Reversal of stage 5 chronic kidney disease by aortic valve replacement in kidney transplant recipient: a case report.

BACKGROUND: Cardiorenal syndrome (CRS) is a group of pathophysiological disorders affecting heart and kidneys. CASE PRESENTATION: We present 44-year-old kidney transplant recipient with acute-on-chronic graft failure in the course of CRS due to acutely decompensated heart failure associated with severe aortic regurgitation successfully treated with aortic valve replacement. Because of graft failure progression and difficult to eradicate infections he was treated with dialysis and radical minimization of immunosuppression. After 74 days of renal replacement therapy the patient regained graft function after successful aortic valve replacement. The dialysis could be stopped and immunosuppressive therapy was reintroduced. Heart and renal function are stable and patient is doing well without dialysis for 3 years. CONCLUSIONS: The return of kidney graft function can occur even after a long period of dialysis therapy due to improved cardiovascular function. Therefore, distinguishing an acute-on-chronic CRS subtype is mandatory to enable specific patient approach.

Outcomes of Prolonged Treatment With Intravenous Immunoglobulin Infusions for Acute Antibody-mediated Rejection in Kidney Transplant Recipients.

BACKGROUND: Treatment of antibody-mediated rejection (AMR) is one of the main problems after kidney transplantation (KTx). The results of intensive AMR treatment with plasmapheresis (PF) and repeated infusions of intravenous immunoglobulin (IVIg) are presented. METHODS: Diagnosis of AMR was based on graft biopsy and the presence of donor-specific antibodies (DSAs). AMR therapy consisted of 5 PF and IVIg infusions given after the last PF. Subsequent IVIg doses were given every 4 weeks for 6 months. Graft biopsy and DSA assessment were repeated at the end of the treatment (ET). RESULTS: Four women and 10 men were included in our study; mean time from KTx to AMR was 79 (range, 3-193) months. During the treatment, 4 patients had graft failure. Graft function at baseline was significantly worse (P = .02) in this group compared with patients who completed the therapy. At baseline, mean flourescence intensity (MFI) was 6574 (range, 852-15,917) in the whole group, 7088 (range, 1054-15,917) in patients who completed treatment, and 4828 (range, 852-11,797) in patients who restarted hemodialysis. At ET, DSA MFI decreased in 8 of 10 patients (80%) who completed the therapy. The MFI decrease was 3946 (range, 959-11,203). Control graft biopsies revealed decreased intensity of C4d deposits in peritubular capillaries in 7 patients (78%) and decreased peritubular capillaritis in 2 patients (22%). CONCLUSION: Intensive, prolonged AMR therapy with PF and IVIg resulted in a decrease in DSA titer and intensity of C4d deposits, but was not associated with reduction of microcirculation inflammation. Treatment was ineffective in patients with baseline advanced graft insufficiency.

The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy.

NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors.

Brain tumors are associated with genetic alterations of oncogenes and tumor suppressor genes. Accumulation of reactive oxygen species (ROS) in cells leads to oxidative stress-induced damage, resulting in tumorigenesis. Here, we showed that the nuclear matrix protein nuclear restricted protein in brain (NRP/B) was colocalized and interacted with NF-E2-related factor 2 (Nrf2). During oxidative stress response, NRP/B expression and its interaction with Nrf2 were upregulated in SH-SY5Y cells. Association of NRP/B with Nrf2 was crucial for NAD(P)H:quinone oxidoreductase 1 (NQO1) expression. NRP/B was localized predominantly in the nucleus of normal brain cells, whereas in primary brain tumors NRP/B was almost exclusively contained in the cytoplasm. In addition, unlike wild-type NRP/B, the expression of NRP/B mutants isolated from primary brain tumors was found in the cytoplasm, and these mutants failed to induce Nrf2-dependent NQO1 transcription. Thus, NRP/B mutations and their altered localization resulted in changes in NRP/B function and deregulation of Nrf2-dependent NQO1 activation in brain tumors. This study provides insights into the mechanism by which the NRP/B modulates Nrf2-dependent NQO1 induction in cellular protection against ROS in brain tumors.

Potentiatied antitumor effectiveness of combined chemo-immunotherapy with interleukin-12 and 5-fluorouracil of L1210 leukemia in vivo.

In this study we investigated the efficacy of a combination of IL-12 and 5-FU, a chemotherapeutic exerting several immunomodulatory effects, in murine L1210 leukemia. Mice inoculated with 1 x 10(5) leukemia cells were treated with a single dose of 5-FU (50 mg/kg) and seven daily doses of IL-12 (100 ng/dose), and were observed for survival. Treatment with IL-12 or 5-FU given alone produced moderate anti-leukemic effects. However, combination of both drugs resulted in a significant prolongation of mouse survival time. Importantly, there were 70% of long-term (>60 days) survivors among mice treated with both agents simultaneously. Moreover, we observed 100% of long-term survivors when mice were treated with a minimally increased dose of IL-12 (170 ng) in combination with 5-FU (50 mg/kg). The antileukemic effects were completely abrogated in scid/scid mice and in mice depleted of peritoneal macrophages and significantly decreased after administration of anti-CD3+, anti-CD4+ or anti-CD8+ monoclonal antibodies. Administration of anti-NK1.1 antibodies did not decrease the antileukemic effects indicating that NK cells are not important effectors of this treatment regimen. Collectively, these results indicate that the combination of IL-12 and 5-FU is inducing strong antileukemic responses that are dependent on the presence and activity of macrophages and T lymphocytes and warrant further studies of combined chemo-immunotherapy with IL-12.

Immunomodulation by anticancer chemotherapy: more is not always better (review).

Chemotherapeutics are the mainstay of the majority of antitumor treatment strategies. These agents are usually administered at or near maximum tolerated doses resulting in frequent dramatic toxicities that compromise the quality of life and the immune response towards microbial pathogens. A number of observations suggest that low-dose treatment with chemotherapeutics is sometimes equal or even superior to high-dose chemotherapy. The efficacy of low-dose chemotherapy can be at least partly explained by the regulation of the antitumor immune response. The immunomodulatory effects of some chemotherapeutics might be further potentiated by combinations with selected biological response modifiers such as recombinant cytokines (IL-2, TNF, IL-12). The effectiveness of such treatment combinations have already proved effective in preclinical animal models. However, the efficacy in humans is still to be demonstrated in rationally designed clinical trials.

Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice.

The ubiquitin-proteasome pathway is becoming an attractive target in cancer therapy. The inhibitors of proteasomes have recently been shown to induce apoptosis of tumor cells in vitro and to exert significant antitumor effects in murine tumor models in vivo. Proteasome inhibitors, also prevent NF-kappa B activation. Since this transcription factor is responsible for counteracting apoptosis induced by numerous agents, and proteasome inhibitors have already proved efficacious in increasing the proapoptotic activity of TNF in vitro, we decided to evaluate the antitumor effects of the combined PSI and TNF treatment against a murine C-26 carcinoma. Both agents separately exerted moderate antitumor efficacy. However, their combination proved to exert dramatic antitumor activity with retardation of tumor growth and prolongation of mice survival time. Moreover, 50% of the mice were completely cured by this drug combination. Unexpectedly, there was no potentiation of the cytostatic/cytotoxic effects of these drugs in in vitro assays which argues against the direct influence on C-26 cells. Similarly, the influence of these drugs on tumor induced angiogenesis does not seem to explain the observed antitumor effects. Further studies are necessary to explain the striking antitumor effects of the PSI and TNF combination.

Potentiation of the anti-tumour effects of Photofrin-based photodynamic therapy by localized treatment with G-CSF.

Photofrin-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing.

Interleukin 12 and indomethacin exert a synergistic, angiogenesis-dependent antitumor activity in mice.

Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence and mortality from colorectal cancer. It has recently been demonstrated that these drugs are capable of suppressing the production of pro-angiogenic factors from tumor cells. The mechanisms of antitumor action of interleukin 12 include the enforced secretion of anti-angiogenic factors and stimulation of antitumor immunity. Therefore, we hypothesized that the combination of a model nonsteroidal anti-inflammatory drug--indomethacin and interleukin 12--would result in enhanced angiogenesis-dependent antitumor effects against a colon-26 carcinoma cells transplanted into syngeneic mice. As expected the combined administration of both agents simultaneously resulted in a strengthened antitumor activity that was manifested as a retardation of tumor growth and prolongation of mouse survival. Importantly some mice were completely cured after the combined treatment. As administration of interleukin 12 and indomethacin resulted in enhanced inhibition of angiogenesis it seems possible that prevention of new blood vessel formation is one of the mechanisms responsible for the observed antitumor effects.

Potentiatied anti-tumor effectiveness of combined therapy with interleukin-12 and mitoxantrone of L1210 leukemia in vivo.

In previous studies we have shown that combined chemo-immunotherapy of L1210 leukemia with IL-12 and doxorubicin results in striking anti-tumor effects producing 100% of long-term survivors. In this study we investigated the efficacy of a combination of IL-12 and mitoxantrone in murine L1210 leukemia. Mice inoculated with 1x105 leukemia cells were treated with a single dose of mitoxantrone and seven daily doses of IL-12, and were daily observed for survival. Treatment with IL-12 or mitoxantrone given alone produced moderate anti-leukemic effects. However, combination of both drugs resulted in a significant prolongation of mouse survival time. Importantly, there were almost 50% of long-term (>60 days) survivors among the mice treated with both agents. This therapeutic effect was completely abrogated by sub-lethal, whole-body X-irradiation, and significantly reduced after macrophage depletion.

Potentiation of antitumor effects of IL-12 in combination with paclitaxel in murine melanoma model in vivo.

The early clinical trials with interleukin-12 (IL-12) have demonstrated substantial toxicity of this cytokine. One way to resolve this problem would be to find other antitumor agents, e.g. chemotherapeutics, synergistically interacting with IL-12. However, analysis of the recent reports on this topic leads to the conclusion that the antitumor effects achieved in such combination treatments are dependent not only on the drug applied but also on the tumor model used. We described previously lack of the potentiation of antitumor effects in combination treatment with IL-12 and paclitaxel in a murine leukemia L1210 model. We investigated whether such treatment could bring therapeutical benefit by using the murine melanoma MmB16 model. significant potentiation of antitumor effects in combination treatment with IL-12 and paclitaxel was observed. These results suggest that combination of IL-12 and paclitaxel could be beneficial in the treatment of certain types of tumors.

[Autoimmune liver diseases. Part II]. / Autoimmunologiczne schorzenia watroby. Czesc II.

Autoimmune hepatis along with primary biliary cirrhosis, primary sclerosing cholagitis and some other not classified primary hepatobiliary pathologies belong to the group of liver diseases which are believed to be caused by autoimmune reactions. The primary causes of those pathological states remain unknown. However, thanks to the recent studies in immunogenetics and on autoantigens, progress has been made in understanding the mechanisms underlying these pathologies. The results of these studies are criteria of diagnosis and treatment of those diseases. In spite of some beneficial results of immunosuppressive treatment of AIH, the disease in some cases progresses and those states are one of the classical indications for allogenic liver transplantation.

[Autoimmune liver diseases. Part I]. / Autoimmunologiczne schorzenia watroby. Czesc I.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) belong to the group of liver diseases which are believed to be caused by autoimmune reactions. The primary causes of these diseases remain unknown. However, thanks to the recent studies in immunogenetics, progress has been made in understanding the mechanisms underlying these pathologies. Moreover, studies are being held on identification of specific autoantigens in these diseases. The results of these studies are criteria of diagnosis and treatment of those diseases. As there is still no specific treatment of PBC and PSC, in many cases best results are achieved with allogenic orthotropic liver transplantation.

Antitumor effects of interleukin-12 in pre-clinical and early clinical studies (Review).

Interleukin-12 (IL-12) previously called cytotoxic lymphocyte maturation factor (CLMF) or NK cell stimulatory factor (NKSF) is a recently characterized heterodimeric cytokine composed of two subunits. Although identified no more than 10 years ago IL-12 has already proved efficacious in numerous pre-clinical tumor immunotherapy studies. Animal studies revealed that IL-12 has powerful antitumor, anti-metastatic and anti-angiogenic activities and seems to be less toxic than other immunotherapeutics such as interferons or IL-2. A number of pre-clinical studies with IL-12 prompted the evaluation of this cytokine in the treatment of human cancers. Results of phase I and early phase II clinical trials have already been reported and these are described here together with a brief discussion concerning IL-12-related toxicities and potential methods of their prevention.

The potentiated antileukemic effects of doxorubicin and interleukin-12 combination are not dependent on nitric oxide production.

In our recent study we described a significant antileukemic efficacy of a combination therapy with interleukin-12 (IL-12) and doxorubicin (DOX) in the L1210 leukemia model. This therapeutic effect was abrogated by elimination of activated macrophages. Activated macrophages produce a variety of factors that can contribute to the elimination of tumor cells in vivo, including proteases, TNF, reactive oxygen intermediates, and nitric oxide (NO). Based on the results of previous reports, the contribution of NO in potentiated antileukemic effects of IL-12 + DOX combination seemed to be highly possible. Both DOX and IL-12 given alone increased the production of NO by peritoneal macrophages, however, macrophages derived from the mice treated with the combination of those agents produced significantly less NO than macrophages from IL-12-alone-treated mice. Production of NO by spleen macrophages after IL-12 + DOX treatment was higher than it was in controls, IL-12-alone or DOX-alone-treated groups. In serum, concentrations of NOx- in IL-12- or IL-12 + DOX-treated mice were significantly higher in comparison with controls, however not significantly different from each other. Addition of L-NAME treatment to the IL-12 + DOX therapy in leukemia-bearing mice did not significantly change the antileukemic efficacy of this therapy. Thus, our results indicate that the augmented antileukemic effects of IL-12 + DOX combination therapy in L1210 model are NO-independent. Therefore, further studies on the possible mechanisms of potentiated antileukemic activity of combination of IL-12 and DOX would be worth pursuing.

Effective chemo-immunotherapy of L1210 leukemia in vivo using interleukin-12 combined with doxorubicin but not with cyclophosphamide, paclitaxel or cisplatin.

It has been well established that chemo-immunotherapy using cytotoxic drugs and appropriate cytokines offers a new approach to increasing the therapeutic index in the treatment of neoplastic diseases. This study investigates the efficacy of combinations of interleukin-12 with cyclophosphamide, paclitaxel, cisplatin or doxorubicin in the murine L1210 leukemia model. Mice inoculated i.p. with 1 x 10(3) or 1 x 10(5) leukemia cells were treated with interleukin-12 and/or chemotherapeutics, and were observed daily for survival. Immunosuppression with X-irradiation or macrophage depletion with injections of silica were used to examine the dependence of the therapeutic effects on the efficiency of the immune system. Treatment with interleukin-12 or one of the studied chemotherapeutics given alone resulted in moderate antileukemic effects. Combination of interleukin-12 with cyclophosphamide or paclitaxel produced no augmentation of anti-leukemic effects in comparison with these agents given alone. Combination of interleukin-12 with cisplatin resulted in prolongation of the survival time; however, in the experiment with mice inoculated with 1 x 10(5) leukemia cells, no long-term survivors (>60 days) were observed; on the contrary, combination of interleukin-12 with doxorubicin resulted in 100% long-term survivors. This effect was completely abrogated either by X-irradiation of mice or by macrophage depletion. We also found that doxorubicin augments IL-12-stimulated production of interferon-gamma in vivo. Our observations demonstrating potentiation of the antileukemic effects of the IL-12 and doxorubicin combination suggest that the combined use of these 2 agents could be beneficial in leukemia therapy.

Potentiated antitumour effects of cisplatin and lovastatin against MmB16 melanoma in mice.

Lovastatin, the drug used in the treatment of hypercholesterolaemia, has previously been reported to exert synergistic antitumour activity in a melanoma model in mice when used together with some immune response modifiers. In this study, we examined the antitumour effect of cisplatin augmented by its combined application with lovastatin, both in vitro and in vivo, in a murine melanoma model. The results of this study suggest that lovastatin may enhance the therapeutic effects of cisplatin in the treatment of malignant melanomas.

Granulocyte colony-stimulating factor demonstrates antitumor activity in melanoma model in mice.

Granulocyte colony-stimulating factor (G-CSF) was found to exert antitumor activity against murine MmB16 melanoma when administered intratumorally. However, subcutaneous administration of this cytokine at a site distant from the growing tumor did not show any antitumor effects. G-CSF did not influence the proliferative activity of MmB16 in vitro. Intraperitoneal administration of G-CSF resulted in decreased secretion of nitric oxide (NO) by peritoneal macrophages and their decreased tumoricidal activity against MmB16.

G-CSF prevents the suppression of bone marrow hematopoiesis induced by IL-12 and augments its antitumor activity in a melanoma model in mice.

BACKGROUND: IL-12 has been successfully used in experimental tumor therapy. However, administration of this cytokine induces dose-dependent suppression of hematopoiesis that could potentially limit its use in clinical trials. We decided to examine whether the myelosuppressive activity of IL-12 could be corrected by the administration of G-CSF. MATERIALS AND METHODS: In the initial experiments the influence of IL-12 and/or G-CSF on bone marrow and spleen GM-CFC was evaluated. To examine whether C-CSF could influence the antitumor activity of IL-12 the combination therapy with these agents was carried out starting on day seven following inoculation of melanoma MmB16 cells into the footpads of B6D2F1 mice. To obtain insight into the mechanism of the observed augmented antitumor activity of the combination therapy with IL-12 and G-CSF, the influence of these cytokines on macrophage activity (cytotoxicity and nitric oxide release) was analyzed. RESULTS: In accord with our expectations, the application of G-CSF partially prevented the suppression of bone marrow myelopoiesis in IL-12 treated mice. Unexpectedly, G-CSF also showed potentiation of antitumor effects of IL-12 in this melanoma model. The augmented antitumor activity of combined IL-12/G-CSF immunotherapy could result from the enhanced stimulation of macrophage NO production and cytotoxicity. CONCLUSION: The simultaneous administration of IL-12 and G-CSF partially prevented suppression of bone marrow myelopoiesis in IL-12-treated mice. Moreover, treatment with these cytokines also results in potentiated antitumor effects in a murine melanoma model.