Michael Neipp

Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation

PURPOSE Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.

Indications for and outcomes after combined lung and liver transplantation: a single-center experience on 13 consecutive cases.

Background. Combined lung and liver transplantation (Lu-LTx) is a therapeutic option for selected patients with coexisting lung and liver disease. For several reasons, Lu-LTx is performed in few centers and information about the technical issues, posttransplant management and long-term outcomes associated with this procedure is limited. Methods. We analyzed data from 13 consecutive patients who underwent combined Lu-LTx at Hannover Medical School (Hannover, Germany) between April 1999 and December 2003. The main indications were cystic fibrosis, &agr;1-proteinase inhibitor deficiency and portopulmonary hypertension. All patients had advanced cirrhosis and severe pulmonary disease manifestation. Results. Ten patients received a sequential double Lu-LTx, one patient received a single Lu-LTx, one received a double lung and split liver transplantation, and one received an en-bloc heart-lung and liver translantation. Immunosuppression was based on cyclosporine in a triple/quadruple regimen. Postoperative surgical complications occurred in eight patients. There were two perioperative deaths; two patients died during the first year on day 67 and 354, respectively, and one patient died at month 53. The overall patient survival rates at 1, 3, and 5 years were 69%, 62%, and 49%, respectively. Conclusion. Combined Lu-LTx is a therapeutic option for highly selected patients with end-stage lung and liver disease with acceptable long-term outcome.

Management of major postsurgical gastroesophageal intrathoracic leaks with an endoscopic vacuum-assisted closure system

BACKGROUND Endoscopic treatment options for postsurgical intrathoracic leaks include injection of fibrin glue, clip application, and stent placement. Endoscopic vacuum-assisted closure (E-VAC) may be an effective treatment option. OBJECTIVE To demonstrate that E-VAC is an effective endoscopic treatment option for closure of major intrathoracic postsurgical leaks. DESIGN AND SETTING A prospective, single-center study at an academic medical center. PATIENTS Eight consecutive patients with major intrathoracic postsurgical leaks. INTERVENTIONS Endoscopic placement of transnasal draining tubes, armed with a size-adjusted sponge at their distal end, in the necrotic anastomotic cavities, followed by continuous suction. Sponge and drainage were changed twice weekly. Patients were followed-up for 193 +/- 137 days. MAIN OUTCOME MEASUREMENT Successful leak closure. RESULTS Successful closure of leaks was achieved in 7 of 8 patients (88%) after a mean of 23 +/- 8 days. A median of 7 endoscopic interventions was necessary. No major treatment-associated short-term or long-term (follow-up, 193 +/- 137 days) complications were noted. LIMITATIONS Small sample size, single-center study, and lack of randomization. CONCLUSION E-VAC is an effective endoscopic treatment modality for major postsurgical intrathoracic leaks. (This study is registered at Clinicaltrials.gov, identifier NCT00876551.).

Liver regeneration in a retrorsine/CCl4 – induced acute liver failure model: do bone marrow-derived cells contribute?

BACKGROUND/AIMS Adult bone marrow contains progenitors capable of generating hepatocytes. Here a new liver failure model is introduced to assess whether bone marrow-derived progeny contribute to liver regeneration after acute hepatotoxic liver failure. METHODS Retrorsine was used to inhibit endogenous hepatocyte proliferation, before inducing acute liver failure by carbon tetrachloride. Bone marrow chimeras were generated before inducing liver failure to trace bone marrow-derived cells. Therefore, CD45 and major histocompatibility complex (MHC) class I dimorphic rat models were applied. RESULTS Early after acute liver failure a multilineage inflammatory infiltrate was observed, mainly consisting of granulocytes. In long-term experiments small numbers of CD90+/CD45- cells of donor origin occurred in clusters associated with portal triads. Bone marrow cell infusion was not able to enhance liver regeneration. Cellular hypertrophy was the predominant way of liver mass regeneration in models applying retrorsine. CONCLUSIONS Retrorsine pretreatment did not affect sensitivity for carbon tetrachloride. A multilineage inflammatory infiltrate was observed in rats whether pretreated with retrorsine or not. Few donor cells co-expressing CD90 (THY 1) were present in recipient livers, which may resemble donor-derived hematopoietic progenitors or oval cells. No other donor cells within liver parenchyma were detected. This is in contrast to other cell infusion models of acute cell death.

Paediatric kidney transplantation in small children – a single centre experience

Kidney transplantation (KTx) remains a challenging procedure in small children. This study presents our centre results. From 1983 to 2004, 40 of 442 paediatric KTx were performed in children with a body weight <11 kg. Median body weight was 9.2 kg (range: 7.2–10.9), median age was 2.7 years (range: 0.9–5.9). Preoperative dialysis was performed in 87.5%. In 24 cases (60%) grafts came from cadaveric (CAD) and in 16 cases (40%) from living related donors (LRD). Median donor age of CAD was 8 years (range: 1–40). The overall 1‐, 5‐, 10‐, 15‐year patient survival was 93%, 90%, 90% and 87% respectively. The overall 1‐, 5‐, 10‐, 15‐year graft survival was 90%, 80%, 66% and 56% respectively. There was no significant difference in survival of CAD or LRD grafts. Median follow‐up was 13.7 years. Initial graft function rate was 100% for LRD and 79% for CAD. The relative glomerular filtration rate (GFR) showed no statistical difference between CAD and LRD. Main reasons for graft loss were chronic transplant nephropathy. Paediatric KTx is the treatment of choice even in very small children. Living donor KTx is the preferable donor source in terms of primary graft function and timing to transplantation.

A partial conditioning approach to achieve mixed chimerism in the rat : Depletion of host natural killer cells significantly reduces the amount of total body irradiation required for engraftment

BACKGROUND Mixed allogeneic bone marrow chimerism induces tolerance to solid organ grafts. Although we previously reported that partially ablative conditioning with 700 cGy of total body irradiation (TBI) is sufficient to allow for bone marrow engraftment in mice, we determined that a minimum of 1000 cGy was required in the rat. Because T cells and NK cells are critical in bone marrow graft rejection, our purpose was to examine whether targeting of radioresistant NK cells and/or T cells in the recipient hematopoietic microenvironment would reduce the TBI dose required for engraftment of allogeneic rat bone marrow. METHODS Wistar Furth rats received either anti-NK3.2.3 monoclonal antibodies on days -3 and -2, anti-lymphocyte serum on day -5, a combination of both or no pretreatment. TBI was performed on day 0 and rats were reconstituted with 100x10(6) T cell-depleted bone marrow cells from ACI donors. RESULTS Engraftment of T cell-depleted rat bone marrow was readily achieved in animals conditioned with 1000 cGy TBI alone (12/12) and the level of donor chimerism averaged 89%. At 900 cGy TBI alone only one of eight recipients engrafted. In striking contrast, 11 of 12 animals pretreated with anti-NK monoclonal antibodies and irradiated with 900 cGy showed donor chimerism at a mean level of 41%. No further enhancement of bone marrow engraftment could be achieved when recipients were pretreated with antilymphocyte serum alone or antilymphocyte serum plus anti-NK monoclonal antibodies. Mixed allogeneic chimeras exhibited stable multilineage chimerism and donor-specific tolerance to subsequent cardiac allografts. CONCLUSION Specific targeting of radioresistant host NK cells allows for a significant reduction of the TBI dose required for allogeneic bone marrow engraftment.

Persistence of Occult Hepatitis B after Removal of the Hepatitis B Virus—Infected Liver

Occult hepatitis B is defined as the persistence of hepatitis B virus (HBV) DNA in persons without HBV surface antigen (HBsAg). The primary site for HBV persistence in persons with occult hepatitis B is considered to be the liver. We provide virological and immunological evidence for long-term persistence of HBV, even after removal of the infected liver, in 25 consecutive, randomly selected liver transplant recipients who tested positive for anti-HBV core antigen (anti-HBcAg) and negative for HBsAg at the time of transplantation. Furthermore, in a cohort of 101 anti-HBcAg-positive/HBsAg-negative patients, 2 showed clinical HBV reactivation after transplantation. Thus, these data indicate that a long-term extrahepatic HBV reservoir exists, which is relevant not only for liver transplantation but also for other types of transplantations, including bone marrow grafting.

Quality of life following living donor nephrectomy comparing classical flank incision and anterior vertical mini-incision

In this study we focused on the quality of life and satisfaction of living kidney donors comparing traditional lumbar (LDN) and mini-incision donor nephrectomy (MIDN). From May 1996 to December 2002, 174 donor nephrectomies including 127 cases of LDN and 47 cases of MIDN were performed. Donors were evaluated using the SF-36 quality-of-life survey as well as a questionnaire dealing with donors‘ attitude towards kidney donation, financial burdens, pain, cosmetic satisfaction and duration of sick leave. Our donors achieved comparable or even higher scores in all the SF-36 categories in comparison to the general US population. Following MIDN, quality of life tended to be superior compared to that of LDN donors; however, statistical significance was reached only in one of the eight categories. Duration of sick leave following surgery was in favor of MIDN compared to LDN donors. Statistically significant differences favoring MIDN were observed regarding postoperative hospital stay and cosmetic satisfaction. The procedure would be again undergone by 94 of LDN and 97% of MIDN donors. Open-donor nephrectomy is a safe and cost-effective procedure. Introduction of the here-described MIDN has led to comparable or even improved results compared to LDN.

Accidental transplantation of a kidney with a cystic renal cell carcinoma following living donation: management and 1 yr follow-up

Abstract: Transmission of cancer is a fatal risk in organ transplantation. We present a case of incidental renal carcinoma in a kidney obtained from a living donor. A 56‐yr‐old father was evaluated for donation for his 28‐yr‐old daughter. An MRT scan revealed two cysts in the right kidney. Right‐sided donor nephrectomy and subsequent transplantation was performed. The wall of the prominent cyst was partially excised prior to transplantation. Histology revealed a high‐grade renal clear cell carcinoma 10 d after transplantation. Following careful evaluation the recipient underwent partial nephrectomy. Immunosuppression was switched to rapamune. The graft function remained stable. Donor and recipient are without evidence of tumor recurrence 1 yr after transplantation. Our policy to obtain the kidney presenting anatomical variations proved to be beneficial for the donor. In case of transmission of cancer partial resection preserving graft function might be justified.

A nonlethal conditioning approach to achieve engraftment of xenogeneic rat bone marrow in mice and to induce donor-specific tolerance1

BACKGROUND The supply of solid organs for transplantation will never meet the growing demand. Xenotransplantation is considered to be a potential solution for the critical shortage of allografts. However, xenograft rejection is currently not controlled by conventional immunosuppressive agents. Bone marrow chimerism induces donor-specific tolerance without the requirement for chronic immunosuppressive therapy. The aim of this study was to develop a nonlethal recipient-conditioning approach to achieve mixed bone marrow chimerism and donor-specific tolerance. METHODS C57BL/10SnJ mice were conditioned with total body irradiation followed by a single injection of cyclophosphamide on day +2. On day 0, mice were reconstituted with untreated bone marrow cells from Fischer 344 rats. Recipients were analyzed by flow cytometry for donor bone marrow engraftment and multilineage chimerism. Donor-specific tolerance was tested by skin grafting. RESULTS One hundred percent of recipients engrafted after irradiation with 600 cGy total body irradiation, transplantation with 80 x 10(6) Fischer 344 bone marrow cells, and injection with 50 mg/kg cyclophosphamide intraperitoneally. Donor chimerism was detectable in all engrafted animals for up to 11 months. This conditioning was nonlethal, because conditioned untransplanted animals survived indefinitely. Mixed xenogeneic chimeras were tolerant to donor-specific skin grafts but rejected third-party (Wistar Furth) grafts as rapidly as naive C57BL/10SnJ mice. In contrast, animals that received less efficacious conditioning regimens and did not exhibit detectable chimerism showed prolonged graft survival, but delayed graft rejection occurred in all animals within 10 weeks. CONCLUSION The induction of bone marrow chimerism and donor-specific tolerance after nonlethal conditioning might be useful to prevent the vigorous cellular and humoral rejection response to xenografts.