Search

Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3 + (FOXP3 + ) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients ( n = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4 + FOXP3 + T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and UBC cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC. Cancer Immunol Res; 6(5); 528-38. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: To determine whether sentinel node detection (SNd) in muscle-invasive urothelial bladder cancer (MIBC) can be performed in patients undergoing neoadjuvant chemotherapy (NAC) and determine whether SNd is feasible in all pT stages, including pT0., Background: Previous published series of SNd in MIBC have not included patients undergoing NAC, and systematic reports of pT0 patients w/wo NAC were absent. Translational immunological tumor research on MIBC focusing on SNd, in the era of NAC, requires technical feasibility. Additionally, SNd in MIBC requests further evaluations as a method for nodal staging., Materials and Methods: Ninety-nine patients with suspected urothelial MIBC were prospectively selected from six urological centers. After TUR-B and primary staging, 65 MIBC patients qualified for radical cystectomy. Precystectomy staging was cT2a-T4aN0M0, including 47 NAC patients and 18 chemo-naïve patients. All 65 patients underwent intraoperative SNd by peritumoral injection of 80 Mbq Technetium and Geiger probe detection. Postcystectomy staging was pT0-T4aN0-N2M0. SNs were defined by two calculations, SNdef1 and SNdef2., Results: Totally 1063 lymph nodes were removed (total SNs; 222-227). NAC patients with pT0 (n = 24) displayed a true positive detection in 91.7 % by either SNdef, with a median of 3.0 SNs. NACpT >0 patients had a true positive detection in 87 % (SNdef1) and 91.3 % (SNdef2). In a univariate analysis, patient group neither NAC nor tumor downstaging influenced detection rates, regardless of SN definition. In total eight patients, 4/22 metastatic nodes were SNs while 18/22 were non-SNs., Conclusions: Sentinel node detection in MIBC is feasible also in NAC patients, regardless of pT stage. SNd played no role in nodal staging.

Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4 + T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-α. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy., (Copyright © 2016. Published by Elsevier Inc.)

Objective: To evaluate the feasibility of performing sentinel node detection in patients with renal cell carcinoma (RCC)., Materials and Methods: An open series of 13 arbitrarily selected patients with T1b-T3b RCC scheduled for radical nephrectomy at a single Tertiary Academic Centre were examined with different modalities of sentinel node detection. Preoperative ultrasonography-guided injection of radioactive isotope, lymphoscintigram and single photon emission computed tomography/computed tomography, followed by intraoperative gamma-probe detection and Patent Blue detection, as well as postoperative scintigram of the main specimen were the planned interventions. These investigations were performed in conjunction with intended open radical nephrectomy., Results: In 10 of the 13 patients sentinel node detection was achieved with 32 sentinel nodes displayed. Radio-guided surgery using an intraoperative gamma-probe resulted in the highest realtive detection rate with detection of sentinel nodes in nine patients. In total, nine metastatic sentinel nodes were detected in three patients. One patient, preoperatively staged as N+, was restaged after sentinel node detection and histopathology as pN0., Conclusions: Sentinel node detection in renal tumours is feasible although evaluation of different modes of detection needs further refinement and standardization. All nodes preoperatively detected by routine computed tomography as suspicious metastatic lesions were confirmed as sentinel nodes, including two nodes considered as metastatic by preoperative routine imaging but ultimately staged as non-metastatic sentinel nodes., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Aim: The authors analyse the patients hospitalized with a neuroischemic diabetic foot. They evaluate experiences and results of the crural arteries percutaneous transluminal angioplasty (PTA) in the diabetic patients., Method: It is a retrospective analysis of the patients hospitalized during years 2005-2008 at the Department of Vascular Surgery of the Teaching Hospital J. A. Reiman Presov with the diabetic foot. During the study period 265 hospitalization in 205 patients were registered for complications of the diabetic foot. PTA of the crural arteries was performed on 74 lower extremities in 68 patients. 133 crural arteries were revascularized in this group of the patients. Indication for execution of the crural arteries PTA in the diabetic patients was critical limb ischemia on 68 revascularized lower extremities (91.9%)., Results: Technical success (residual stenosis no more than 30%, unobstructed revascularized crural artery to periphery) was achieved on 93 revascularized crural arteries (69.92%). They have control examination minimally 12 months after PTA in 54 revascularized lower extremities of the 68 patients with the neuroischemic diabetic foot. From this subset of the patients 28 lower extremities (51.85%) are healed according to clinical examination, on 7 lower extremities (12.96%) clinical signs of critical limb ischemia remain, 10 times (18.52%) low amputation was performed and 9 times (16.67%) high amputation was executed., Conclusion: The authors believe that PTA of the crural arteries is safe and effective method of critically ischemic diabetic foot revascularization. If revascularization is successful, it can effectively contributes to the lower extremity salvage of the patient with neuroischemic diabetic foot.

Aim: Authors in the work analyse the patients hospitalized with thrombosis of the surgical infrainguinal reconstruction. They evaluate the causes of reconstructions occlusions, therapeutic options in the treatment and their experiences with treatment of these patients., Method: It is the retrospective analysis of the patients hospitalized during years 2001-2006 at the Department of Vascular Surgery of the Teaching Hospital J. A. Reimana in Presov with thrombosis of the surgical infrainguinal reconstruction. During the study period 723 surgical infrainguinal revascularization procedures were performed. The basic therapeutic approach in the care of these patients is anticoagulation and digital subtraction angiography, then they decide between percutaneous endovascular treatment, surgical thrombectomy, reoperation with implantation of the new reconstruction or conservative treatment. In the phase of irreversible ischemia high amputation is indicated., Results: Thrombosis of the reconstruction was occured in 109 subjects (15.8%). Prothesis was thrombosed in 71 subjects (65.14%), vein in 38 subjects (34.86%). Percutaneous endovascular treatment was indicated in 3 subjects (2.8%), surgical thrombectomy with correction of the stenosis in 23 subjects (21.1%), reoperation with implantation of the new reconstruction in 53 subjects (48.6%),conservative approach in 21 subjects (19.3%), high amputation in 9 subjects (8.2%). The secondary patency after 12 months according to the life table method analysis after percutaneous endovascular treatment was 75%, after surgical thrombectomy of the graft with correction of stenosis 37% and after reoperation with implantation of the new reconstruction 72%., Conclusion: Authors believe that the best treatment in the care of the patients with thrombosis of the surgical infrainguinal reconstruction and critical limb ischemia is implantation of the new secondary reconstruction with autologous vein.

We report the achievement of a highly versatile imager consisting of a tunable fluidic lens with a wide tuning range and three fixed lenses. The device has a volume of less than 1 cm(3) and a short total track length of 12.5 cm. It can function as a regular camera with an ultrawide autofocusing range and as a microscope with 3 microm resolution.

Purpose: Renal cell carcinoma (RCC) is the most common malignancy of the kidney composed of specific tumor types. The sporadic conventional RCCs are, in contrast to the other RCC types, characterized by a high rate of von Hippel-Lindau (VHL) mutations and hypermethylation. The majority of these tumors lack functional VHL protein (pVHL) that leads to increased hypoxia-inducible factor 1alpha (HIF-1alpha) expression. The pVHL is the physiologic regulator of the activity of HIF-1alpha by targeting it to the proteasome for degradation under normoxia. Both pVHL and HIF-1alpha target other genes that are important for cancer survival and proliferation. Expression of HIF-1alpha has been linked to poor prognosis in different malignancies, although few studies have been done on the relation between HIF-1alpha and clinical variables in RCC., Experimental Design: HIF-1alpha protein expression was analyzed in tumor tissue from 92 patients with RCC. HIF-1alpha was quantified by Western blot relative to a positive control., Results: The HIF-1alpha protein was expressed as two bands which strongly correlated (r = 0.906, P < 0.001); therefore, they were added and the sum evaluated against clinicopathologic variables. There was no association between HIF-1alpha and gender, stage, grade, tumor size, or vein invasion. Conventional RCCs had significantly higher HIF-1alpha expression compared with papillary and chromophobe RCCs and kidney cortex. In conventional RCC, HIF-1alpha was an independent prognostic factor., Conclusion: HIF-1alpha levels varied significantly between the different RCC types. In conventional RCC, HIF-1alpha was an independent prognostic factor. These data indicate that HIF-1alpha is involved in tumorogenesis and progression of RCC. Evaluation of other HIF target gene products and correlation to angiogenesis seems warranted.

The possibility that computerized image analysis could increase the reproducibility of grading of bladder carcinoma as compared to conventional subjective grading made by pathologists was investigated. Object, texture and graph based analysis were carried out from Feulgen stained histological tissue sections. The object based features were extracted from gray scale images, binary images obtained by thresholding the nuclei and several other images derived through image processing operations. The textural features were based on the spatial gray-tone co-occurrence probability matrices and the graph based features were extracted from the minimum spanning trees connecting all nuclei. The large numbers of extracted features were evaluated in relation to subjective grading and to factors related to prognosis using multivariate statistical methods and multilayer backpropagation neural networks. All the methods were originally developed and tested on material from one patient and then tested for reproducibility on entirely different patient material. The results indicate reasonably good reproducibility for the best sets of features. In addition, image analysis based grading showed almost identical correlation to mitotic density and expression of p53 protein as subjective grading. It should thus be possible to use this kind of image analysis as a prognostic tool for bladder carcinoma.

Image analysis of histological sections was used to achieve a more objective malignancy grading of transitional cell carcinoma of the bladder. Images from Feulgen-stained sections from a clinical material of 197 tumours were analyzed. Features at various levels of analysis, e.g. mainly related to individual objects, neighbouring objects and the entire image, were analyzed. The features used were based on relational rather than individual nuclear features. With this technique, typical tissue architecture and degree of order/disorder can be described. These characteristics were compared by means of multivariate statistical methods with the subjective grading of the pathologists at our institution. This comparison provided the best subset of features and the agreement between the subjective and computer-based classification was 73%. The size, orientation and variation of the grey scale of the nuclei were particularly powerful. On a continuous scale, from grade 1 to 2A and 2B to 3, the four grades formed two distinct classes, low and high grade. In this distribution, the intermediate grade 2A was identified as a displaced grade 1 and the other intermediate grade 2B as a displaced grade 3.

The properties of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methyl-arginyl-glycyl-aspartyl-penicillamine-amide] as a GPIIb/IIIa antagonist have been studied in vitro and compared with those of the parent molecule, Ac-RGDS-NH2. Ac-RGDS-NH2 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 530 +/- 73 nM. In canine platelet rich plasma Ac-RGDS-NH2 produced a concentration related inhibition of adenosine diphosphate-induced platelet aggregation following preincubation for 3 min with an IC50 of 91 +/- 1 microM. However, incubation in platelet rich plasma for 3 hr abolished the activity of Ac-RGDS-NH2. SK&F 106760 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 477 +/- 57 pM. SK&F 106760 inhibited adenosine diphosphate-induced platelet aggregation in human platelet rich plasma with an IC50 of 230 +/- 60 nM but did not inhibit the von Willebrand Factor receptor (GPIb/IX)-mediated platelet agglutination produced by ristocetin. In canine platelet rich plasma SK&F 106760 inhibited aggregation produced by adenosine diphosphate, collagen and epinephrine/U-46619 with IC50 values of 355 +/- 35, 260 +/- 20, and 490 +/- 90 nM, respectively and in gel filtered platelets inhibited thrombin-mediated aggregation with an IC50 of 188 +/- 10 nM. Preincubation of SK&F 106760 in platelet rich plasma for three hours had no significant effect on its ability to inhibit adenosine diphosphate-induced platelet aggregation. SK&F 106760 produced insurmountable inhibition of adenosine diphosphate-induced platelet aggregation in the presence of constant fibrinogen concentrations, but produced competitive inhibition of the concentration-response curve to fibrinogen in adenosine diphosphate-activated platelets with a Kb of 8.0 +/- 1.0 nM. Thus, SK&F 106760 is a potent, stable competitive GPIIb/IIIa antagonist with no detectable activity at the von Willebrand Factor receptor (GPIb/IX).

Conventional subjective visual grading of malignancy in bladder carcinoma suffers from poor standardization. In an attempt to improve this by image analysis we carried out a texture analysis of a total of 197 images from Feulgen-stained histological tissue sections. The textural features used were based on the spatial gray-tone co-occurrence probability matrices for step-lengths 3, 4 and 6 pixels. These features were compared to the subjective grading by multivariate statistical methods. Using a two-stage hierarchical classifier 84.3% agreement was obtained between the subjective and computer-based classification. This was verified through the jackknifed classification technique.

Proliferative cell nuclear antigen (PCNA) expression was analyzed in formalin-fixed and paraffin-embedded specimens from patients with urinary bladder cancer using three different anti-PCNA monoclonal antibodies. In 20 recent cases a positive correlation was found between the extent and intensity of PCNA staining and grade of malignancy. In 95 specimens, three to six years old, extensive positive staining was detected in 15 and 23% of grade 2B and 3-4 tumors, respectively. No equivalent staining was found in the grade 1 and 2A tumors. In material more than six years old, a remarkably weak staining was observed regardless of grade. Similarly, in a test of archival material of tonsils a very weak immuno-reactivity was found as compared with fresh material. However, antigen retrieval by microwave heating of the tissue sections was possible in the majority of all cases, and the difference in extent and intensity of the staining between low and high grade tumors remained.

The effect of neoadjuvant chemotherapy regimen utilizing cisdiaminodichloroplatinum (CDDP) with continuous 5-day infusion of 5-fluorouracil (5-FU) was analyzed during the treatment of 23 patients with histologically established epidermoid carcinoma of the oral cavity. All but four patients were in clinical stage III or IV of the disease and seven of them had an inoperable tumor. No one had been treated previously. Complete response after three courses of the chemotherapy was obtained in 13 patients (56.5%) and partial response in 8 (34.8%). The overall response amounted to 91.3%. Only two tumors showed no response to the therapy after one and two courses respectively. The former patient did not continue the chemotherapy due to toxicity and the latter because of its minimal effect. During therapy the disease did not progress in any of the patients studied. Neoadjuvant chemotherapy with CDDP and continuous 5-FU infusion lasting 120 hours was found to be both tolerable and an effective part of the complex management of oral cavity carcinoma without the risk of delaying subsequent definitive treatment. (Tab. 9, Ref. 18).

The research aimed at studying metabolic changes of erythrocytes in the calves surviving for a long period with total artificial heart of BRNO VII type. The authors studied partly the count of erythrocytes, the plasma levels of free hemoglobin and activity of glucose-6-phosphate-dehydrogenase enzyme. The changes found were compared with the levels measured in a group of 10 healthy calves. Constant decrease of erythrocyte count, slightly increased concentration of free hemoglobin in plasma and repeatedly decreased activity of the enzyme studied were found in the group of 4 experimental calves, from the 5th to 17th weeks of surviving. These changes can be explained by a long-term action of mechanical stress on the erythrocytes that pass through the pump of the total artificial heart. The cells damaged mechanically have the decreased energetic metabolism and, consequently, shortened viability. As young healthy animals with normal erythropoiesis which is stimulated by the application of drugs during the experiment are used, compensated anaemia develops, but it is not a limiting factor for the surviving of the calves with total artificial heart.

Based on data in the literature and their own experience the authors summarize eleven imaging systems using ionizing energy and fifteen non-X-ray techniques from the aspect of the dental surgeon. Perspective methods include CT, DSA, xeroradiography, electrography in addition to classical X-ray techniques incl. intervention radiodiagnosis. As to non-X-ray techniques sonography (echography, USG), thermography and magnetic resonance prove useful.

This report describes a patient who survived rupture of the left ventricular free wall following a myocardial infarction and who then subsequently went on to develop a pseudoaneurysm. The rupture became clinically recognized when the patient developed cardiac tamponade. A large hemopericardium was evacuated by performing a thoracotomy and a pericardiotomy. Although not evident at the time of the initial catheterization, a pseudoaneurysm developed over the ensuing months. The aneurysm was initially recognized by radionuclide angiography and confirmed by left ventricular angiography at a second cardiac catheterization. The aneurysm was successfully resected, and the patient was alive and functioning normally 18 months after rupture and 12 months after aneurysmectomy.

The intensity and dynamism of the toxicity of the neoadjuvant chemotherapy regimen utilizing cis-diaminodichloro-platinum (CDDP) with continuous 5-day infusion of 5-fluorouracil (5-FU) was recorded and analyzed during the treatment of 23 patients with histologically established epidermoid carcinoma of the oral cavity. The most frequent sign of toxicity was leukopenia and nausea/vomiting, both occurring in 78% of cases. Leukopenia was more frequent and serious than reported in other studies. On the contrary, nephrotoxicity was mild and less frequent (17%) compared to literary data. Diarrhea was associated with the administration of CDDP in 31%, minimal hair loss was recorded in 21% of cases. Other signs of toxicity were rare and mild. The degree of severity of toxicity was increasing with the number of treatment courses only with respect to hematologic parameters. No life-threatening complications were recorded. In seven cases continuous treatment had to be interrupted after three days due to leukopenia. With regard to toxicity, the applied treatment schedule (three courses) is fully acceptable, safe and suitable as neoadjuvant chemotherapy in the complex management of oral cavity carcinoma without the risk of delaying subsequent definitive treatment.

An air gun pellet cardiac injury, in which there was penetration through the right ventricle, interventricular septum, and anterior papillary muscle and ejection from the left ventricle, is described. The pellet embolus was removed from the left popliteal artery with restoration of flow. The particular implications of pellet embolization are discussed and contrasted with those of bullet embolism.