Update on Biomarkers of Chronic Inflammatory Processes Underlying Diabetic Neuropathy.

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy.

Cardiovascular Effects of Herbal Products and Their Interaction with Antihypertensive Drugs-Comprehensive Review.

Hypertension is a highly prevalent population-level disease that represents an important risk factor for several cardiovascular complications and occupies a leading position in mortality statistics. Antihypertensive therapy includes a wide variety of drugs. Additionally, the potential antihypertensive and cardioprotective effects of several phytotherapy products have been evaluated, as these could also be a valuable therapeutic option for the prevention, improvement or treatment of hypertension and its complications. The present review includes an evaluation of the cardioprotective and antihypertensive effects of garlic, Aloe vera, green tea, Ginkgo biloba, berberine, ginseng, Nigella sativa, Apium graveolens, thyme, cinnamon and ginger, and their possible interactions with antihypertensive drugs. A literature search was undertaken via the PubMed, Google Scholar, Embase and Cochrane databases. Research articles, systematic reviews and meta-analyses published between 2010 and 2023, in the English, Hungarian, and Romanian languages were selected.

Pathways of Coagulopathy and Inflammatory Response in SARS-CoV-2 Infection among Type 2 Diabetic Patients.

Chronic inflammation and endothelium dysfunction are present in diabetic patients. COVID-19 has a high mortality rate in association with diabetes, partially due to the development of thromboembolic events in the context of coronavirus infection. The purpose of this review is to present the most important underlying pathomechanisms in the development of COVID-19-related coagulopathy in diabetic patients. The methodology consisted of data collection and synthesis from the recent scientific literature by accessing different databases (Cochrane, PubMed, Embase). The main results are the comprehensive and detailed presentation of the very complex interrelations between different factors and pathways involved in the development of arteriopathy and thrombosis in COVID-19-infected diabetic patients. Several genetic and metabolic factors influence the course of COVID-19 within the background of diabetes mellitus. Extensive knowledge of the underlying pathomechanisms of SARS-CoV-2-related vasculopathy and coagulopathy in diabetic subjects contributes to a better understanding of the manifestations in this highly vulnerable group of patients; thus, they can benefit from a modern, more efficient approach regarding diagnostic and therapeutic management.

The Management of COVID-19-Related Coagulopathy: A Focus on the Challenges of Metabolic and Vascular Diseases.

The course of COVID-19 is highly dependent on the associated cardiometabolic comorbidities of the patient, which worsen the prognosis of coronavirus infection, mainly due to systemic inflammation, endothelium dysfunction, and thrombosis. A search on the recent medical literature was performed in five languages, using the PubMed, Embase, Cochrane, and Google Scholar databases, for the review of data regarding the management of patients with a high risk for severe COVID-19, focusing on the associated coagulopathy. Special features of COVID-19 management are presented, based on the underlying conditions (obesity, diabetes mellitus, and cardiovascular diseases), emphasizing the necessity of a modern, holistic approach to thromboembolic states. The latest findings regarding the most efficient therapeutic approaches are included in the article, offering guidance for medical professionals in severe, complicated cases of SARS-CoV-2 infection. We can conclude that severe COVID-19 is closely related to vascular inflammation and intense cytokine release leading to hemostasis disorders. Overweight, hyperglycemia, cardiovascular diseases, and old age are important risk factors for severe outcomes of coronavirus infection, involving a hypercoagulable state. Early diagnosis and proper therapy in complicated SARS-CoV-2-infected cases could reduce mortality and the need for intensive care during hospitalization in patients with cardiometabolic comorbidities.

Automated Cobb Angle Measurements for Scoliosis Diagnosis and Assessment: AI Applications and Accuracy Enhancement Through Image Processing Techniques.

Introduction Scoliosis is characterized by an abnormal curvature of the spine in the coronal plane. Idiopathic scoliosis is the most prevalent type, though specific causes are sometimes identifiable. Genetic factors significantly influence adolescent idiopathic scoliosis (AIS), which is diagnosed through clinical and radiographic evaluations, primarily using the Cobb angle to measure curvature severity. The classification of scoliosis severity ranges from mild scoliosis, where sometimes the absence of pain is encountered, to moderate and severe, which is usually associated with lancinating pain. Early onset and high progression rates in idiopathic scoliosis are indicative of poorer prognoses. Methods The study analyzed 197 radiographic images from a private clinic database between December 2023 and April 2024. Inclusion criteria focused on anteroposterior images of the thorax and abdomen, excluding unclear and non-spinal images. Manual Cobb angle measurements were performed using RadiAnt DICOM Viewer 2020.2, followed by automated measurements using the Cobb Angle Calculator software. Discrepancies led to further image processing with enhanced color contrast for improved visualization. Data were analyzed using GraphPad InStat to assess error margins between manual and automated measurements. Results Initial results indicated discrepancies between manual and automated Cobb angle measurements. Enhanced image processing improved accuracy, demonstrating the efficacy of both manual and automated techniques in evaluating spinal deformities. Statistical analysis revealed significant error margins, prompting a refined approach for minimizing measurement errors. Discussion The study highlights the importance of accurate Cobb angle measurement in diagnosing and classifying scoliosis. Manual measurements, while reliable, are time-consuming and prone to human error. Automated methods, particularly those enhanced by machine learning algorithms, offer promising accuracy and efficiency. The integration of image processing techniques further enhances the reliability of scoliosis evaluation. Conclusion Accurate assessment of scoliosis through Cobb angle measurement is crucial for effective diagnosis and treatment planning. The study demonstrates that combining manual techniques with advanced automated methods and image processing significantly improves measurement accuracy. Such an approach is intended to support better clinical outcomes. Future research should focus on refining these technologies for broader clinical applications.

Sequential Surgical Correction of Macrodactyly: A Case Report and Literature Review.

This report discusses the case of a young female patient diagnosed with macrodactyly of the toes, a condition that significantly affected her daily life. From the age of three to 11, she underwent treatment due to the severe impact of her deformity, particularly on her ability to move comfortably and wear suitable footwear. The patient's macrodactyly presented a complex clinical challenge, necessitating multiple surgical procedures to manage it effectively. These surgeries included soft tissue reduction to decrease the bulk of the enlarged digits, epiphysiodesis to halt the growth of the affected bones, and amputations to address the disproportionate enlargement of the toes. Each surgical intervention was aimed at improving both the function and appearance of the affected foot, with a focus on enhancing the patient's mobility and comfort. Despite the difficulties associated with recovery, the patient showed significant improvements in her ability to walk and in the aesthetic appearance of her foot. This case underscores the importance of developing individualized treatment plans that consider the unique needs of each patient and setting realistic expectations for outcomes. It also highlights that, while surgical interventions can lead to functional and cosmetic benefits, the extent of these improvements may be limited due to the inherent complexities of macrodactyly. The case calls attention to the need for ongoing research and the accumulation of clinical experience to refine treatment approaches for macrodactyly. Such advancements are crucial for optimizing therapeutic outcomes and improving the quality of life for patients affected by this rare condition.

Finite Element Analysis of Various Osteotomies Used in the Treatment of Developmental Hip Dysplasia in Children.

Late-discovered developmental hip dysplasia deformities often necessitate complex surgical treatments and meticulous preoperative planning. The selection of osteotomies is contingent upon the patient's age and the specific structural deformity of the hip. In our anatomical hip model, derived from the data of a 12-year-old patient, we performed virtual osteotomies that are commonly recommended for such cases. We precisely constructed geometric models for various osteotomies, including the Dega, Pemberton, Tönnis, Ganz, Chiari pelvic, and Pauwels femoral osteotomies. We employed Autodesk Inventor for the finite element analysis of the hip joint and the corrective osteotomies. In comparing one-stage osteotomies, we noted that the Dega and Ganz pelvic osteotomies, especially when combined with the Pauwels femoral osteotomy, yielded the most favorable outcomes. These combinations led to enhanced femoral head coverage and reduced intra-articular pressure. Furthermore, we calculated the femoral head-to-acetabulum volume ratio for both the Dega and Pauwels osteotomies. The encouraging results we obtained advocate for the integration of finite element analysis in virtual osteotomies of the pelvis and femur as a preoperative tool in the management of developmental hip dysplasia.

Cough-Induced Multiple, Bilateral, Asymmetrical Rib Fractures in a Scoliosis Patient: A Case Report.

Cough-induced rib fractures represent infrequent complications of strenuous and prolonged coughing, mostly provoked by respiratory tract infections, with localized chest pain being the most indicative component of the clinical picture. This paper reports a case of a 27-year-old female patient who presented with four cough-induced rib fractures following the contraction of an upper respiratory tract infection. The unique character of this case is provided by the young age of the patient, the presence of multiple and bilaterally located rib fractures, and the absence of predisposing factors related to her bone physiology. Furthermore, three of the four fractures were revealed on the left side, where a scoliotic sinistro-convex thoracic curvature is described. Following conservative treatment, the patient experienced a complete resolution of symptoms and favorable clinical outcomes. Even in the seemingly low-risk category, the diagnosis of cough-induced rib fractures should be taken into consideration, and their correlation to pre-existing rib deformities, such as the ones secondary to scoliosis, should be thoroughly investigated.

Finite Element Analysis of Normal and Dysplastic Hip Joints in Children.

From a surgical point of view, quantification cannot always be achieved in the developmental deformity in hip joints, but finite element analysis can be a helpful tool to compare normal joint architecture with a dysplastic counterpart. CT scans from the normal right hip of an 8-year-old boy and the dysplastic left hip of a 12-year-old girl were used to construct our geometric models. In a three-dimensional model construction, distinctions were made between the cortical bone, trabecular bone, cartilage, and contact nonlinearities of the hip joint. The mathematical model incorporated the consideration of the linear elastic and isotropic properties of bony tissue in children, separately for the cortical bone, trabecular bone, and articular cartilage. Hexahedral elements were used in Autodesk Inventor software version 2022 ("Ren") for finite element analysis of the two hips in the boundary conditions of the single-leg stance. In the normal hip joint on the cartilaginous surfaces of the acetabulum, we found a kidney-shaped stress distribution in a 471,672 mm2 area. The measured contact pressure values were between 3.0 and 4.3 MPa. In the dysplastic pediatric hip joint on a patch of 205,272 mm2 contact area, the contact pressure values reached 8.5 MPa. Furthermore, the acetabulum/femur head volume ratio was 20% higher in the dysplastic hip joint. We believe that the knowledge gained from the normal and dysplastic pediatric hip joints can be used to develop surgical treatment methods and quantify and compare the efficiency of different surgical treatments used in children with hip dysplasia.

Oxidative stress and peripartum outcomes (Review).

Pregnancy, labor and childbirth are accompanied by excessive oxidative aggression. The excessive formation of free radicals [reactive oxygen species (ROS), reactive nitrogen species (RNS), chlorine reactive species (CRS)] causes cellular oxidative damage, which can be scavenged by enzymatic or non-enzymatic antioxidants in normal healthy pregnancy, physiological labor and delivery without any complications. An imbalance between the pro-oxidant and antioxidant factors may lead to oxidative stress, which contributes to the development of many diseases. This oxidative aggression can be a precursor for pathologies in the pregnant woman including eclampsia, miscarriage, preterm labor, and intrauterine growth retardation; in the offspring it may lead to bronchopulmonary dysplasia/chronic lung disease, necrotizing enterocolitis, retinopathy of prematurity, and periventricular leukomalacia. This review summarizes the studies conducted to identify the mechanisms of oxidative stress and the effect of cell membrane oxidation, the mechanisms that are behind oxidative stress-related diseases, and also those studies which have demonstrated the effect of antioxidants in preventing diseases or diminishing the effects of oxidative stress in the body, in obstetrics and neonatology.

The immunoexpression of aquaporin 1, PAX2, PAX8, connexin 36, connexin 43 in human fetal kidney.

INTRODUCTION: The kidney develops from two mesodermal primordia. Aquaporin 1 (AQP1) is a membrane protein characteristic to epithelial and endothelial cell of the human body. The Pax family of genes encodes transcription factors with important role in intrauterine development. Connexins are transmembrane proteins found in gap junctions. We monitored the changes in the expression of AQP1, paired box gene 2 (PAX2), paired box gene 8 (PAX8), connexin 36 (Cx36) and connexin 43 (Cx43) proteins in fetal renal tissue. MATERIALS AND METHODS: We studied 34 post mortem fetuses of 9 to 24 weeks from the Laboratory of Pathology, Emergency County Hospital of Târgu Mures, Romania, using immunohistochemistry. RESULTS: AQP1 expression appeared in the apical and basolateral parts of cells, lining the proximal convoluted tubules and the descending limb of Henle's loop, then in the tubule pole of Bowman's capsule also. Nuclear expression of PAX2 was observed in structures developed both from the ureteric bud and the metanephric mesenchyme, and of PAX8 was observed in the proximal convoluted tubule's epithelium, Henle's loop, and collecting ducts. Cytoplasmic expression of Cx36 was localized to nephrons in different developmental stages, glomerular vessels and collecting ducts, and of Cx43 was localized to the endothelium of glomerular and peritubular vessels, as well as to the epithelium of the proximal tubules. DISCUSSIONS AND CONCLUSIONS: Nephrogenesis begins in the embryonic period, and continues into the fetal period as well. It is regulated by a wide array of markers. The current study supplements literature data regarding immunoexpression of these markers during renal development in the fetal period.

Allele-specific PCR method for identification of EGFR mutations in non-small cell lung cancer: formalin-fixed paraffin-embedded tissue versus fresh tissue.

UNLABELLED: The study of epidermal growth factor receptor (EGFR) gene mutations in lung adenocarcinoma patients has a special clinical significance in the selection of patients for tyrosine-kinase inhibitor therapy. The aim of this study was to identify patients with EGFR mutations using allele-specific polymerase chain reaction (PCR), from formalin-fixed paraffin-embedded (FFPE) tissue and fresh tissue (FT). MATERIALS AND METHODS: We performed a retrospective study using 13 cases of FFPE lung adenocarcinoma, and a prospective study using seven fresh samples of lung carcinomas (FT), collected by intraoperative dissection of the tumors. Using the DNA extracted from the FFPE tissue and FT, we attempted to identify deletions of exon 19 and point mutations of exon 21, according to the allele-specific PCR method described by Dahse et al. (2008). RESULTS: In all seven cases of FT (three adenocarcinomas, three squamous carcinomas, one large-cell carcinoma), we identified the wild type allele and the internal control in case of exon 19, and the wild type allele for exon 21, but not the mutated alleles. Considering that no standard method for formalin fixation and paraffin embedding has been implemented at the Laboratory of Pathology, the DNA extracted from these samples became fragmented and damaged, which compromised the results of PCR testing aimed at the detection of EGFR mutations. CONCLUSIONS: The presented method can be implemented at our laboratory to identify these mutations from fresh tissue collected during surgical resection. Additionally, standardization of formalin fixation and paraffin embedding of surgical samples is required, in order the enable subsequent processing using molecular biology methods.

Comparative study of HER2, EGFR, p53 and PTEN expression in the human gastrointestinal tract during fetal period.

INTRODUCTION: HER2, EGFR, p53 and PTEN are important in organization of the germ layers, in embryonic development and morphogenesis, in the development and differentiation of certain organ systems and in embryonic morphogenesis. Our goal is the comparative examination of the expression of these markers in the digestive tract of 9-24-week-old fetuses. MATERIALS AND METHODS: We studied using immunohistochemical techniques esophagus, stomach, small and large intestine tissue samples collected from 18 post mortem fetuses of 9-24 weeks. RESULTS: HER2 and PTEN expression appears as early as the 9-12 weeks period in the digestive tract, but HER2 expression decreases in the 21-24 weeks period and then disappears. EGFR expression appears only during the 13-16 weeks period. The expression of p53 is strong until week 21, and then it is restricted to the deeper layers of the epithelium. CONCLUSIONS: Our findings suggest that these markers have role also in the fetal period and complete the scarce data found in literature about the expression of the studied markers in the development of the digestive tract.

Human vomeronasal epithelium development: An immunohistochemical overview.

The vomeronasal organ (VNO) is the receptor structure of the vomeronasal system (VNS) in vertebrates. It is found bilaterally in the submucosa of the inferior part of the nasal septum. There are ongoing controversies regarding the functionality of this organ in humans. In this study we propose the immunohistochemical evaluation of changes in components of the human vomeronasal epithelium during foetal development. We used 45 foetuses of different age, which were included in three age groups. After VNO identification immunohistochemical reactions were performed using primary antibodies against the following: neuron specific enolase, calretinin, neurofilament, chromogranin, synaptophysin, cytokeratin 7, pan-cytokeratin and S100 protein. Digital slides were obtained and following colorimetric segmentation, surface area measurements were performed. The VNO was found in less than half of the studied specimens (42.2%). Neuron specific enolase and calretinin immunoexpression showed a decreasing trend with foetal age, while the other neural/neuroendocrine markers were negative in all specimens. Cytokeratin 7 expression increased with age, while Pan-Ctk had no significant variations. S100 protein immunoexpression also decreased around the VNO. The results of the present work uphold the theory of regression of the neuroepithelium that is present during initial stages of foetal development.

Changes in immunoexpression of p53, Ki-67, Ets-1, APAF-1 and PTEN in serrated and conventional colon adenomas.

UNLABELLED: The balance between apoptosis and proliferation is tipped towards a decrease of apoptosis as the colonocyte progresses in the adenoma to carcinoma sequence of colon carcinogenesis. According to literature data, proteins like p53, Ki-67, APAF-1, Ets-1, PTEN contribute to inhibition of apoptosis and stimulation of proliferation. AIM: Considering the complex interference among colorectal carcinogenetic mechanisms, our aim was to study the markers Ets-1 and APAF-1 relative to p53, Ki-67 and PTEN expression in colon adenomas/polyps (A/P). MATERIALS AND METHODS: We performed immunohistochemistry on 99 colon A/P cases from the material of the Department of Pathology, Emergency County Hospital of Tirgu Mures, Romania. Secondary EnVision Flex/HRP (Horseradish peroxidase) (20 minutes) was used for signal amplification. RESULTS: The majority of A/P show increased Ki-67, p53, Ets-1 expression, decreased APAF-1 expression and preserved PTEN expression. p53, Ki-67, Ets-1 and APAF-1 demonstrated statistically significant correlations with histological type and grade of dysplasia. We also observed that expression of these proteins in the intestinal crypts has a typical distribution according to histological type and grade of dysplasia. CONCLUSIONS: In case of hyperplastic polyps APAF-1 expression decreases as p53 and Ki-67 expression increases, followed by a decrease in PTEN expression in serrated adenomas, and an increase of Ets-1 expression in conventional adenomas.

Real-time quantitative PCR detection of WT1 and M-BCR-ABL expressions in chronic myeloid leukemia.

UNLABELLED: The Philadelphia chromosome and the resulting BCR-ABL fusion gene represent the hallmark event in chronic myeloid leukemia (CML) and their discoveries radically changed the management of these patients. Currently Wilms tumor 1 gene (WT1) is intensively investigated as high WT1 expression levels have been demonstrated in case of multiple solid tumors and malignant hematological syndromes (acute myeloid and lymphoid leukemia, myelodysplastic syndromes and chronic myeloid leukemia). The aim of our study was to investigate the WT1 expression in CML patients and its possible contribution to disease evolution. PATIENTS AND METHODS: In the Laboratory of Molecular Biology, University of Medicine and Pharmacy of Tirgu Mures, Romania, we regularly determined the M-BCR-ABL and WT1 expression levels by RQ-PCR (real-time quantitative polymerase chain reaction) testing in case of 19 CML patients: six patients monitorized from the diagnosis and 13 patients first tested during therapy. RESULTS: Eight CML (four advanced stage and four CP) patients showed high WT1 expression level, and in case of 11 patients the WT1 expression levels were undetectable or lower than 0.02%. The only significant difference between the high and low WT1 expression groups was represented by the clinical stage. In the majority of pretreated patients (10 out of 13 patients), the WT1 expression levels were low or undetectable. CONCLUSIONS: High WT1 expression in CML patients is detected especially in the advanced stages of the disease. Efficient Imatinib therapy may contribute to low WT1 levels in CP patients.

Immunohistochemical study of Ki67, CD34 and p53 expression in human tooth buds.

AIM OF THE STUDY: Establishment of Ki67, p53 and CD34 expression in human tooth buds of different stages of odontogenetic development. MATERIALS AND METHODS: Tissue samples containing tooth buds were removed from the incisor areas of human fetuses in different stages of development (weeks 9-10, 12-13, 13-16, 21-24), and from the canine and molar areas of 21-24 weeks fetuses. The tissue fragments were fixed using formalin and were processed using common histological techniques with paraffin embedding. Immunostaining for Ki67, p53 and CD34 has been performed using the dextran method and moist heat antigen retrieval (except for CD34). The resulting slides were photographed and quantitatively evaluated. RESULTS: Ki67 immunoexpression decreases with advancement of the developmental stage of the tooth bud: in the inner enamel epithelium, between weeks 9 and 16 (IEE), in the preameloblasts (PB) between weeks 13 and 16, in the ameloblasts (AB) between weeks 21 and 24; outer enamel epithelium (OEE); stratum intermedium (SI); in the dental papilla: between weeks 9 and 10 in the dental papilla (DP), between weeks 13 and 16 in the outer layer of the dental papilla (DP1) and in the central layer of the dental papilla (DP2). Likewise, we noted Ki67 expression in the odontoblast layer (O) and pulp (P), between weeks 21 and 24. Concerning CD34 expression, we observed a decrease from weeks 9-10 until weeks 13-16, followed by an increase until weeks 21-24 of intrauterine life. From weeks 9-10, we observed a constant decrease of expression until weeks 13-16, followed by an increase during weeks 21-24. CONCLUSIONS: All Ki67, p53 and CD34 have been identified in the tooth bud. Ki67 expression gradually decreases with the embryonic development of the tooth, while p53 and CD34 expression decreases from weeks 9-10 to weeks 13-16 of intrauterine life, followed by an increase until weeks 21-24.

An immunohistochemical study of colon adenomas and carcinomas: E-cadherin, Syndecan-1, Ets-1.

It is thought that dysregulation of E-cadherin, syndecan-1 (CD138) and Ets-1 is involved in carcinoma development. E-cadherin is an important epithelial cell adhesion molecule; syndecan-1 (CD138) is a regulatory proteoglycan in both cell-cell and cell-matrix adhesion and Ets-1 is a proto-oncogene and transcription factor, which takes part in extracellular matrix remodeling. Our goal was to study the changes in the expression of these molecules during colon carcinoma development and progression. We tested 117 colon adenomas and 149 de novo and ex adenoma carcinomas of the colon, using the Ultravision Polymer system. The positive reaction rate was 100% for E-cadherin, 98.3% for syndecan-1 and 22.4% for Ets-1 in adenomas, while in carcinomas it was 88.5%, 62.4% and 56.3% respectively. We found decreasing expression of E-cadherin and syndecan-1 throughout colon carcinoma progression and an opposite regulation for the Ets-1 protein. Decrease in expression of syndecan-1 is more pronounced in carcinomas compared to E-cadherin. De novo carcinomas have lower E-cadherin and syndecan-1 expression, and higher Ets-1 expression compared to ex adenoma carcinomas. These findings support the hypothesis that there are differences in the carcinogenesis of these tumors.