Kay Kohlhaw

Photodynamic therapy in patients with non-resectable hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study

BACKGROUND Median survival of patients with non-resectable hilar cholangiocarcinoma is 3 to 6 months, even after biliary drainage. Therefore, a single-arm phase II study was conducted (July 1996 to October 1998) to investigate the effect of local photodynamic therapy; a significant improvement in survival (74%) was noted at 6 months. The present study is an analysis of the long-term follow-up for patients enrolled in that phase II study. METHODS Five-year follow-up data for the 23 patients enrolled in the original prospective study were analyzed by using Kaplan-Meier log-rank analysis. RESULTS Median survival after treatment was 11.2 months for patients without distant metastases (M0) and 9.3 months for all patients (M0+M1). The 1-year, 2-year, 3-year, and 4-year survival rates were estimated to be 47%, 21%, 11% and 5%, respectively, for patients with stage M0 cholangiocarcinoma, and 39%, 17%, 9%, and 4%, respectively, for patients with stages M0 and M1. Of the patients who died, 73.9% (n=17) were because of tumor progression; 26.1% (n=6) died as a result of cholangitis (n=4), septic shock (n=1), or appendicitis/peritonitis (n=1). For all patients, except one with diffuse liver metastases, there was improvement in cholestasis, performance, and quality of life, which was maintained for an extended period. CONCLUSIONS This 5-year follow-up study confirms that photodynamic therapy is safe and effective for non-resectable hilar cholangiocarcinoma, although it does not prevent progression of the disease.

Expression of the p53 homologues p63 and p73 in multiple simultaneous gastric cancer

The tumour‐suppressor protein p53 has recently been shown to belong to a family that includes two structurally related proteins, p63 and p73. This study investigated the status of p53 and its two homologues in multiple simultaneous gastric carcinomas. Expression and mutation of p53, p73 and p63 including the two major isotypes TAp63 and ▴Np63, were examined by direct DNA‐sequencing, in situ hybridization, western blotting and immunohistochemistry in 68 gastric carcinomas of 32 patients. The results obtained were correlated with pathohistological stage (according to UICC16) and several other histopathological factors and finally with patient survival. p53 mutations were detected in 23/68 carcinomas (34%) from 18 patients with a discordant mutation pattern. Independently of p53 mutation status, p73 transcripts and protein expression were found in 33/68 carcinomas from 24 patients. p63 positivity was found in 21 patients; 25 out of 68 tumours expressed p63. The number of cells containing p63 and their distribution depend on the degree of tumour differentiation. High grade carcinomas of the diffuse type exhibited a significantly higher p63 expression. In intestinal metaplasia and atrophic gastritis, an increase of TAp63 and ▴Np63 staining was also observed. Specific mutations of p73 or p63 causing amino acid substitutions were not identified. Neither p53, p73 nor p63 were related to prognosis. p73 and p63 have rarely been found to be mutated in gastric carcinomas, but both proteins were expressed in only a subset of tumours. The status of these p53 homologues was discordant in all patients with multiple simultaneous gastric carcinomas. The increased expression of p63 (TAp63 and ▴Np63) in less well differentiated gastric carcinomas may indicate that p63 can act to promote neoplastic growth in the gastric epithelium. Copyright

Apoptosis and the expression of Fas and Fas ligand (FasL) antigen in rejection and reinfection in liver allograft specimens.

BACKGROUND AND METHODS To investigate the frequency of apoptosis and the expression of Fas/Fas ligand (FasL) in liver allografts, we examined 97 biopsy specimens from 62 patients after orthotopic liver transplantation. The results of the biopsies were as follows: acute allograft rejection (n=32); hepatitis C virus (HCV) reinfection (n=18); cytomegalovirus infection (n=5); acute rejection plus HCV reinfection (n=3); and stable graft function (n=30); and after treatment of acute rejection (n=9). RESULTS Apoptotic cells were found in all cases examined, and their frequency increased significantly during acute rejection (0.17 vs. 9.0; P<0.05). The immunoreactivity of Fas and FasL antigen was higher in specimens with acute rejection than in those with stable graft function. Increased apoptosis, Fas, and FasL expression, however, were also seen in HCV reinfection. CONCLUSION We conclude that apoptosis plays an important role in the hepatocellular damage observed in acute rejection and also in HCV reinfection. However, these parameters are, taken by themselves, not useful as indicators of acute rejection or HCV reinfection.

Induction therapy including antithymocyte globulin induces marked alterations in T lymphocyte subpopulations after liver transplantation: results of a long-term study

Abstract.Various immunosuppressive regimens aim to reduce the incidence of acute rejection after liver transplantation. The efficacy of antithymocyte globulin (ATG) induction therapy and short-term effects on the cellular response have been demonstrated in several studies. Nevertheless, information about long-term effects of ATG therapy on cellular responses and frequency of complications is limited. Therefore, we analyzed the effect of ATG administration within a cyclosporine-based induction therapy, including azathioprine and prednisolone, on lymphocyte subsets and activation markers. We divided 35 liver transplant recipients into two groups according to their initial postoperative immunosuppression: a triple group without (n=15) and a quadruple group with ATG (n=20). The minimum observation time (flow cytometry analysis, clinical follow-up) was 2 years. Patients treated with ATG had persistently lower percentages of T cells for at least 2 years postoperatively (P<0.001). The CD4/CD8 ratios were lower in the quadruple group (P<0.005). The patients in the ATG group revealed a drop in CD25+ T cells within 2 years (P<0.05). However, the percentage of CD71+ and HLA-DR+ T cells was temporarily higher in patients with ATG treatment (P<0.05). Patients with ATG treatment showed persistently higher levels of CD8+/CD57+ double positive cells in the late postoperative phase (P<0.05). In contrast, no differences could be observed between the two groups for major parameters of clinical outcome (acute rejections, severe infections, patient survival). We conclude that ATG therapy induces long-lasting alterations in T-cell subset composition. However, no beneficial clinical effect could be confirmed after liver transplantation.

Percutaneous liver core biopsy in rats: an alternative to minilaparotomy

Summary Sampling of rat hepatic tissue for histomorphological analysis is usually performed in two different ways: either by killing the animals or by minilaparotomy. In this study we describe a percutaneous core biopsy technique which has been used on day 7, 14 and 21 after allogeneic rat liver transplantation (DA → LEW) in order to examine grafts for rejection in different treatment groups. Fifty-two liver biopsies were performed in 24 animals using a 16-gauge intravenous cannula. Forty-five provided usable specimens which were sufficient for both light or electron microscopy and immunohistochemical analyses to determine the degree of graft rejection. In 7 cases (13.5%) sampling was unsuccessful, especially on day 21 after transplantation, as the plastic cannula could not penetrate the hardened tissue. In 3 animals (5.8%) puncture was immediately followed by death due to perforation of the diaphragm or ether intoxication. In conclusion, this technique is a reliable method for providing ample tissue samples from the rat liver with a low risk of complications.

Chirurgische Therapie der Folgen der chronischen Pankreatitis

Ziele der chirurgischen Therapie bei der chronischen Pankreatitis (CP) sind die Verhinderung von Komplikationen, der Erhalt der exokrinen und endokrinen Funktion sowie Schmerzfreiheit. Von 1993–1997 wurden 54 Patienten mit CP operiert: OP nach Kausch-Whipple (KW, n = 19), duodenumerhaltende Pankreaskopfresektion (DP, n = 8), Zystojejunostomie (n=13), Pankreaslinksresektion (n = 4) u.a. (n = 4). Therapierefraktare Schmerzen (n =17), Choledochusstenose (n = 16), Karzinomverdacht (n = 9), Duodenalstenose (n = 3) sowie Pseudozysten mit Komplikationen (n = 7) stellten die OP-Indikation dar. Die OP-Letalitat war 0%. Sechsmal wurden postoperative Komplikationen mit Notwendigkeit zur Relaparotomie beobachtet. Ein gastrointestinaler Lebensqualitatsindex ergab die besten Ergebnisse nach KW und DP, ohne signifikante Unterschiede. Die Art der OP richtet sich nach der Morphologie, wobei die DP als organerhaltender Eingriff gegenuber der KW bevorzugt werden sollte.