Liver Transplantation for Hepatocellular Carcinoma: A Single Center Resume Overlooking Four Decades of Experience

Background. This is a single center oncological resume overlooking four decades of experience with liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods. All 319 LT for HCC that were performed between 1975 and 2011 were included. Predictors for HCC recurrence (HCCR) and survival were identified by Cox regression, Kaplan-Meier analysis, Log Rank, and χ2-tests where appropriate. Results. HCCR was the single strongest hazard for survival (exp⁡B=10.156). Hazards for HCCR were tumor staging beyond the histologic MILAN (exp⁡B=3.645), bilateral tumor spreading (exp⁡B=14.505), tumor grading beyond G2 (exp⁡B=8.668), and vascular infiltration of small or large vessels (exp⁡B=11.612, exp⁡B=18.324, resp.). Grading beyond G2 (exp⁡B=10.498) as well as small and large vascular infiltrations (exp⁡B=13.337, exp⁡B=16.737, resp.) was associated with higher hazard ratios for long-term survival as compared to liver transplantation beyond histological MILAN (exp⁡B=4.533). Tumor dedifferentiation significantly correlated with vascular infiltration (χ2p=0.006) and intrahepatic tumor spreading (χ2p=0.016). Conclusion. LT enables survival from HCC. HCC dedifferentiation is associated with vascular infiltration and intrahepatic tumor spreading and is a strong hazard for HCCR and survival. Pretransplant tumor staging should include grading by biopsy, because grading is a reliable and easily accessible predictor of HCCR and survival. Detection of dedifferentiation should speed up the allocation process

Qualitätssicherungssystem zur Bewertung eines HNO-Facharztrepetitoriums

Background!#!Residency training is often characterized by locally influenced training content and focus, which can lead to heterogeneous training outcomes. Refresher courses before the speciality certificate examinations can harmonize the situation.!##!Objective!#!The current publication aims to present a quality management system for evaluation of a postgraduate refresher course for otolaryngology residents.!##!Materials and methods!#!The teaching sessions of a postgraduate course were evaluated using questionnaires. Descriptive statistics and multivariable binary logistic regression analysis were performed. To evaluate the factors leading to a negative perception of a teaching session, the focus was set on the worst 15% of all total ratings. An exemplary strength/weakness profile of a lecturer was created for individual feedback.!##!Results!#!Analysis of the evaluation results showed an overall average rating of 12.8 (±2.4) out of a maximum of 15 possible points. Multivariable regression determined the items 'friendliness,' 'systematic structure,' 'own involvement,' 'prior knowledge,' and 'efficient teaching session' to be significant for a negative perception of a teaching session. Using the lecturer profile, the strengths and weaknesses of the individual lecturer can be shown in an objective manner.!##!Conclusion!#!The developed questionnaire represents a good tool for quality management of a postgraduate refresher course for otolaryngology residents. This is achieved by regression analysis and creation of an individual lecturer profile, which provides an objective basis for improving the individual teaching session through detailed feedback to the lecturer

A Depleting Anti-CD45 Monoclonal Antibody as Isolated Conditioning for Bone Marrow Transplantation in the Rat

Objective A monoclonal antibody (mAb) against the leukocyte common antigen CD45 (RT7 in rats) could facilitate bone marrow transplantation (BMT). This study in rats evaluates a depletive rat anti-RT7(a) mAb as isolated tool for BMT conditioning without using irradiation or any chemotherapeutic /immunosuppressive agent. Methods The model used a CD45 di-allelic polymorphism (RT7(a)/RT7(b)). The anti-RT7(a) mAb was intravenously administered to LEW. 1W rats (RT1(u)RT7(a)) at 5, 10 and 15 mg/kg. 1x10(8) BM cells of MHC syngeneic (RT1(u)), MHC disparate (RT1(l)) or MHC haploidentical (RT1(u/l)) donors were transplanted. All BM donor strains carried the RT7(b) allele so that their CD45(+) cells were not affected by the anti-RT7(a) mAb. Recipients were monitored for reconstitution and donor-chimerism in blood leukocytes. Results mAb dosages of 5 or 10mg/kg were myelosuppressive, whereas 15mg/kg was myeloablative. Multi-lineage donor-chimerism at day 100 indicated engraftment ofMHC syngeneic BM after any used mAb dosage (5 mg/kg: 46+/-7%; 10mg/kg: 62+/-5%; 15mg/kg: 80+/-4%). MHC disparate BM resulted in autologous reconstitution after conditioning by 10mg/kg of the mAb and caused transient chimerism ending up in death associated with aplasia after conditioning by 15mg/kg of the mAb. MHC haploidentical BM (F1 to parental) engrafted only after conditioning by 15 mg/kg (chimerism at day 100: 78+/-7%). Abandonment of alpha/beta TCR+ cell depletion fromBMgrafts impaired the engraftment process after conditioning using 15 mg/kg of the mAb in theMHC syngeneic setting (2 of 6 recipients failed to engraft) and the MHC haploidentical setting (3 of 6 recipients failed). Conclusion This depletive anti-RT7(a) mAb ismyelosuppressive and conditions for engraftment of MHC syngeneic BM. The mAb also facilitates engraftment ofMHC haploidentical BM, if amyeloablative dose is used. RT7(b) expressing, BM- seeded alpha/beta TCR+ cells seem to impair the engraftment process after myeloablative mAb conditioning

Transplantation of BM with or without depletion of donor-derived α/β TCR⁺ cells.

<p>Transplantation of BM with or without depletion of donor-derived α/β TCR⁺ cells.</p

Biodistribution and effects of biotinylated anti-RT7^a mAb in lympho-hematopoietic compartments of RT7^a/RT7^b chimeras.

<p><i>To enable reliable flowcytometric gating of lymphocyte subsets, which will be strongly depleted by the anti-RT7^a mAb, six mixed chimeras carrying disparity only in the RT7 (CD45) antigen were generated by sublethal TBI of 7 Gy. Reconstituted rats showed a multi-lineage RT7^a-chimerism of 10 to 30 percent differing between lineages and compartments (day 0 = before mAb application). The biotinylated anti-RT7^a mAb was applied once (2 mg/kg) before the tissue compartments were analysed by flow cytometry at days 3, 7, 14, 21 and 35. The fraction of persisting RT7^a positive cells is given as percentage of all CD45⁺ cells per lineage (column height). The black column gives the fraction of RT7^a positive cells that is coated by the biotinylated anti-RT7^a mAb. T-lymphocytes (α/βTCR⁺) and NK cells (NKR-P1⁺) were strongly and compartment independently depleted, whereas B-lymphocytes (CD45RA⁺) were coated by anti-RT7^a mAb, but were not significantly reduced in cell number despite high-graded coating. (PB–peripheral blood, THY–thymus, LN–lymph node, SP–spleen, BM–bone marrow).</i></p

Effects of anti-RT7^a mAb on bone marrow level.

<p><i>A single dosage of 10 mg/kg of anti-RT7^a was injected into LEW.1W rats (n = 4). (A) BMC were analysed 7 days after mAb injection, whereby BMC were categorized by CD45 expression density and granularity using flow cytometry. Myelopoiesis showed a right shift, whereby SSC^low/CD45^low early progenitors as well as SSC^low/CD45^high lymphoid progenitors were markedly reduced. (B) Histology verified the right shift in myelopoiesis.</i></p

Multi-lineage chimerism in stable recipients of MHC haploidentical BM grafts conditioned by 15 mg/kg of anti-RT7^a mAb at day 200.

<p><i>Blood samples of long-term surviving recipients of MHC haploidentical BMT (F1 (LEW.7B x LEW.1U-7B: RT1^l/u RT7^b) → LEW.1W: RT1^u, RT7^a) were analysed by flow cytometry for donor-derived chimerism (RT7^b) within leukocyte lineages at day 200. Used mAbs were anti-α/β TCR mAb (R73) for T-lymphocytes, anti-CD45RA (OX33) for B-lymphocytes, anti-granulocytes (HIS48) for granulocytes and anti-RT7^b (HIS41) for donor-derived cells.</i></p

Reconstitution of donor and recipient derived leukocytes after MHC-disparate and MHC-haploidentical BMT conditioned by 15 mg/kg of the anti-RT7^a mAb.

<p><i>LEW.1W recipients (RT1^u, RT7^a, n = 6 per group) received anti-RT7^a mAb (15 mg/kg) 3 days prior to BMT. BMC of MHC disparate LEW.7B (RT1^l, RT7^b) and MHC haploidentical (LEW.1U-7B x LEW.7B (RT1^u/l, RT7^b)) donors were depleted from α/β TCR⁺ cells in vitro and intravenously injected (1x 10⁸ BMC per BMT). Numbers of surviving animals per group are indicated above the diagram. Total counts of leukocytes in peripheral blood are given. Donor- and host-derived fractions were determined by flow cytometry using a donor-specific anti-RT7^b mAb. Mean values of leukocytes from recipient origin (□) and from donor origin (■) are depicted. (A) Recipients of MHC disparate BMC lost chimerism over time, developed pancytopenia and died between days 26 and 41. (B) Recipients of MHC haploidentical BMC developed permanent chimerism and survived indefinitely.</i></p