Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes.

BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.

Is a proliferation index of cancer cells a reliable prognostic factor after hepatectomy in patients with colorectal liver metastases?

BACKGROUND: In spite of many reports focusing on prognostic factors after hepatectomy in patients with colorectal liver metastases, few studies have investigated pathological factors, eg, fibrous pseudocapsulation, growth pattern at the tumor margin, and proliferation activity of cancer cells, other than histological type and surgical margin. The aim of the present study was to investigate whether absence of pseudocapsulation, infiltrative growth pattern of metastases, and higher proliferation of cancer cells shown by Ki-67 immunohistochemical reactivity were associated with poorer survival after hepatectomy among patients with colorectal liver metastases. METHODS: Between 1988 and 1998, 221 patients underwent hepatic resection of colorectal metastases with curative intent in our institution. Pathology analyses were focused on pseudocapsulation of liver metastases, growth pattern at the tumor edge, and Ki-67 labelling index (Ki-67 LI) of cancer cell nuclei. Univariate analyses of survival and of disease-free survival were performed for several clinicopathological factors, and multivariate analyses of survival and disease-free survival were also performed. RESULTS: The univariate survival analyses showed that pseudocapsulation, growth pattern, and Ki-67 LI were significant prognostic factors, besides synchronous versus metachronous occurrence of metastases, carcinoembryonic antigen level before hepatectomy, and number of metastases. A multivariate analysis showed that Ki-67 labeling index was the most reliable prognostic factor of survival. In addition, Ki-67 LI and microscopic growth pattern were multivariately predictive factors of disease-free survival. CONCLUSIONS: This large single-institution study showed that investigation of cancer cell proliferation and pathologic characteristics of the tumor margin are major prognostic factors.

Comparative evaluation of Celsior solution versus Viaspan in a pig liver transplantation model.

BACKGROUND: In a pig liver transplantation model, we compared the effects of Celsior solution (CS), an extracellular preservation solution, with Viaspan (University of Wisconsin solution, UW) on graft function and animal survival. METHODS: Pig livers were flushed with either CS or UW solution and cold-stored for 12 hr (group 1) or for 8 to 10 hr (group 2). Grafts were transplanted orthotopically. Intrahepatic reduced and oxidized glutathione and adenine nucleotides were evaluated 1 hr after reperfusion. Liver function of transplanted animals was monitored for up to 6 days by serum transaminases, total bilirubin, purine nucleoside phosphorylase, and prothrombin levels. RESULTS: In group 1, all animals died within 24 hr after reperfusion regardless of the preservation solution used. In group 2, no significant difference was seen in survival between the CS (72%) and the UW (67%) groups 6 days after transplantation, and there were no statistically significant differences in the biochemical data. There were no differences in histological evaluation of the livers at the time of death or killing of the animals between the CS and UW groups. CONCLUSION: Within the limits of this pilot study, CS is equivalent to UW in terms of graft function and animal survival.

Engraftment and albumin production of intrasplenically transplanted rat hepatocytes (Sprague-Dawley), freshly isolated versus cryopreserved, into Nagase analbuminemic rats (NAR).

Banking of cryopreserved hepatocytes is a prerequisite for large-scale hepatocyte transplantation in the clinic. We compared the efficacy of intrasplenic transplantation into Nagase analbuminemic rats (NAR) of freshly isolated (FIH) and cryopreserved (CH) hepatocytes. Hepatocytes were cryopreserved using a controlled rate freezing protocol. Albumin production of thawed CH and FIH was measured in vitro in culture by ELISA and by Western blot. After in vivo intrasplenic transplantation of NAR with either FIH or CH we assessed 1) albumin in the serum of recipients by ELISA and by Western blotting analysis at different time intervals, and 2) hepatocyte engraftment by albumin immunohistochemical staining into spleens and livers at euthanasia. In vitro, albumin was produced up to day 4 of culture in both CH and FIH. In vivo, no intrasplenic engraftment of hepatocytes occurred. Intrahepatic engraftment of CH (cell number/mm2) was significantly (twofold) lower than that of FIH and appeared only as isolated cells and small (<10 cells) clusters, while bigger clusters (>10 cells) were observed with FIH. In the FIH group, serum albumin production was observed up to 32-49 days posttransplantation while in the CH group no serum albumin production was detected. Our results emphasize the need to improve 1) hepatocyte transplantation procedures either by repeated hepatocytes injections and/or by transplantation under a regeneration response, and 2) the freeze/thaw protocols of hepatocytes.

Removal of primate xenoreactive natural antibodies by extracorporeal perfusion of pig kidneys and livers.

Organ perfusion is one of the possible strategies to attenuate rejection of discordant xenografts by reducing the levels of the recipient's xenoreactive natural antibodies (XNA). Its efficacy in terms of XNA removal was studied in models of primate blood or plasma perfusion through porcine kidneys or livers, with special attention to haematological consequences and potential side-effects. We first perfused the blood of rhesus monkeys through pig kidneys and livers, and demonstrated that the perfusion of a pig liver resulted in higher XNA adsorption (72 +/- 13%) than the perfusion of a pig kidney (51 +/- 25%). However, when we normalized for the weight of the perfused organs and for levels of natural antibodies in individual monkeys, livers adsorbed less antibody (1.4 +/- 0.9 U antibody/g) than kidneys (7.2 +/- 7 U antibody/g). Histological signs of rejection were observed in perfused kidneys, but not in perfused livers. A major drawback of the perfusion of blood through livers was a considerable decrease in the primates' haemoglobin and platelet levels. To avoid this, we developed a plasma liver perfusion device. This method allowed a significant improvement in the haemodynamic state of primates and was particularly effective in preventing anaemia. Moreover, plasma liver perfusion was as effective as blood liver perfusion to remove natural antibodies and, resulted in a marked decrease in their functional activity as assessed by complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). The level of other plasma proteins was not significantly affected, apart from a dilution effect. After xenoperfusion a strong antibody response was evidenced by ELISA, CDC and ADCC between days 7 and 14 and then decreased progressively. We conclude that the separation of blood to allow the perfusion of plasma through a pig organ is safer than the perfusion of unseparated blood and is associated with efficient natural antibody removal. However, organ perfusion is limited by a rebound in antibody levels after a few days, and thus will have to be associated with anti-B cell immunosuppressive therapy for long-term or repeated applications.

[Immunohistochemistry in the differential diagnosis of mesothelioma and adenocarcinoma. Evaluation of 5 new antibodies and 6 traditional antibodies]. / L'immunohistochimie dans le diagnostic différentiel entre mésothéliome et adénocarcinome. Evaluation de 5 nouveaux anticorps et réévaluation de 6 anticorps traditionnels.

The aim of this study was to evaluate three recently marketed putative mesothelioma-binding antibodies, calretinin, HBME-1 and thrombomodulin, and two putative adenocarcinoma-binding antibodies, AUA1 and MOC31, on paraffin sections from 28 mesotheliomas and 30 adenocarcinomas. Moreover, the expression of ACE, BerEP4, CA125, CA19.9, LeuM1 and vimentin was assessed. Calretinin, HBME-1 and thrombomodulin, which showed a 100%, 89% and 43% sensitivity, and a 50%, 70% and 87% specificity for mesothelioma respectively, were less efficient than vimentin (100% specificity and 67% sensitivity) for the positive identification of mesothelioma. AUA1, BerEP4 and MOC31 were 100% sensitive to adenocarcinoma, with BerEP4 and MOC31 having the highest specificity (86% each). The immunophenotype "vimentin-positive, ACE-negative, CA19.9-negative" yielded 100% sensitivity and 97% specificity for diagnosis of mesothelioma. We advocate the use of the four-marker panel of ACE, CA19.9, MOC31 (or BerEP4) and vimentin for differentiating mesothelioma from adenocarcinoma.

Auxiliary liver transplantation: regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure--a multicenter European study.

Auxiliary liver transplantation (LT) is a special procedure of LT which could be proposed to patients with fulminant hepatic failure (FHF) and has for aim that complete regeneration of the native liver (NL) left in place will allow the graft recipient to resume normal liver function after allograft withdrawal. We report 30 cases of auxiliary LT performed for FHF in 12 European centers. Twenty-five of 30 patients were younger than 50 years. The cause of FHF was hepatitis A virus (HAV) in 4 patients, hepatitis B virus (HBV) in 7, paracetamol overdose in 5, ecstasy in 2, hepatotoxic drugs in 4, autoimmune hepatitis in 2, liver lesions of preeclampsia in 1 and unknown in 5. A postoperative, both clinical and histological follow-up of more than 3 weeks was obtained in 22 patients, enabling us to look for indicators predictive of NL regeneration and outcome. Histological changes observed in the NL included complete regeneration in 68%, incomplete regeneration with obvious fibrous sequelae in 14% and severe liver fibrosis or cirrhosis in 18%, of the 22 patients studied. The percentage and distribution of necrosis observed in tissue samples of the NL at the time of transplantation was not related to the final outcome. Complete NL regeneration was observed in 15 patients, out of whom 14 were younger than 40 years. Patients with complete regeneration were mainly affected by FHF due to HAV, HBV, or paracetamol overdose. After a follow-up of 18/11 (mean/median) months (range, 3 to 67 months), 19 of the 30 patients (63%) survived and 13 of them (68%), i.e., 43% of the 30 patients, had resumed normal NL function, with interrupted immunosuppression, the ultimate goal of emergency auxiliary LT. We conclude that, in patients with FHF, auxiliary LT is a procedure feasible in a number of centers and is associated with a complete regeneration capability of the NL in a majority of survivors, especially in those younger than 40 years. Confirmation of these encouraging preliminary results by large-scale prospective studies is required.

Auxiliary liver transplantation for fulminant and subfulminant hepatic failure.

We report the first series of 9 auxiliary liver transplantations performed as a bridge to recovery in 8 patients with fulminant and subfulminant hepatic failure. Hepatic failure was due to hepatitis A virus (n = 3), hepatitis B virus (n = 1), hepatotoxic drugs (n = 2), autoimmune disease (n = 1), or it was of unknown origin (n = 1). The donor liver was reduced to a left lobe (n = 2), a left liver (n = 4), or a right liver (n = 3), and was implanted in an orthotopic position beside the native liver after it was resected by a left or a right hepatectomy. Conventional immunosuppression was used to prevent rejection. Six patients regained normal consciousness within 2 weeks, without any sequelae. Two patients had persisting encephalopathy due to graft initial dysfunction, one of whom showed portal vein thrombosis, which was successfully cleared. The other one showed hepatic vein stenosis and was retransplanted at day 15. Five of eight patients had to be reoperated because of a surgical complication. Five patients showed rapid regeneration of their native liver, but one died at day 45 from severe herpes virus broncholitis. The auxiliary grafts were removed (n = 3) or left to atrophy by tapering immunosuppression (n = 1). One patient developed cirrhosis of the native liver and died of infectious complications at day 42. The native livers of the two remaining patients are still atrophic, one at 4 months and one at 1 month posttransplant. Finally, 6 of 8 patients are alive with a follow-up of 1 to 17 months. Four of them have permanently stopped their immunosuppressive therapy. Our experience demonstrates that auxiliary orthotopic liver transplantation (1) is feasible in children and adults, using either a left or a right liver graft, (2) is efficient in providing adequate liver function, and (3) gives a real chance to the native liver to regenerate, offering these patients a future free of immunosuppression.

Production and characterization of monoclonal antibodies recognising defined regions of the human oestrogen receptor.

Mouse monoclonal antibodies were raised against the N-terminal (amino acids 151-165) and the very C-terminal (amino acids 578-595) regions of the human oestrogen receptor (hER). These antibodies recognise the hER by enzyme-linked immunosorbent assay, immunocytochemistry, immunoblotting, immunoprecipitation and gel retardation assays. The presence of hER is used prognostically in human breast cancer. We have tested the reactivity of our monoclonal antibodies on breast cancer sections, comparing with the commonly used Abbott rat monoclonal antibody H222. These studies show that the two monoclonal antibodies described here are highly versatile and will be useful tools for in vivo and in vitro studies of hER function. Furthermore, we show that the corresponding epitopes can be used as molecular "tags" for heterologous proteins and offer a powerful means of purifying and/or characterizing over-produced fusion proteins containing these regions.

[En bloc transplantation of liver, stomach, pancreas and small intestine in an infant. Apropos of a case]. / Transplantation en bloc du foie, de l'estomac, du pancréas et de l'intestin grêle chez un tout-petit. A propos d'un cas.

The now common practice of joint kidney and pancreas or heart or lung transplantation is being completed by other combinations. This is shown by our case of en bloc liver-pancreas-stomach-duodenum-small bowel transplantation in an 18-month-old infant with small bowen atresia complicated by biliary cirrhosis secondary to total parenteral feeding, after the failure of an intraperitoneal visceral transplant at 1 year of age. The graft was taken from an 8-year-old donor and was not pretreated. Being made of the whole intraperitoneal visceral mass, it had to be adapted to the recipient's size by ex vivo exeresis of the right liver, of the spleen, of the terminal ileon and of the colon. Following intraperitoneal visceral exenteration in the recipient, the graft was inserted in an orthoptic position with a digestive reconstruction by esogastric anastomosis and terminal ileostomy. Immunosuppression combined steroids, azathioprine, ciclosporine, and the biological and immunological follow-up regarded the hepatic and pancreatic functions. The intestinal graft was controlled by repeated biopsies through the stomy. Rectal biopsies and lymphocyte typing in the peripheral blood allowed watching for the occurrence of a possible graft-versus-host disease. The outcome was marked by the persistence of massive lymphorrhea during three months and severe central neurological disorders caused by the difficulties to adapt the level of ciclosporine. The hepatic and pancreatic functions became normal within a few days, and the intestinal function allowed progressively suppressing parenteral feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

[Malignant mesothelioma of the pleura. Analysis of its immunohistochemical aspects]. / Mésothéliomes malins de la plèvre. Analyse de leurs aspects immunohistochimiques.

To evaluate the usefulness of immunohistochemistry in the diagnostic distinction between pleural mesothelioma and metastatic adenocarcinoma to the pleura, the authors studied formalin-fixed paraffin-embedded tissue sections from 14 pleural mesotheliomas and 20 primary adenocarcinomas of the lung, stomach, ovary and breast by using 16 commercially available antibodies to cytokeratin (KL1), vimentin, EMA, CEA, CA19.9, CA125, Egp 34 (detected by HEA 125), secretory component, S100 protein, SP1-béta 1, Leu M1, alpha-1-AT, alpha-1-ACT, lysozyme, desmin and factor VIII. Keratin positivity was found in all mesotheliomas and adenocarcinomas. A coexpression of keratin and vimentin was present in 8/14 (57%) mesotheliomas but only in 2/20 (10%) adenocarcinomas. CEA and CA 19.9 were detected in 80% and 65% of the adenocarcinomas respectively, but not in any of the mesotheliomas. Interestingly, two adenocarcinomas (of the ovary and the stomach) that failed to stain for CEA, were immunoreactive to anti-CA 19.9 antibody. Thus, the combined use of anti-CEA and anti-CA 19.9 antibodies results in staining 90% of the adenocarcinomas. S100 protein, SP1-beta and Leu M1 were also absent in mesotheliomas but present only in less than half of the adenocarcinomas. Adenocarcinomas and mesotheliomas did not significantly vary in reaction to the remaining above mentioned antibodies. The authors conclude that the coexpression of keratin and vimentin and the absence of CEA and CA 19.9 might be the best criteria in the distinction of mesothelioma from metastatic non mucosecreting adenocarcinoma.

[Malignant peritoneal mesothelioma in a child. Diagnostic difficulties in a locally "non tumoral" form, revealed by cervical lymph node metastasis]. / Mésothéliome malin péritonéal chez un enfant. Difficultés diagnostiques devant une forme localement "non tumorale", à présentation métastatique ganglionnaire cervicale.

We report the unusual case-history of a ten-year-old girl who presented with enlarged cervical and supraclavicular lymph nodes apparently due to sinus histiocytosis upon initial histological evaluation. However, they were shown to be nodal metastases from an epithelial form of malignant mesothelioma coexpressing keratin, vimentin, and desmin. Exploratory laparotomy disclosed a diffuse "non tumoral" peritoneal mesothelioma. The neoplastic cells were so highly differentiated that analysis of peritoneal fluid pointed to reactive mesothelial hyperplasia. Intensive combination chemotherapy failed to achieve complete remission, but the child's condition was satisfactory after two and a half years follow-up. On the basis of data from the literature, we review the course, immunohistochemical features, and differential diagnosis of malignant peritoneal mesothelioma.