Is histological diagnosis of primary liver carcinomas with fibrous stroma reproducible among experts?

AIMS: In the era of targeted therapeutics, histological typing of hepatobiliary carcinomas has major clinical implications. Little is known about the reproducibility of the pathological diagnosis of primary liver carcinomas. Therefore, this study aimed to evaluate the worldwide variation in the pathological expert diagnoses of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis. METHODS: A single set of slides was selected from 25 tumours, and this set was reviewed independently by 12 pathologists who have worldwide expertise in liver tumours. Reproducibility of the diagnoses was evaluated by Light's kappa, and diagnoses were clustered by multidimensional scaling. Immunohistochemistry was performed after histological review. RESULTS: The interobserver reproducibility for diagnosis of hepatocellular carcinoma subtypes and cholangiocarcinomas was poor (kappa 0.23-0.52), even when the experts considered that the diagnosis required no additional stains or clinical information. Interestingly, multidimensional scaling revealed three main clusters of tumours: hepatocellular carcinoma with no other specifications (n = 13), fibrolamellar hepatocellular carcinoma (n = 3) and cholangiocarcinoma (n = 9). Using immunohistochemistry, these histological clusters correlated with expression of anti-hepatocyte and anti-cytokeratin 19 (p<0.001). CONCLUSIONS: The results demonstrate the poor reproducibility among experts of the pathological diagnosis of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis, and highlight that the systematic use of immunohistochemistry may improve the diagnostic accuracy.

Building safer systems by ecological design: using restoration science to develop a medication safety intervention.

BACKGROUND: Experts call for stronger safety cultures and transparent reporting practices to increase medication safety in today's strained healthcare environments. The field of ecological restoration is concerned with the effective, efficient, and sustainable repair and recovery of ecosystems that have been degraded, damaged, or destroyed. A study was undertaken to determine whether the lessons of restoration science can be adapted to the study of medication safety issues. METHODS: Working with 26 practitioners, the principles of good restoration were used to design and pilot an innovative multifaceted medication safety intervention. The intervention included focus groups with practitioners, the construction and administration of a research based medication safety inventory, repeat digital photography of environmental safety issues, and targeted environmental modifications. RESULTS: Participants were most concerned about staff education and the physical environment for medication administration. Ward staff used the research to build a healthy reporting culture, introduce regular discussions of near misses, develop education strategies, redesign delivery and storage processes, and renovate the environment. CONCLUSIONS: Members of a busy hospital ward successfully adapted methods of restoration science to study, redesign, and strengthen medication safety practices and ward safety culture within existing resources. Further research will be conducted to test the merits of restoration science for health care.

Evolution of aroma compounds from orange juice stored in polyethylene terephthalate (PET).

The evolution of aroma compounds from orange juice made from concentrate and stored in glass, standard monolayer polyethylene terephthalate (PET 1), multilayer PET (PET 2) and plasma-treated PET (internal carbon coating) (PET 3) was investigated. Bottles were stored at room temperature (20 degrees C) under artificial light. Volatile compounds in orange juice samples and corresponding packaging materials were analysed at zero time and after 2, 3 and 5 months of storage. After 5 months of storage, from 0.2 to 0.3% of the initial amounts of limonene and beta-myrcene in the orange juice had been absorbed by the plastic packaging materials. Statistical analyses showed that the evolution of aroma compounds was strongly correlated to the duration of storage, but not to the type of packaging material. Indeed, whatever the stored orange juice samples, the same evolutions were observed, with a decrease in aldehydes and ketones, esters, aliphatic alcohols, sesquiterpene and monoterpene alcohols, and an increase in two aliphatic and monoterpene alcohols (i.e. furfural and 4-vinylguaicol). The results suggest that the losses of aroma compounds from the juice could be attributed to the high acidity of the matrix, implying acid-catalysed reactions. Finally, PET packaging materials and their corresponding oxygen permeabilities showed no correlation with the loss of aroma compounds.

A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence.

BACKGROUND AND AIM: Autoimmune hepatitis (AIH) has been reported to recur after orthotopic liver transplantation (OLT) in 10-35% of patients in small series with a short follow up. The aim of the present study was to examine the clinical and histological outcome more than 10 years after OLT for AIH. PATIENTS AND METHODS: Seventeen women with a mean age of 30 (12) years at the time of OLT, selected from among 44 patients transplanted for AIH, were followed for more than 10 years. The criteria for definite AIH, as established by the International Autoimmune Hepatitis Group, were met in every case. Liver biopsies were performed 1, 2, 5, and 10 years after OLT, and when indicated by abnormal liver function tests. Specimens were examined for evidence of recurrent AIH, namely interface hepatitis, lobular activity, portal lymphoplasmocytic infiltration, and fibrosis. Other signs of recurrence included hypertransaminasaemia, serum autoantibodies, and the response to steroid reintroduction or significant steroid dose increments. RESULTS: AIH recurred in 7 (41%) of 17 patients. In four patients histological abnormalities were detected by means of protocol biopsies 1-5 years before the onset of biochemical abnormalities. Two patients developed severe recurrences after 10 and 15 years, respectively, and required treatment with steroids and tacrolimus. In the other three patients histological recurrence was detected 0.6-3 years post-OLT, concomitantly with biochemical abnormalities. CONCLUSIONS: AIH recurred in 41% of patients followed for more than 10 years after OLT. As histological signs preceded biochemical abnormalities in four patients (23.5%), regular liver biopsy is warranted after OLT. Detection of isolated histological signs may call for closer follow up and/or a change in immunosuppressive therapy.

Intestinal peptide transporter PepT1 is over-expressed during acute cryptosporidiosis in suckling rats as a result of both malnutrition and experimental parasite infection.

Cryptosporidium parvuminfection induces amino acid malnutrition leading to growth retardation in children. Owing to the nutritional efficiency of peptides compared to free amino acids and the resistance of the di-tripeptide transporter PepT1 to mucosal injury, we analyzed the intestinal expression of PepT1 during experimental acute cryptosporidiosis in suckling rats from day 4 to day 50. PepT1 mRNA levels were increased at the peak of infection (day 10) all along the small intestine and normalized after spontaneous clearance of the parasite (day 21). Immunolocalization of PepT1 showed that its expression was maintained in the brush border membrane of enterocytes in infected rats from day 4 to day 50 all along the small intestine. Our results suggest a transcriptional up-regulation during acute cryptosporidiosis in response to both C. parvum-induced malnutrition and parasite implantation. As no treatment is available, a semi-elemental diet should be considered part of the treatment of cryptosporidiosis.

The chemotherapy of metastatic gastric adenocarcinomas with hypersecretion of alpha-fetoprotein or beta-human chorionic gonadotrophin: report of two cases.

The chemotherapy of advanced gastric adenocarcinomas (GAs) is based on agents such as cisplatin, 5-fluorouracil and anthracyclins. Reproducible objective response rates are reported as approximately 40%. However, the median survival remains short, not exceeding 10 months. Amongst GA, a subset of tumours with increased plasma alpha-fetoprotein (alphaFP) and/or beta human chorionic gonadotrophin (betaHCG) levels form a well-defined histopathological entity. This subgroup has been associated with poor prognosis, due to the presence of poorly differentiated and rapidly proliferating cells. No specific chemotherapy has been proposed for this particular form of GA. We report two cases of patients with GA and hypersecretion of alphaFP and/or betaHCG. Despite bulky liver metastases and resistance to two standard chemotherapy regimens, both patients exhibited sensitivity to chemotherapy combining bleomycin, oxaliplatin and etoposide. These results suggest that patients with this particular subset of GA may benefit from chemotherapy regimens similar to those given to germ-cell tumour patients.

Primary non-Hodgkin's lymphomas of the liver with nodular and diffuse infiltration patterns have different prognoses.

BACKGROUND: Primary liver non-Hodgkin's lymphomas have peculiar clinical and biological patterns. This study correlates these patterns with pathology and outcome. PATIENTS AND METHODS: Clinical records and histology of patients with primary liver non-Hodgkin's lymphoma, treated at our institution over a 20-year period, were reviewed. Lymphoproliferations occurring after liver transplantation were excluded. Survival analyses were performed with patients from the other published series (62 patients). RESULTS: Our series included eight patients. Three patients had a nodular liver infiltration, corresponding to a large B-cell lymphoma. Five patients had a diffuse liver infiltration, of whom three had a T-cell lymphoma with predominant sinusoid infiltration, and two had a large B-cell lymphoma. Patients with diffuse liver infiltration presented with hepatomegaly, and two of these also had acute liver failure. Diffuse infiltration had a worse prognosis than nodular infiltration (P = 0.0033). Among these latter patients, those treated with an anthracycline-based chemotherapy had a better outcome (P < 0.0001). CONCLUSIONS: Patients with primary liver lymphomas can be classified in two groups, depending on the type of infiltration. Those with nodular infiltration may benefit from anthracycline-based chemotherapy. Diffuse infiltration has a bad prognosis, and should be suspected in patients presenting with altered liver functions and hepatomegaly.

Inflammatory arthropathy in MRL hematopoietic chimeras undergoing Fas mediated graft-versus-host syndrome.

OBJECTIVE: To determine whether overexpression of the Fas ligand (FasL) on activated lpr T lymphocytes could induce arthritic lesions when grafted into syngeneic wild-type MRL mice expressing normal Fas receptor levels. METHODS: Lethally irradiated MRL+/+ mice were reconstituted with congenic MRL/lpr bone marrow cells and splenocytes overexpressing FasL. Fas-mediated cytotoxic properties of repopulating lpr splenic lymphocytes were evaluated in vitro. Simultaneously, the hind paw ankles of the hematopoietic chimeras were histologically examined. RESULTS: The lpr lymphocytes repopulating the spleen overexpressed FasL and had in vitro Fas-mediated cytotoxic activity. Simultaneously, in vivo, articular (synovitis, pannus) and periarticular (periostitis) inflammation with bone resorption were observed. CONCLUSION: Arthritic lesions may be induced in Fas-expressing recipients by persistent engrafted syngeneic lymphocytes overexpressing FasL.

Histological, genomic and clinical heterogeneity of clear cell hepatocellular carcinoma.

AIMS: The aim of the study was to determine whether clear cell type hepatocellular carcinoma should still be regarded as a separate uniform diagnostic entity. METHODS AND RESULTS: We retrospectively studied 118 cirrhotic patients with hepatocellular carcinoma treated by orthotopic liver transplantation, and 31 noncirrhotic patients with hepatocellular carcinoma treated by either liver surgical resection or transplantation. The pathology of all liver resections was reviewed. Microsatellite instability was performed on paraffin-embedded samples at loci located on chromosomes 2p, 3p, 5q, 8q, 9p, 13q, 16q and 17p. Among the 118 cirrhotic patients, 10 (8.5%) had a clear cell hepatocellular carcinoma; these had clinical characteristics and prognosis similar to the other cirrhotic patients. No genetic alterations were detected in these tumours. Among the 31 noncirrhotic patients, one (3.2%) had a clear cell hepatocellular tumour. This 170-mm tumour had a lipid density on computed tomography, and its histology resembled chromophobe cell renal carcinoma. Furthermore, this tumour had unusual genomic alterations, with microsatellite instability in 6/8 chromosome loci. CONCLUSIONS: Clear cell hepatocellular carcinoma is a heterogeneous entity in which a chromophobe cell subtype should be identified.

Hepatocellular carcinoma with lymphoid stroma: a tumour with good prognosis after liver transplantation.

AIMS: Carcinomas with lymphoid stroma arising in non-liver-organs have a better prognosis than other carcinomas and may be associated with Epstein-Barr virus. We determined the frequency, characteristics and prognosis of hepatocellular carcinomas with lymphoid stroma. METHODS AND RESULTS: Histology of the livers of 162 patients with hepatocellular carcinoma, who underwent an orthotopic liver transplantation, was reviewed independently by three pathologists. Hepatocellular carcinoma with lymphoid stroma was diagnosed when all tumour samples contained more lymphocytes than tumour cells. Epstein-Barr virus was detected by in-situ hybridization and by polymerase chain reaction. Five patients (3.6%) were classified as hepatocellular carcinomas with lymphoid stroma. All patients were males. Cirrhosis was present in four/five patients. Serum alpha-fetoprotein levels were normal. Inter-observer histological reproducibility was good. Tumour cells did not contain Epstein-Barr virus. The five patients were alive without tumour at three years, although two of them had adverse prognostic factors at the time of transplantation (more than one tumour with a diameter > or = 40 mm). Only one patient had tumour recurrence, but he survived 7.6 years post-transplantation. The 5-year survival of patients with hepatocellular carcinoma with lymphoid stroma was better than that of the patients with other types of hepatocellular carcinomas (P = 0.04). CONCLUSIONS: Hepatocellular carcinoma with lymphoid stroma should be considered as a distinct clinicopathological and prognostic entity.

Influence of liver hepatitis C virus RNA and hepatitis C virus genotype on FAS-mediated apoptosis after liver transplantation for hepatitis C.

BACKGROUND: Recurrent hepatitis C virus (HCV) infection after liver transplantation is characterized by a high level of intrahepatic HCV replication and more severe liver damage in case of genotype 1b infection. We investigated the involvement of apoptosis in recurrent HCV liver disease, and its possible links with histological findings, HCV genotype, liver HCV RNA level, and liver Fas mRNA level. METHODS: We studied 61 liver graft biopsy specimens from 25 patients transplanted for HCV-related cirrhosis. DNA fragmentation was determined semi-quantitatively by in situ end labeling. HCV RNA and liver Fas mRNA were determined in parallel by quantitative polymerase chain reaction, with ribosomal 28S RNA as internal standard. RESULTS: Apoptotic lesions were predominantly portal (nonhepatocytic) or lobular (hepatocytic). Both were correlated with serum aminotransferase levels. The degree of portal apoptosis correlated with acute rejection (P<0.001), although lobular apoptosis was associated with lobular hepatitis (P<0.02), and HCV genotype 1b (P=0.04). In multivariate analysis, liver Fas mRNA level independently correlated with HCV-related chronic active hepatitis (P=0.04), age (P=0.01), and liver HCV RNA level (P=0.0007). CONCLUSIONS: After liver transplantation, 1) apoptosis is involved in HCV-related liver damage; 2) HCV type 1b may induce more severe apoptotic lesions than other genotypes; and 3) Fas transcription may be up-regulated by intrahepatic HCV replication.

[Evaluation of the effect of pathology slide review on clinical practice in an oncology center]. / Evaluation de l'influence de la relecture histologique sur la prise en charge médicale des patients traités dans un centre d'oncologie.

Our aim was to evaluate the clinical impact of pathology review in an oncology center, in which review is not performed for every patient. This retrospective study involved 100 consecutive patients, whose slides were reviewed in our center. A standardized data sheet was filled out by oncologists for each patient. Pathology review was considered as responsible for a major (35%), moderate (40%), or mild or no (25%) modification of clinical practice. Modification concerned either initial investigations, treatment or medical follow up, and was independent of the reason for which review was performed. Eleven patients underwent a second biopsy. Whatever the possible discrepancies between initial and review diagnosis, our results show that pathological review has a major influence on clinical practice in patients with cancer.

Free volatile components of passion fruit puree obtained by flash vacuum-expansion.

Purple passion fruits were processed by the flash vacuum-expansion process. Volatile components were analyzed in purees from steam-heated fruits, steam-heated then vacuum-expanded fruits and their aromatic liquors, and fruit rind, in comparison with a reference single-strength juice. After steam heating, the puree was enriched in esters arising from the rind. Steam-heated then vacuum-expanded fruits yielded a puree impoverished in volatiles due to evaporation of approximately 10% of water. These volatile compounds were mostly recovered in aromatic liquors.

Increased risk of antibody-mediated rejection of reduced-size liver allografts.

Because of the shortage of liver allografts in children, transplantation of reduced-size liver allografts from adult cadaveric donors or living, related donors is being done more frequently. Reduced-size liver allografts may be used in cases of ABO incompatibility and T-cell warm cross-match positivity. This experimental study in inbred rats was undertaken to determine if reduced-size liver allografts are more sensitive to antibody-mediated rejection than full-size liver allografts. Brown-Norway (BN) (RT1(n)) rats were sensitized by three successive skin grafts at 10-day intervals. Then orthotopic Lewis (LEW) (RT1(1)) liver grafts were transplanted into these BN rats. Full-size liver allografts were compared with reduced-size liver allografts (70% of donor liver). Control groups were composed of full-size and/or reduced-size isografts. Titers of specific antibodies were assayed using a complement-dependent assay before and after orthotopic liver transplantation. Histological and immunofluorescence studies (IgG, IgM, C(3), and fibrinogen deposits) were assessed. Recipients of reduced-size liver allografts died of hyperacute rejection at 36.6 +/- 4.1 h, significantly earlier than recipients receiving full-size liver allografts, which died of accelerated acute rejection at 259.2 +/- 25.2 h (P < 0.001). Either full-size or reduced-size isograft recipients survived indefinitely. A decrease in the titers of donor-specific antibodies was observed in both groups of animals. Slight deposits of IgG, IgM, C(3), and fibrinogen were observed in recipients of reduced-size liver allografts, whereas larger deposits were observed in recipients of full-size liver allografts. Our data demonstrate that there is an increased risk of antibody-mediated rejection of reduced-size liver allografts in sensitized recipients. This may have important clinical implications for partial liver grafting in cases of ABO incompatibility and T-cell warm cross-match positivity.

Long-term ganciclovir therapy for hepatitis B virus infection after liver transplantation.

BACKGROUND/AIMS: Hepatitis B virus (HBV) disease on a liver graft is associated with florid viral replication and graft failure. The aim of this study performed between 1992 and 1995 was to investigate the safety and efficacy of long-term intravenous ganciclovir for HBV infection in liver transplant recipients. METHODS: Twelve patients with HBV re-infection and four with de novo HBV infection were studied. HBV DNA was positive in all (median titer: 437.5 pg/ml) and HBeAg was positive in seven. Intravenous ganciclovir was started after a median of 14.5 months from HBsAg positivation and continued for a median of 10 months. RESULTS: A complete response with HBV DNA negativation was seen in ten cases, a partial response with a decrease of more than 50% of initial HBV DNA levels in four and no response in two. Overall tolerance was good. Among the ten complete responders, two seroconverted for both HBsAg and HBeAg and one for HBsAg alone. Among these ten patients, three were re-transplanted for liver failure: two of them are alive; three had a viral breakthrough during treatment; and four remained HBV DNA negative: two are alive and two died. Partial responders and nonresponders were treated with other antiviral agents and three were re-transplanted, two of them are alive. Overall 12 out of 16 patients (75%) survived with a median follow up of 46 months. CONCLUSIONS: Long-term intravenous ganciclovir can persistently inhibit HBV DNA replication in liver transplant recipients and is well tolerated. Further evaluation should be encouraged, especially for HBV recurrence after first-line treatments.

A case of disseminated histoplasmosis likely due to infection from a liver allograft.

Disseminated histoplasmosis in immunosuppressed patients rarely occurs in nonendemic areas. Reported here is a case of disseminated histoplasmosis in a patient who had undergone orthotopic liver transplantation and had never traveled outside of France. The infection was most likely transmitted via the liver allograft, since the organ donor had lived in an area highly endemic for the disease (French Guiana) 20 years earlier. Two years post-transplantation, none of the other patients who received allografts (heart, cornea, kidneys) from the same donor had developed signs of infection.

"Silent" presentation of veno-occlusive disease after liver transplantation as part of the process of cellular rejection with endothelial predilection.

Hemorrhagic centrilobular necrosis and fibrous stenosis of hepatic venules, suggesting veno-occlusive disease (VOD) have rarely been observed after orthotopic liver transplantation (OLT). The aim of this study was to determine the prevalence of this syndrome after OLT in relation to the course with particular reference to acute rejection and to azathioprine administration. VOD was identified in 19 of 1,023 patients transplanted over a 9-year period. VOD occurred at a median of 30 days posttransplantation, without clear cut clinical evidence for hepatic vein outlet obstruction. Seventeen of the 19 patients had an episode of acute rejection before or at the time of VOD. These episodes were compared with that of patients without VOD. In patients with VOD, portal inflammation and endothelialitis were enhanced (P =.014 and P =.048) and endothelialitis was also higher than bile duct damage (P =.03). The incidence of a centrilobular endothelialitis for both groups was not different although an increased trend was observed in the study group (64% vs. 46%; P =.18). The incidence of persistent rejection was similar between both groups (47% vs. 41%). The incidence of chronic rejection was higher in the study group (29% vs. 10%; P =. 04). All patients with VOD received azathioprine as part of immunosuppressive regimen. Despite azathioprine withdrawal, zone 3 changes persisted in 57% of patients. In conclusion, the incidence of VOD was 1.9% after OLT. The association of prominent endothelial involvement and VOD with acute rejection in most cases suggests an immunological phenomenon.

Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery.

CONTEXT: Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy. OBJECTIVE: We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible. PATIENTS AND METHODS: From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (> 5 cm), multinodular (> 4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team. RESULTS: In 151 patients, the size of liver metastases decreased by > 50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19-28 months), with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61). CONCLUSION: This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.