Decreased mebrofenin uptake in patients with non-colorectal liver tumors requiring liver volume augmentation-a single-center analysis.

BACKGROUND: Posthepatectomy liver failure (PHLF) remains a life-threatening complication after hepatectomy. To reduce PHLF, a preoperative assessment of liver function is indispensable. For this purpose, 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT (MSPECT) can be used. The aim of the current study was to evaluate the predictive value of MSPECT for PHLF in patients with non-colorectal liver tumors (NCRLT) compared to patients with colorectal liver metastasis (CRLM) undergoing extended liver resection. METHODS: We included all patients undergoing extended liver resections via two-stage procedures between January 2019 and December 2021 at the University Medical Center Hamburg-Eppendorf, Germany. All patients received a preoperative MSPECT. RESULTS: Twenty patients were included. In every fourth patient, PHLF was observed. Four patients had PHLF grade C. There were no differences between patients with CRLM and NCRLT regarding PHLF rate and future liver remnant (FLR) volume. Patients with CRLM had higher mebrofenin uptake in the FLR compared to those with NCRLT (2.49%/min/m2 vs. 1.51%/min/m2; p = 0.004). CONCLUSION: Mebrofenin uptake in patients with NCRLT was lower compared to those patients with CRLM. However, there was no difference in the PHLF rate and FLR volume. Cut-off values for the mebrofenin uptake might need adjustments for different surgical indications, surgical procedures, and underlying diseases.

Organ recipients suffering from undifferentiated neuroendocrine small-cell carcinoma of donor origin: a case report.

BACKGROUND: Transmission of donor-derived cancer by organ transplantation is rare, but the risk has been increasing due to the aging donor pool. Undifferentiated neuroendocrine small-cell carcinoma is an aggressive tumor with the tendency to spread. Herein we have demonstrated different approaches to treat organ recipients with transmitted tumors. METHODS AND RESULTS: Grafts were retrieved from a decreased donor without any history of previous diseases. Autopsy was not performed after donation. The recipient of the liver graft presented with suspected nodules on routine abdominal ultrasound. After computed tomography (CT) scan, biopsy confirmed the diagnosis of a small-cell carcinoma. Donor origin was unequivocally identified by DNA fingerprinting. Despite chemotherapy the patient died 7 months after orthotopic liver transplantation (OLT). All involved transplantation centers were informed immediately following diagnosis. The male kidney recipient underwent detailed diagnostic work-up to exclude tumor transmission. One year after transplantation, liver metastases caused by a histologically proven small-cell carcinoma from the same donor were apparent. Chemotherapy was immediately started and the graft was removed. Despite continued treatment the tumor progressed and the patient died after repeated intestinal complications. The pathological examination of the explanted second kidney graft did not show any tumor infiltration. CONCLUSION: Therapeutic regimens in recipients suffering from donor-derived carcinoma differ depending on the transplanted organ. Graft removal of non-life-sustaining organs and discontinuation of immunosuppressive medication should result in complete tumor rejection. Minimizing the risk of tumor transmission, a CT scan might be advisable in donors of more advanced age.

Palladium-Catalyzed Enantioselective Organic Transformations.

Many palladium-catalyzed organic reactions with tailored ligands, besides the princess of asymmetric catalysis, allylic alkylation, are suitable for enantioselective organic synthesis. This is clearly illustrated by the large number of promising examples such as the Heck reaction, and Wacker-type oxidations, cycloadditions, cycloisomerizations, carbonylations, and copolymerization of alkenes with carbon monoxide.

Inheritance of post-vaccinal resistance against Plasmodium berghei infection in mice.

The protective effect of specific vaccination against Plasmodium berghei (P. berghei) was compared in terms of survival percentage in DBA/2, C3H, outbred albino mice and in two lines of mice produced by selective breeding for either high or low antibody responsiveness to sheep erythrocyte (H and L lines respectively). The efficacy of induced protection varies according to genetic constitution. It is very strong in H line and albino mice, intermediate in DBA/2 and very weak in L line and C3H. The inheritance of post-vaccinal resistance to infection was studied in F1 hybrids and backcrosses between C3H and the other lines. The control was polygenic in all cases. The dominance of the characteristic depends on the strain combination. On the whole the results suggest the non-identity of the genes controlling protection in the various lines. The lack of a quantitative parameter for a more precise genetic analysis of protective immunity in inbred lines is stressed, since both anti-P. berghei antibody production and parasitaemia proved to be unreliable.

Tolerance to human gamma globulin in mice selected for high or low antibody responsiveness.

The injection of aggregate-free or tolerogenic human gamma globulin (t-HGG) induced tolerance in two lines of mice selected for high or low antibody responsiveness (high responder (H) or low responder (L) lines, respectively). In L mice, the tolerance state was very short and could no longer be obtained when the challenge injection was delayed for four weeks after tolerogenic treatment. At that time, an antibody response to t-HGG was observed in both lines; in H mice, however, this was followed by a partial tolerance state. These results and those previously obtained concerning tolerance induction to bovine serum albumin and rabbit gamma globulin in H and L mice suggest at least partial independent genetic control of antibody responsiveness and susceptibility to tolerance induction.

Quantitative effect of H-2-linked gene(s) on antibody response to human gamma-globulin.

H-2-linked gene(s) have been found to play a role in the quantitative regulation of response to human gamma-globulin (HGG) in mice selected for high or low antibody responsiveness to sheep erythrocytes. Unexpectedly, in a random genetically heterogeneous population of F2 interline hybrids, the gene(s) linked to the H-2 phenotype of H mice has a "low" effect, and the gene(s) linked to the H-2 phenotype of L mice a "high" effect on the magnitude of antibody response to HGG. In H and L mice, the non-specific polygenic control of antibody responsiveness is able to compensate/counteract the inverse effect of HGG-specific H-2-linked gene(s) since the usual interline difference is observed.

Both genetic background and environmental factors modify the phenotypic expression of H-2 associated genes participating in the polygenic control of antibody responsiveness to Salmonella antigens.

The genetic control of responsiveness to flagellar (f) and somatic (s) antigens of Salmonellae was studied in high (H) and low (L) lines of mice selected for the character 'antibody response to sheep erythrocytes'. The minimal immunogenic dose was, for the two antigens, lower in H than in L mice and the dominance of the responder phenotype was then greater in F1 hybrid females than in males. Genes associated with H-2 locus intervene in the responses to each antigen. Their expression was found to vary according to the conditions of immunization and to the sex. The quantifiable H-2 effect was measured in interline hybrids, i.e. on an heterogeneous genetic background equivalent to that of F2. In the case of the flagellar (f) antigen, the H-2 locus was responsible in secondary response for about 50% of the interline difference in the two sexes. In the primary response, the H-2 effect was only observed in females. It was smaller (25% of the interline difference) and independent of the antigen dose. In contrast, with somatic (s) antigen the H-2 locus did not intervene in the control of secondary response. The H-2 effect in the primary response was again only found in females. Unexpectedly, the allele linked to the H-2 phenotype of L mice had a more favourable effect on hybrid responsiveness than that linked to the phenotype of H mice.

Tolerance induction in mice selected for high or low antibody responsiveness.

Induction of tolerance to bovine serum albumin was studied in mice selected for high (H) or low (L) antibody responsiveness and in their F1 hybrids. No high or low zone tolerances were obtained in H mice whereas L mice were susceptible to tolerance induction by the two schedules. H mice were immunized by repeated injections of tolerogenic BSA for low zone tolerance induction but not after the administration of a single high dose of tolerogenic BSA. Resistance to tolerance induction is dominant in F1 hybrids.

[Genetic control of immune responsiveness to bovine serum albumin in the high and low antibody producer lines of mice (author's transl)]. / Régulation génétique de la réponse immune à la séralbumine bovine chez les souris bonnes et mauvaises productrices d'anticorps.

Mice genetically selected for high or low antibody responsiveness to sheep erythrocytes (SRBC) were used for a genetic analysis of the antibody response to an optimal dose of heat-aggregated bovine seralbumin (BSA). About 4 independent loci intervene in the quantitative genetic regulation of the response to BSA, while in these two lines the response to the selection antigen (SRBC) was found to be regulated by about 10 loci; one of them was linked to the major histocompatibility complex of the mouse (H-2). Such an H-2 linkage was not demonstrated for the regulation of the response to BSA. Dominance effect in F1 hybrids was shown to vary according to the strength of the immunization procedure used. This result raises the question of the phenotypic cellular expression of the quantitative genetic regulation of the immune response.

Correlation between genetic regulation of antibody responsiveness and protective immunity induced by Plasmodium berghei vaccination.

High (H) and low (L) antibody responder lines of mice were produced by two independent bidirectional selective breedings for quantitative antibody responsiveness to heterologous erythrocytes (selection I and selection II). In both selections the antibody response to P. berghei antigens was 8- to 10-fold higher in H than in L lines. The character "high response" presents an incomplete dominance o- 18% in selection I and 67% in selection II. In selection II the variance analysis indicates that at least three independent loci intervene in the regulation of responsiveness to P. berghei antigens. The innate resistance and the protective efficacy of vaccination against P. berghei infection induced by parasitized erythrocytes was measured in H and L lines and in the interline hybrids F1, BcH, and BcL of selections I and II. No very significant difference was observed in the innate resistance to P. berghei infection between H and L mice of both selections. Vaccination induced a very efficient protection in the two H lines (94 and 95% survival), whereas only a weak protection was induced in the two L lines (16 and 31% survival); the degree of protection is intermediate in interline hybrids F1, BcH, and BcL. In both selections a good linear correlation was demonstrated between the level of vaccination-induced antibody and the degree of resistance measured as percentage of survival. The present results indicate that the vaccination-induced P. berghei immunity is essentially due to the antibody response, whereas the bactericidal activity of macrophages and the cell-mediated immunity do not play a determinant role.

Genetic analysis of antibody responsiveness to sheep erythrocytes in crosses between lines of mice selected for high or low antibody synthesis.

Two selective breedings of mice for minimal or maximal agglutinin response to heterologous erythrocytes were carried out (selection I and II). Preliminary reported data indicated that for both selections the heritability was between 0.18 and 0.36 and the number of relevant loci from 7--13. The results reported in this article are definitive since the data of ten to twenty generations at selection limit are available and large populations of interline hybrids F1, F2 and both backcrosses were analysed. The character 'high response' was partially dominant in F1 hybrids of both selections, the degree of this incomplete dominance was 0.27 in selection I and 0.54 in selection II. In selection I, 38% of the F2 variance was due to genetic factors (VG) and 62% to environmental effects (VE). The partition of phenotypic variance of F2 and backcrosses into additive variance (VA) and dominance variance (VD) was made according to three methods and the mean results were: VA = 0.72 and VD = 0.05. The resulting mean heritability was 0.35 and the number of relevant loci about ten. In selection II, 69% of the F2 variance was due to VG and 31% to VE. The three methods of variance calculation give somewhat discordant results. According to the more probable estimation (see discussion) VA = 0.95, the mean heritability was 0.23 and the number of loci, about 6. The results obtained in crosses between homologous lines of the two selections indicate that the two 'high' lines have probably identical homogeneous genetic constitution while the two 'low' lines contain some different 'high' effect loci.

Deficiency of high-affinity anti-beta-D-galactosidase antibodies in selected low immune responder mice.

Amount and affinity of anti-beta-D-galactosidase-activating antibodies (AAb) were studied in two lines of mice obtained by selective breeding for antibody response to heterologous erythrocytes. These lines, referred to as high (H) and low (L) lines, differ also in their responses to many antigens. Concerning AAb amounts, the maximal titer in H mice is higher than in L mice. However, the AAb levels in H mice decreased with increasing immunizing doses and became lower than in L mice for the highest dose. This fact can be explained in terms of intramolecular competition or suppression. Whereas the usual maturation pattern was observed in H mice, no AAb of high affinity were found in L mice, even after a minimal immunizing dose. At any dose tested, no maturation of AAb occurred until three months after immunization. This deficiency may be ascribed to B lymphocyte or macrophage modifications. A correlation between the deficiency of high-affinity AAb in L mice and their genetically induced low antibody responsiveness cannot be proved.

[Immune responsiveness of high and low antibody producing lines of mice against an antigen non-cross-reacting with the selection antigen (author's transl)]. / Réponse immunologique des souris de lignées bonnes et mauvaises productrices d'anticorps envers un antigène non apparenté à l'antigène de sélection.

Mice genetically selected for high (HL) or low (LL) antibody responsiveness to sheep erythrocytes (SE) also differed in the immune response to other antigens. We have studied in details the non-specific effect of the selection on responsiveness to bovine seralbumin (BSA) that is an antigen non cross-reacting with SE. BSA has been used either heat-aggregated (H-BSA) or alum-precipitated (Al-BSA). The characteristics of the response to H-BSA and to SE both injected intravenously were similar in several aspects: ranges of interline difference in agglutinin response were equivalent; minimal immunogenic doses were lower in HL than in LL mice. As for SE, the use of an adjuvant (Al-BSA) increased the response of LL more than that of HL mice, so the interline difference decreased. The interline difference between minimal immunogenic doses was weaker with Al-BSA than with H-BSA (100 times and 10,000 times respectively). The threshold dose for induction of immunologic memory was lower in the HL than in LL mice. For Al-BSA this threshold dose was higher than the minimal immunogenice dose in both lines; for H-BSA it was higher (in HL) or equal (in LL) to the minimal immunogenic dose. The results of this article confirm that the selective breeding for SE responsiveness has modified the antibody response to BSA in a similar way. The group of genes controlling the level of antibody response are also responsible for the induction of immunological memory.

Genetic regulation of macrophage functions.

Normal phagocytic function is genetically determined but maintained in a rather narrow range of variation. Phagocytosis stimulation induced by different agents is variable according to species, strains or individuals. Variation is environmental, to a great extent, but has also a genetic component which differs in each case. Selective breeding for macrophage responsiveness to triolein stimulation was successful. However, the relevant genes have only a small effect on antibody synthesis. Macrophages of mice selected for high and low antibody synthesis have a similar phagocytic function but their capacities of antigen processing are quite different.