Transforming growth factor ß repressor, SnoN, is overexpressed in human gastrointestinal stromal tumors.

PURPOSE: The transforming growth factor bgr; (TGF-ß)/ Smad pathway is implicated in the development of interstitial cells of Cajal. The aim of this study was to examine the role of this pathway in human gastrointestinal stromal tumors (GISTs). METHODS: The expression of TGF-ß receptor II (TßRII), phosphorylated Smad2 (p-Smad2), SnoN, p21(WAF17sol;CIP1) and p27(KIP1) was examined by immunohistochemistry in 30 hu-man GISTs in relation to prognostic factors. RESULTS: TßRII was expressed in 76.9% of the cases. All cases were positive for p-Smad2 and SnoN, with significantly higher expression levels in small intestinal compared to gastric GISTs. Downregulation of p21(WAF1/CIP1) and p27(KIP1) was found in 78.6% and 46.4% of the cases respectively, while cytoplasmic expression of p27(KIP1) was also noted in 50% of GISTs. CONCLUSIONS: TGF-ß/Smad pathway may contribute to GIST pathogenesis. SnoN overexpression and low levels of p21(WAF1)/CIP1 and p27(KIP1) may be of importance in GISTs.

Metallosis after contemporary metal-on-metal total hip arthroplasty. Five to nine-year follow-up.

BACKGROUND: Authors of recent studies have reported early periprosthetic osteolysis in patients who have been treated with a contemporary metal-on-metal total hip arthroplasty and have suggested that metal hypersensitivity associated with an immunologic response to metal may be of etiologic importance. We evaluated the results and histologic findings in patients who had undergone revision of a failed contemporary metal-on-metal total hip arthroplasty. METHODS: Two hundred and seventeen total hip arthroplasties (SL-Plus stem and Bicon-Plus cup) with a Sikomet metal-on-metal articulation were implanted in 194 consecutive patients, and the results were retrospectively reviewed at a mean of seventy-seven months postoperatively. Clinical follow-up with the Harris hip score and plain radiographic evaluation were performed. Periprosthetic tissues from fourteen hips that had undergone revision arthroplasty were subjected to histologic analysis. RESULTS: The mean Harris hip score improved from 45 points preoperatively to 88 points at the final evaluation. Fourteen hips (6.5%) were revised: nine because of aseptic loosening, two because of technical failure, and three because of septic failure. Histologic examination of the retrieved periprosthetic tissues from the eleven patients who had undergone revision because of aseptic loosening or technical failure showed metallosis and extensive lymphocytic and plasma-cell infiltration around the metal debris. With removal of the component because of aseptic loosening as the end point, survivorship was 93% for the stem and 98% for the cup. CONCLUSIONS: Our findings are in agreement with those in recent publications and support the possibility that periprosthetic osteolysis and aseptic loosening in hips with a metal-on-metal articulation are possibly associated with hypersensitivity to metal debris. Prospective, comparative, randomized long-term studies are necessary to determine the cause(s) of loosening of prostheses with this particular articulation.

Concentration of iron and distribution of iron and transferrin after experimental iron overload in rat tissues in vivo: study of the liver, the spleen, the central nervous system and other organs.

The purpose of this study was to estimate the iron concentration in the liver, spleen and brain of control rats and rats overloaded with iron and to determine the distribution of iron and of transferrin (TF). Iron was administered to Wistar rats by food supplemented with 3% carbonyl iron for 3 months, or intraperitoneally, or intraveneously as iron polymaltose for 4 months (total administered dose: 300 or 350 mg/rat, respectively). Iron concentration was estimated by atomic absorption spectrophotometry and iron- and TF-distribution histochemically and immunohistochemically, respectively. In control rats the organ with the highest iron content was the spleen, followed by the liver and brain. After iron loading the increase of iron in the liver was greater than that of the spleen; iron concentration in the brain did not change significantly. Distribution of iron in the liver was in Kupffer cells throughout the lobule and in hepatocytes at its periphery. No difference in the number of positive cells or staining intensity for TF was observed between control rats and iron overloaded animals in the liver or central nervous system (CNS); the spleen was negative for TF. Distribution of TF in the liver showed a centrilobular localisation in hepatocytes. TF reaction in the brain occurred in oligodendrocytes, vessel walls, choroid plexus epithelial cells and some neurons. In conclusion, experimental iron overload in rats leads to iron uptake mainly by reticuloendothelial (RE) cells and hepatocytes, indicating that hepatocytes are of particular importance for iron metabolism. Iron uptake by the brain was not significant, probably because the brain is protected against iron overload. Iron overload did not influence location and quantity of TF in the liver and CNS, whereas the visualisation of iron and TF did not coincide. This indicates that TF may have other functions beyond iron transport.

Response to interferon alfa-2b therapy in mutitransfused children with beta-thalassemia and chronic hepatitis C.

Hepatitis C virus is responsible for the majority of cases of post-transfusion non-A non-B hepatitis in patients with thalassemia major. Interferon alfa is an effective treatment for patients with chronic hepatitis C. Response to therapy is related to the duration of treatment, the viral load in serum, and the hepatitis C virus genotype. The purpose of this study was to estimate the response of multitransfused children with beta-thalassemia and chronic hepatitis C to interferon alfa-2b therapy. Thirteen patients with beta-thalassemia and chronic hepatitis C, (mean age+/-SD, 14.1 +/- 1.7 years) participated in the study. Liver biopsy, estimation of HCV RNA, and virus genotyping were performed before onset of treatment. All patients were positive for HCV RNA in a low concentration; two patients carried the la genotype, four had genotype 3, and seven had genotype 4. Patients were treated with 3 x 10(6) U of subcutaneous interferon alfa-2b three times weekly. Eleven of 13 patients received therapy for 18 months; the remaining two underwent therapy for 6 months. Six of 13 patients responded completely to therapy, four responded partially, and three did not respond at all. The grade of inflammation and stage of fibrosis was lower in complete responders. Complete responders had lower ferritin values compared with the values for partial and nonresponders before starting therapy. The results suggest that interferon therapy should be recommended for children with beta-thalassemia major complicated by a low viral concentration of hepatitis C.

Influence of iron overload on manganese, zinc, and copper concentration in rat tissues in vivo: study of liver, spleen, and brain.

Although hemochromatosis and pathological situations due to chronic iron overload have been extensively described, there is little information about the influence of iron on other trace elements in the cell. The aim of this study was to investigate changes in the concentration of zinc, manganese, and copper in the liver, spleen, and brain of rats after iron overload. Iron overload in Wistar rats was achieved by iron-supplemented diet or by intraperitoneal or intravenous injection of polymaltose iron. Iron, zinc, manganese, and copper were determined by atomic absorption spectrophotometry. Iron overload in rats, regardless of the route of its application, resulted in an increase not only of iron but also of zinc and manganese in the liver and the spleen, whereas the content of these metals in the brain did not change. The copper content of the liver, spleen, and brain remained the same after iron overload. The increase of zinc and manganese in the liver and spleen following iron overload was probably a result not only of increased intestinal absorption but also of increased uptake from the cell. This is also supported by the fact that no increase in the zinc and manganese concentrations occurred in the brain since, despite iron overload, the iron content remained constant.

Evolution of disc degeneration in lumbar spine: a comparative histological study between herniated and postmortem retrieved disc specimens.

This is a prospective comparative histological study on blood supply between lumbar herniated discs and postmortem retrieved ones. The aim of this study is to observe the evolution of disc degeneration in relation to its blood supply changes. Disc vascularization is present early in life, but the nucleus pulposus becomes avascular after adolescence. Vascularization of the annulus fibrosus (AF) probably also occurs late in life in association with degenerative changes and in response to trauma. Capillary neoformation and hypervascularity in degenerated discs have also been mentioned, based on animal cases. In the present study, intervertebral lumbar disc specimens were surgically removed from 84 patients with an average age of 41 years (range 24-60 years) operated on for disc herniation. In addition, control autopsy specimens were selected from 24 cadavera with an age of 39 years (range 24th gestation week to 80 years). The material was fixed in neutral buffered formalin, and 4-microm-thick sections were stained with hematoxylin-eosin and reticulin. In addition, with use of an immunohistochemical avidin-biotin complex technique, paraffin sections were stained for Ulex europaeus agglutinin receptors (UEA-1) after binding UEA-1 to the tissue. In surgical specimens, small blood vessels were identified in 45% of the disc cases. They were of the capillary-type vessels and were intermingled with proliferating endothelial cells, fibroblasts, and few mononuclear cells. All of them were located along the edges of the surgically retrieved fibrocartilage fragments. Sometimes thin bands of fibrin were attached to them and extravasated erythrocytes were occasionally seen. In autopsy specimens, blood vessels were identified in 78% of the retrieved discs. In contrast to the edge neovascularity observed in surgical specimens, capillaries were observed at the outer layer of AF surrounded by dense hyalinized and inactive-appearing collagen. From these results it is concluded that the blood vessels in extruded tissue from every type of herniation are newly formed, possibly through metaplasia of undifferentiated mesenchymal cells. It is also possible that they are derived from blood vessels that have invaded the AF as a result of disc degeneration. The finding of detection of progressive disc degeneration in both groups after 20-25 years seems to be of special interest because disc degeneration is a process that may not be directly correlated to disc herniation in these age groups.

Intrahepatic bile duct injury and nodular regenerative hyperplasia of the liver in a patient with polyarteritis nodosa.

Although involvement of the hepatic vasculature in patients with polyarteritis nodosa is not unusual, biliary manifestations are very rare. We describe a patient with polyarteritis nodosa presenting with a febrile cholestatic anicteric syndrome. Histological examination of the liver revealed necrotizing arteritis of small hepatic arteries associated with significant lesions of intrahepatic bile ducts of the sclerosing cholangitis type, i.e. fibrous collar around the ducts, periductal inflammation and ductal proliferation. Concomitant nodular regenerative hyperplasia was found, a condition which has rarely been described in association with polyarteritis nodosa. We think that hepatic arteritis compromising arterial blood flow to the liver was responsible for the most likely ischemic nature of the bile duct injury and the nodular regenerative hyperplasia seen in our patient.

Lack of transmission of hepatitis C in household contacts of children with homozygous beta-thalassaemia.

Forty-eight household contacts of 25 children with homozygous beta-thalassaemia and chronic hepatitis C (index cases) were evaluated for antibodies against hepatitis C virus (HCV) and increased transaminase values in the blood. The mean age +/- SD of the household contacts was 36.4 +/- 17.0 years (range 5-67) and 20 of them were males. All thalassaemic patients (age 14.3 +/- 3.0 years, range 8-19) were positive for anti-HCV antibodies by repeated determinations. HCV-RNA was detected in the blood of 22 of 23 patients tested by polymerase chain reaction. Liver biopsies were performed in 18 patients and showed chronic active hepatitis in 14 and chronic persistent hepatitis in 4. The mean duration of contact between the index cases and the household contacts while the index cases were anti-HCV positive was 45.3 +/- 10.2 months (range 17-57). None of the household contacts was found to be positive for anti-HCV antibodies nor did they have elevated transaminases in the two examinations performed within an interval of about 2 years. Among the HCV-negative household contacts are included 14 who mentioned needlestick injuries with needles used by the index cases.

Refracture of a healed tibial shaft fracture after irradiation for post-traumatic squamous-cell carcinoma.

A 58-year-old man, who had been operated on 17 years ago for an open Grade III tibial shaft fracture, developed 14 years after the fracture had healed a poorly differentiated squamous cell carcinoma at the site of the old scar. Seventeen years after the original injury, the carcinoma was completely excised and the area irradiated. Fourteen months later a spontaneous fracture of the tibial shaft occurred at the same site. After radical excision of the necrotic bone and affected skin, AO-external osteosynthesis was performed which failed, and 8 months after surgery a septic pseudarthrosis occurred which persisted, though no local recurrence of the carcinoma was clinically or histologically diagnosed. Amputation in the upper third of the tibia was successful without local or systematic recurrence during follow-up.

Latent solitary tuberculous psoas abscess 52 years after healed thoracolumbar tuberculous spondylitis.

STUDY DESIGN: This study reports on an extremely rare case of tuberculous psoas abscess and describes the mode of diagnosis and treatment. OBJECTIVE: This patient is presented to emphasize that cases of solitary psoas abscess resulting from tuberculosis exist today. SUMMARY OF BACKGROUND DATA: No recent cases of latent solitary tuberculous psoas abscess have been reported, to the authors' knowledge. METHODS: A tuberculous psoas abscess associated with fistula to the greater trochanter may remain dormant for years after tuberculous spondylitis has healed, as a distinct entity without concomitant active bone infection. In our 58-year-old female patient, the diagnosis of a psoas abscess was greatly aided by the "three pass" technetium bone scan and computed tomography, but the anamnesis also was important. RESULTS: Anti-tuberculosis medication (streptomycin, aminosalicylic, and isoniazid) combined with open drainage, curettage of the psoas, and simultaneous revision of the fistula eradicated the disease, making the course of the disease uneventful until the 5-year follow-up evaluation. CONCLUSIONS: Orthopedic surgeons must be aware of the rare, delayed appearance of a solitary psoas abscess after tuberculous spondylitis.

Primary osteosarcoma of the L2 lamina presenting as "silent" paraplegia: case report and review of the literature.

Primary osteosarcomas of the vertebral column are not common, and to our knowledge a total of 78 cases, mostly located in the vertebral body, have been previously reported. We report a primary osteosarcoma of the spine with an extremely rare location--the lamina of the second lumbar vertebra. The patient, a 38-year-old woman, was admitted with paraplegia of a short duration without pain. Preoperatively, the patient underwent CT scanning for staging (Enneking IIB) followed by a needle biopsy and local preoperative arterial embolization. An emergency decompressive laminectomy was performed, and stabilization was carried out using methylacrylate. The patient showed a complete neurologic recovery. Combined chemotherapy and local irradiation did not prevent tumor recurrences, which occurred 12 and 19 months after the initial intervention and were associated with recurrent neurologic impairment. The patient died 19 months after the initial presentation, while in paraplegia, from lung metastases. Based on our unique observation, it seems that in primary osteosarcomas located in the posterior elements of the spin, the symptoms are not specific, and the disease may only become manifest when the tumor is no longer resectable. When the tumor is associated with neurologic impairment, spinal canal decompression should be performed even though it does not radically resect the tumor because it significantly improves the quality of the patient's life.

Anterior decompression and fusion for Aspergillus osteomyelitis of the lumbar spine associated with paraparesis.

STUDY DESIGN: A very rare case of Aspergillus fumigatus osteomyelitis of the spine is described. The differential diagnosis, medical and operative treatment, and follow-up evaluation are reported. OBJECTIVES: To increase knowledge about the pathogenesis and treatment of vertebral osteomyelitis resulting from Aspergillus and to emphasize that such cases still exist. SUMMARY OF BACKGROUND DATA: Vertebral osteomyelitis from Aspergillus species is an infrequently described disease in Europe and only few cases have been previously reported. METHODS: A 48-year-old woman with Aspergillus fumigatus spondylitis in the lumbar spine and tuberculosis-lung infection and concomitant debilitating systemic disease was afflicted with incomplete paraplegia and underwent successful combined operative and medical treatment. RESULTS AND CONCLUSIONS: Early anterior decompression with spinal fusion, combined with Amphotericin B therapy, was crucial in bringing about complete neurologic recovery and maintaining the sagittal lumbar profile. Excellent clinical and radiologic results were shown in the 42-month follow-up period.

Evolution of aggressive granulomatous periprosthetic lesions in cemented hip arthroplasties.

The authors analyzed the histologic findings from material retrieved during 17 revision operations from 15 patients who had cemented total hip arthroplasty or hemiarthroplasty. In 13 patients, the indication for revision was aseptic loosening. In four patients, technical error during implantation of the prostheses made revision necessary. The histologic pictures in the loosened and nonloosened prostheses were similar, characterized by the presence of a synovial-like membrane at the site corresponding to the hip joint cavity or abutting the implant, underneath which were found aggregates of histiocytes and foreign-body giant cells within a dense fibrous matrix. The main foreign material in all patients consisted of fine granules or larger cement particles. A few polyethylene fibers were also observed in some patients. Metal deposits were found in three patients with titanium alloy implants and extensive loosening. The most interesting aspect of this series was the opportunity it provided to study the progressive development of the synovial-like membrane and the first appearance of the cement granulomas in non-loosened cases. The first signs of the synovial membrane appeared 2.5 months postoperatively, whereas the first cement debris were observed as early as seven months after the implantation of the prosthesis. The hip joint newly formed membrane in the nonloosened cases did not differ histologically from that in the loosened cases. Because the histology of loosened and technically poorly placed nonloosened-prostheses are the same, the authors believe that the mechanism of failure associated with cell macrophage-mediated osteolysis may be the same.

Liver involvement in hemorrhagic fever with renal syndrome.

Hemorrhagic fever with renal syndrome is an acute febrile nephropathy caused by several viruses of the genus Hantavirus of the family Bunyaviridae. During the past 8 years, 32 cases of hemorrhagic fever with renal syndrome have been diagnosed. Nine out of the 32 patients (28%) had raised (twofold upper normal limits) transaminases during hospitalization. Four out of the nine patients (44%) died. In contrast, only three out of the 23 patients (13%) without raised transaminases died. Five patients had slightly increased serum alkaline phosphatase and gamma-glutamyl-transpeptidase, whereas six patients had prolonged prothrombin time. Liver histology showed midzonal necrosis in hepatic lobules with extravasation of red cells and mild mononuclear infiltrate. Liver involvement seems to be an ominous prognostic factor in such patients and is correlated with severe renal failure and thrombocytopenia.

Primary non-Hodgkin's lymphoma of the urinary bladder.

Primary non-Hodgkin's lymphoma of the bladder is a rare entity and when found in such an unusual location is often difficult to distinguish from other vesical or extravesical neoplasms. Understanding of the pathobiological characteristics of this malignancy has been hampered not only because of its rarity but also by the previous confusion in its nomenclature. Factors that influence survival most strongly are the stage and the bulk of disease at presentation and the histologic classification of the tumor. We report a case of primary non-Hodgkin's lymphoma of the bladder presenting as a large pelvic mass which dramatically regressed with systemic chemotherapy with simultaneous restoration of the upper dilated urinary tracts. In addition, the incidence, clinical picture, staging procedures, histologic classification and treatment modalities of this disease are reviewed.

Detection of hepatitis B surface antigen in fixed tissues of patients with cirrhosis and hepatoma.

HBsAg has been sought by light microscopy in liver specimens from patients with cirrhosis (79 cases) and hepatoma (99 cases). The study was carried out on fixed material using orcein staining, immunoperoxidase technique and indirect immunofluorescence. HBsAg was detected in the serum by radio-immunoassay (RIA) using Ausria II-125 in 38 patients with cirrhosis and in 36 with hepatoma. In the 38 seropositive cases of cirrhosis HBsAg-positive cells were observed in 31 (81.6%) by the orcein staining and in 32 (84.2%) by the peroxidase and immunofluorescence staining. Among the 36 seropositive patients with hepatoma, HBsAg was detected in the surrounding non-neoplastic part of the liver, cirrhotic or not, in 30 (83.3%) by orcein staining and in 34 (94.4%) by the immunoperoxidase method and immunofluorescence. Positive solitary-cells were seen occasionally in the tumor tissue in 16 cases using orcein, in 9 using peroxidase and in 7 by fluorescence, out of the 36 seropositive patients with hepatoma. The results of this study do not support the hypothesis of a direct oncogenic effect of HBsAg on the liver cells, since this antigen was detected mainly in the non-neoplastic part of the liver tissue and only occasionally in the tumor cells. Of the 63 cases of seronegative hepatoma, 3 showed some round orcein-positive inclusion bodies in the cytoplasm of the neoplastic and the non-neoplastic cells; these bodies were not stained by the two immunological methods.