Abstract 666
Results of haploidentical stem cell transplantation (SCT) after standard extensive T-cell depletion for advanced leukemias are poor (Ciceri et al, 2008). In contrast, significant ...leukemia-free-survivals are produced after T-cell replete SCT from matched related, unrelated and cord-blood donors, even in advanced phases of disease (Kolb HJ, 2009). New protocols based on T-cell repletion are warrented in patients receiving haplo-SCT, in order to offer to all candidates patients with advanced leukemia the potential of cure of allogeneic SCT.Rapamycin is an immunosuppressive drug that arrests cell cycle in G1 phase through the inhibition of DNA transcription, RNA translation and protein synthesis. Morover, in contrast to calcineurin inhibitors, it promotes the generation and expansion of T regulatory cells (Tregs).
We investigated the safety of infusion of T-cell replete unmanipulated peripheral blood stem cells (PBSC) from family haploidentical donor with a combination Rapamycin, Mycophenolate and ATG as GvHD prophylaxis, to preserve early Treg function (TrRaMM study, Eudract 2007-5477-54).
Since 2007, forty-six patients underwent allogeneic transplantation for AML (25 pts), ALL (7 pts), sAML (6 pts), MDS (3 pts), CML-BC (2 pts), NHL (2 pts) or HD (1 pt). The median age was 50 years (range 14-69). At time of transplantation 5 pts were in early phase, and 41 were in advanced phase. Median time from diagnosis to transplantation was 351 days (range 81-1387); 8 patients were enrolled for relapse after allogeneic SCT from MRD or MUD. Median comorbodity index score was 1 (0-5). The conditioning regimen included Treosulfan (14 g/m2 for 3 days), Fludarabine (30 mg/m2 for 5 days) and an in vivo T and B-cell depletion, by ATG-Fresenius (10 mg/kg for 3 times) and Rituximab (a single 500 mg dose). All pts received allogeneic peripheral blood cells from an HLA-haploidentical related donor without any in vitro positive selection of CD34+ cells. GvHD prophylaxis consisted of Rapamycin (target level 8-15 ng/ml, till day +60) and MMF (15 mg/kg tid till day +30).
All patients engrafted, and all but eight were in disease remission at first marrow evaluation on day +30. Cumulative incidence of grade 2-4 aGvHD was 33% (95% CI: 18-48); cumulative incidence of grade 3-4 aGvHD was 12% (95% CI: 2-22). Interestingly, half of patients with GvHD developed it at immunosuppressive prophylaxis withdrawal for disease relapse. Only six patients developed cGvHD. Cumulative incidence of TRM and relapse incidence were 26% (95% CI: 11-41) and 53% (95% CI: 35-71) respectively. None developed EBV reactivation. Patients experienced an early and sustained immunoreconstitution with a median 221 circulating CD3+cells/μL (range 43-1690) from day 30. The immune-reconstitution was polarized towards central memory cells (CD45RA-CD62L+ cells 32.7% ± 4.8) that produced IL-2 (IL-2+ cells 26.2% ± 5.3). Of interest, at day +90 from transplant, Tregs were significantly expanded (CD4+CD25+CD127-Foxp3+ cells 15.6% ± 4.8 on total CD3+ cells, P<0,05 vs donor controls). After a median follow-up of 6 months, overall survival is 64% (95% CI: 50-78), and projected OS at 1 year is 46% (95% CI: 31-61).
Rapamycin-Mycophenolate-ATG are effective to prevent GvHD in T-cell replete unmanipulated haploidentical peripheral stem cell transplantation for advanced haematological malignancies. This associates with an early T-cell immunoreconstitution characterized by the in vivo expansion of early-differentiated T cells and Tregs, and translates in promising leukemia-free survival in patients with advanced resistant leukemia. Further studies are warranted to gain insight on the role of rapamycin as platform for exploitation of Tregs in allogeneic HSCT from mismatched donor.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To retrospectively compare sensitivity and specificity of magnetic resonance (MR) imaging, three-dimensional (3D) MR spectroscopy, combined MR imaging and 3D MR spectroscopy, and carbon 11 ...(11C)-choline positron emission tomography (PET)/computed tomography (CT) for intraprostatic tumor sextant localization, with histologic findings as reference standard.
The local ethics committee on human research provided approval and a waiver of informed consent for the retrospective study. MR imaging, 3D MR spectroscopy, and 11C-choline PET/CT results were retrospectively reviewed in 26 men with biopsy-proved prostate cancer (mean age, 64 years; range, 51-75 years) who underwent radical prostatectomy. Cancer was identified as areas of nodular low signal intensity on T2-weighted MR images. At 3D MR spectroscopy, choline-plus-creatine-to-citrate and choline-to-creatine ratios were used to distinguish healthy from malignant voxels. At PET/CT, focal uptake was visually assessed, and maximum standardized uptake values (SUVs) were recorded. Agreement between 3D MR spectroscopic and PET/CT results was calculated, and ability of maximum SUV to help localize cancer was assessed with receiver operating characteristic analysis. Significant differences between positive and negative sextants with respect to mean maximum SUV were calculated with a paired t test.
Sensitivity, specificity, and accuracy were, respectively, 55%, 86%, and 67% at PET/CT; 54%, 75%, and 61% at MR imaging; and 81%, 67%, and 76% at 3D MR spectroscopy. The highest sensitivity was obtained when either 3D MR spectroscopic or MR imaging results were positive (88%) at the expense of specificity (53%), while the highest specificity was obtained when results with both techniques were positive (90%) at the expense of sensitivity (48%). Concordance between 3D MR spectroscopic and PET/CT findings was slight (kappa=0.139).
In localizing cancer within the prostate, comparable specificity was obtained with either 3D MR spectroscopy and MR imaging or PET/CT; however, PET/CT had lower sensitivity relative to 3D MR spectroscopy alone or combined with MR imaging.
GM1 ganglioside containing a hydroxylated fatty acid moiety, GM1(OH), was synthesized starting from lyso-GM1 and D-(+)-2-hydroxystearic acid. The aggregative, geometrical and distribution properties ...of GM1(OH) were compared with those of stearic acid containing GM1 ganglioside; laser light scattering measurements, differential scanning calorimetry and fluorescence spectroscopy were used. GM1 and GM1(OH) are present in solution as micelles with a hydrodynamic radius of 58.7 and 60.0 A, and molecular mass of 470 and 570 kDa, respectively. The surface area occupied by the monomer of GM1(OH) at the lipid-water interface of the aggregate was calculated to be 117 A2, which is 3 A2 lower than that determined for GM1. Proton NMR analyses of GM1 and GM1(OH) suggest different three-dimensional structures at the ganglioside lipid-water interface. Both GM1(OH) and GM1 inserted into dipalmitoylphosphatidylcholine (DPPC) vesicles undergo segregation phenomena, with the formation of ganglioside-enriched microdomains, but GM1(OH) shows a higher degree of dispersion in the DPPC matrix and exerts a lower rigidifying effect than does GM1.
Background and Objective: The use of ionizing irradiation as radiation therapy (RT) for tumor treatment represents a well-established method. The use of photodynamic therapy (PDT), especially with ...Photofrin II, for tumor treatment is also known. Chemical modifiers enhancing the action of radiation therapy are well known and widely used in medicine. None of these compounds, however, is a selective radiosensitizer. Materials and Methods: Several series of animal experiments were performed, The highly differentiated human bladder cancer cell line RT4 was implanted subcutaneously in nude mice. The mice were injected 10 mg/kg Photofrin II and irradiated with 5 Gy. Results: Photofrin II has proved to be a chemical modifier of ionizing irradiation, enhancing the tumor doubling time (tumor growth) from 6.2 to 10.9 days in the control group with the use of irradiation and injection of porphyrin. Conclusion: Photofrin II shows a high activity as radiosensitizer and, in the future, can be used as a selective radiosensitizer for tumor treatment with ionizing radiation.
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