A New Method of Artificial-Intelligence-Based Automatic Identification of Lymphovascular Invasion in Urothelial Carcinomas.

The presence of lymphovascular invasion (LVI) in urothelial carcinoma (UC) is a poor prognostic finding. This is difficult to identify on routine hematoxylin-eosin (H&E)-stained slides, but considering the costs and time required for examination, immunohistochemical stains for the endothelium are not the recommended diagnostic protocol. We developed an AI-based automated method for LVI identification on H&E-stained slides. We selected two separate groups of UC patients with transurethral resection specimens. Group A had 105 patients (100 with UC; 5 with cystitis); group B had 55 patients (all with high-grade UC; D2-40 and CD34 immunohistochemical stains performed on each block). All the group A slides and 52 H&E cases from group B showing LVI using immunohistochemistry were scanned using an Aperio GT450 automatic scanner. We performed a pixel-per-pixel semantic segmentation of selected areas, and we trained InternImage to identify several classes. The DiceCoefficient and Intersection-over-Union scores for LVI detection using our method were 0.77 and 0.52, respectively. The pathologists' H&E-based evaluation in group B revealed 89.65% specificity, 42.30% sensitivity, 67.27% accuracy, and an F1 score of 0.55, which is much lower than the algorithm's DCC of 0.77. Our model outlines LVI on H&E-stained-slides more effectively than human examiners; thus, it proves a valuable tool for pathologists.

Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features.

Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients' muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.

The Value of ER∝ in the Prognosis of GH- and PRL-Secreting PitNETs: Clinicopathological Correlations.

Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their benign evolution, in some cases, prolactin (PRL) and growth hormone (GH)-secreting PitNETs may have aggressive behavior. In this study, we investigated the potential predictive role of ER∝, alongside the clinicopathological classification of PitNETs (tumor diameter, tumor type, and tumor grade). A retrospective study was conducted with 32 consecutive cases of PRL- and mixed GH- and PRL-secreting PitNETs (5 patients with prolactinomas and 27 with acromegaly, among them, 7 patients with GH- and PRL- co-secretion) who underwent transsphenoidal intervention. Tumor specimens were histologically and immunohistochemical examined: anterior pituitary hormones, ki-67 labeling index, CAM 5.2, and ER∝; ER∝ expression was correlated with basal PRL levels at diagnosis (rho = 0.60, p < 0.01) and postoperative PRL levels (rho = 0.58, p < 0.001). In our study, the ER∝ intensity score was lower in female patients. Postoperative maximal tumor diameter correlated with Knosp grade (p = 0.02); CAM 5.2 pattern (densely/sparsely granulated/mixed densely and sparsely granulated) was correlated with postoperative PRL level (p = 0.002), and with ki-67 (p < 0.001). The IGF1 level at diagnosis was correlated with the postoperative GH nadir value in the oral glucose tolerance test (OGTT) (rho = 0.52, p < 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter (p = 0.63, p < 0.001). At univariate logistic regression, GH nadir in OGTT test at diagnostic, IGF1, gender, and invasion were independent predictors of remission for mixed GH- and PRL-secreting Pit-NETs; ER∝ can be used as a prognostic marker and loss of ER∝ expression should be considered a sign of lower differentiation and a likely indicator of poor prognosis. A sex-related difference can be considered in the evolution and prognosis of these tumors, but further studies are needed to confirm this hypothesis.

Brachial and subclavian arteries aneurysms due to tuberous sclerosis complex mechanisms - case report and literature review.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant condition characterized by cutaneous, cerebral, and other multiorgan involvement. Aneurysms due to TSC pathogenic mechanism are rarely present, mainly aortic, renal, or intracranial and very few associated with peripheral circulation. A TSC patient, aged 31 years, who developed brachial and subclavian arteries aneurysms is presented. The question of a random association of the aneurysms with TSC versus aneurysms within pathogenic released mammalian target of rapamycin (mTOR) pathway effect was raised. CASE PRESENTATION: Patient's file, available from the age of six months, was analyzed for demonstration of the TSC diagnosis. Patient was examined, and cerebral magnetic resonance imaging (MRI) was repeated. Surgery and angiographic reports and images were reviewed. Pathology of the aneurysmal wall available from surgery was reexamined and special stainings and immunohistochemistry markers were applied. Genetic characterization of the patient was performed. Definite TSC was diagnosed based on major criteria [ungual fibromas, shagreen patch, cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytoma (SEGA)], minor criteria (confetti skin lesions, dental enamel pits, gingival fibromas), genetic result showing heterozygous variant in exon 8 of TSC1 gene (c.733C>T-p.Arg245*). Pathology analysis revealed markedly thickened aneurysmal wall due to smooth muscle cells (SMCs) proliferation in media and neoformation vessels with similar characteristics in the aneurysmal wall. DISCUSSIONS AND CONCLUSIONS: This is a rare case with aneurysms related to TSC, with an exceptional peripheral localization. Pathology exam is the key investigation in demonstrating the TSC-related pathogenic mechanism. A literature review showed 73 TSC cases presenting aneurysms published until now.

Muscle involvement with pseudohypertrophy in systemic light chain amyloidosis: Case report.

RATIONALE: Muscle pseudohypertrophy is a rare manifestation of light chain amyloidosis (AL) amyloidosis. PATIENT CONCERNS: A 63-year-old woman presented with a 2-year history of progressive asthenia, macroglossia, dysphonia, cachexia, hypotension, paresthesia, and lower limb muscle hypertrophy. DIAGNOSIS: Free serum lambda light chains were increased, and fat pad biopsy demonstrated Congo red-positive deposits. Additionally, electromyography showed a myopathic pattern, whereas muscle biopsy revealed amyloid deposits. A diagnosis of λAL with cardiac, renal, nervous system, and skeletal muscle involvement was established. INTERVENTIONS AND OUTCOMES: The patient received 3 subsequent lines of therapy over the following 23 months, with very slow hematological remission followed by resolution of organ dysfunction. LESSONS: Despite its rarity, muscle involvement should be considered in patients diagnosed with AL amyloidosis associated with unexplained muscle hypertrophy or weakness associated with macroglossia or elevated troponin T levels in the absence of clear cardiac involvement.

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy - a case report.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disorder mostly caused by sarcomeric gene mutations, but almost 10% of cases are attributed to inherited metabolic and neuromuscular disorders. First described in 2008 in an American-Italian family with scapuloperoneal myopathy, FHL1 gene encodes four-and-a-half LIM domains 1 proteins which are involved in sarcomere formation, assembly and biomechanical stress sensing both in cardiac and skeletal muscle, and its mutations are responsible for a large spectrum of neuromuscular disorders (mostly myopathies) and cardiac disease, represented by HCM, either isolated, or in conjunction with neurologic and skeletal muscle impairment. We thereby report a novel mutation variant in FHL1 structure, associated with HCM and type 6 Emery-Dreifuss muscular dystrophy (EDMD). CASE PRESENTATION: We describe the case of a 40 year old male patient, who was referred to our department for evaluation in the setting of NYHA II heart failure symptoms and was found to have HCM. The elevated muscular enzymes raised the suspicion of a neuromuscular disease. Rigid low spine and wasting of deltoidus, supraspinatus, infraspinatus and calf muscles were described by the neurological examination. Electromyography and muscle biopsy found evidence of chronic myopathy. Diagnosis work-up was completed by next-generation sequencing genetic testing which found a likely pathogenic mutation in the FHL1 gene (c.157-1G > A, hemizygous) involved in the development of X-linked EDMD type 6. CONCLUSION: This case report highlights the importance of multimodality diagnostic approach in a patient with a neuromuscular disorder and associated hypertrophic cardiomyopathy by identifying a novel mutation variant in FHL1 gene. Raising awareness of non-sarcomeric gene mutations which can lead to HCM is fundamental, because of diagnostic and clinical risk stratification challenges.

A rare case of mitochondriopathy with autosomal dominant progressive external ophthalmoplegia diagnosed through skeletal muscle biopsy.

Mitochondriopathies are a heterogeneous group of genetic diseases of all ages, with a very diverse clinical presentation related to genetic heteroplasmy. The clinical symptoms display a large variability and generally, the more severe phenotypes have an early onset, even from the neonatal period, while milder ones are manifested later in the adulthood. Most publications have already demonstrated deletions or point mutations in mitochondrial deoxyribonucleic acid (DNA), but in recent years, the field of investigation has expanded to syndromes caused by mutations in the nuclear DNA (nDNA), with a Mendelian inheritance. We present the case of a male patient with a mitochondriopathy with phenotype of chronic progressive external ophthalmoplegia (PEO), due to an autosomal dominant mutation in nDNA, in the DNA polymerase subunit gamma (POLG) gene, the pathogenic variant c.2864A>G (p.Tyr955Cys), morphologically investigated and diagnosed using a skeletal muscle biopsy. The aim of this presentation is to emphasize the diagnostic value of the muscle biopsy both in cases of clinical suspicion and in more challenging cases of mitochondrial diseases with atypical or unusual features. Although genetic testing may be the initial test of choice in cases with suggestive clinical presentation, muscle biopsy is an alternative diagnostic aid with high value even in our molecular era. We present pathological and ultrastructural data to confirm the diagnosis.

Dendritic cell distribution in mycosis fungoides vs. inflammatory dermatosis and other T-cell skin lymphoma.

Dendritic cells (DCs) are antigen-presenting cells with an important role in the innate and adaptive immune system. In skin lesions, cutaneous DCs (Langerhans cells, dermal DCs and plasmacytoid DCs) are involved in immune activation in inflammatory benign lesions, as well as in malignant lymphoid proliferations. Density and distribution of DCs in the dermal infiltrate can be helpful to differentiate benign, reactive infiltrate from malignant nature of the lymphoid population. We performed a retrospective study including 149 patients: 35 with mycosis fungoides, 35 with spongiotic dermatitis, 35 with psoriasis, 35 with lupus and 9 with cutaneous T-cell lymphomas (other than mycosis fungoides), diagnosed using histopathological and immunohistochemical stains. Density and distribution of DCs were evaluated using specific markers (CD1a, CD11c and langerin). In all cases, numerous DCs were identified in the dermal infiltrate. Their number was significantly increased in mycosis fungoides and T-cell lymphomas and moderately increased in inflammatory lesions. Variable patterns of distribution were identified such as clusters of DCs with arachnoid extension in mycosis fungoides, nodular pattern in inflammatory lesions and dispersed distribution with peripheric accumulation in T-skin lymphomas. Therefore, immunohistochemical characterization of DC distribution can be an adjuvant tool in differential diagnosis in inflammatory dermatosis and skin lymphomas.

Current and future applications of confocal laser scanning microscopy imaging in skin oncology.

Confocal laser scanning microscopy (CLSM) is a modern imaging technique that enables the in vivo or ex vivo characterization of skin lesions located in the epidermis and superficial dermis with a high quasi-microscopic resolution. Currently, it is considered to be the most promising imaging tool for the evaluation of superficial skin tumors. The in vivo mode adds the advantage of noninvasive, dynamic, in real-time assessment of the tumor associated vasculature and inflammation. It offers the possibility to repeatedly examine the same skin area without causing any damage and to monitor disease progression and treatment outcome. Furthermore, this novel technology allows the evaluation of the entire lesion and can be used to guide biopsies and to define tumor margins before surgical excision or other invasive therapies. CLSM diagnostic features may differentiate between the various histologic subtypes of skin tumors and therefore helps in choosing the best therapeutic approach. In this study, we present the CLSM characteristic features of the most common melanocytic and non-melanocytic skin tumors, as well as future possible CLSM applications in the study of experimental skin tumorigenesis on animal models.

Comparative analysis of CEACAM1 expression in thin melanomas with and without regression.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a key molecule in several intracellular and intercellular signaling pathways, with multiple functional and structural roles. CEACAM1 expression in melanoma is often described in the invading part of the tumor and has been associated with increased melanoma cells invasion and migration. We studied CEACAM1 expression in regressing versus non-regressing thin melanomas, knowing that phenomenon of regression represents a valuable model for understanding tumor immunity. In melanoma, through homophilic interactions, CEACAM1 inhibits natural killer cell activity, inhibits effector functions of tumor infiltrating lymphocytes, such as cytotoxicity and interferon-γ release. We present a retrospective study including 53 consecutive cases of thin melanoma, 21 with regression and 32 without regression. Comparative analysis of CEACAM1 expression in regressed and non-regressed areas from melanomas with regression and in non-regressed melanomas was performed. We used three different clones of CEACAM1: AA 1-428, extracellular domain, rabbit; AA 1-428, mouse, clone 8B6E2F4; and AA 1-468, full length, mouse, clone 2F6. All three clones had similar reactivity. We identified membrane positivity of tumor cells in non-regressed melanomas and in non-regressed areas in melanomas with regression. Remaining tumor cells in regressed areas were mostly negative for CEACAM1. In non-regressed lesions, there was a stronger positivity of CEACAM1 in the deep invasive front. In thin melanomas, CEACAM1 overexpression is related with invasiveness, suggesting that CEACAM1-positive melanomas are more aggressive. Also, in areas of regression tumor cells lose CEACAM1 expression, probably correlated with the presence of natural killer cells.

Dangerous Liaison: Helicobacter pylori, Ganglionitis, and Myenteric Gastric Neurons: A Histopathological Study.

Chronic inflammation induced by Helicobacter pylori (H. pylori) infection plays a major role in development of gastric cancer. However, recent findings suggested that progression of inflammation and neoplastic transformation in H. pylori infection are more complex than previously believed and could involve different factors that modulate gastric microenvironment and influence host-pathogen interaction. Among these factors, gastric myenteric plexus and its potential adaptive changes in H. pylori infection received little attention. This study is aimed at identifying the impact of H. pylori-associated gastritis on number and morphology of nerve cells in the stomach. The distribution of density, inflammation, and programmed cell death in neurons was immunohistochemically assessed in full-thickness archival tissue samples obtained from 40 patients with H. pylori infection who underwent surgery for gastric cancer and were compared with findings on samples collected from 40 age- and sex-matched subjects without bacteria. Overall, significant differences were noted between H. pylori-positive and H. pylori-negative patients. The analysis of tissue specimens obtained from those with infection revealed higher density and larger surface of the myenteric nervous plexus, as well as a significant increase in the number of gastric neuronal cell bodies and glial cells compared to controls. A predominant CD3-immunoreactive T cell infiltrate confined to the myenteric plexus was observed in infected subjects. The presence of mature B lymphocytes, plasma cells, and eosinophils was also noted, but to a lesser extent, within the ganglia. Myenteric ganglionitis was associated with degeneration and neuronal loss. Our results represent the first histopathological evidence supporting the hypothesis that H. pylori-induced gastric inflammation may induce morphological changes in myenteric gastric ganglia. These findings could help gain understanding of some still unclear aspects of pathogenesis of H. pylori infection, with the possibility of having broader implications for gastric cancer progression.

Myokines as Possible Therapeutic Targets in Cancer Cachexia.

Cachexia is an extremely serious syndrome which occurs in most patients with different cancers, and it is characterized by systemic inflammation, a negative protein and energy balance, and involuntary loss of body mass. This syndrome has a dramatic impact on the patient's quality of life, and it is also associated with a low response to chemotherapy leading to a decrease in survival. Despite this, cachexia is still underestimated and often untreated. New research is needed in this area to understand this complex phenomenon and ultimately find treatment methods and therapeutic targets. The skeletal muscle can act as an endocrine organ. Signaling between muscles and other systems is done through myokines, cytokines, and proteins produced and released by myocytes. In this review, we would like to draw attention to some of the most important myokines that could have potential as biomarkers and therapeutic targets: myostatin, irisin, myonectin, decorin, fibroblast growth factor 21, interleukin-6, interleukin-8, and interleukin-15.

Neuroimmune cross-talk in Helicobacter pylori infection: analysis of substance P and vasoactive intestinal peptide expression in gastric enteric nervous system.

It is suggested that different neuropeptides are actively involved in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastritis acting as important effectors of the neuroimmune complex interactions, but the available data is limited and contradictory. The aim of this study was to determine whether the chronic infection generates changes in substance P (SP) and vasoactive intestinal peptide (VIP) gastric level and to evaluate the dependence of these potential effects on the degree of bacterial colonization or the severity of the inflammatory infiltrate. Therefore, immunohistochemical tests were performed to examine SP and VIP expression in mucosal nerve endings and myenteric neurons. Both SP and VIP levels were significantly higher in gastric samples of patients infected with H. pylori compared to uninfected individuals, confirming that these neuropeptides are neuroimmune modulators involved in the pathogenesis of H. pylori infection. Although their expression did not correlate with the intensity of mucosal inflammation nor with the bacterial density, we observed a strong association between SP neuronal level and the degree of myenteric ganglionitis, which in turn correlated with the severity of mucosal T-cell infiltration. These findings suggest that the mechanisms of neuroimmune cross-talk depend on some other factors that remain to be determined.

The role of skin and muscle biopsy in the diagnosis of main connective tissue diseases.

Systemic involvement in autoimmune diseases is often unclear and organ changes are confounding, thus making it difficult to have an early accurate diagnosis. In those situations, both clinical and paraclinical findings might orientate the diagnosis, but only histological or immunohistochemistry changes might be accurate enough. The skin histological changes are relevant and sometimes might have a tremendous role in the accurate diagnosis of autoimmune rheumatic diseases, due to the correlation with the clinical systemic manifestations of the diseases and through the accessibility of biopsy. In the same time, muscle biopsy can provide important support for physicians improving diagnosis and optimizing management of connective tissue diseases.

Non-invasive imaging of actinic cheilitis and squamous cell carcinoma of the lip.

An early diagnosis is of overwhelming importance for the management and prognosis of mucocutaneous cancer. Actinic cheilitis (AC), defined by the clonal expansion of genomically unstable keratinocytes, is the most common potentially malignant lesion affecting the lips. Squamous cell carcinoma (SCC) is the most frequent oral malignancy, and there is strong evidence that the majority of the SCCs of the lip originate from AC. There is considerable difficulty in discerning between dysplasia and invasive carcinomas solely on a clinical basis. Although dermoscopy has become an essential tool for skin tumor evaluation, reflectance confocal microscopy (RCM) is a non-invasive imaging technology that has proved itself extremely useful in the diagnosis and monitoring of several skin diseases, including AC and SCC. The present study aimed to re-emphasize the usefulness of RCM in the early detection of malignant transformation, using AC and SCC of the lips as working examples. Due to the apparent innocuousness of AC for numerous patients, it is not possible to overstress the importance of a correct and early diagnosis, proper treatment and long-term patient follow-up as being essential for preventing the progression to lip SCC, or for its timely diagnosis.

Discovery of a new mutation in the desmin gene in a young patient with cardiomyopathy and muscular weakness.

A 25-year-old woman with a five years history of syncope, mild left ventricular hypertrophy and moderately enlarged atria, was diagnosed with third degree atrioventricular heart block alternating with atrioventricular heart block 2:1, and received a dual chamber pacemaker. After three years of evolution, she developed atrial fibrillation, marked biatrial enlargement, severely depressed longitudinal myocardial velocities, associated with mild girdle weakness and slight increase in creatine kinase level. The diagnosis of restrictive cardiomyopathy with mild skeletal myopathy imposed the screening for a common etiology. Skeletal muscle biopsy revealed the morphological picture of myofibrillar myopathy with sarcoplasmic aggregates, immunoreactive for desmin and other ectopic proteins on immunohistochemistry, appearing as granulofilamentous material at ultrastructural level. Western blot analysis confirmed the desmin overexpression. Genetic testing identified a heterozygous missense variant DES rs869025381, c.1297C>A, p.(Pro433Thr), not previously reported. This is not only the first confirmed Romanian patient with myofibrillar myopathy with clinical features of severe restrictive cardiomyopathy associated with mild skeletal myopathy, but also a case which adds up to the known mutational spectrum in desminopathy.

Vascular endothelial growth factor - key mediator of angiogenesis and promising therapeutical target in ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease, triggered by an inappropriate immune response of colonic mucosa. Angiogenesis is an important part of inflammatory process, enhancing inflammation in a vicious circle that aggravates mucosal damage and remodeling. The most important pathway for angiogenesis in ulcerative colitis involves vascular endothelial growth factor (VEGF) and endoglin (CD105) and can be used as target for adjuvant therapy in order to improve patients' outcome. We present a retrospective cohort study evaluating mucosal expression of VEGF and CD105 and their correlation with patients' evolution and risk of relapse. In our study, patients with UC have correlated increases of VEGF expression and microvessel density (evaluated with CD105 staining), sustaining the hypothesis that angiogenesis is not just a passive process driven by inflammation, but an active player of mucosal lesions in ulcerative colitis.

Proliferation activity in bladder tumors does not correlate with the pathological grading.

Worldwide, bladder cancer is the seventh most frequent cancer in men and the 17th most frequent cancer in women, respectively. In men, this type of cancer is the second most frequent type of cancer localized in the genitourinary system, after prostate cancer. The incidence of bladder cancer is ever growing and the etiopathogenic factors of bladder cancer are numerous and still not fully understood. Smoking is the most common risk factor incriminated in the onset of urinary tract cancer, the incidence of bladder cancer being directly connected to the smoking duration and the tobacco amount intake. Regarding the histopathological types, more than 90% of bladder cancer is represented by transitional cell carcinomas. Histopathology assessment of bladder cancer is a constant challenge regarding the connection between tumor grading, depth of invasion, extension and clinical prognosis. We evaluated here a number of 32 confirmed bladder tumors and we aimed to find common patterns of expression for markers like cytokeratin 7 (CK7), CK20, vascular endothelial growth factor (VEGF), CD34, matrix metalloproteinases (MMPs) 2, 8 and 9, as well as for the Ki67 proliferation index. Our study showed that both CK7 and CK20 were present in different tumor areas and tumor gradings, MMP9 was more constantly expressed compared to the more variable expression of MMPs 2 and 8, vascular densities did not seem to increase in high-grade invasive tumors compared to low-grade tumors. Interestingly, while high Ki67 proliferating indexes were present especially in high-grade superficially tumors, compared to low-grade papillary tumors; this correlation was inversed for the advancing edges of the tumor. This common feature of invasive urothelial tumors will thus require further studies in order to elucidate the cellular signaling pathways by which these tumors increase their overall invasiveness.

Expression Profile of p53 and p21 in Large Bowel Mucosa as Biomarkers of Inflammatory-Related Carcinogenesis in Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease that slightly increases the risk of colorectal cancer in patients with long-standing extended disease. Overexpression of p53 and p21 in colonic epithelia is usually detected in UC patients when no dysplasia is histologically seen and it is used by pathologists as a discriminator between regenerative changes and intraepithelial neoplasia, as well as a tissue biomarker useful to predict the risk of evolution toward malignancy. We present a one-year prospective observational study including a cohort of 45 patients with UC; p53 and p21 were evaluated in epithelial cells. p53 was positive in 74 samples revealed in 5% to 90% of epithelial cells, while 63 biopsies had strong positivity for p21 in 5% to 50% of epithelial cells. Architectural distortion was significantly correlated with p53 overexpression in epithelial cells. Thus, we consider that architectural distortion is a good substitute for p53 and p21 expression. We recommend use of p53 as the most valuable tissue biomarker in surveillance of UC patients, identifying the patients with higher risk for dysplasia. Association of p21 is also recommended for a better quantification of risk and for diminishing the false-negative results.

Correlations Between the Density of Tryptase Positive Mast Cells (DMCT) and that of New Blood Vessels (CD105+) in Patients with Gastric Cancer.

Mast cells proteases, tryptase and chymase are directly involved in the growth and progression of solid tumors due to their important role in tumor angiogenesis. We examined the density of tryptase positive mast cells and the mean density of new blood vessels in gastric malignant tumors of patients with and without Helicobacter pylori infection, using immunohistochemical staining for tryptase (for mast cells) and CD 105 (for new vessels). Tryptase and CD 105 expression was detected in gastrectomy specimens. In this study, mast cell density correlates with angiogenesis and the growth and progression of gastric cancer. It also shows that the participation of Helicobacter pylori infection in the growth and progress of gastric neoplasia is due to an increase of peritumoral angiogenesis, with subsequent local and distant tumor spread and perivascular growth, but without perineural and nodal involvement.