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BACKGROUND Metastasis occurs as a late event in the natural history of hepatocellular carcinoma (HCC), and most patients die of liver failure attributed to the tumor supplanting the liver. Conversely, the brain is a less common metastatic site. CASE SUMMARY We describe a rare case of hepatitis C virus-related multiple HCC metastasizing to the cavernous sinus, Meckel’s cave, and the petrous bone involving multiple cranial nerves in an 82-year-old woman. At admission imaging studies including Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (MRI) revealed multiple HCC nodules in both right and left lobes. Ultrasound guided biopsy of the left lobe revealed moderately differentiated HCC. Molecular targeted therapy with Lenvatinib (8 mg/d for 94 d, per os) and Ramucirumab (340 mg/d and 320 mg/d, two times by intravenous injection) were administered for 4 mo, resulting in progression of the disease. Three months after the start of molecular target therapy, the patient presented with symptoms of hyperalgesia of the right face and limited abduction of the right eye, indicating disturbances in the right trigeminal and abducens nerves. Brain MRI disclosed a mass involving the cavernous sinus, Meckel’s cave and the petrous bone. Contrast-enhanced MRI with gadolinium-chelated contrast medium revealed a well-defined mass with abnormal enhancement around the right cavernous sinus and the right Meckel’s cave. CONCLUSION The diagnosis of metastatic HCC to the cavernous sinus, Meckel’s cave, and the petrous bone was made based on neurological findings and imaging studies including MRI, but not on histological examinations. Further studies may provide insights into various methods for diagnosing HCC metastasizing to the craniospinal area.

症例は67歳，男性．幽門側胃切除術，BillrothII法再建の既往歴あり．心窩部痛を主訴に近医を受診．保存的加療を施行されるも症状が悪化したため，当院紹介となる．来院時，右上腹部に著明な圧痛と筋性防御を認めた．腹部CT検査において，膵頭十二指腸部周囲後腹膜腔の気腫像と液体貯留像を認めた．十二指腸穿孔の術前診断のもと緊急開腹術を施行した．膵頭部周囲後腹膜腔に膿瘍を認め，十二指腸下行脚内側の膵後筋膜を切開したところ褐色泥状物の貯留と穿孔した2cm大の憩室を認めた．十二指腸傍乳頭部憩室穿孔と診断し，憩室切除術・胆道ドレナージ術・十二指腸外瘻術を施行した．術後，憩室切除術部の縫合不全をきたしたが，保存的に軽快した．幽門側胃切除術・BillrothII法再建後の十二指腸傍乳頭部憩室穿孔の1例を経験したので文献的考察を加えて報告する．

Background. In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed. Methods. Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography. Results. The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. Conclusions. FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy.

The role of NF-kappaB, the rapid-response transcription factor for multiple genes, in cold ischemia-reperfusion (I/R) injury was examined after syngeneic transplantation of liver grafts. Lewis rat recipients were killed 1-48 h after reperfusion of three different liver grafts: 1) uninfected control, 2) infected ex vivo with control adenoviral vector (AdEGFP), and 3) infected ex vivo with AdIkappaB. In uninfected control livers, NF-kappaB was activated biphasically at 1-3 and 12 h after reperfusion with aspartate transaminase (AST) levels of 4,244 +/- 691 IU/l. The first peak of NF-kappaB activation associated with an increase of mRNA for TNF-alpha, IL-1beta, and IL-10. AdEGFP transfection resulted in similar outcomes. Interestingly, AdIkappaB-transfected liver grafts suffered more severe I/R injury (AST9,000 IU/l). Transfected IkappaB was detected in transplanted livers as early as 6 h, and this correlated with the abrogation of the second, but not the first, peak of NF-kappaB activation at 12-48 h and increased apoptosis. Thus inhibition of the second wave of NF-kappaB activation in IkappaB-transfected livers resulted in an increase of liver injury, suggesting that NF-kappaB may have a dual role during liver I/R injury.

After a short course of tacrolimus, Lewis rat liver allografts induce donor-specific nonreactivity in Brown Norway recipients that is immunosuppression­ independent after 28 days. To clarify the role of donor major histocompatibility complex (MIle) class II'" cells, we investigated the migration to the recipient splenic T- and B-cell compartments of different sub­ sets of Lewis MIle class II'" passenger leukocytes. The rise and decline of immune activation were monitored in the hepatic allograft and in the host spleen by anal­ yses of BrdU'" (proliferating) leukocytes, TUNEL + (ap­ optotic) cells, apoptosis-associated molecules, THlI TH2 cytokine profiles, and histoimmunocytochemical examination of graft and splenic tissues. Serial flow . cytometry studies during the 28-day period of drug­ assisted "hepatic tolerogenesis" showed that migra­ tory MIle class II+ cells accounted for less than half of the donor cells in the host spleen. The class II+ cells consisted mostly ofB cells that homed to splenic B-cell follicles with only a sp8J."Se representation of dendritic cells that were exclusively found in the splenic peri­ arteriolar lymphoid sheath. In parallel studies, trans­ plantation of the less tolerogenic heart produced a diminutive version of the same events, but with far fewer donor cells in the host spleen, evidence of sus­ tained immune activation, and the development of chronic rejection by 100 days. The data are consistent with the paradigm that migration of donor leukocytes is the prime determinant of variable tolerance induc­ tion induced by transplantation of the liver and other organs, but without regard for donor MIle class 11+ expression.

To investigate the monoclonality of hepatocellular carcinoma (HCC) and dysplastic nodule (DN) and the origin of multiple lesions, patterns of inactivation of X-linked human androgen receptor gene were studied. Fourteen of 15 patients (93%) were heterozygous in the size of the target, and were informative for clonal analysis. Monoclonal composition was demonstrated in all 17 HCCs and two DNs, whereas all non-cancerous hepatic tissues were polyclonal. Of four patients with more than two lesions of HCC or DN, two patients had two lesions with different patterns of X-chromosome inactivation, indicating that the two lesions were multicentric in origin.

Recent evidence has shown that passenger leukocytes that are normal constituents of all organs migrate after transplantation and are replaced by recipient cells of the same hematolymphopoietic lineages (1–5). With engraftment, the “accepted” organ and the recipient become genetic composites in that a trace population of the donor leukocytes survives peripherally in lymphoid and nonlymphoid recipient tissues (microchimerism) as well as in the allograft. Acute contemporaneous graft-versus-host (GVH) and host-versus-graft (HVG) immune reactions and the subsequent persistence of multilineage microchimerism have been proposed to be essential for successful organ transplantation and the variable development of donor-specific nonreactivity (tolerance). The quantity and lineage profiles of the passenger leukocytes contained in different kinds of organ grafts strongly influences the quantity and lineages of the chimerism found in the recipients, the relative strengths of the interactive HVG and GVH reactions, graft survival, and graft function (5–7). The passenger leukocytes of the liver and bone marrow cells (BMC), both of which include large numbers of immature leukocytes and cells of myeloid origin, have been shown to be more tolerogenic with a lower risk of graft-versus-host disease (GVHD) than the intestinal passenger leukocytes, which are rich in mature lymphocytes (5). In the experiments reported here, the hypothesis was tested that modification of the intestinal passenger leukocytes with ex vivo irradiation and the adjunct infusion of donor BMC would improve the control of rejection in a fully allogeneic small intestinal transplantation (SITx) model without causing GVHD. The irradiation doses were designed to eliminate or substantially reduce the mature lymphoid elements of the passenger leukocytes, without destroying precursor hematopoietic cells and without causing irradiation injury to the intestinal epithelial components. The irradiated intestinal grafts were transplanted alone or simultaneously with intravenously infused donor BMC. The efficacy of these treatments was assessed by recipient and graft survival, recipient weight maintenance, graft histopathology, and the quality and quantity of donor leukocyte microchimerism in Lewis (LEW)-to-Brown Norway (BN) and BN-to-LEW rat strain combinations. We have previously shown that the former combination was GVHD prone in that recipient animals developed fatal GVHD after SITx under a short course of immunosuppression (5–7). Although the lymphocyte migration patterns are similar in both strain combinations, BN-to-LEW transplantation is not complicated by GVHD. Thus, we were able to examine the effect of treatment strategies on the GVH and HVG immune responses in GVHD-prone and GVHD-resistant settings.

To understand the recurrence rate and transplantability after liver resection (LR), which are essential factors to predict the prognosis of initial resection and salvage transplantation for hepatocellular carcinoma (HCC), we reviewed the clinical records of 279 consecutive HCC patients who met the Milan criteria and underwent LR between 1990 and 2000. Recurrence-free survival rates after 1, 2, 3, 5, and 10 years following LR were 84%, 62%, 49%, 29%, and 17%, respectively. Multivariate analysis using clinical factors such as age, sex, histological differentiation, serum levels of alpha-fetoprotein and 7S domain of type IV collagen (7S collagen), platelet counts, indocyanin green retention test after 15 minutes, and type of LR (resection of one or more segments, or less than one segment) revealed 7S collagen to be a independent factor that significantly affects recurrence-free survival. Yearly recurrence rates up to 5 years after resection ranged from 14% to 27%, averaging 20%. Concerning 169 patients who underwent tests for 7S collagen, the average yearly recurrence rate (27%) in patients with 7S collagen levels 8.0 ng/mL or higher was remarkably greater than that in the patients with levels less than 8.0 ng/mL (16%). The transplantability rate at the time of recurrence meeting the Milan criteria was roughly 60%. There were no pre-LR factors that significantly predicted transplantability. This result indicates that patients with lower 7S collagen levels are more eligible for initial LR and then salvage LT rather than primary LT.

To characterize hepatocellular carcinoma (HCC) cells with mutant (m) p53 protein histologically, we examined 68 main nodules and 20 accessory lesions of 72 patients with HCC who underwent hepatic resection between October 1990 and September 1993. Some sections were fixed in periodate-lysine-paraformaldehyde, embedded in OCT compound, and stained with the mouse monoclonal antibody PAb1801 to m-p53 protein by the immunoperoxidase technique with avidin-biotin complexes. Other sections were fixed in 20% buffered formalin, embedded in paraffin, and stained with the mouse monoclonal antibody DO-1 to m-p53 protein in the same way. Lesions in which cells had nuclei stained for m-p53 protein were defined as being positive for the protein; 25 of the 68 main nodules and 14 of the 20 accessory lesions were positive. Large main nodules were more likely to be positive than small ones. Microscopic examination showed that a larger proportion of poorly differentiated main nodules than well differentiated nodules were positive. Larger proportions of main nodules with extracapsular invasion, septa, portal thrombi, or intrahepatic metastases were positive than main nodules without these features. Accessory lesions that seemed to be metastatic were almost all positive, but few accessory lesions that seemed to be of multicentric occurrence were positive. Our results suggest that lesions with m-p53 protein had a high grade of malignancy and metastasized readily.

1993年末までの主腫瘍径2cm以下の小肝細胞癌 (肝癌) 切除82例を対象に, 術式と肝機能評価法, 予後との関係を検討した. 施行術式はHr2: 8例, Hr1: 11例, HrS: 20例, Hr0: 43例であり, 広範囲切除例の肝機能は良好であったが, 術式決定には術中の肝肉眼所見が最も重視されていた. 82例中39例が残肝再発したが, Hr2の予後は他の肝切除術式より良好であった. そこでHr2可能条件をICGR1515%以下, CS1, Z1以下と仮定すると, Hr2未満切除74例中12例がHr2可能例であったが, 再発は2例にすぎなかった. 逆にHr2未満施行で再発をきたした37例のうちHr2を行えば切除領域に再発病巣が含まれた症例は7例であったが, Hr2可能例は1例に過ぎなかった. 小肝癌に対する切除術式は再発からみると, 術前の肝機能成績および術中所見を考慮した現行の基準が適切であると考えられた.

高齢者肝細胞癌に対する拡大肝切除の限界と対策を検討するため, 肝切除施行肝癌391例のうち70歳以上を高齢者 (34例), 75歳以上を超高齢者 (7例) と定義, これらを他の非高齢者 (357例) と対比した. 非高齢者群の術死, 在院死は13例4%であったが, 高齢者群では6例15%であった (p

From October 1983 to January 1995, we performed microwave coagulo-necrotic therapy (MCN) in 21 patients in whom another cancer nodules were detected intraoperatively or liver resection was dangerous due to severe cirrhosis. Seven were treated with MCN alone, other 13 cases were treated with MCN combined with partial hepatic resection, and one case was done with portal vein ligation. Preoperative results of fifteen minutes retention rate of indocyanine green were 6.4 to 45.8 (mean ; 27.0) %. The needle-electrode was punctured into various site of the tumor one to fifty times, and coagulations with microwave energy of 80 watts for 30 seconds at 15 seconds intervals were done. The treated lesions changed to avascular areas on dynamic CT at 1 and 6 postoperative months, and these lesions were completely necrotic histologically. The postoperative courses of 7 patients who received MCN therapy alone were uncomplicated except for one patient with severe cirrhosis. Long term prognosis after MCN were almost the same as that after liver resection. MCN is useful for treatment of unresectable HCC with minimal invasiveness.

症例は57歳の女性,繰り返す上腹部痛の精査時,肝左葉を中心とする限局性肝内胆管拡張によりCaroli病(以下本症)と診断,尾状葉を含む肝左葉切除を施行した.肉眼的に悪性所見はなかったが,病理組織学的に拡張胆管の粘膜上皮内に限局する胆管細胞癌と診断された.諸家の報告では本症の約8%に胆管細胞癌を合併し,その要因として肝内結石による慢性刺激,長期間の胆汁鬱滞,繰り返す胆管炎さらには先天性の胆道奇形が考えられている.これらの発癌機序は総胆管拡張症や膵胆管合流異常症でも指摘されているが自験例は総胆管拡張や肝内結石を合併しない上皮内癌症例であった.また本例は拡張胆管上皮に著明な過形成や腸上皮化生がみられ,その部分に連続して癌化が認められ,発癌の背景を推測するには貴重な症例と考えられた.

This case is a 69-year-old woman. We diagnosed gastric cancer and cholecystolithiasis by close inspection of abdominal pain. Because preoperative diagnosis was T2N0M0, Stage I B, we performed an operation. Many lesser tubercles were shown, and were diagnosed as peritoneal metastases pathologically. The tumor in corpus ventriculi infiltrated out of gastric serosa. We judged that curative resection was impossible and finished the operation after giving an intra-abdominal dosage of cisplatin(CDDP)at 85mg. After operation, 3 courses of performed S-1/CDDP combination chemotherapy were performed. Because we observed contraction of the main lesion and could not point out the peritoneal metastases and ascitis, we performed a second look operation. All the nodules found with peritoneal and rectouterine excavation had disappeared and we performed distal gastrectomy. The postoperative diagnosis was pT2(MP), pN0CY0, Stage I B, Cur A, therapy grade 1a. Chemotherapy does succeed, and this is a valuable case in which a radical operation could be performed.

早期の微小肝細胞癌(肝癌)ならびにその境界病変における門脈血流の関与を検討するため,肝切除の術中あるいは術後に担癌門脈枝より色素を注入し,術後の病理標本上での結節内色素の有無を観察し,被膜形成ならびに分化度との関係を検索した.対象とした14例17結節を病理組織学的に検討したところ被膜形成のない高分化型肝癌は6結節(腫瘍径:10±7mm)であり,全例結節内に門脈域がみられたが,結節内に色素がみられたものは2結節に過ぎなかった.他の11結節のうち中分化型肝癌(29±26mm)は7結節で,被膜を有さない1結節にのみ色素がみられた.なお残りの4結節(34±10mm)は術前治療のため完全壊死に陥っていた.結節内色素の有無は各結節の組織学的分化度より被膜の有無とよりよく相関しており,肝癌の発育過程で被膜が形成されるに伴い腫瘍内門脈血流が低下することが示唆された.

A 52-year-old man underwent distal gastrectomy for gastric cancer in July 2000. In July 2005, abdominal CT and barium study of the colon revealed peritoneal recurrence, and chemotherapy of S-1 was started. Within 2 courses, the serum CEA level increased, so combination chemotherapy of S-1 and cisplatin (CDDP) was begun. After 7 courses, the regimen was switched to S-1+paclitaxel (PTX). However, the patient developed digital numbness within 8 courses and single-agent chemotherapy with S-1 was restarted. In July 2007, he developed abdominal distension, and abdominal CT showed a large amount of ascites. S-1+CDDP was administered again, however, and we had to change the regimen within 3 courses due to fatigue and appetite loss. S-1 was restarted, but soon severe fatigue and appetite loss restricted the use of chemotherapeutic agents, and he died in December. This patient had been alive for 2 years and 5 months since peritoneal recurrence was diagnosed. We concluded that S-1-based sequential chemotherapy was effective for recurrent gastric cancer.

The case is a 66-year-old woman. CT showed multiple metastasis of the liver and lung after operation by colectomy for ascending colon carcinoma. A close inspection showed progressive stomach cancer with lymph node metastasis. Metastasis was considered an effect when it was of colon cancer origin, and treatment by mFOLFOX6 was started. In the results, we confirmed contraction of the liver and lung metastasis and contraction of the regional lymph node metastasis of the stomach by CT. The gastric cancer lesion became only a cicatrix with endoscopic examination. For gastric cancer, the availability of mFOLFOX6 was suggested.

The patient was a 47-year-old man who was discovered to have Borrmann type 4 cancer of the cardiac region of the stomach associated with esophageal invasion during upper GI endoscopy and was histopathologically diagnosed with poorly-differentiated adenocarcinoma. Invasion of the aorta was suspected based on a CT examination, and resection was judged to be impossible. Since the tumor was associated with impaired patency, after first inserting a metallic stent, the patient was treated with 4 cycles of S-1 100 mg/body for 2 weeks and paclitaxel (PTX) 120 mg/body by intravenous drip infusion on days 1 and 15 for 2 weeks followed by a 2-week rest period. The tumor regressed considerably, and total gastrectomy and lower esophagectomy with D1+ a lymph node resection through a left thoracolaparotomy became possible. A bypass operation or palliative resection is sometimes performed when complicated by impaired patency. In our patient, after achieving an improvement in QOL by stenting, resection became possible as a result of a response to chemotherapy with S-1. However, when considering resection after chemotherapy it seemed necessary to be careful to insert the stent as close as possible to the proximal margin of the tumor so as not to broaden the extent of the esophageal resection.

This study including prevention and rescue experiments was performed to examine the efficacy of FK778 and its interactions with FK506. In the prevention experiment, Brown-Norway rats transplanted with a 7 Lewis livers received day-course of FK778 or a combination of FK778 and FK506 treatment. For the rescue experiment, the recipients were additionally treated with FK778 from days 7 to 13. Blood chemistry and histopathological findings were used to examine the host and the graft condition. Donor-specific IgM was measured using enzyme-linked immunosorbent assays. The serum trough level of FK778 was examined by high-performance liquid chromatography. FK778 suppressed acute rejection in a dose-dependent manner. The optimal FK778 dosage was 20 mg/kg body weight (BW) d. FK778 treatment from days 7 to 13 rescued liver grafts from ongoing rejection. The combination of FK506 (0.125 mg/kg BW/d) and FK778 (20 mg/kg BW/d) maintained better graft condition than FK778 (20 mg/kg BW/d) monotherapy. In conclusion, FK778 prevents acute rejection in and rescues transplant recipients from ongoing rejection after rat liver transplantation. The optimal monotherapy dosage of FK778 was 20 mg/kg BW/d. Combination therapy with FK506 was more beneficial than FK778 monotherapy.

We have shown that tacrolimus (TAC)-induced liver allograft acceptance is associated with migration and persistence of donor B cells and dendritic cells (DC). To clarify whether these MHC class II+ leukocytes have favorable roles in inducing tolerance, we analyzed recipient T cell reactions after allogeneic B or DC infusion. LEW rat B cells localized exclusively in BN host B cell follicles without any direct contact with host T cells. While few donor DC migrated to T cell areas and marginal zones, they were captured by host APC, suggesting that allogeneic MHC class II+ cells may induce immune reactions via the indirect pathway. Although DC-infused non-immunosuppressed recipients showed enhanced ex vivo anti-donor responses, persistent in vitro donor-specific hyporeactivity was seen equally with donor DC or B cell infusion under TAC. The results indicate that donor MHC class II+ APC are capable of regulating recipient immune reactions under TAC. Possible involvement of the indirect pathway of allorecognition is discussed.

Although small bowel transplantation (SBTx) has become a clinical option, there have been few studies of long-term function and histopathology of intestinal grafts. Unrelated mongrel dogs received autologous (n = 4) or allogeneic (n = 11) orthotopic SBTx under oral cyclosporine. Intestinal graft function and routine/immunohistopathology of full-thickness intestine were studied. Six allograft and all isograft recipients had comparable body weight gain and are currently alive (> 420 days). Five allograft recipients were sacrificed because of significant body weight loss and malnutrition at a median of 119 days. Analyses of intestinal function in long-surviving recipients revealed marginal reduction of D-xylose/cyclosporine absorption, intestinal transit time, in vitro muscle contractility, and mucosal enzyme activity compared with normal dogs. However, these changes were insignificant and no statistical difference was seen between auto and long-surviving allografts. In histopathological analysis, long-surviving allografts had normal mucosa with submucosal, muscularis propria, and perineural (Auerbach's plexus) inflammation. Five allorecipients with malnutrition had mucosal atrophy/erosion and significantly reduced intestinal absorption and motility. Thus, denervated intestinal allografts are able to efficiently digest and absorb nutrients to support life. Results also indicate that these allografts experienced low-grade chronic rejection as evidenced in the submucosa and muscle layers, despite the lack of clinical symptoms.

The intestinal transplantation procedure obligates an early functional deficit in intestinal grafts. Graft irradiation has been used to modulate post-transplant immune reactions; however, irradiation may cause further deterioration of the function of the transplanted intestine. Using the canine model, we investigated the influence of the transplant procedures, with and without ex vivo graft irradiation, on early intestinal graft function and histopathology. Outbred hound dogs underwent autointestinal transplantation with (n = 8) or without (n = 5) 7.5 Gy ex vivo graft irradiation. Mucosal cytochrome P450 and P-glycoprotein, routine immunohistopathology, and intestinal absorptive function were studied. Weight gain was slow after surgery, but was comparable in the irradiated and nonirradiated groups. During the early post-transplant period, both groups showed defects in intestinal absorption, associated with decreased cytochrome P450 3A4 activity and reduced P-glycoprotein expression, regardless of graft irradiation. These changes returned to normal in both groups by day 28. Histopathologically, epithelial apoptosis showed a slight increase 1 hour after transplantation; however, there was no evidence of histopathologic abnormalities including arterial changes associated with irradiation. In addition, the frequency of T and B lymphocytes in the lamina propria were not significantly influenced by the transplant surgery or ex vivo irradiation. Thus, early after transplantation, intestinal function was impaired and effectiveness of orally administered immunosuppressive drugs was significantly altered. Graft irradiation did not induce further defects in intestinal function or cause histopathologic abnormalities.

The outcome of small bowel transplantation (SBTx) has improved during the last 10 years1; however, information on function and morphology of intestinal allografts long term after SBTx is limited.2 Using canine allo-SBTx model, this study investigated the absorption, motility, and histopathology of long-surviving intestinal allografts.

Passenger leukocytes, normal constituents of whole organs, migrate after transplantation and produce microchimerism, which is suggested to be essential for sustained survival of allografts.1 Canines have been widely used as a more clinically relevant outbred large animal transplantation model, rather than inbred rodent, and provided important information to directly improve the results of clinical transplantation. However, the analysis of microchimerism in this species is hampered by the lack of reagents. In this study, we demonstrate recently developed quantitative PCR analysis of chimerism in dog samples using primers specific for the sex determining region-Y (SRY) gene. Profitability of this method to determine the level of chimerism after organ transplantation was also shown in samples obtained from sex-mismatched canine small bowel transplantation (SBTx).

Chronic rejection (CR) is the major obstacle of long-term successful organ transplantation. Using a recently developed rat model of CR, we found that heart allografts susceptible to development of CR showed an early (

The phase S ratio in cell cycles were analyzed in livers with hyperplastic foci (HPF) and in livers without HPF by nuclear DNA determinations using flow cytometry, and by staining with argyrophilic proteins of the nucleolar organizer region (AgNOR). Flow cytometric analysis was done on 50 fresh frozen specimens of livers resected from 50 patients with hepatocellular carcinoma (HCC). Paraffin sections from the same patients were analyzed using AgNOR staining. There were 25 cases each with and without HPF. We examined the stage of fibrosis and the grade of inflammatory activity according to the modified Scheuer and Desmet scale. The incidence of HCC recurrence among these patients was also studied. The average phase S ratio of the livers of the patients with HPF was 6.5 +/- 3.2%, and that of the livers of the patients without HPF was 4.0 +/- 2.5%. The ratio differed significantly between the two groups (P0.01). The average AgNOR score for HPF lesions of the HPF-positive cases was 1.60 +/- 0.34, that for non-HPF lesions in the HPF-positive cases was 1.29 +/- 0.12, and that for the HPF-negative cases was 1.19 +/- 0.14. Significant differences were found between the average AgNOR scores for HPF lesions of the HPF-positive cases and the non-HPF lesions of the HPF-positive cases (P0.01), as well as between the non-HPF lesions in the HPF-positive cases and the HPF-negative cases (P0.05). Severe fibrosis (stage 3) and cirrhosis (stage 4) were found in 76% of HPF-positive cases and 48% of HPF-negative cases. The livers of HPF-positive patients were significantly more cirrhotic than those of HPF-negative patients (P0.05). The association between HPF and the inflammatory grade was not significant (P0.05). The incidence of HCC recurrence among HPF-positive cases was significantly higher than that among the HPF-negative cases (P0.05). The average phase S ratio of the recurrent HPF-positive patients was 7.48 +/- 3.48%, significantly higher than that of HPF negative cases (5.57 +/- 3.06%, P0.05). Hyperplastic foci of the liver was shown to be a highly proliferative lesion. The proliferative activity of the non-HPF lesions in the HPF-positive patients was also higher than that of the HPF-negative patients. Hyperplastic foci tended to be present in cirrhotic livers, but it was not associated with the grade of inflammatory activity of the liver. Hyperplastic foci may represent an important predictor of recurrence after hepatic resection.