The majority of patients with acute liver failure (ALF) die waiting for orthotopic liver transplantation (OLT). No other treatment modality is shown to improve survival. This study was conducted to assess the safety and feasibility of hepatocyte transplantation (HT) and subsequent engraftment and function of donor cells. Functional and structural integrity of cryopreserved and thawed human hepatocytes were assessed by their morphological characteristics, induction of P-4501A1 transcription, and survival in vivo by xenotransplantation into rats. Five patients with severe ALF underwent intrasplenic (4 patients) and/or intrahepatic (2 patients) HT through angiography under cyclosporine immunosuppression. All patients had grade III to IV encephalopathy and factor V levels less than 0.5 U/mL, were ventilator and dialysis dependent, and were not OLT candidates. Three of the 5 patients who survived 48 hours after HT had substantial improvement in encephalopathy scores, arterial ammonia levels, and prothrombin times. Clinical improvement was paralleled by an increase in aminopyrine and caffeine clearances. All 3 patients lived substantially longer than expected based on clinical experience after HT (12, 28, and 52 days) but eventually died. Postmortem examination showed the presence of transplanted hepatocytes in liver and spleen by light microscopy and fluorescent in situ hybridization (FISH). Cryopreserved and thawed human hepatocytes can be transplanted into recipients with ALF with some acceptable but definite complications. Engraftment of donor hepatocytes was proven by histological examination and FISH by both transjugular biopsy and at autopsy. Improvement in brain edema, encephalopathy grade, and clearance of antipyrine and caffeine suggested function, albeit with a 24- to 72-hour delay posttransplantation.

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We report six malignant and six benign large cell calcifying Sertoli cell tumors of the testis and compare the features of malignant and benign cases based on these cases and those in the literature. All the tumors in this report consisted of sheets, nests, solid tubules, and cords of eosinophilic cells, with focal calcifications, as well as a substantial neutrophilic infiltrate in 11 of them. Analysis of our cases and those in the literature showed that the malignant tumors were unilateral and solitary and occurred at a mean age of 39 years (range 28-51 years), whereas the benign neoplasms were bilateral and multifocal in 28% of cases and occurred at a mean age of 17 years (range 2-38 years). Only one malignant tumor occurred in a patient with evidence of a genetic syndrome (Carney syndrome), whereas 36% of benign tumors had various genetic syndromes or endocrine abnormalities. Most of the tumors in the latter cases were bilateral and multifocal. There were strong associations of malignant behavior with size >4 cm, extratesticular growth, gross or microscopic necrosis, high-grade cytologic atypia, vascular space invasion, and mitotic rate greater than three mitoses per 10 high-power fields. All malignant cases exhibited at least two of these features, whereas all benign cases lacked any of them. The presence of any one of these features in a solitary large cell calcifying Sertoli cell tumor, especially in a patient >25 years of age, should be viewed as suspicious for malignant behavior, whereas the presence of two or more of these features indicates a strong probability of a malignant course. "Low" percentages (< or =35%) of tumor cells staining for proliferating cell nuclear antigen (PCNA) also may correlate with benign behavior, but some benign tumors have high PCNA values. Ki-67 values (MIB-1 antibody) did not correlate with biologic behavior, nor did immunostains for p53 protein.

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Background. Dedifferentiated chordoma is an unusual and aggressive variant of chordoma which is likely to metastasize. Few reports exist of treatment of these tumors with chemotherapy. Methods. In 1988, two patients with dedifferentiated sacral chordomas were seen at the University of Chicago Hospitals. Both developed metastatic disease less than a year after sacral resection and radiation therapy. These patients' diagnoses, courses, and treatments were reviewed along with the literature on chemotherapy in both conventional and dedifferentiated chordomas. Results. Both patients obtained complete remissions, one to a six‐drug regimen and the other to ifosfamide. Conclusions. A trial of reasonably aggressive chemotherapy is warranted in patients with metastatic dedifferentiated chordoma. The optimum regimen is unclear, but agents active in high‐grade sarcomas are logical choices.

Cryptosporidium parvum (CP) is an apicomplexan parasite that causes trivial diarrhea in healthy subjects 1 and lifethreatening hepatobiliary, gastrointestinal, or respiratory tract infection in subjects with acquired immune deficiency syndrome 2-4 or CD154 deficiency (which causes X-linked immunodeficiency with hyper IgM [XHIM]). 5 The parasite is difficult to culture, and experimental studies have mostly used immunodeficient mice, particularly those with severe combined immunodeficiency (SCID), as models. 6-8 The infection in SCID mice is generally biphasic with gastrointestinal involvement for 4 to 6 weeks, followed by spread of the organism to the biliary tract. 9 SCID mice occasionally recover from CP infection spontaneously, a phenomenon linked with their intestinal flora. 10 Mice with intact immune systems eliminate cryptosporidia within 4 weeks of infection, and parasites are not generally found outside the small and large intestine. The transfer of spleen cells, and specifically CD4 cells, from immunologically intact mice to CP-infected SCID recipients is followed by clearing of the infection in 2 to 4 weeks. 11-13 Our previous studies indicated that mice with disrupted genes for CD154 and CD40 (the natural ligand of CD154, a member of the tumor necrosis factor family of cell surface receptors) are also unable to eliminate CP, 14 providing an animal model for this infection in boys with CD154 deficiency. Interferon gamma (IFN-␥) and interleukin-12 are also known to contribute to immunity to CP as shown by experiments in which these cytokines are neutralized by specific antibodies. 15,16 Recently, Theodos et al. 17 and Mead et al. 18 showed that CP infection can be rapidly fatal in mice with disrupted IFN-␥ genes. The interleukin-12, IFN-␥, CD40, and CD154 pathways interact at several levels, so it is unclear whether a single mechanism (such as IFN-␥ pathwaydependent apoptosis 19 ) accounts for the persistence or severity of CP infection in these immunodeficient strains or whether multiple pathways are involved.Although immunodeficient mice are established models for gastrointestinal infection by CP, less attention has been paid to the consequences of CP infection for the biliary tree. The fibrosis that develops around the portal tracts of AIDS patients with chronic cryptosporidial infections can mimic the histological changes seen in primary sclerosing cholangitis. 20 CP-infected XHIM patients also develop sclerosing cholangitis, and up to one third of these patients die from bile duct-related cancers. 5 CP infection has recently been reported to cause apoptosis of cultured human biliary epithelial cells (BEC), 21 raising the possibility that direct toxicity for BEC might be responsible for biliary tract damage in humans. The studies reported here were undertaken to determine whether apoptosis of CPinfected BEC would follow infection in vivo and whether mice with defective CD40/CD154 would also model the liver and biliary tree pathology associated with CP infection in humans. Our choice of immunodeficien...

While evidence in both sporadic and inherited human colorectal cancer and MIN mice implicate the tumor suppressor gene, APC, in the causation of colorectal carcinogenesis, this gene has not been confirmed to be involved in rodent chemically-induced colon cancer models (RCCM). These experimental models are widely used to elucidate mechanisms involved in colon carcinogenesis (initiation, promotion and progression) as well as studies on chemoprevention (dietary and other) and intervention. To validate the RCCM as relevant models for sporadic human colorectal cancer, and to facilitate research on the role of the APC gene in colon carcinogenesis, we investigated the role of APC in azoxymethane (AOM)-induced colorectal tumors in mice. Using an antibody that recognizes the carboxy terminus of APC, we have characterized the pattern of staining observed in normal mouse intestinal tissue, in MIN mouse intestinal adenomas and in AOM-induced mouse colon tumors. The APC protein was localized in the cytoplasm of normal colonic epithelial cells. In the small intestine there was APC immunoreactivity along the villous and staining of the Paneth cells at the base of the glands. In the proximal and distal colonic crypts there appeared to be a gradient of staining which increased towards the luminal surface. This gradient was not as apparent in the small intestinal villi. Nuclei and mucus in the goblet cells showed no immunoreactivity. MIN mouse small bowel and colonic adenomas, known to have lost APC, stained negatively for APC. AOM-induced adenomas and carcinomas also consistently stained negatively using this antibody. This study demonstrates for the first time the loss of wild-type APC protein in AOM-induced mouse colon tumors and suggests that alterations in expression of this tumor suppressor gene, which is so commonly mutated in human colon cancer, is also involved in this animal model of colon cancer.