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Type 1 diabetes (T1D) is a disorder of impaired glucoregulation due to lymphocyte-driven pancreatic autoimmunity. Mobilizing dendritic cells (DC) in vivo to acquire tolerogenic activity is an attractive therapeutic approach as it results in multiple and overlapping immunosuppressive mechanisms. Delivery of agents that can achieve this, in the form of micro/nanoparticles, has successfully prevented a number of autoimmune conditions in vivo. Most of these formulations, however, do not establish multiple layers of immunoregulation. all-trans retinoic acid (RA) together with transforming growth factor beta 1 (TGFβ1), in contrast, has been shown to promote such mechanisms. When delivered in separate nanoparticle vehicles, they successfully prevent the progression of early-onset T1D autoimmunity in vivo. Herein, we show that the approach can be simplified into a single microparticle formulation of RA + TGFβ1 with surface decoration with the T1D-relevant insulin autoantigen. We show that the onset of hyperglycemia is prevented when administered into non-obese diabetic mice that are at the mid-stage of active islet-selective autoimmunity. Unexpectedly, the preventive effects do not seem to be mediated by increased numbers of regulatory T-lymphocytes inside the pancreatic lymph nodes, at least following acute administration of microparticles. Instead, we observed a mild increase in the frequency of regulatory B-lymphocytes inside the mesenteric lymph nodes. These data suggest additional and potentially-novel mechanisms that RA and TGFβ1 could be modulating to prevent progression of mid-stage autoimmunity to overt T1D. Our data further strengthen the rationale to develop RA+TGFβ1-based micro/nanoparticle “vaccines” as possible treatments of pre-symptomatic and new-onset T1D autoimmunity.

Despite rapid growth in the significance of dermoscopy in dermatological oncology, relatively little is yet known about the dermoscopic patterns of eyelid margin tumors. The aim of the study was to analyze the dermoscopic features of eyelid margin tumors. This was a retrospective, single-center, consecutive study which included clinical and dermoscopic analysis of eyelid margin tumors diagnosed at the Department of Dermatology, Venereology and Allergology at the Medical University of Gdańsk from 1 June 2016 to 31 December 2020. Dermoscopic features significantly more prevalent in malignant non-melanocytic lesions compared to benign ones were alteration in eyelash growth, structureless pink areas, starry milia-like cysts, and perpendicular vessels. In contrast, there were no dermoscopic features that occurred significantly more frequently in malignant melanocytic lesions when compared to benign ones. Basal cell carcinoma, in comparison to hidrocystoma, more commonly presented with ulceration and structureless pink areas. The main features differentiating basal cell carcinoma from dermal nevus were the presence of ulceration, alteration in eyelash growth, structureless pink and structureless white areas, and perpendicular vessels within the tumor with each of these features observed more commonly in basal cell carcinoma. Blue nevus, hemangioma, or pigmented hidrocystoma presenting exclusively with blue structureless areas may be difficult to differentiate based on dermoscopy. The study offers additional dermoscopic clues in the assessment of eyelid margin tumors. Some observations reported previously to be typical of basal cell carcinoma (e.g., linear vessels arranged perpendicularly to the eyelid margin) were documented also within the normal eyelid margin accompanying other cases, and according to our study, cannot be useful as a pathognomonic feature. In contrast, it seems that yellow structures (half-moon sign, starry milia-like cysts) may be important dermoscopic features, though further studies are needed to confirm our observations., (© 2022 Japanese Dermatological Association.)

Background: Although basal cell carcinoma (BCC) can, in the majority of cases, be diagnosed based on clinical and dermoscopic assessment, a potential overlap with benign adnexal skin tumours seems to exist, including trichoblastic tumours (TT). Methods: Retrospective analysis of clinical and dermoscopic features of benign TT and BCC cases was performed to develop a diagnostic algorithm with a potential utility in clinical practice. Results: In the study, 502 histopathologically confirmed BCC cases were compared with 61 TT (including 44 TB (72.13%), 10 TE (16.39%) and 7 DTE (11.48%]). Patients in the BCC group were statistically older (mean age was 71.4 vs. 64.4 years, respectively; p = 0.009). BCC presented generally as larger tumours (mean tumour size 11.0 vs. 8.2 mm for the TT group; p = 0.001) and was more frequently associated with clinically visible ulceration (59.4% vs. 19.7%, respectively; p < 0.001). Comparison of lesion morphology, clinically visible pigmentation, and anatomical location did not show significant differences between the analysed groups. Dermoscopically visible ulceration was significantly more common in the BCC group compared to the TT group (52.2% vs. 14.8%; p < 0.0001). Pigmented structures, specifically brown dots and brown globules, were significantly more prevalent in the TT group (32.8% vs. 11.4%; p = 0.0001 and 29.5% vs. 8.2%; p <0.0001). Similarly, TT more commonly than BCC showed the presence of cloudy/starry milia-like cysts (26.2% vs. 11.6%; p = 0.0031) and yellow globules (16.4% vs. 7.2%; p = 0.033). Conclusions: Despite differences in frequency of clinical and dermoscopic features between BCC and TT in the studied group, differential diagnosis based on these variables is not reliable. Histopathological examination remains a diagnostic gold standard in differentiation of BCC and TT.

Introduction: Cutaneous T-cell lymphomas (CTCL) are malignant lymphoproliferative disorders accompanied by persistent pruritus. Pruritogenic role of interleukin-31 (IL-31) has been studied extensively and was proven in atopic dermatitis (AD), while its role in CTCL is still rather vague., Aim: To investigate IL-31 serum level along with IL-31, IL-31 receptor α (IL-31RA) and oncostatin M receptor β (OSMR) skin expression in CTCL and compare it to controls: AD and healthy volunteers., Material and Methods: The level of IL-31 in serum was measured using ELISA, while IL-31 and receptors' expression in the skin were measured using immunohistochemistry and correlated with the stage of disease and pruritus severity., Results: Expression of IL-31 and IL-31 receptor in serum and skin were significantly higher in CTCL and AD in comparison to healthy controls. No significant correlation between the IL-31 serum level and pruritus severity in CTCL patients was found. There was also no correlation between IL-31/IL-31RA/OSMR expression in the skin and CTCL pruritus, while IL-31 and IL-31RA in CTCL skin negatively correlated with the stage of disease., Conclusions: Our data indicate that IL-31 does not play a crucial role in pruritus in CTCL but it is rather involved in the pathogenesis of the disease. It seems that IL-31 plays an essential role in the pruritus pathomechanism that is unique to AD., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Termedia.)

Background: Deregulation of signal transducer and activator of transcription (STAT) signaling is known to participate in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). However, published results regarding STAT expression in different stages of CTCLs are conflicting. The aim of the study was to define the pattern of STAT expression in skin and detect any differences between pruritic and nonpruritic patients but also different stages of disease., Methods: Thirty-nine skin biopsies from CTCL patients and 24 biopsies from healthy volunteers were taken. Immunohistochemical staining for STAT 3, 5a, 5b, and 6 was performed in formalin-fixed paraffin-embedded sections of mycosis fungoides (MF) and Sezary syndrome (SS) specimens., Results: We found increased expression of STAT proteins in CTCL: MF and SS skin in comparison to the control group. STAT5 but also STAT6 and to a lesser extent STAT3 seems to be constitutively activated in MF and SS. Moreover, also downregulation of STAT5b protein in advanced-stage CTCL appears to contribute to its pathogenesis. There were no significant associations between expression of STATs and pruritus severity., Conclusions: Our results confirm the possible pathogenetic role of STATs in CTCL. STATs seem to be a promising target for new effective therapeutic agents in CTCL., (© 2020 the International Society of Dermatology.)

Cutaneous T-cell lymphomas (CTCLs) comprise a group of chronic heterogeneous diseases of unknown pathogenesis, characterized by non-specific skin lesions such as patches, plaques and tumours. CTCL is accompanied by persistent pruritus poorly responding to antihistamines and therefore significantly reducing quality of life in patients with lymphomas. According to research data, interleukin-31 (IL-31) contributes to initiation and maintenance of the inflammatory process of the skin and pruritus in inflammatory dermatoses such as atopic dermatitis (AD), which is well established. The studies of a similar role of IL-31 in CTCLs are less homogenous. Due to contradictory reports concerning IL-31 and CTCL we have analysed available literature to summarize its role, focusing on CTCL and AD., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2020 Termedia Sp. z o. o.)

Background: The molecular pathogenesis of basal cell carcinoma (BCC) is still not precisely described and is the subject of ongoing studies. The role of signal transducers and activators of transcription (STATs) in human epithelial carcinogenesis has been poorly investigated, but in the era of studies on inhibitors targeting STAT proteins this topic seems worth exploring. Increased expression of STAT3 in human nonmelanoma skin cancer (NMSC) has been confirmed in a few studies, but to our knowledge, expression of STAT5A, STAT5B and STAT6 in BCC has not been previously evaluated., Aim: To measure expression of STAT3, STAT5A, STAT5B and STAT6 expression in different histopathological subtypes of human BCC and its correlation with selected clinical variables., Methods: Immunohistochemistry was used to assess 60 BCC tumour specimens [20 superficial (s)BCCs, 20 nodular (n)BCCs and 20 infiltrative (i)BCCs] and to compare with specimens of healthy skin. There was no significant difference in age or sex between the three groups of patients with BCC. As many tumours showed heterogeneity of staining, the H-score system was applied to calculate the intensity of immunoexpression., Results: Expression of STAT3, STAT5A, STAT5B and STAT6 was observed in all histopathological subtypes of BCC, and was stronger than the expression within the adjacent epidermis and also stronger than the expression within the epidermis in the healthy control group. Statistical analysis revealed no significant differences in mean H-scores calculated for sBCCs, nBCCs and iBCCs. There were no statistically significant associations between STAT3, STAT5A, STAT5B and STAT6 expression and patient sex/age, and tumour size/site., Conclusion: Our results confirm a possible role of STATs in the pathogenesis of BCC and should encourage future investigations on the possible therapeutic implications of this finding., (© 2019 British Association of Dermatologists.)

Basal cell carcinoma (BCC) environment consists of stromal and inflammatory cells which produce variety of cytokines, chemokines and growth factors that may affect tumor behavior. One of the cytokines suggested to be involved in the pathogenesis of BCC is IL-6, which is the upstream element of IL-6/JAK/STAT3 pathway. The correlation between polymorphisms of the genes related to this pathway and cancer risk/prognosis have been previously investigated in several neoplasia, but available data concerning BCC are scarce. In the present study, rs1800795 (-174 G/C) IL-6 gene polymorphism and two polymorphisms in the STAT3 gene, namely rs2293152 (intron 11, C/G) and rs4796793 (-1697, C/G) were assessed in relation to the BCC risk and clinical course. Additionally, IL-6 serum level was assessed in relation to IL-6 genotype and clinical variables. The study included 254 unrelated patients with BCC and of mean age 70.39 ± 11.43 (69.83 ± 12.32 women, 71.03 ± 10.31 men) and 198 healthy, unrelated age- and sex-matched volunteers. IL-6 and STAT3 polymorphisms were analyzed using polymerase chain reaction with sequence-specific primers (SSP-PCR). Serum concentration of IL-6 was measured using the ELISA test. We have found that the presence of C allele in rs1800795 IL-6 gene polymorphism was associated with increased risk of BCC (aOR 1.86; 95% CI 1.22-2.84; p = 0.004). The presence of CC genotype in STAT3 rs2293152 polymorphism was associated with increased BCC risk in recessive model analysis (aOR 3.94; 95% CI 1.59-9.77; p = 0.003). In contrast, the presence of GC genotype in overdominant model was associated with decreased risk of BCC (aOR = 0.24; 95% CI 0.12-0.49; p < 0.0001). The presence of C allele in STAT3 rs2293152 polymorphism was associated with increased risk of BCC (aOR 1.31; 95% CI 1.01-1.69; p = 0.04). The presence of GG genotype in STAT3 rs4796793 polymorphism was associated with increased BCC risk in recessive model analysis (aOR 3.66; 95% CI 1.33-10.10; p = 0.012). The presence of G allele in STAT3 rs4796793 polymorphism was associated with increased risk of BCC (aOR 1.59; 95% CI 1.01-2.49; p = 0.04). IL-6 serum level positively correlated with the tumor size.

Sarcomas represent less than 1% of all malignant tumors found in the thyroid. Of these, primary extraosseoussarcoma has been reported only a few times in the past decade. We present the case of a 34-year-old male who had a fast-growing hard mass in the lower left neck. FNA was inconclusive. Core needle biopsy revealed the diagnosis of an Ewing sarcoma/primitive neuroectodermal tumor. Mutation of EWSR1 was confirmed using the FISH method. Following treatment by neoadjuvant chemotherapy, we observed clinical, radiological, and finally histopathological remission. This was followed by a left-sided isthmolobectomy with unilateral cervical lymph node dissection by lateral lymphadenectomy, which revealed no residual disease. Posttreatment radiotherapy was administered but discontinued upon the patient's request. After 18 months of observation, the patient had no recurrence or metastasis and required l-thyroxine supplementation. We discuss our case using a comparative literature review to the few other known case reports.

Bones are the most common metastatic site of relapse in breast cancer patients and the prediction of bone metastases (BM) risk might prompt developing preventive and therapeutic strategies. The aim of the study was to correlate immunohistochemical (IHC) expression of selected proteins in primary breast cancer with the occurrence of BM. We analyzed expression of proteins potentially associated with BM in primary tumors of 184 patients with metastatic breast cancer (113 with- and 71 without BM). Expression of estrogen receptor (ER) in primary tumor was more common in patients with- compared to those without BM (74 vs. 45 % respectively, p = 0.0001), whereas in this subset less common was expression of parathyroid hormone related protein receptor type 1 (16 vs. 34 %, respectively, p = 0.007) and cytoplasmic expression of osteopontin (OPNcyt; 1.9 vs. 14 %, respectively, p = 0.002). The relationship between expression of ER and OPNcyt and the occurrence of BM was confirmed in the multivariate analysis. The ER-positive/OPNcyt negative phenotype was significantly more common in patients with- compared to those without BM (75 and 25 %, p < 0.0001, respectively; HR 1.79, p = 0.013). Luminal A (43 vs. 23 % respectively, p = 0.009) and luminal B/HER2-positive (16 vs. 4.9 % respectively, p = 0.032) subtypes were more common in patients with- compared to those without BM, whereas triple negative breast cancer subtype was less common (16 vs. 38 %, p = 0.002).

Aim of the Study: Evaluation of the relationships between increased expression of VEGF-C (vascular endothelial growth factor-C) and vessel density in the tumour-surrounding stroma, patient survival, and other conventional prognostic factors in patients with pT3-4 colon cancer., Material and Methods: Expression of VEGF-C and vessel density were immunohistochemically assessed in 104 specimens of primary, locally advanced (pT3-4) colon adenocarcinoma after surgical resection., Results: A significant relationship was found between the expression of VEGF-C and increased vessel density in the tumour-surrounding stroma (p = 0.03). A relationship between VEGF-C expression and location of the tumour in the left side of the colon was also found (p = 0.003). Expression of VEGF-C was likely to occur in well-differentiated tumours. No relationship between patient overall survival and the expression level of VEGF-C in locally advanced colon cancer was observed., Conclusions: The study results indicate that expression of VEGF-C in cells of locally advanced pT3-4 adenocarcinoma of the colon does not affect the survival time of the patients. Increased expression of VEGF-C is accompanied by a significant increase in vessel density in the pT3-4 tumour stroma. Increased expression of VEGF-C in cancer cells is related to the tumour location in the left side of the colon and better tumour differentiation.

Tumour vessel network formation, including blood and lymph vessels, is a major step involved in the process of carcinogenesis. The discovery of vascular growth factors has led to a better understanding of tumour biology, thus, creating new possibilities for cancer treatment that targets angiogenesis within tumour-associated stroma, including therapy for colon cancer patients. The present study evaluated the relationships between increased expression of lymphangiogenic factors (VEGF-C and VEGF-D) and vessel density in the tumour-surrounding stroma, patient survival and other standard prognostic factors. The expression of VEGF-C and VEGF-D and vessel density were immunohistochemically assessed in 114 primary tumour specimens from colon adenocarcinoma patients after surgical resection between January 1, 2003 and December 31, 2008. Concomittant overexpression of VEGF-C and VEGF-D was found in 51 (44.7%) colon tumours and low expression was observed in 63 (55.3%) cases. Mean vessel density was 52.87/field. A significant correlation was found between the expression of factors influencing lymph vessel growth and increased vessel density in the tumour-surrounding stroma (p=0.03). A relationship between lymphangiogenic factor overexpression and left-sided tumour location was also found (p=0.00002). Overexpression of these factors was likely to occur in well-differentiated tumours (p=0.003). No association between patient survival and the expression levels of lymphangiogenic factors was observed. The study results indicate that the overexpression of lymphangiogenic factors tends to be associated with tumours of favourable prognosis, i.e. well-differentiated and those localized in the left-side of the colon.

Background: There are no clinically useful biomarkers predictive of brain metastases (BM) in breast cancer. In this study, we investigated the correlation between expression of selected proteins in the primary tumor and the risk of BM in patients with metastatic breast cancer (MBC)., Methods: The study included 198 MBC patients (96 with and 102 without BM). Using tissue microarrays derived from the primary tumor, we assessed by immunohistochemical expression of ER, PR, HER2, Ki-67, CK5/6, EGFR, HER3, CXCR4, Rad51, E-cadherin, and claudin 3 and 4., Results: Ki-67 ≥14% (hazard ratio [HR] 2.76; P < 0.001), cytoplasmic expression of Rad51 (HR 1.87; P = 0.014) and ER-negativity (HR 1.72; P = 0.029) were associated with increased risk of BM in the multivariate analysis. A three-biomarker profile including ER, Ki-67 and Rad51 vs. other subtypes combined yielded an HR of 4.43 (P < 0.001)., Conclusions: ER-negativity, cytoplasmic expression of Rad51 and high Ki-67 are associated with increased risk of BM., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The specificity of brush cytology for detection of malignant pancreatobiliary strictures is high, but its sensitivity is moderate. Fluorescence in situ hybridization (FISH) can be used to detect chromosomal aneuploidy in biliary brushing specimens, and, according to some reports, it may improve the sensitivity of routine cytology., Objective: To assess the role of routine cytology and FISH in detection of malignant pancreatobiliary strictures., Design: Prospective study performed between September 2008 and August 2010., Setting: University hospital., Patients: This study involved 81 patients with bile duct or pancreatic duct strictures., Intervention: Brush cytology obtained during ERCP from pancreatic duct or bile duct strictures and analysis of smears by routine cytology and FISH., Main Outcome Measurements: Sensitivity, specificity, and positive and negative predictive values of routine cytology and FISH calculated with a 95% confidence interval., Results: The sensitivity of routine cytology was 35.19%, and specificity was 100%. When atypia was identified as positive, the resultant sensitivity was 53.7%, and specificity was 100%. Sensitivity of FISH was 51.85%, and specificity was 88.89%. When either routine cytology was positive or atypia was observed or when the FISH result was positive, sensitivity was the highest (72.22%), and it was statistically significant in comparison with both routine cytology with atypia (P < .036) and FISH (P < .023), but specificity was lower than that of routine cytology (88.89% vs 100%)., Limitations: Use of a DNA probe set that was designed for detection of urothelial carcinoma. Limited number of patients., Conclusion: FISH improved the sensitivity of routine cytology. Pancreatic duct brushings were a reliable material for detection of chromosomal abnormalities by FISH. The best diagnostic result was achieved by combining routine cytology with FISH., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

The nature of multiple sprint sports such as soccer, hockey, and rugby is such that deceleration plays an important part in the movement patterns of players during a game and training. The purpose of this study was to investigate the effect of deceleration on fatigue during repeated sprint efforts. A group of 18 elite field hockey players (all men) performed a running repeated sprint ability test (6 x 40 m using maximal effort and departing every 30 seconds). In one condition, there was no deceleration zone, and in the second condition, the test had a deceleration component (rapid deceleration to a stop within 6 m of the end of each sprint). Sprint times under each condition were compared using a repeated-measures analysis of variance. No significant difference was seen between the 2 conditions for mean sprint times (p > 0.05) or for the mean fatigue index (p > 0.05). However, results showed a divergent trend, and further analysis extrapolating the data for an increased number of sprints showed that a significant difference (p < 0.05) would have been seen at the 11th sprint. Although this study found that the deceleration zone had little effect on the 6-sprint protocol, it was clear that the deceleration component would have shown an effect, giving rise to greater fatigue and slower sprint times, if the number of sprints had been increased. The implications are that deceleration training should be introduced into general fitness training programs for those competing in multiple sprint sports.