Improving hybrid image and structure-based deformable image registration for large internal deformations.

Objective.Deformable image registration (DIR) is a widely used technique in radiotherapy. Complex deformations, resulting from large anatomical changes, are a regular challenge. DIR algorithms generally seek a balance between capturing large deformations and preserving a smooth deformation vector field (DVF). We propose a novel structure-based term that can enhance the registration efficacy while ensuring a smooth DVF.Approach.The proposed novel similarity metric for controlling structures was introduced as a new term into a commercially available algorithm. Its performance was compared to the original algorithm using a dataset of 46 patients who received pelvic re-irradiation, many of which exhibited complex deformations.Main results.The mean Dice Similarity Coefficient (DSC) under the improved algorithm was 0.96, 0.94, 0.76, and 0.91 for bladder, rectum, colon, and bone respectively, compared to 0.69, 0.89, 0.62, and 0.88 for the original algorithm. The improvement was more pronounced for complex deformations.Significance.With this work, we have demonstrated that the proposed term is able to improve registration accuracy for complex cases while maintaining realistic deformations.

Comparison of Meal Patterns Across Common Racial Groups in the UK and the USA, Examining Associations with Weight Status and Diet Quality: a Secondary Analysis of NDNS and NHANES Datasets.

OBJECTIVE: Understanding diets of population subgroups is essential for monitoring health of diversifying populations, but currently, meal patterns of many population subgroups are not widely known. This paper aimed to identify meal patterns of racial groups in the UK and USA, considering if racial groups exhibit similar patterns of intake irrespective of location and relationships between meal patterns and health parameters. DESIGN: Data were extracted from the UK (National Diet and Nutrition Survey) and the USA (National Health and Nutrition Examination Survey) national dietary surveys. Temporal and content meal patterns among racial groups in the UK and USA (White, Black, Asian and Other, n = 1780 and n = 4339, respectively) were examined. Kruskal-Wallis tests were applied to understand differences across groups. Logistic regression models identified associations between meal patterns and body mass index and diet quality. RESULTS: Black groups consumed fewer eating occasions than White and Other groups in both countries, while UK racial groups consumed significantly more snacks than USA groups. Food group contribution to eating occasion consumption was similar across countries where Asian groups in the USA and UK had the lowest meat intake at lunch and dinner. Meal frequency was positively associated with diet quality. CONCLUSIONS: Overall, meal patterns differ across racial groups within a single country, and some differences were observed within groups of the same race across countries. Learnings from this research highlight the differences in consumption patterns across racial groups and the importance of considering a meal-based approach to dietary guidelines by racial group.

Seasonal Dynamics of Dissolved Iron on the Antarctic Continental Shelf: Late-Fall Observations From the Terra Nova Bay and Ross Ice Shelf Polynyas.

Over the Ross Sea shelf, annual primary production is limited by dissolved iron (DFe) supply. Here, a major source of DFe to surface waters is thought to be vertical resupply from the benthos, which is assumed most prevalent during winter months when katabatic winds drive sea ice formation and convective overturn in coastal polynyas, although the impact of these processes on water-column DFe distributions has not been previously documented. We collected hydrographic data and water-column samples for trace metals analysis in the Terra Nova Bay and Ross Ice Shelf polynyas during April-May 2017 (late austral fall). In the Terra Nova Bay polynya, we observed intense katabatic wind events, and surface mixed layer depths varied from ∼250 to ∼600 m over lateral distances <10 km; there vertical mixing was just starting to excavate the dense, iron-rich Shelf Waters, and there was also evidence of DFe inputs at shallower depths in the water column. In the Ross Ice Shelf polynya, wind speeds were lower, mixed layers were <300 m deep, and DFe distributions were similar to previous, late-summer observations, with concentrations elevated near the seafloor. Corresponding measurements of dissolved manganese and zinc, and particulate iron, manganese, and aluminum, suggest that deep DFe maxima and some mid-depth DFe maxima primarily reflect sedimentary inputs, rather than remineralization. Our data and model simulations imply that vertical resupply of DFe in the Ross Sea occurs mainly during mid-late winter, and may be particularly sensitive to changes in the timing and extent of sea ice production.

Preclinical development of siRNA therapeutics for AL amyloidosis.

Amyloid light chain (AL) amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonal immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed small interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL amyloidosis, we have demonstrated that these siRNAs can significantly reduce local production and circulating levels of LC. This model system highlights the therapeutic potential of siRNA for AL amyloidosis.

HTLV-III infection in brains of children and adults with AIDS encephalopathy.

Unexplained debilitating dementia or encephalopathy occurs frequently in adults and children with the acquired immune deficiency syndrome (AIDS). Brains from 15 individuals with AIDS and encephalopathy were examined by Southern analysis and in situ hybridization for the presence of human T-cell leukemia (lymphotropic) virus type III (HTLV-III), the virus believed to be the causative agent of AIDS. HTLV-III DNA was detected in the brains of five patients, and viral-specific RNA was detected in four of these. In view of these findings and the recent demonstration of morphologic and genetic relatedness between HTLV-III and visna virus, a lentivirus that causes a chronic degenerative neurologic disease in sheep, HTLV-III should be evaluated further as a possible cause of AIDS encephalopathy.

HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV.

Heterosexual transmission by vaginal intercourse accounts for most transmission of human immunodeficiency virus-type 1 (HIV-1) in Africa and Asia but is less important in the HIV-1 epidemics of the United States and Western Europe. Epithelial Langerhans' cells (LCs) represent a possible source of initial cell contact for vaginal infection. Fifteen primary isolates of HIV-1 from U.S. homosexuals and 18 HIV-1 isolates from Thailand heterosexuals were evaluated for growth in LCs of U.S. origin. All the viruses from the Thai heterosexuals, which were subtype E, grew more efficiently in the LCs than any of the viruses from the U.S. homosexuals, which are subtype B. These results suggest that LC tropism is associated with the efficiency of heterosexual transmission of HIV.

Characterization of biologically active, platelet-derived growth factor-like molecules produced by murine erythroid cells in vitro and in vivo.

Platelet-derived growth factor (PDGF) is an important serum regulator of erythropoiesis in vitro. We have now obtained evidence suggesting that PDGF-like molecules may also modulate erythropoiesis in vivo. Western blot analysis of cytoplasmic extracts from Rauscher murine erythroleukemia cells and phenylhydrazine-treated mouse splenic erythroid cells revealed the presence of several PDGF-like proteins. The presence of PDGF-like proteins in the cytoplasm of these two erythroid cell types was confirmed by immunohistochemical staining. Using a serum-free biologic assay, PDGF-like biological activity was found in cell lysates and conditioned medium of both Rauscher cells and phenylhydrazine-treated mouse erythroid cells. Subcellular localization experiments revealed the biological activity to be concentrated in the cytosolic fraction. Using a series of antibodies to hematopoietic growth factors we demonstrated that PDGF-like biological activity was specifically immunoprecipitated by both monoclonal and polyclonal anti-human PDGF antibodies but not by antibodies to burst-promoting activity, granulocyte-macrophage colony-stimulating factor, IL-3, or erythropoietin. Taken together, the data are consistent with the hypothesis that PDGF-like molecules play a role in the regulation of mammalian erythropoiesis in vivo.

Characterization of an epithelial and a tumor-associated human small cell lung carcinoma glycoprotein antigen.

The small cell carcinoma (SCC) antigens recognized by LAM2 and LAM8 antibody were characterized by comparison of their tissue expression and analysis of their biochemical composition. LAM2, but not LAM8 antigen could be demonstrated in lipid extracts of SCC cells. By immunohistochemical staining the SCC antigen LAM2 was shown to be an epithelial type membrane antigen. Immunoblotting experiments and competition solid phase radioimmunoassays showed LAM2 antigen to be a native conformation of a glycoprotein with major bands at Mr 100,000-120,000 and a minor band at Mr 210,000. L-Fucose was a dominant part of the epitope which appeared to be closely related to the carbohydrate epitope of the blood group antigen H(O). The tumor-associated membrane antigen LAM8 was shown to be a glycoprotein with major bands at Mr 90,000-135,000 and a minor band at Mr 200,000. Neuraminic acid was the predominant part of the carbohydrate epitope. LAM8 antibody recognized a structure in the saliva of Lea positive probands, but untreated and neuraminidase-treated SCC extracts were unreactive with anti-Lea antibody. Anti CA 19-9 (sialo-Lea antigen) and LAM2 antibodies did not compete for LAM8 binding in direct radioimmunoassays. The sialo-GP90-135 antigen recognized by LAM8 antibody therefore is likely to represent a novel tumor antigen.

Tumor-associated membrane sialoglycoprotein on human small cell lung carcinoma identified by the IgG2a monoclonal antibody SWA20.

A mouse IgG2a monoclonal antibody, SWA20, defining a tumor-associated cell surface antigen on small cell carcinoma of the lung (SCC) was generated. The reactivity of the antibody with cell lines was examined by indirect immunofluorescence staining and solid phase radioimmunoassay and the reactivity with tissues by immunoperoxidase staining. The antibody reacts with a proportion of small cell carcinoma cell lines (4 of 8) and tissues (7 of 12), but not with other pulmonary or extrapulmonary cell lines (0 of 30) or tumor tissues (0 of 78). The antibody was unreactive with primary cultures of normal bronchial epithelial cells, RBC, and WBC. Immunoperoxidase staining of normal tissues showed rare antigen-positive cells in suprabasal layers of bronchial epithelium and less than 10% of positive cells in colon epithelium. Immunoblots of SCC extracts demonstrated antibody reactivity with a doublet band at Mr 40,000, a broader band at Mr 100,000, and a band at Mr 180,000. The antigen was not present in crude lipid extracts of SCC cells. Solid phase radioimmunoassays and immunoblots showed binding competition with the lectin Triticum vulgaris, sensitivity of the antigen to neuraminidase, and a partial sensitivity to treatment with periodate. The antigen was coexpressed on SCC cell lines with the antigen sGP90-135 defined first by antibody LAM8 (R. Waibel, C. J. O'Hara, and R. A. Stahel. Cancer Res., 47:3766-3770, 1987) but differed from it by lack of reactivity with Lea-positive saliva and partial resistance to periodate treatment. There was no binding competition between radiolabeled antibodies SWA20 and LAM8 to SCC target cells. The IgG2a antibody SWA20 identifies a previously undescribed tumor-associated surface membrane antigen, sGP100, expressed selectively on a proportion of SCC.

Detection and characterization of a high molecular weight human lung carcinoma-associated glycoprotein.

We have defined a human lung carcinoma antigen using murine monoclonal antibodies (DF-L1 and DF-L2) prepared against a primary adenocarcinoma of the lung. This antigen is expressed on the surface of human lung carcinoma cell lines and has an apparent Mr of 350,000-420,000. Immunoperoxidase staining has demonstrated expression of the antigen in the cytoplasm and membranes of adenocarcinomas and squamous cell carcinomas but not small cell tumors of the lung. Immunoprecipitation of the antigen following radiolabeling has demonstrated the presence of both protein and carbohydrate. Antigen purified by immunoaffinity was used to study the epitopes defined by monoclonal antibodies DF-L1 and DF-L2. The results indicate that the DF-L1 epitope primarily involves a peptide structure, while the DF-L2 epitope is comprised in part by peptide and O-linked carbohydrate. In contrast, there was no detectable evidence for the presence of N-linked glycosylation. The results also demonstrate that this antigen circulates at elevated levels in patients with carcinoma of the lung. These findings are similar to previous reports of high molecular weight glycoproteins in breast and ovarian carcinomas. Indeed, the present results in lung cancer identify another member of this heterogeneous family of human carcinoma-associated glycoproteins.

Tumor necrosis factor expression by human ovarian carcinoma in vivo.

Tumor necrosis factor (TNF) is a cytokine produced by monocytes and other cells with selective cytolytic activity against some but not all tumor cells. Cellular resistance to the cytolytic effects of TNF has been reported to be associated with autocrine production of TNF by the target cells. The purpose of this study was to determine whether or not human tumors produce tumor necrosis factor in vivo. Ovarian carcinoma tissue from 25 patients with ovarian carcinoma was examined for the presence of TNF. Four of 5 ascites fluid specimens and tissue sections of 16 of 20 patients were positive for TNF by immunoperoxidase staining. The source of the immunoreactive protein was further examined by in situ hybridization studies. TNF mRNA was detectable in each of the ascites specimens and 7 of 16 tissue sections that were positive by immunoperoxidase staining. These findings suggest that TNF is produced by some human tumors in vivo and that the association between TNF production and resistance to TNF antitumor action may be clinically relevant.

Tumor selective reactivity of a monoclonal antibody prepared against a recombinant peptide derived from the DF3 human breast carcinoma-associated antigen.

The DF3 antigen is a member of a family of high molecular weight glycoproteins aberrantly expressed in malignant mammary epithelium. We have generated a monoclonal antibody (MAb), designated DF3-P, against a recombinant DF3/beta-galactosidase fusion protein. Characterization of this MAb has demonstrated reactivity with immature precursors of DF3 antigen and not with the secreted form. These findings are in contrast to those obtained with MAb DF3, a previously described antibody with predominant reactivity against the mature glycoprotein. The finding that deglycosylation of secreted DF3 antigen with neuraminidase and endo-alpha-N-acetylgalactosaminidase is associated with increased MAb DF3-P reactivity provided additional support for the selectivity of this antibody against the protein core. Epitope mapping studies demonstrate that both the DF3-P and DF3 epitopes are located at a TRPAPGS domain in the 20-amino acid tandem repeat. The results of competition studies with synthetic peptides indicate that the proline in this domain is involved in both epitopes, while the potential glycosylation sites at threonine and serine may contribute to the differential reactivity of MAbs DF3 and DF3-P. Taken together, these findings suggest that both antibodies react with a similar epitope that is modified by the presence of carbohydrate moieties. The results of immunoperoxidase staining studies further demonstrate that while MAb DF3-P reacts with formalin-fixed sections of breast carcinomas, this antibody exhibits little if any reactivity with normal mammary epithelium. Selective expression of the DF3-P epitope in malignant breast cells may be useful in identifying this transformed phenotype.

Cytotoxic murine monoclonal antibody LAM8 with specificity for human small cell carcinoma of the lung.

The reactivity of the murine immunoglobulin monoclonal antibody LAM8 directed against a membrane antigen of human small cell carcinoma (SCC) of the lung was investigated on human cell lines and tissues. Indirect immunofluorescence staining, radioimmunoassays, and cytotoxicity assays showed LAM8 antibody to selectively react with SCC but not with non-SCC lung cancer cell lines and extrapulmonary tumor cell lines. Unlike other SCC antibodies, including those we have previously described, highly preferential reactivity with SCC tissues was also demonstrated by immunoperoxidase staining of deparaffinized formalin-fixed tissue sections. Membrane and cytoplasmic staining was seen in of 9 of 12 SCC tissues. No significant staining was seen in non-SCC lung cancer and a wide range of other tumors, including mesothelioma and bronchial carcinoids. Significant LAM8 reactivity was also absent in normal tissues of all major organs. Few tumors and epithelial tissues, including bronchial epithelium had rare LAM8 positive cells which were always less than 2% of the entire cell population. In vitro treatment with antibody and human complement was highly cytotoxic to SCC cells, but had not effect on bone marrow progenitor cells. Immunoblotting of membrane extracts separated on sodium dodecyl sulfate-polyacrylamide gels showed the LAM8 antigen to have a band of an approximate molecular weight of 135,000 and a cluster of bands with approximate molecular weights of 90,000. This reactivity was lost after incubation of the extracts with periodate. LAM8 antibody shows a highly preferential reactivity with SCC cell lines and formalin-fixed paraffin-embedded SCC tissues and is selectively cytotoxic to cells expressing LAM8 antigen.

Monoclonal antibody SEN7 recognizes a new epitope on the neural cell adhesion molecule present on small cell lung cancer but not on lymphocytes.

In our continuing attempt to select monoclonal antibodies for immunotargeting of small cell lung carcinoma (SCLC) we have developed the IgG1 murine antibody SEN7 which by immunofluorescence stained all SCLC cell lines tested. On frozen tumor section six of seven SCLCs were positively stained. The reactivity of this antibody in a series of lung tumors and on normal tissues has some similarities with cluster 1 antibodies and cluster w4 antibodies, as defined by the First and Second International Workshop on Lung Cancer Antigens [P.C.L. Beverley, Y. Olabrian, J.A. Ledermann, L.G. Bobrow, and R.L. Souhami, Br. J. Cancer, 63 (Suppl): 10-19, 1991], particularly with regard to staining of neuroendocrine tissues. The similarities in staining of neuroendocrine tissues between antibody SEN7 and cluster 1 and cluster w4 antibodies prompted us to examine the binding of SEN7 with transfectants expressing the respective antigens. On the murine lymphoma cells B-9, stably transfected with a complementary DNA clone coding for an M(r) 140,000 isoform of human SCLC neural cell adhesion molecule (NCAM), antibody SEN7 reacted positively whereas the cluster w4 antibody was negative. The reaction of antibody SEN7 with the NCAM transfected murine lymphoma cells was unexpected in view of its lack of binding to peripheral blood mononuclear cells which regularly stain positive with NCAM antibodies. Western blotting of a renatured SCLC extract revealed a strong band around M(r) 180,000 in contrast to other cluster 1 antibodies which recognized a broad polydisperse band with a molecular weight of 140,000 to 210,000. Antibody binding was sensitive to tunicamycin treatment, suggesting the epitope to reside on an N-linked carbohydrate structure. No significant competition for SEN7 binding on SCLC cells was seen with other NCAM antibodies against the three distinct epitopes described on SCLC. This finding together with the lack of staining of peripheral blood mononuclear cells and the selected reactivity with the M(r) 180,000 band of NCAM indicate the antibody SEN7 recognizes an epitope on NCAM which has not been described previously. Biodistribution studies with radiolabeled SEN7 in nude mice bearing s.c. SCLC xenografts demonstrated the selective localization of more than 30% of the total injected dose per g tissue at day 4 following i.v. injection. The homogeneous binding to SCLC, the lack of binding to peripheral blood mononuclear cells, and the favorable tumor localization in a xenograft model indicates that SEN7 is a good antibody for immunotargeting of SCLC.

Genetically programmed selective islet beta-cell loss in diabetic subjects with Wolfram's syndrome.

Insulin-producing beta-cells were selectively absent from the islets of Langerhans in postmortem specimens from two patients with Wolfram's syndrome. In families with multiple cases of this syndrome, we found a very high concordance rate (r = .910, P less than .001) among siblings for age at onset of diabetes mellitus. Taken together with the lack of markers for an autoimmune process, these findings suggest that diabetes mellitus in this syndrome results from genetically programmed selective beta-cell death.

Mortality within 30 days following systemic anti-cancer therapy, a review of all cases over a 4 year period in a tertiary cancer centre.

BACKGROUND: The national confidential enquiry into patient outcomes and death (NCEPOD) set important benchmarks in assessing the quality of care received by patients dying within 30 days of systemic anticancer therapy (SACT). Monthly morbidity and mortality audits conducted to recommendations in the NCEPOD were commenced at the Christie NHS Foundation Trust in 2009, specifically to assess and improve patient outcomes. METHODS: We evaluated the outcomes of patients who died within 30 days of SACT over a 4 year period 2009-2013. We collated audit findings to determine the number of treatment related deaths, clinical characteristics of patients, causes of death and quality of care received. We examined the benefit of the audit in decreasing 30 day mortality during the 4 years and considered factors that may be associated with an increased risk of SACT related death. RESULTS: A total of 31,183 patients were treated at the Christie from 2009 to 2013. Of these 4% died within 30 days of SACT. Death was treatment related in 11%. The decision to treat with SACT was appropriate in 87% of but there was room for improvement in care in 24%. Mortality decreased over the 4 years. Possible factors associated with 30 day mortality post SACT included performance status ⩾2, presence of comorbidities, treatment type and treatment setting. CONCLUSIONS: We demonstrated that our audit process is feasible and robust. Further areas of research to determine predictive scores for patient treatment selection and improve outcomes were highlighted and are ongoing.

Trends in survival for teenagers and young adults with cancer in the UK 1992-2006.

BACKGROUND: Although relatively rare, cancer in teenagers and young adults (TYA) is the most common disease-related cause of death and makes a major contribution to years of life lost in this age group. There is a growing awareness of the distinctive needs of this age group and drive for greater understanding of how outcomes can be improved. We present here the latest TYA survival trends data for the United Kingdom (UK). METHODS: Using national cancer registry data, we calculated five-year relative survival for all 15-24 year olds diagnosed with cancer or a borderline/benign CNS tumour in the UK during the periods 1992-1996, 1997-2001 and 2002-2006. We analysed trends in survival for all cancers combined and for eighteen specified groups that together represent the majority of TYA cancers. We compared our data with published data for Europe, North America and Australia. RESULTS: Five-year survival for all cancers combined increased from 75.5% in 1992-1996 to 82.2% in 2002-2006 (P<0.001). Statistically significant improvements were seen for all disease groups except osteosarcoma, rhabdomyosarcoma, non-gonadal and ovarian germ cell tumours and ovarian and thyroid carcinomas. During the earliest time period, females had significantly better survival than males for five of the twelve non-gender-specific disease groups. By the latest period, only melanomas and non-rhabdomyosarcoma soft tissue sarcomas had differential survival by gender. Survival in the UK for the most recent period was generally similar to other comparable countries. CONCLUSION: Five-year survival has improved considerably in the UK for most cancer types. For some disease groups, there has been little progress, either because survival already approaches 100% (e.g. thyroid carcinomas) or, more worryingly for some cancers with poor outcomes, because they remain resistant to existing therapy (e.g. rhabdomyosarcoma). In addition, for a number of specific cancer types and for cancer as a whole males continue to have worse outcomes than females.

An improved method for examination of cerebrospinal fluid cells.

A new collection technique allows cytologic examination up to 2 weeks after lumbar puncture without loss of cells or morphologic detail. Cerebrospinal fluid (CSF) was allowed to flow directly from a lumbar puncture needle into a solution of Carbowax in ethanol and was then processed with a cytocentrifuge. Two groups of patients were studied -- those undergoing spinal anesthesia and those having myelography for low back pain. Lymphocytes, polymorphonuclear neutrophils, and ependymal cells were regularly found in the CSF; a definite difference was found in the quantity and cell types in the two patient populations. The proposed method may be sensitive enough to aid in the identification of other neurologic diseases with low cell counts.

Infiltration of the lower respiratory tract by helper/inducer T lymphocytes in HTLV-1-associated adult T-cell leukemia/lymphoma.

The human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL), a disorder in which peripheral blood and multiple organs are infiltrated by malignantly transformed T lymphocytes. We investigated the nature of pulmonary disease in a patient with serologic evidence of HTLV-1 infection. In this case, endobronchial biopsy specimens showed infiltration of the bronchial mucosa by pleomorphic cells exhibiting a high degree of nuclear irregularity. These cells were morphologically identical in appearance to malignant cells found in peripheral blood and infiltrating the dermis, expressed the OKT4/Leu3 phenotype and the receptor for interleukin 2, and, by analogy to gene rearrangement studies on leukemic blood cells, were monoclonal in origin. However, in situ hybridization of endobronchial biopsy specimens with full-length HTLV-1 probes failed to detect retroviral RNA or proviral DNA. These studies indicate that T lymphocytic involvement of the lower respiratory tract in HTLV-1-associated ATLL is characterized by expression of a malignant phenotype despite the inability to document actual cellular infection with this retrovirus by a molecular hybridization technique.

Malignant epithelioid hemangioendothelioma of the liver in young women. Relationship to oral contraceptive use.

Epithelioid hemangioendothelioma (EH) is a vascular neoplasm that occurs predominantly in soft tissue and is not infrequently misdiagnosed as an epithelial neoplasm or angiosarcoma. Only a few cases of hepatic EH have been described, and a relationship to oral contraceptive (OC) use in patients with the hepatic lesions has not generally been recognized. We present a series of five patients with malignant epithelioid hemangioendothelioma of the liver. Confirmation of the endothelial origin of these tumors was provided by positive immunoperoxidase staining for Factor-VIII-related antigen in the four cases studied by that technique, and by the demonstration of Weibel-Palade bodies in two tumors examined by electron microscopy. All five patients were young women (mean age 33 years) and all five gave a history of OC use of 4-7 years' duration. The clinical course varied from indolent but progressive to rapid death. One patient who underwent resection of the primary tumor has survived 3 years without evidence of disease, and one patient with metastatic disease who was treated with radiation and chemotherapy has survived for 8 years with disease. Three patients with extrahepatic spread have died of the tumor. Early diagnosis of this distinctive tumor might offer the hope of salvage by resection or liver transplantation.