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Abstract Background Advanced renal cell carcinoma in some cases causes malignant intravascular thrombus with the potential for growth into the inferior vena cava or even the right atrium. Renal cell carcinoma is accompanied by malignant intravascular thrombus in up to 10% of cases. We present an overview of three patients diagnosed as having renal cell carcinoma with malignant intravascular thrombus requiring radical nephrectomy combined with inferior vena cava thrombectomy. Case presentation Three patients diagnosed as having renal cell carcinoma were indicated for renal cell carcinoma combined with inferior vena cava thrombectomy between 2014 and 2017 at our department: a 69-year-old white Caucasian woman, a 74-year-old white Caucasian woman, and a 58-year-old white Caucasian woman. According to the Novick classification of inferior vena cava tumor thrombus, there was one infrahepatic (level II) and two supradiaphragmatic (level IV) malignant intravascular thrombi. The average age of these patients was 67 years (range 58–74 years). All patients underwent radical nephrectomy combined with inferior vena cava thrombectomy through transabdominal approach. In patients with level IV malignant intravascular thrombus, transesophageal echocardiogram was used to guide the placement of the inferior vena cava cross-clamp above the diaphragm. In one patient the pericardium was opened to place a cross-clamp above a tumor just below the right atrium. There were no postoperative mortalities to date with an average follow-up of 23 months (range 2–48 months). To date, no patient has demonstrated recurrent inferior vena cava malignant intravascular thrombus requiring secondary inferior vena cava thrombectomy or any other treatment. A comparison of estimated blood loss and transfusion rate was not significantly different in all three cases. Conclusion Despite the technical complexity of the procedure, caval thrombectomy combined with radical nephrectomy currently represents the only radical treatment for renal cell carcinoma accompanied by malignant intravascular thrombus with good mid-term oncological outcomes.

Background: Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in a preclinical model., Methods: We performed autologous internal jugular vein interposition grafting in porcine carotid arteries for one month. Four grafts were supported with a FRAME mesh, while seven unsupported grafts served as controls. The conduits were examined through flowmetry, angiography, macroscopy, and microscopy., Results: The one-month patency rate of FRAME-supported grafts was 100% (4/4), whereas that of unsupported controls was 43% (3/7, Log-rank p = 0.071). On explant angiography, FRAME grafts exhibited significantly more areas with no or mild stenosis (9/12) compared to control grafts (3/21, p = 0.0009). Blood flow at explantation was higher in the FRAME grafts (145 ± 51 mL/min) than in the controls (46 ± 85 mL/min, p = 0.066). Area and thickness of neo-intimal hyperplasia (NIH) at proximal anastomoses were similar for the FRAME and the control groups: 5.79 ± 1.38 versus 6.94 ± 1.10 mm 2 , respectively ( p = 0.558) and 480 ± 95 vs. 587 ± 52 μm 2 /μm, respectively ( p = 0.401). However, in the midgraft portions, the NIH area and thickness were significantly lower in the FRAME group than in the control group: 3.73 ± 0.64 vs. 6.27 ± 0.64 mm 2 , respectively ( p = 0.022) and 258 ± 49 vs. 518 ± 36 μm 2 /μm, respectively ( p = 0.0002)., Conclusions: In our porcine model, the external mesh FRAME improved the patency of vein-to-carotid artery grafts and protected them from stenosis, particularly in the mid regions. The midgraft neo-intimal hyperplasia was two-fold thinner in the meshed grafts than in the controls.

Theranostics is a novel paradigm integrating therapy and diagnostics, thereby providing new prospects for overcoming the limitations of traditional treatments. In this context, perfluorocarbons (PFCs) are the most widely used tracers in preclinical fluorine-19 magnetic resonance ( 19 F MR), primarily for their high fluorine content. However, PFCs are extremely hydrophobic, and their solutions often display reduced biocompatibility, relative instability, and subpar 19 F MR relaxation times. This study aims to explore the potential of micellar 19 F MR imaging (MRI) tracers, synthesized by polymerization-induced self-assembly (PISA), as alternative theranostic agents for simultaneous imaging and release of the non-steroidal antileprotic drug clofazimine. In vitro, under physiological conditions, these micelles demonstrate sustained drug release. In vivo, throughout the drug release process, they provide a highly specific and sensitive 19 F MRI signal. Even after extended exposure, these fluoropolymer tracers show biocompatibility, as confirmed by the histological analysis. Moreover, the characteristics of these polymers can be broadly adjusted by design to meet the wide range of criteria for preclinical and clinical settings. Therefore, micellar 19 F MRI tracers display physicochemical properties suitable for in vivo imaging, such as relaxation times and non-toxicity, and high performance as drug carriers, highlighting their potential as both diagnostic and therapeutic tools., (© 2024 The Authors. Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Gastrointestinal tract is the most common locality for well-differentiated neuroendocrine tumors (NET). While their occurrence in patients with ulcerative colitis (UC) is uncommon, it has been well documented. However, the causal relationship between development of NET and chronic intestinal inflammation or dysplasia remains controversial. The presence of NET in the ileal pouch in UC patients has been described only in a few reports to date. In this article, we present a case of such a tumor arising in the pouch in a patient with primary sclerosing cholangitis-associated UC, who underwent a restorative proctocolectomy with ileal pouch anal anastomosis and liver transplantation. The case is supported by a review of a relevant literature.   Correspondence address: Ondrej Fabian Clinical and Transplant Pathology Centre Institute for Clinical and Experimental Medicine Videnska 1958/9 Prague, 14021 Czech Republic ondrej.fabian@ikem.cz; ondrejfabian5@gmail.com.

Background: Recurrence of immunoglobulin A nephropathy (IgAN) limits graft survival in kidney transplantation. However, predictors of a worse outcome are poorly understood., Methods: Among 442 kidney transplant recipients (KTRs) with IgAN, 83 (18.8%) KTRs exhibited biopsy-proven IgAN recurrence between 1994 and 2020 and were enrolled in the derivation cohort. A multivariable Cox model predicting allograft loss based on clinical data at the biopsy and a web-based nomogram were developed. The nomogram was externally validated using an independent cohort (n = 67)., Results: Patient age <43 years {hazard ratio [HR] 2.20 [95% confidence interval (CI) 1.41-3.43], P < .001}, female gender [HR 1.72 (95% CI 1.07-2.76), P = .026] and retransplantation status [HR 1.98 (95% CI 1.13-3.36), P = .016] were identified as independent risk factors for IgAN recurrence. Patient age <43 years [HR 2.77 (95% CI 1.17-6.56), P = .02], proteinuria >1 g/24 hours [HR 3.12 (95% CI 1.40-6.91), P = .005] and C4d positivity [HR 2.93 (95% CI 1.26-6.83), P = .013] were found to be associated with graft loss in patients with IgAN recurrence. A nomogram predicting graft loss was constructed based on clinical and histological variables, with a C statistic of 0.736 for the derivation cohort and 0.807 for the external validation cohort., Conclusions: The established nomogram identified patients with recurrent IgAN at risk for premature graft loss with good predictive performance., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models., Methods: In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n = 396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR., Findings: Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively., Interpretation: Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month 3., Funding: Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031., Competing Interests: Declaration of interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/. All authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

We performed a histological and immunohistochemical analysis of myocardia from 3 patients who underwent radiosurgery and died for various reasons 3 months to 9 months after radiotherapy. In Case 1 (death 3 months after radiotherapy) we observed a sharp transition between relatively intact and irradiated regions. In the myolytic foci, only scattered cardiomyocytes were left and the area was infiltrated by immune cells. Using immunohistochemistry we detected numerous inflammatory cells including CD68+/CD11c+ macrophages, CD4+ and CD8+ T-lymphocytes and some scattered CD20+ B-lymphocytes. Mast cells were diminished in contrast to viable myocardium. In Case 2 and Case 3 (death 6 and 9 months after radiotherapy, respectively) we found mostly fibrosis, infiltration by adipose tissue and foci of calcification. Inflammatory infiltrates were less pronounced. Our observations are in accordance with animal experimental studies and confirm a progress from myolysis to fibrosis. In addition, we demonstrate a role of pro-inflammatory macrophages in the earlier stages of myocardial remodeling after stereotactic radioablation for ventricular tachycardia., (Copyright © 2022. Published by Elsevier Inc.)

Skin changes in patients with diabetic foot (DF) are relatively common. The most frequent lesions feature papillae or cilia of various forms. The condition known as "verrucous skin lesions on the feet in diabetic neuropathy" (VSLDN) occurs in patients with distal diabetic sensorimotor neuropathy and is commonly located in places of high mechanical pressure. However, there is a scarcity of published data on the diagnosis and treatment of VSLDN. Our paper describes various types of VSLDN skin pathology, summarizes the diagnostic procedure options available, and documents the experience of our diabetic foot clinic in applying short-term VSLDN therapies as part of routine podiatric practice.

Several studies have been published in the last decade on the effects of low glucose degradation product (GDP) neutral pH (L-GDP/N-pH) dialysis solutions on peritoneal morphology and function during the long-term PD treatment. Compared to conventional solutions, the impact of these solutions on the morphological and functional alterations of the peritoneal membrane is discussed, including those of effluent proteins that reflect the status of peritoneal tissues. Long-term PD with conventional solutions is associated with the loss of mesothelium, submesothelial and interstitial fibrosis, vasculopathy, and deposition of advanced glycosylation end products (AGEs). L-GDP/N-pH solutions mitigate these alterations, although vasculopathy and AGE deposition are still present. Increased vascular density was found in some studies. Small solute transport increases with PD duration on conventional solutions. Initially, higher values are present on L-GDP/N-pH treatment, but these may be reversible and remain stable with PD duration. Consequently, ultrafiltration (UF) is lower initially but remains stable thereafter. At 5 years, UF and small pore fluid transport are higher, while free water transport decreased only slightly during follow-up. Cancer antigen 125 was initially higher on L-GDP/N-pH solutions, suggesting better mesothelial preservation but decreased during follow-up. Therefore, L-GDP/N-pH solutions may not prevent but reduce and retard the peritoneal alterations induced by continuous exposure to glucose-based dialysis fluids.

Background: Cardiovascular surgery is confronted by a lack of suitable materials for patch repair. Acellular animal tissues serve as an abundant source of promising biomaterials. The aim of our study was to explore the bio-integration of decellularized or recellularized pericardial matrices in vivo. Methods: Porcine (allograft) and ovine (heterograft, xenograft) pericardia were decellularized using 1% sodium dodecyl sulfate ((1) Allo-decel and (2) Xeno-decel). We used two cell types for pressure-stimulated recellularization in a bioreactor: autologous adipose tissue-derived stromal cells (ASCs) isolated from subcutaneous fat of pigs ((3) Allo-ASC and (4) Xeno-ASC) and allogeneic Wharton’s jelly mesenchymal stem cells (WJCs) ((5) Allo-WJC and (6) Xeno-WJC). These six experimental patches were implanted in porcine carotid arteries for one month. For comparison, we also implanted six types of control patches, namely, arterial or venous autografts, expanded polytetrafluoroethylene (ePTFE Propaten® Gore®), polyethylene terephthalate (PET Vascutek®), chemically stabilized bovine pericardium (XenoSure®), and detoxified porcine pericardium (BioIntegral® NoReact®). The grafts were evaluated through the use of flowmetry, angiography, and histological examination. Results: All grafts were well-integrated and patent with no signs of thrombosis, stenosis, or aneurysm. A histological analysis revealed that the arterial autograft resembled a native artery. All other control and experimental patches developed neo-adventitial inflammation (NAI) and neo-intimal hyperplasia (NIH), and the endothelial lining was present. NAI and NIH were most prominent on XenoSure® and Xeno-decel and least prominent on NoReact®. In xenografts, the degree of NIH developed in the following order: Xeno-decel > Xeno-ASC > Xeno-WJC. NAI and patch resorption increased in Allo-ASC and Xeno-ASC and decreased in Allo-WJC and Xeno-WJC. Conclusions: In our setting, pre-implant seeding with ASC or WJC had a modest impact on vascular patch remodeling. However, ASC increased the neo-adventitial inflammatory reaction and patch resorption, suggesting accelerated remodeling. WJC mitigated this response, as well as neo-intimal hyperplasia on xenografts, suggesting immunomodulatory properties.

Background: The prognostic role of intimal arteritis of kidney allografts in donor-specific antibody negative (DSA-) antibody-mediated rejection (ABMR) remains unclear. Methods: Seventy-two out of 881 patients who had undergone kidney transplantation from 2014 to 2017 exhibited intimal arteritis in biopsies performed during the first 12 months. In 26 DSA negative cases, the intimal arteritis was accompanied by tubulointerstitial inflammation as part of T cell-mediated vascular rejection (TCMRV, N = 26); intimal arteritis along with microvascular inflammation occurred in 29 DSA negative (ABMRV/DSA-) and 19 DSA positive cases (ABMRV, DSA+, N = 17). In 60 (83%) patients with intimal arteritis, the surveillance biopsies after antirejection therapy were performed. Hundred and two patients with non-vascular ABMR with DSA (ABMR/DSA+, N = 55) and without DSA (ABMR/DSA-, N = 47) served as controls. Time to transplant glomerulopathy (TG) and graft failure were the study endpoints. Results: Transplant glomerulopathy -free survival at 36 months was 100% in TCMRV, 85% in ABMR/DSA-, 65% in ABMRV/DSA-, 54% in ABMR/DSA+ and 31% in ABMRV/DSA+ (log rank p < 0.001). Death-censored graft survival at 36 months was 98% in ABMR/DSA-, 96% in TCMRV, 86% in ABMRV/DSA-, 79% in ABMR/DSA+, and 64% in ABMRV/DSA+ group (log rank p = 0.001). In surveillance biopsies, the resolution of rejection was found in 19 (90%) TCMRV, 14 (58%) ABMRV/DSA-, and only 4 (27%) ABMRV/DSA+ patients ( p = 0.006). In the multivariable model, intimal arteritis as part of ABMR represented a significant risk for TG development (HR 2.1, 95% CI 1.2-3.8; p = 0.012) regardless of DSA status but not for graft failure at 36 months. Conclusions: Intimal arteritis as part of ABMR represented a risk for early development of TG regardless of the presence or absence of DSA. Intimal arteritis in DSA positive ABMR represented the high-risk phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Novotny, Hruba, Kment, Voska, Kabrtova, Slavcev and Viklicky.)

Stereotactic body radiotherapy (SBRT) has been suggested as a promising therapeutic alternative in cases of failed catheter ablation for recurrent ventricular tachycardias (VTs) in patients with structural heart disease. This case series is the first postmortem immunohistochemical analysis of morphologic changes in the myocardium early and late after SBRT. The present findings are in line with experimental observations on apoptosis followed by fibrosis. This may explain why the effect of SBRT on VT is not predominantly immediate. Together with observation of early recurrences after SBRT for VT, these data suggest that this strategy may have rather delayed antiarrhythmic effects., Competing Interests: Funding Support and Author Disclosures This work was supported by grant project AZV NU20-02-00244 from the Ministry of Health of the Czech Republic and by funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 945119. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Molecular assessment of renal allografts has already been suggested in antibody-mediated rejection (ABMR), but little is known about the gene transcript patterns in particular renal compartments. We used laser capture microdissection coupled with quantitative RT-PCR to distinguish the transcript patterns in the glomeruli and tubulointerstitium of kidney allografts in sensitized retransplant recipients at high risk of ABMR. The expressions of 13 genes were quantified in biopsies with acute active ABMR, chronic active ABMR, acute tubular necrosis (ATN), and normal findings. The transcripts were either compartment specific ( TGFB1 in the glomeruli and HAVCR1 and IGHG1 in the tubulointerstitium), ABMR specific ( GNLY ), or follow-up specific ( CXCL10 and CX3CR1 ). The transcriptional profiles of early acute ABMR shared similarities with ATN. The transcripts of CXCL10 and TGFB1 increased in the glomeruli in both acute ABMR and chronic active ABMR. Chronic active ABMR was associated with the upregulation of most genes ( SH2D1B , CX3CR1 , IGHG1 , MS4A1 , C5 , CD46 , and TGFB1 ) in the tubulointerstitium. In this study, we show distinct gene expression patterns in specific renal compartments reflecting cellular infiltration observed by conventional histology. In comparison with active ABMR, chronic active ABMR is associated with increased transcripts of tubulointerstitial origin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Trailin, Mrazova, Hruba, Voska, Sticova, Slavcev, Novotny, Kocik and Viklicky.)

The tubulitis with/without interstitial inflammation not meeting criteria for T-cell-mediated rejection (minimal allograft injury) is the most frequent histological findings in early transplant biopsies. The course of transcriptional changes in sequential kidney graft biopsies has not been studied yet. Molecular phenotypes were analyzed using the Molecular Microscope ® Diagnostic System (MMDx) in 46 indication biopsies (median 13 postoperative days) diagnosed as minimal allograft injury and in corresponding follow-up biopsies at 3 months. All 46 patients with minimal injury in early biopsy received steroid pulses. MMDx interpreted indication biopsies as no-rejection in 34/46 (74%), T-cell-mediated rejection (TCMR) in 4/46 (9%), antibody-mediated rejection in 6/46 (13%), and mixed rejection in 2/46 (4%) cases. Follow-up biopsies were interpreted by MMDx in 37/46 (80%) cases as no-rejection, in 4/46 (9%) as TCMR, and in 5/46 (11%) as mixed rejection. Follow-up biopsies showed a decrease in MMDx-assessed acute kidney injury (P = 0.001) and an increase of atrophy-fibrosis (P = 0.002). The most significant predictor of MMDx rejection scores in follow-up biopsies was the tubulitis classifier score in initial biopsies (AUC = 0.84, P = 0.002), confirmed in multivariate binary regression (OR = 16, P = 0.016). Molecular tubulitis score at initial biopsy has the potential to discriminate patients at risk for molecular rejection score at follow-up biopsy., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

The Banff 2019 kidney allograft pathology update excluded isolated tubulitis without interstitial inflammation (ISO-T) from the category of borderline (suspicious) for acute T cell-mediated rejection due to its proposed benign clinical outcome. In this study, we explored the molecular assessment of ISO-T. ISO-T or interstitial inflammation with tubulitis (I + T) was diagnosed in indication biopsies within the first 14 postoperative days. The molecular phenotype of ISO-T was compared to I + T either by using RNA sequencing (n = 16) or by Molecular Microscope Diagnostic System (MMDx, n = 51). RNA sequencing showed lower expression of genes related to interferon-y (p = 1.5 *10 -16 ), cytokine signaling (p = 2.1 *10 -20 ) and inflammatory response (p = 1.0*10 -13 ) in the ISO-T group than in I + T group. Transcripts with increased expression in the I + T group overlapped significantly with previously described pathogenesis-based transcript sets associated with cytotoxic and effector T cell transcripts, and with T cell-mediated rejection (TCMR). MMDx classified 25/32 (78%) ISO-T biopsies and 12/19 (63%) I + T biopsies as no-rejection. ISO-T had significantly lower MMDx scores for interstitial inflammation (p = 0.014), tubulitis (p = 0.035) and TCMR (p = 0.016) compared to I + T. Fewer molecular signals of inflammation in isolated tubulitis suggest that this is also a benign phenotype on a molecular level.

The study was intended to compare pancreas graft survival rates in two groups of pancreas and kidney transplant recipients prospectively randomized to treatment either with sirolimus or MMF. From 2002 to 2013, 238 type 1 diabetic recipients with end-stage kidney disease were randomized 1:1 to sirolimus or MMF treatment. Noncensored pancreas survival at 5 years was 76.4 and 71.6% for sirolimus and MMF groups, respectively (P > .05). Death-censored pancreas survival was better in the sirolimus group (P = .037). After removal of early graft losses pancreas survival did not differ between groups (MMF 83.1% vs sirolimus 91.6%, P = .11). Nonsignificantly more grafts were lost due to rejection in the MMF group (10 vs 5; P = .19). Cumulative patient 5-year survival was 96% in the MMF group and 91% in the sirolimus group (P > .05). Five-year cumulative noncensored kidney graft survival rates did not statistically differ (85.6% in the sirolimus group and 88.8% in MMF group). Recipients treated with MMF had significantly more episodes of gastrointestinal bleeding (7 vs 0, P = .007). More recipients in the sirolimus group required corrective surgery due to incisional hernias (21 vs 12, P = .019). ClinicalTrials No.: NCT03582878., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The objectives of this study were to evaluate patients with aortic abdominal aneurysm (AAA) with regard to immunoglobulin (Ig)G4-related disease (IgG4-RD). IgG4-RD represents a recently defined condition comprised of a collection of disorders characterized by IgG4 hypergammaglobulinemia, the presence of IgG4-positive plasma cells in organs affected with fibrotic or sclerotizing changes and typical histopathological features. It was identified as a possible cause of vasculitis in large vessels. Studies have been published on a possible association between inflammatory aortic or cardiovascular disease and IgG4-RD. We examined 114 patients with AAA requiring surgery in order to identify findings which are characteristic of IgG4-RD. Aneurysm samples from seven patients showed histopathological features consistent with IgG4-RD and the presence of IgG4 + plasma cells. Only two of these seven patients showed elevated IgG4 serum levels higher 1·35 g/l. In five of the patients, the concentration of serum IgG4 was lower than 1·20 g/l, with the number of IgG4 + plasma cells being higher than 50/high-power field. These findings were consistent with AAA being a heterogeneous group of inflammatory diseases with different pathogenesis., (© 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6-12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher ( p < 0.05-0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies.

Background: Advanced renal cell carcinoma in some cases causes malignant intravascular thrombus with the potential for growth into the inferior vena cava or even the right atrium. Renal cell carcinoma is accompanied by malignant intravascular thrombus in up to 10% of cases. We present an overview of three patients diagnosed as having renal cell carcinoma with malignant intravascular thrombus requiring radical nephrectomy combined with inferior vena cava thrombectomy., Case Presentation: Three patients diagnosed as having renal cell carcinoma were indicated for renal cell carcinoma combined with inferior vena cava thrombectomy between 2014 and 2017 at our department: a 69-year-old white Caucasian woman, a 74-year-old white Caucasian woman, and a 58-year-old white Caucasian woman. According to the Novick classification of inferior vena cava tumor thrombus, there was one infrahepatic (level II) and two supradiaphragmatic (level IV) malignant intravascular thrombi. The average age of these patients was 67 years (range 58-74 years). All patients underwent radical nephrectomy combined with inferior vena cava thrombectomy through transabdominal approach. In patients with level IV malignant intravascular thrombus, transesophageal echocardiogram was used to guide the placement of the inferior vena cava cross-clamp above the diaphragm. In one patient the pericardium was opened to place a cross-clamp above a tumor just below the right atrium. There were no postoperative mortalities to date with an average follow-up of 23 months (range 2-48 months). To date, no patient has demonstrated recurrent inferior vena cava malignant intravascular thrombus requiring secondary inferior vena cava thrombectomy or any other treatment. A comparison of estimated blood loss and transfusion rate was not significantly different in all three cases., Conclusion: Despite the technical complexity of the procedure, caval thrombectomy combined with radical nephrectomy currently represents the only radical treatment for renal cell carcinoma accompanied by malignant intravascular thrombus with good mid-term oncological outcomes.

Giant cell myocarditis is known as a rare and frequently fatal type of myocarditis that is usually characterized by progressive congestive heart failure and frequent ventricular arrhythmias. We report a rare case of giant cell myocarditis in a 64-year-old previously healthy woman. The case was complicated by the rapid development of progressive acute heart failure, which required the comprehensive care of our heart team. Using a broad spectrum of therapeutic approaches, the patient successfully underwent heart transplantation., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

We report a case of phaeohyphomycosis caused by Alternaria infectoria in a 61-year-old heart transplant recipient with multiple skin lesions and pulmonary infiltrates. The infection spread via the haematogenous route from the primary cutaneous lesions into the lungs. The diagnosis was based on the histopathological examination, direct microscopy, skin lesion cultures and detection of Alternaria DNA in the bronchoalveolar lavage fluid using molecular methods. The treatment consisted of a combination of surgical excision and systemic antifungal therapy. Voriconazole was the first agent used but had a weak effect. Posaconazole was subsequently used to achieve a successful response. The isolate was identified as A. infectoria by sequencing of the rDNA ITS region and the partial β-tubulin gene.

Background: Antibody-mediated rejection (AMR) is a serious complication of organ transplantation, and its treatment is complex. The aim of this study was to assess immunoadsorption (IA) for treatment-immunized patients before heart transplantation (HTX) and as the first step of AMR treatment after HTX., Methods: The cohort consisted of 10 patients (8 men, 2 women; age range, 20-57 years). For 3 of these patients, IA was included in the desensitization protocol before HTX; for 7 patients, IA was the first step of the treatment protocol. One patient underwent IA before and after HTX., Results: A comparison of values before IA and after the last procedure showed a decrease in immunoglobulin subgroups (G, M, and A). In patients before HTX, a decline was noted in panel reactive antibodies. After HTX, IA procedures led to a significant decrease in donor-specific antibody (DSA) class I; DSA class II fell in 6 of 7 patients, with 51% falling below the detection limit., Conclusions: IA in patients during HTX is safe procedure for reducing DSA. The removal of antibodies is the first step in comprehensive treatment and must be followed by a procedure that prevents their further development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Whether nerve fiber loss, a prominent feature of advanced diabetic neuropathy, can be reversed by reestablishment of normal glucose control remains questionable. We present 8-year follow-up data on epidermal nerve fiber (ENF) density and neurological function in patients with type 1 diabetes after simultaneous pancreas and kidney transplantation (SPK) with long-term normoglycemia. Distal thigh skin biopsies with ENF counts, vibration perception thresholds (VPTs), autonomic function testing (AFT) and electrophysiological examinations were performed at time of SPK and 2.5 and 8 years after SPK in 12 patients with type 1 diabetes. In comparison to controls, baseline ENF density, VPT and AFT results of patients indicated severe neuropathy. At follow-up, all SPK recipients were insulin independent with excellent glycemic control and kidney graft function; however, the severe ENF depletion present at baseline had not improved, with total ENF absence in 11 patients at 8-year follow-up. Similarly, no amelioration occurred in the VPT and AFT results. Numerical improvement was seen in some electrophysiological parameters; however, statistical significance was achieved only in median motor nerve conduction velocity. ENF loss and functional deficits in advanced diabetic peripheral neuropathy are rarely reversible, even by long-term normoglycemia, which underscores the importance of neuropathy prevention by early optimal glycemic control., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Solid-phase assays (SPA) have facilitated detection and definition of antibodies to human leukocyte antigens (HLA) and major histocompatibility complex class I chain-related antigen A (MICA). However, clinical consequences of pretransplant SPA results in heart transplantation have been studied insufficiently in the current era of immunosuppression and rejection surveillance. Pretransplant sera, panel-reactive antibodies (PRA), pretransplant crossmatch, and clinical data were retrospectively analyzed in 264 adult heart transplant recipients. The specificity of HLA and MICA antibodies and C1q-binding activity of donor-specific antibodies (DSA) were defined using SPA. Pretransplant HLA antibodies were detected in 57 (22%) individuals, in 28 individuals (11%); these antibodies were DSA after transplant. Preformed DSA and elevated peak PRA were independent predictors of pathologic AMR, which occurred in 19 individuals (7%). The increasing number of DSA and the cumulative mean fluorescence intensity of DSA were associated with AMR. C1q-binding assay was a suboptimal predictor of AMR in our cohort. Pretransplant allosensitization and MICA antibodies were related neither to impaired graft survival nor to other adverse clinical events during a median follow-up of 39 months. Identification of preformed DSA by SPA, in addition to PRA monitoring, may predict AMR in the contemporary era of heart transplantation., (© 2015 Steunstichting ESOT.)

Variability of pancreatic donors may significantly impact the success of islet isolation. The aim of this study was to evaluate donor factors associated with isolation failure and to investigate whether immunohistology could contribute to organ selection. Donor characteristics were evaluated for both successful ( n = 61) and failed ( n = 98) islet isolations. Samples of donor pancreatic tissue ( n = 78) were taken for immunohistochemical examination. Islet isolations with 250000 islet equivalents were considered successful. We confirmed that BMI of less than 25 kg/m 2 ( P < 0.001), cold ischemia time more than 8 hours ( P < 0.01), hospitalization longer than 96 hours ( P < 0.05), higher catecholamine doses ( P < 0.05), and edematous pancreases ( P < 0.01) all unfavorably affected isolation outcome. Subsequent immunohistochemical examination of donor pancreases confirmed significant differences in insulin-positive areas ( P < 0.001). ROC analyses then established that the insulin-positive area in the pancreas could be used to predict the likely success of islet isolation ( P < 0.001). At the optimal cutoff point (>1.02%), sensitivity and specificity were 89% and 76%, respectively. To conclude, while the insulin-positive area, determined preislet isolation, as a single variable, is sufficient to predict isolation outcome and helps to improve the success of this procedure, its combination with the established donor scoring system might further improve organ selection.

A 53-year-old female with idiopathic hypereosinophilic syndrome underwent recurrent tricuspid valve replacement for Löffler's endocarditis. We review the literature on tricuspid valve surgery in patients with this uncommon disorder., (© 2014 Wiley Periodicals, Inc.)

Smallpox vaccine based on live, replicating vaccinia virus (VACV) is associated with several potentially serious and deadly complications. Consequently, a new generation of vaccine based on non-replicating Modified vaccinia virus Ankara (MVA) has been under clinical development. MVA seems to induce good immune responses in blood tests, but it is impossible to test its efficacy in vivo in human. One of the serious complications of the replicating vaccine is eczema vaccinatum (EV) occurring in individuals with atopic dermatitis (AD), thus excluding them from all preventive vaccination schemes. In this study, we first characterized and compared development of eczema vaccinatum in different mouse strains. Nc/Nga, Balb/c and C57Bl/6J mice were epicutaneously sensitized with ovalbumin (OVA) or saline control to induce signs of atopic dermatitis and subsequently trans-dermally (t.d.) immunized with VACV strain Western Reserve (WR). Large primary lesions occurred in both mock- and OVA-sensitized Nc/Nga mice, while they remained small in Balb/c and C57Bl/6J mice. Satellite lesions developed in both mock- and OVA-sensitized Nc/Nga and in OVA-sensitized Balb/c mice with the rate 40-50%. Presence of mastocytes and eosinophils was the highest in Nc/Nga mice. Consequently, we have chosen Nc/Nga mice as a model of AD/EV and tested efficacy of MVA and Dryvax vaccinations against a lethal intra-nasal (i.n.) challenge with WR, the surrogate of smallpox. Inoculation of MVA intra-muscularly (i.m.) or t.d. resulted in no lesions, while inoculation of Dryvax t.d. yielded large primary and many satellite lesions similar to WR. Eighty three and 92% of mice vaccinated with a single dose of MVA i.m. or t.d., respectively, survived a lethal i.n. challenge with WR without any serious illness, while all Dryvax-vaccinated animals survived. This is the first formal prove of protective immunity against a lethal poxvirus challenge induced by vaccination with MVA in an atopic organism.

Background & Aims: The Wnt signaling pathway is required for maintenance of the intestinal epithelia; blocking this pathway reduces the proliferative capacity of the intestinal stem cells. However, aberrant Wnt signaling leads to intestinal cancer. We investigated the roles of the Wnt pathway in homeostasis of the intestinal epithelium and during malignant transformation in human cells and mice., Methods: We performed chromatin immunoprecipitation (ChIP) with DNA microarray analysis (ChIP-on-chip) to identify genes regulated by Wnt signaling in human colorectal cancer cells Colo320, DLD1, LS174T, and SW480. Formation of intestinal tumor was induced in C57BL/6J mice using azoxymethane and dextran sulfate. Intestinal tissues from these mice, as well as Apc(+/Min) and Apc(CKO/CKO)/Lgr5-EGFP-IRES-CreERT2 mice, were analyzed by immunohistochemistry and in situ hybridization., Results: We identified promoter regions of 960 genes that interacted with the Wnt pathway nuclear effector T-cell factor 4 in 4 different human colorectal cancer-derived cell lines; 18 of these promoters were present in all chromatin precipitates. Wnt signaling up-regulated a member of the tumor necrosis factor receptor superfamily called TROY. Levels of TROY messenger RNA were increased in human cells with deficiencies in the adenomatous polyposis coli (APC) gene and in cells stimulated with the Wnt3a ligand. Expression of Troy was significantly up-regulated in neoplastic tissues from mice during intestinal tumorigenesis. Lineage tracing experiments revealed that Troy is produced specifically by fast-cycling intestinal stem cells. TROY associated with a unique marker of these cells, leucine-rich repeat-containing G-protein coupled receptor (LGR) 5. In organoids established from the intestinal crypts, Troy suppressed signaling mediated by R-spondin, a Wnt agonist., Conclusions: TROY is up-regulated in human colorectal cancer cell lines and in intestinal tumors in mice. It functions as a negative modulator of the Wnt pathway in LGR5-positive stem cells., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Electrospun gelatin and poly-ε-caprolactone (PCL) nanofibers were prepared using needleless technology and their biocompatibility and therapeutic efficacy have been characterized in vitro in cell cultures and in an experimental model of a skin wound. Human dermal fibroblasts, keratinocytes and mesenchymal stem cells seeded on the nanofibers revealed that both nanofibers promoted cell adhesion and proliferation. The effect of nanofibers on wound healing was examined using a full thickness wound model in rats and compared with a standard control treatment with gauze. Significantly faster wound closure was found with gelatin after 5 and 10 days of treatment, but no enhancement with PCL nanofibers was observed. Histological analysis revealed enhanced epithelialisation, increased depth of granulation tissue and increased density of myofibroblasts in the wound area with gelatin nanofibers. The results show that gelatin nanofibers produced by needleless technology accelerate wound healing and may be suitable as a scaffold for cell transfer and skin regeneration.

Object: Among several non-invasive methods of liver fat analysis, the most important role is played by MR imaging and spectroscopy (MRS). This study describes the 1H MRS at 3T measurement of liver fat volume fraction Φ(fat) in a group of liver transplant patients, an at-risk group for the development of de novo steatosis., Materials and Methods: Seventy-seven liver transplant recipients who underwent routine protocolar posttransplant examination were divided into three groups: CON-PAT (control group for the cross validation test, 48 patients), PAT-PAT (patients test group for the cross validation test, 29 patients), and PAT (pooled data). Single voxel 1H MRS at 3T was used for the determination of Φ(fat) and histology results (His) were used as the reference standard., Results: Linear and non-linear regression models were used to describe the relationship between Φ(fat) and His. Strong correlation was found for both models with r = 0.83-0.94 (P < 0.001); a higher r was found for non-linear regression in all tested groups. Areas under receiver operation curves were calculated for cut points His ≥ 5 and > 33% and were found in the range of 0.77-0.86. Fibrosis influences the calculation of Φ(fat) and different slopes were obtained for fibrosis stages F0-F1 and F2-F3, respectively., Conclusion: Significant correlation was found between the results of histology and 1H MRS measurement of liver fat content. The method is suitable for non-invasive repetitive examination of liver fat in liver-transplants patients between protocol biopsies and for the screening of steatosis in other liver diseases.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions., (© 2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Metabolic syndrome is responsible for increasing the fat content of the liver. Among several non-invasive methods of liver fat analysis, the most important role is played by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). This pilot study describes the methodology for measurements of triglycerides in the liver in a group of liver transplant patients using 1H MRS at 3T., Methods and Results: Thirty-eight patients (12 Female, 27 male, aged 19-71) who underwent routine preventive examination at IKEM were included in the MRS study. The fat content of liver biopsies was classified according to the number of affected hepatocytes, HIS. Based on this classification, there were 20 patients with a steatosis score of S0, 15 patients with a score of S1, 2 patients with a score of S2 and 1 patient with a score of S3. 1H MR spectra were measured from three positions in the liver. Following Longo et al, the concentration of fat phi(fat), was calculated from the signal intensities of water and triglycerides. Linear correlation between the number of affected hepatocytes and fat content was described by the equation: HIS = 6.4 phi(fat) -2.1; r2 = 0.85; p = 0.001., Conclusions: The pilot study confirmed that examination of fat content using 1H MRS at 3T is well tolerated by patients. Significant correlation was found between the results of histology and 1H MRS measurement of liver fat content. The method is suitable for non-invasive repetitive and screening examination measurement of fat in the liver.