublines expressing Pgp, MRP and/or LRP showed that BNP1350 was significantly more effective than SN-38 (p < 0.05) and that the activity of BNP1350 was not reduced in multidrug-resistant cells. For in vivo experiments, BNP1350 was given 1.0 mg/kg i.p. or 1.5 mg/kg p.o. daily x 5 and CPT-11 20 mg/kg i.p. daily x 5 being equitoxic schedules in nude mice bearing s.c. human tumor xenografts. The schedules were studied in colon cancer xenografts COLO320, COLO205 or WiDr as well as in two Pgp-positive xenografts 2780AD and BRO/mdr1.1 and the parental Pgp-negative A2780 ovarian cancer xenografts and BRO melanoma xenografts. Growth inhibition of >50% was obtained for BNP1350 given i.p. in six out of the seven xenografts studied. BNP1350 was similarly effective when given i.p. or p.o. CPT-11 was as effective as BNP1350, except in BRO and BRO/mdr1.1 xenografts. Pgp expression in xenografts in vivo confirmed that there was no negative influence on the efficacy of BNP1350. In conclusion, BNP1350 shows a broad spectrum of activity in experimental human tumors and is a suitable candidate for oral treatment of cancer., (Copyright 2000 Wiley-Liss, Inc.)

Objective: To evaluate digital voice recognition in free text mode., Study Design: A standard medical text (182 words and punctuation marks) was dictated four times each by six people using a commercially available voice recognition system., Results: The time used, including the time needed for making corrections, decreased from a median of 14.5 (6.3-18.8) minutes in the first session to a median of 6.7 (5.1-15.7) in the fourth session. the number of corrections necessary in the last session was a median of 20.5 (15-97)-i.e., 11% of the number of words in the text. All users described working with the system as highly strenuous. Dictating the same text with a dictaphone took median 1.4 (0.9-1.6) minutes and about five minutes of typing and correction time., Conclusion: Although the total time was about the same with the two methods, the time for the pathologist increased fourfold when using the voice recognition system. To obtain acceptable input speed, an appropriate template module is essential.

The usefulness of quantitative nuclear image features (QNI) for the histological classification of lung carcinomas was investigated. As no clear distinction could be established between the distributions of these features for the nuclei of squamous cell, adenocarcinoma, and large cell carcinoma, the attention was restricted to the discrimination between small cell lung carcinoma (SCLC) and non-small cell carcinoma (NSCLC). This discrimination is the crucial one in discussions about the choice of treatment. The differences between SCLC and NSCLC are statistically highly significant for various QNI features. The use of more than one QNI feature hardly raised the discriminatory performance with respect to the distinction between SCLC and NSCLC. Inferences were made about the probability and confidence interval of SCLC for a given QNI feature. It is concluded that in cases of uncertainty or disagreement, nuclear characteristics are useful for the discrimination between SCLC and NSCLC.

Seventy-eight patients were investigated by magnetic resonance (MR) imaging using optimal scan parameters and a surface coil. Forty-two patients were also examined by computer tomography (CT). Sixteen patients underwent laryngectomy. MR imaging of cancerous tissue in the larynx, and particularly of non-invaded and invaded cartilages, was examined by comparing MR images with sliced surgical specimens. Pre-operative CT and MRI findings were evaluated by comparing them with postoperative histopathological findings. MR T1-weighted images demonstrate localisation and extent of cancerous tissue. With combined use of T1-weighted and proton-density images MR imaging is superior to CT for showing cartilage invasion. Unfortunately, gross movement artifacts, which resulted in non-diagnostic images, occurred in 16% of the examinations.

A feasibility study showed that quantitative nuclear image (QNI) analysis, in which the morphology of the nucleus is described by a number of mathematical parameters, can be used to make the therapeutically and prognostically important distinction between small cell lung carcinoma (SCLC) and non-SCLC, which can be difficult to make with subjective histologic typing. In the present study, the effects of sample size and sample site on the QNI features were investigated. For all sample sites in a given tumor, comparison was made between the histologic classification, the ultrastructural findings and the classification based on the QNI features. Using a running mean, it was found that a sample size of 25 nuclei is sufficiently large. Histologic and quantitative classifications of samples from different sites of the same tumors were in agreement with regard to the separation of SCLC and non-SCLC in 19 of 20 sections. In the case in which disagreement occurred in one section, the ultrastructural findings supported the quantitative classification. These data indicate that sampling from different sites has no essential influence on the QNI classification of lung carcinomas.

By means of a special apparatus a superficial lesion was made in the common bile duct of the rabbit; the healing of the lesion was studied by transmitted light microscopy and scanning electron microscopy. Within a few hours the cells in the epithelial margin became flattened and started to migrate over the bottom of the defect. In most cases the lesion was closed after 16 to 24 hours by epithelial migration. After 24 hours a sharp increase in the mitotic activity occurred, first especially in the crypts, later also in the superficial epithelium. A blood clot on or necrosis of the wound basis seemed to stop the migration of the epithelium. Necrosis of the connective tissue in the central part of the lesion occurred after 24 hours if the lesion was not epithelialized, possibly by the action of bile. In that case the lesion healed by secondary intention. After 2-8 weeks all lesions were healed completely, no strictures being observed.

Forty-four consecutive patients with laryngeal carcinomas presenting at different stages of the disease were investigated by magnetic resonance (MR) imaging. Twelve patients (six with primary lesions and six with recurrent tumors) underwent laryngectomy, and the macro- and microscopic appearance of the slice specimens were correlated with MR imaging. In the remaining patients surgery was not performed, and MR results are compared with the laryngoscopic findings. Cancerous tissue was seen on T1-weighted images as a homogeneous mass of intermediate signal intensity. slightly higher than infrahyoid muscles. The MR examinations failed mainly in patients with tumor recurrence who had undergone previous radiation treatment.

A model is described which enables the detailed study of epithelial regeneration in experimentally produced lesions in the common bile duct of the rabbit. The circular on slightly oval defect of 1 mm diameter produced by a specially developed apparatus has a perfectly smooth base. Epithelial migration in this model has been investigated using light microscopy of transverse sections and scanning electron microscopy of whole preparations. Typical changes in the border cells, characterised by the formation of tapered protusions, can be observed as early as two hours after the lesion has been made. Later the cells in the flattened edge of the moving border also show various types of protrusion which rest on the substratum. Mitotic activity in the surface epithelium and crypts in the surrounding region only increases after closure of the lesion, which usually takes place within 16--24 h.