Background TGF-β 1 expression has been described to increase along with time from transplantation and has also been linked to allograft dysfunction and toxic effects of cyclosporine. Our aim was to correlate intragraft TGF-β 1 expression with cyclosporine exposure after kidney transplantation. Methods Altogether 53 kidney allograft protocol biopsies from 42 patients on a low-dose cyclosporine-based regimen obtained at 3, 6, and 12 months were classified according to Banff and the chronic allograft damage index (CADI). TGF-β 1 expression in tubules, glomeruli, vessels, and inflammatory cells was semi-quantitatively scored and correlated with cyclosporine concentrations (C0 and C2), CADI, and graft function. Results TGF-β 1 expression was mildly increased along time from transplantation, but the results were not statistically significant. TGF-β 1 expression was neither related to CADI nor to the use of ACE inhibitors/ARB. TGF-β 1 expression in the kidney was not correlated with C0 or C2 levels or kidney graft function during follow-up. Conclusion In protocol biopsies from patients on low-dose cyclosporine regimen, expression of TGB-β 1 was not significantly increased along time since transplantation, and did not correlate with cyclosporine exposure. Our findings suggest that the toxic effects of low-dose cyclosporine on TGF-β expression may be milder than previously thought.
Abstract Purpose Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). The aim of this study was to assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen). Methods From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate. Six pathologists individually reviewed the pathology slides of the prostate biopsies. The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss’ weighted kappa ( κ ) and Model-based kappa for associations were computed to estimate the combined agreement between individual pathologists. Results GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG1–5) vs. benign was excellent (Model-based kappa 0.90, Fleiss’ kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG2–5 vs. GG0 vs. GG1), it was good (Model-based kappa 0.70, Fleiss’ kappa κ 0.67). Conclusions Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.
p53 is a transcription factor that participates in cell cycle checkpoint processes and apoptosis. The protein product of the murine double minute gene 2 (mdm-2) plays a central role in the regulation of p53. In response to DNA-damaging agents, the wild-type p53-activated fragment 1 (WAF1 also known as p21) is an important downstream effector in the p53-specific growth arrest pathway. In breast cancer patients, it is unclear whether measuring p53, mdm-2, or p21 expression provides information on how patients will respond to chemotherapy. Mib-1 monoclonal antibody recognizes the proliferation-related antigen Ki-67. High tumor proliferation has previously been associated with response to chemotherapy. p53, mdm-2, p21, and mib-1 expression were assessed by immunohistochemical methods in primary tumors derived from 134 patients who took part in a randomized multicenter trial comparing docetaxel to sequential methotrexate and 5-fluorouracil (MF) in advanced breast cancer. Low mib-1 staining correlated with negative p53 staining (P = 0.001), and mdm-2 and p21 stainings correlated positively with each other (P < 0.001). p53, mdm-2, p21, and mib-1 expression were not significantly associated with response to chemotherapy, time to progression, or overall survival in the whole patient population or in the docetaxel group. However, in the MF group, a low mib expression (<25%) and a high mdm-2 expression (> or =10%) predicted a better response (P = 0.014 and P = 0.046, respectively) to treatment and a longer time to progression in both univariate and multivariate analyses. p53 staining status was not associated with response to treatment in either group. Interestingly, tumors with both negative mdm-2 and p21 expression, irrespective of p53 status, had a high response rate to docetaxel but no response to MF. Although highly preliminary, the findings suggest that different tumor biological factors may predict response to different chemotherapy regimens with distinct mechanisms of action. The results of our phenotype analysis also indicate that it is more likely that a panel of tumor biological factors instead of only one single factor may be needed for better prediction of chemotherapy response.
385 We have previously shown that allografts from IL-10 KO recipients have accelerated cardiac rejection that is associated with compensatory increases in IFN-γ. In addition, we have shown that recipient IFN-γ gene deficiency inhibits the development of smooth muscle cell (SMC) rich vascular thickening in cardiac allografts. Hence, we hypothesized that IFN-γ contributes to vascular thickening in cardiac allografts placed in IL-10 KO mice. To study the influence of IL-10 on graft vessels, we placed BALB/c hearts into IL-10 KO C57-recipients and treated them with anti-CD4/8 mAb (30 days) ±anti-IFN-γ mAb (biweekly) to neutralize IFN-γ. Luminal occlusion (Verhoeff elastin stained sections) and% α-smooth muscle actin immunopositivity in all graft vessels was quantitated by image analysis. Cardiac allografts placed in IL-10 KO±mAb recipients had severe parenchymal rejection characterized by infiltrating CD45 immunopositive cell in myocardium and perivascular vascular space. ISHLT scores (scale 0-4) were significantly higher in IL-10±mAb groups, 3.7±0.4 and 3.8±0.5, compared with wild type group, 2.3±0.3, p<0.0001. Hearts from IL-10 KO±mAb recipients developed severe vascular occlusion(Table) with little α-actin positivity in neointima compared to wild type, p<0.0001. There was SMC loss in the media layer of graft vessels from IL-10 KO recipients that was diminished by anti-IFN-γ mAb administration. Taken together, recipient IL-10 deficiency was associated with accelerated rejection, media necrosis and prominent arteritis-like vascular occlusion (rather than true arteriosclerosis characterized by SMC accumulation). Media necrosis was inhibited by anti-IFN-γ mAb administration suggesting that IFN-γ may promote SMC destruction in arteriosclerosis, possibly through macrophage ways. In conclusion, suppressive effects of IL-10 provide some protection against vasculitis associated with cardiac allograft rejection.
Background.The recurrence of IgA nephropathy (IgAN) in the allograft is common. Factors related to IgA recurrence are unclear. The aims of this study were to determine the incidence of IgAN recurrence as assessed by protocol biopsies and to identify predictive factors for recurrence.
Different donor parameters and baseline biopsy have been used to assess the quality of donor organs. There is, however, no consensus which risk factors and chronic changes in the donor kidney can be accepted for transplantation. The study included 481 deceased organ donors and their 829 kidney recipients transplanted during 1995-2005. The biopsies were re-evaluated according to the Banff 97 classification. The prognostic significance of donor risk factors and Chronic Allograft Damage Index (CADI) was analyzed. We propose a new donor risk score, calculated as the count of positive risk factors from a defined set of factors in the medical history of the donor. This donor risk score predicts histological quality of the kidney, graft function, and survival. Transplantations from donors with donor risk score >4 had significantly decreased graft survival compared to those with donor risk scores 0-4; the five-yr death-censored graft survivals were 83% vs. 93%, respectively. High donor CADI score (>3) was associated with worse graft function and survival. Three-yr glomerular filtration rate declined from 82 to 49 mL/min with donor CADI increase from 0 to ≥4. Our results show that high donor risk score and CADI value reflect low functional reserve and risk for poor graft outcome.
Abstract Aims Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are inflammatory cardiomyopathies sharing histopathological and clinical features. Their differentiation is difficult and susceptible of confusion and apparent mistakes. The possibility that they represent different phenotypes of a single disease has been debated. Methods and results We made a retrospective audit of 73 cases of GCM diagnosed in Finland since the late 1980s. All available histological material was reanalyzed as were other examinations pertinent to the distinction between GCM and CS. Finding granulomas in or outside the heart was considered diagnostic of CS and exclusive of GCM. Altogether 45 of the 73 cases of GCM (62%) were reclassified as CS. In all except one case, this was based on finding sarcoid granulomas that either had been originally missed ( n = 29) or misinterpreted ( n = 11) or were found in additional posttransplant myocardial specimens ( n = 3) or samples of extracardiac tissue ( n = 1) accrued over the disease course. Supporting the reclassification, patients relocated to the CS group had less heart failure at presentation (prevalence 20% vs. 46%, P = 0.017) and better 1 year transplant‐free survival (82% vs. 45%, P = 0.011) than patients considered to represent true GCM. Conclusions Recognizing granulomas in or outside the heart remains a challenge for the pathologist. Given that CS and GCM are considered distinct diseases and granulomas exclusive of GCM, many cases of GCM, if thoroughly scrutinized, may need reclassification as CS. However, whether CS and GCM are truly different entities or parts of a one‐disease continuum has not yet been conclusively settled.
Abstract Purpose Dive-induced cardiac and hemodynamic changes are caused by various mechanisms, and they are aggravated by cold water. Therefore, aging divers with pre-existing cardiovascular conditions may be at risk of acute myocardial infarction, heart failure, or arrhythmias while diving. The aim of this study was to assess the effect of a single decompression CCR dive in arctic cold water on cardiac function in Finnish technical divers. Methods Thirty-nine divers performed one identical 45 mfw CCR dive in 2–4 °C water. Hydration and cardiac functions were assessed before and after the dive. Detection of venous gas embolization was performed within 120 min after the dive. Results The divers were affected by both cold-water-induced hemodynamic changes and immersion-related fluid loss. Both systolic and diastolic functions were impaired after the dive although the changes in cardiac functions were subtle. Venous inert gas bubbles were detected in all divers except for one. Venous gas embolism did not affect systolic or diastolic function. Conclusion A single trimix CCR dive in arctic cold water seemed to debilitate both systolic and diastolic function. Although the changes were subtle, they appeared parallel over several parameters. This indicates a real post-dive deterioration in cardiac function instead of only volume-dependent changes. These changes are without a clinical significance in healthy divers. However, in a population with pre-existing or underlying heart problems, such changes may provoke symptomatic problems during or after the dive.
