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Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine. [ABSTRACT FROM AUTHOR]

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.

This pictorial essay aims to navigate through the complexities and challenges of renal transplantation (RT), by weaving together visual imagery with clinical insights within a comprehensive illustrative surgical guide. Herein, we provide a detailed visual exploration of the intricate anatomy and surgical processes necessary for both renal graft retrieval from the donor and also for an adequate implantation in the recipient. Regarding graft retrieval, after reviewing the relevant retroperitoneal surgical anatomy, and donor nephrectomy techniques, graft preservation and optimal backbench graft dissection principles were meticulously analyzed. Thereafter, the recipient surgical strategy for graft implantation was addressed, focusing on preoperative preparations, the site of implantation selection, exposure, operative bed dissection, graft revascularization, and urinary tract reconstruction. Careful donor and recipient selection, meticulous surgical execution, and rigorous postoperative management clearly hold a pivotal role in optimizing patient outcomes. Fostering a deeper understanding of the surgical nuances and clinical management practices that contribute to successful results post-RT, we hope to provide a useful practical tool for clinicians about to embark on the treacherous road of RT surgery. Innovative technologies and surgical practices that have already significantly improved the safety and effectiveness of RT stand testament to the importance of further scientific inquiry, conceptual developments, and clinical integration. Moving forward, it is essential that the medical community continues to refine these strategies and advocate for equitable access to transplantation, ensuring that advancements in the field translate into real-world benefits for all patients grappling with ESRD. The collaborative efforts of multidisciplinary teams are essential in addressing the complex clinical challenges associated with RT, with the ultimate goal of improving patient survival, enhancing graft longevity, and reducing healthcare disparities. [ABSTRACT FROM AUTHOR]

The effective staging of prostate cancer is essential for optimizing treatment and predicting outcomes. This study assessed the correlation between detailed preoperative diagnostic scores and postoperative outcomes to evaluate the accuracy of cancer restaging and its impact on treatment decisions and prognosis after prostatectomy. This retrospective study analyzed 133 prostate cancer patients who underwent prostatectomies at "Pius Brinzeu" Clinical Emergency Hospital in Timisoara over five years. Preoperative Gleason scores increased significantly across risk categories, from an average of 6.21 in low-risk patients to 7.57 in high-risk patients. This trend continued postoperatively, with scores rising from 7.04 to 8.33, respectively. The average increase in Gleason scores from preoperative to postoperative assessments was most pronounced in high-risk patients, at 0.76. Significant changes in clinical staging included increases in NCCN risk, where high-risk patients showed a 30% increase, and ISUP grade, with a 26.7% increase in the high-risk category. Notably, nodal status changes were also significant in high-risk patients, showing a 23.3% increase. The incidence of MRI-detected adenopathy was notably higher in the high-risk group (50%). Furthermore, there were significant correlations between the preoperative CAPRA score and postoperative ISUP grade (r = 0.261) and the preoperative PIRADS score and postoperative ISUP grade (r = 0.306). Similar observations were made between the preoperative and postoperative Gleason scores (r = 0.286) and the number of positive fragments (r = 0.227) with the postoperative ISUP grading. Furthermore, the preoperative CAPRA score was significantly correlated (r = 0.261) with the postoperative ISUP grading. Preoperative MRI findings, which included assessments of adenopathy and seminal vesicle invasion, were also significantly correlated (r = 0.218) with the postoperative pathological findings. Additionally, a significant correlation was found between the preoperative PIRADS score and postoperative ISUP grade (r = 0.306). In forecasting the aggressiveness and staging of prostate cancer following surgery, preoperative PSA levels showed an AUC of 0.631; the preoperative Gleason score had an AUC adjusted to 0.582, and the number of positive biopsy fragments indicated an AUC of 0.566. These results highlight the necessity of accurate and comprehensive preoperative assessments to better predict disease progression and refine treatment strategies. [ABSTRACT FROM AUTHOR]

Background/Aim: Warthin's tumor, the second most frequent neoplasia of the parotid gland, is characterized by a proliferation of both epithelial and lymphoid components. In addition to epithelial and lymphoid cells, various other cell types are implicated to varying degrees in the immune response. Notably, mast cells have long been recognized as a consistent cell population within this tumor. Despite the historical acknowledgment of mast cell presence, their true distribution and significance within Warthin's tumor remain unclear. In this study, we aimed to elucidate the distribution and significance of mast cells in Warthin's tumor. Materials and Methods: Histochemical and immunohistochemical methods were employed for the evaluation of mast cells within tumor specimens. Results: Our study revealed a notable concentration of mast cells in the epithelial component of Warthin's tumor. Microscopic examination showed predominant lymphoid and epithelial elements with occasional cystic formations. Immunohistochemical analysis identified mast cells in both components, emphasizing their role in the tumor microenvironment. Double immunostaining (mast cell tryptase and CD34) revealed no significant correlation between mast cells and blood vessels. Intraepithelial mast cells (IEMCs) had a significantly higher density in the epithelial component, suggesting a potential association with the tumor's benign nature. The relationship between IEMCs and epithelial cells, especially in the presence of cystic structures, offers valuable insights into the unique features of Warthin's tumor. Conclusion: Our study contributes to the understanding of mast cells in Warthin's tumor, highlighting a substantial concentration within the epithelial component. This knowledge may pave the way for further investigations into the roles of mast cells in the pathogenesis and treatment of Warthin's tumor. [ABSTRACT FROM AUTHOR]

Plurihormonal pituitary neuroendocrine tumors (PitNETs) are rare forms of tumors that express more than one hormone. The most common association is between growth hormone (GH) and prolactin (PRL), but other unusual combinations have been reported, such as GH and ACTH. Usually, the clinical dominance in these cases is related to GH hypersecretion. In these cases, immunohistochemistry (IHC) of transcription factors (TFs) is very useful for an accurate diagnosis. We included 42 patients diagnosed with pituitary neuroendocrine tumors (PitNETs): 37 patients with a confirmed diagnosis of acromegaly, and 5 patients with prolactinomas. All patients underwent transsphenoidal surgical intervention. We correlated the immunohistochemical features of plurihormonal PitNETs with clinical, hormonal, and imaging data. Tumor specimens were histologically and immunohistochemically examined. Based on the 2022 WHO classification, using IHC, 13 patients exhibited positive staining for more than one hormone, while unusual combinations like GH + ACTH and PRL + ACTH were also identified in other cases. Unusual cell combinations that produce hormones unrelated histogenetically, biochemically, or through regulatory mechanisms can appear and may display aggressive behavior, persistent disease, and high recurrence. We have not identified a clear correlation with the prognosis of these rare PitNETs. [ABSTRACT FROM AUTHOR]

Cutaneous malignancies represent a real concern and burden for the healthcare system, not only due to their increased frequency, but also due to the significant number of deaths attributed to these types of cancer. The genesis of tumors, their progression and metastasis are highly complex and researched subjects; apparently, mast cells (MCs) constitute an important piece in the complicated jigsaw puzzle of cancer. This article reviews the current knowledge of the roles MCs might play in the development of cutaneous malignancies. Besides their well-known and studied role in allergic reactions, MCs are linked to multiple and various disorders, including cancer. MCs exhibit incredible heterogeneity, being able to secrete numerous mediators that influence the tumor microenvironment and tumor cells. They are involved in many physiological and pathological processes, such as inflammation and angiogenesis. In this context, it is paramount to explore the advancements made so far in elucidating the roles that MCs have in skin cancer because they might provide valuable therapeutic targets in the future. Controversial and conflicting results were obtained across the studies examined. [ABSTRACT FROM AUTHOR]

Objectives: We examined the histoarchitecture of the anterior cruciate ligament [ACL] stumps in different stages of evolution after injury and we analyzed the correlation with the expressions of protein S100 and neurofilament associated protein [NFAP]. Materials and Methods: A total number of 102 cases of ruptured ACL was included in our study. Immunohistochemistry was performed for protein S100 [56 cases] and NFAP [46 cases] in order to evaluate the nervous structures located in the ligament and in the synovial tissue. Results: Protein S100 and NFAP were identified in the quasi-normal ligament, in the disrupted ligament and in the synovial tissue. Protein S100 was positive in the nervous structures of the synovial tissue. The nervous fibers from the ligament also reacted to protein S100. The synovial tissue reacted to NFAP at the level of the small nervous fibers and free nerve endings. In the ligament, NFAP expression was predominantly found in the small nervous fibers and in the free nerve endings. The quasi-normal ligament showed a greater number of NFAP positive free nerve endings. Conclusions: We found significant differences between the quasi-normal and the disrupted ligament regarding the expressions of protein S100 and NFAP. The low number of nervous structures identified using the two markers may suggest a time- and injury-dependent loss of nervous fibers following post-rupture ligament remodeling. The persistence of nervous fibers in the remnant stumps of the ruptured ACL is not ‘absolute’ and may not always ensure a successful recovery of the patient after ACL reconstruction

Background and Objectives: Even if they are cells of controversial origin (mesenchymal, perivascular, or fibroblastic), follicular dendritic cells (FDC) are present in all organs. The aim of this study was to establish the FDC expression pattern and its interrelation with HPV 18 expression in laryngeal squamous cell carcinoma (LSCC). Materials and Methods: Fifty-six cases of LSCC were evaluated by simple and double immunostaining. The following score was used: 0 (negative or few positive cells), 1 (10–30% of positive cells), 2 (30–50% of cells), and 3 (over 50% of cells). Results: The expression of CD 21-positive cells with dendritic morphology (CDM) was noticed in the intratumoral area of conventional (well and poorly differentiated types and HPV 18 positive cases with a value of 2 for the score) and papillary types (HPV-18 negative cases with a score of 1). The highest value of 2 for the score of CDM in HPV-18 positive cases was found in the peritumoral area of well- and poorly-differentiated conventional LSCCs. A significant correlation was found between scores of CDM from the intratumoral area and those of the peritumoral area (p = 0.001), between CDM and non-dendritic morphology cells (NDM) of the intratumoral area (p = 0.001), and between HPV-18 status and peritumoral NDM cells (p = 0.044). Conclusions: The FDC and NDM cell score values of intratumoral and peritumoral areas may represent important parameters of LSCCs. This may contribute to a better stratification of laryngeal carcinoma cases and the individualized selection of clinical treatment protocols. [ABSTRACT FROM AUTHOR]

Mast cell (MC) active mediators promote inflammation through changes induced in the connective tissue components of human gingiva. The aim of this study was to evaluate the distribution, mast cell density and their relationship with the degree of inflammatory infiltrate in gingiva from patients with periodontal disease. Thirty-nine cases with periodontal disease and 12 cases without significant changes to the gingival mucosa were investigated. MCs were identified on paraffin-embedded specimens by immunohistochemistry using anti-mast cell tryptase. The inflammatory infiltrate was scored from 0 to 3, and the MCs were counted using the hotspot method. Intraepithelial MCs were scored from 0 to 2. We found a significant increase of mast cell density in cases with mild and moderate inflammatory changes, and a slight decrease in patients with severe periodontal disease. We noticed a higher degranulation rate in patients with periodontal disease compared to those with healthy mucosa. Intraepithelial MCs were found in cases with periodontal disease only and were correlated with the severity of the inflammatory lesion. MCs are important cellular components of the early stages of periodontal disease. Contrary to other studies, we found that MC density and activation increases with moderate inflammation but decreases in severe inflammatory lesions. Our data suggest that MCs are key players in the progression of inflammatory lesions of the gingiva. In advanced-stage periodontal disease, intraepithelial MCs apparently play an important role, although their biological significance remains to be fully understood.

Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide with a high mortality. Immunohistochemical overexpression of the p53 protein was correlated with a poor prognosis in various human malignancies, including HCC. In our study, 45 resected HCCs were examined to evaluate the expression of p53 and its correlation with clinicopathological parameters. Immunohistochemical detection of p53 with monoclonal human antibody, revealed its overexpression in 20 tumors (44%), including diffuse positive in 7 cases (35%), heterogeneous in 5 (25%), and focal in 8 (40%). We considered a positive reaction only in the presence of immunostained nuclei in brown shades in more than 5% of the tumor nuclei. To elucidate the significance of p53 in HCC, we correlated its protein expression with major clinicopathological features. We did not observe significant correlation with sex, age, presence of cirrhosis, chronic hepatitis status, tumoral necrosis and tumor size. The density and intensity of p53 revealed significant correlation with histological grade (P=0.008 and P=0.014) and tumor stage (P=0.005 and P=0.007). In conclusion, our results suggest that overexpression of p53 is associated with HCC progression and contributes to disease progression. Moreover, p53 expression may be a valuable marker of HCC prognosis.

The aspect of reticular fibers is not considered in the current classifications of lung fibrosis. The aim of our study was to evaluate the distribution and the architecture of the reticular fibers for potential use as a tissue marker of fibrosis severity. We included in our study 25 pulmonary samples obtained by video-assisted thoracoscopy surgery (VATS) from a number of 20 cases. The cases were subdivided according to four criteria into: degree II, III and IV. We noticed no significant changes in the reticular network from interalveolar septa to the cases scored with 0, an accumulation of reticular fibers in the interalveolar septa (stage II), the condensation and thick bundles with network disorganization in all areas affected by fibrosis (stage III), partial to full depletion of reticular fibers (stage IV). Depletion of reticular fibers was constantly associated with advanced fibrosis stages.

There is little information about the exact trigger mechanisms of vascular endothelial growth factor (VEGF) expression in hematolymphoid malignancies. The aim of this study was to investigate the expression of VEGF in malignant non-Hodgkin lymphoma (NHL), in terms of its immunohistochemical distribution and clinicopathological significance. We evaluated the distribution in tumor cells, macrophages and in non-tumoral cells. VEGF immunoreactivity was estimated according to this score: 0 (0% positive cells); 1 (30%). Histopathological evaluation revealed 18 cases of diffuse type lymphoma and 3 cases of follicular type lymphoma. VEGF was positive in 95.23% of cases and in one case, VEGF was negative in all cell types. We noticed a significant correlation in VEGF expression between tumor cells and macrophages (p=0,001), tumor cells and non-tumoral cells (p=0,002). In non-Hodgkin lymphoma, the main mechanism of angiogenesis seems to be dependent on the VEGF pathway and its expression particularly by stromal cells.

Breast cancer is the most frequent malignancy in women worldwide. In spite of its questionable reliability, the TNM (Tumor, Node, Metastasis) staging system is widely used for the prognosis of this disease. On the other hand, angiogenesis is considered to have an essential role in the evolution of breast cancer and the Vascular Endothelial Growth Factor (VEGF) has proven to be the key regulator of this process. Quantitation of VEGF and the tumor vasculature might play an important role in predicting tumor behavior and patient management. The aim of our study was to evaluate the potential correlation between the VEGF expression, microvessel density (MVD) in the tumor tissues and TNM staging in breast cancer. We included 34 patients with breast cancer who had undergone surgical treatment and evaluated each case clinically, histopathologically and by immunohistochemistry for VEGF and CD31 expression in the tumor tissues. VEGF expression was evaluated by calculating the average percentage of cytoplasmic positive cells from 3 high power fields. MVD was expressed as the average number of the CD31+ microvessels from 3 high power fields. Expression of VEGF was significantly associated with the number of lymph nodes with metastasis, the number of cells in mitosis, the presence of necrosis and the T-stage (inverse correlation). MVD correlated very well with the histological grading, the number of cells in mitosis, the presence of inflammation and the presence of necrosis. No correlation could be established between VEGF expression and MVD. Although their relationship with TNM staging remains unclear, VEGF expression and MVD proved to be important indicators of the malignant status in breast cancer, confirming the major involvement of angiogenesis in this type of cancer. Both of them are valuable prognostic factors in breast cancer, but the pattern of their relationship needs further analysis of the VEGF receptors in order to be described.

OBJECTIVES AND BACKGROUND To examine the morphological features of the anterior cruciate ligament (ACL) stumps following injury and to assess their correlation with protein S100 and neurofilament associated protein (NFAP). MATERIALS AND METHODS We selected a total number of 102 cases of ruptured ACLs. 56 cases out of the total number of cases were immunohiatochemically assessed for protein S100 and 46 cases out of the total number of cases were immunohiatochememically assessed for NFAP. RESULTS Both markers were identified in the synovial tissue, in the quasi-normal ligament and in the disrupted ligament. Protein S100 was positive in the nervous structures of the synovial and ligament tissues. NFAP expression was predominantly found in the free nerve endings and small nervous fibers of the synovial tissue and ligament tissue. A greater number of NFAP positive free nerve endings were detected in the quasi-normal ligament. CONCLUSIONS Ruptured ACL specimens do not present an arbitrary persistence of nervous fibers in the remnant stumps and may not ensure a successful recovery of the patient following ACL reconstruction procedures in all clinical cases. Figure 1. NFAP expression in the synovial tissue, in the quasi-normal ligament and the disrupted ligament. Note the presence of small positive nervous structures (a) and the presence of large nervous fibers showing a midlow, focal reaction, restricted to the cytoplasm of a few Schwann cells (b). REFERENCES 1. Anderson MJ, Browining WM 3rd, Urband CE, Kluczynski MA, Bisson LJ. A Systematic Summary of Systematic Reviews on the Topic of the Anterior Cruciate Ligament. Orthop J Sports Med. 2016;4:2325967116634074, doi: 10. 1177. 2. Sanders JO, Brown GA, Murray J, Pezold R, Savarino KS. Treatment of anterior cruciate ligament injuries. J Am Acad Orthop Surg. 2016; Epub ahead of print. 3. Hsia AW, Anderson MJ, Heffner MA, Lagmay EP, Zavodovskaya R, Christiansen BA. Osteophyte formation after ACL rupture in mice is associated with joint restabilization and loss of range motion. J Orthop Res. 2016;doi: 10. 1002.