Cellular Senescence in Germ Cell Neoplasia In Situ (GCNIS) and Other Histological Types of Testicular Cancer.

Background and Objectives: The presence and contribution of senescent cells in premalignant lesions is well documented, but not in germ cell neoplasia in situ. The purpose of this study is to identify the presence of senescent cells in pre-malignant testicular conditions and in different histological types of testicular cancer. Materials and Methods: Thirty patients who underwent orchiectomy due to testicular tumors were included. Formalin-fixed paraffin-embedded (FFPE) testicular tissue for each patient was available. Sections from these specimens were examined by immunohistochemical analysis with the following markers: GL13 for cellular senescence, p21WAF1/Cip1 for cell cycle arrest, and Ki67 for cell proliferation. Results: Thirteen (43.3%) suffered from seminoma with a mean total proportion of GCNIS senescence of 20.81 ± 6.81%. In the group of embryonal testicular tumors, nine (30%) patients were included, with an average rate of 6.64 ± 5.42% of senescent cells in GCNIS. One (3.3%) patient suffered from chondrosarcoma in which 7.9% of GL13+ cells were detected in GCNIS. Four (13.4%) patients suffered from teratoma and three (10%) from yolk sac tumors, while GCNIS senescence was detected in a range of 4.43 ± 1.78% and 3.76 ± 1.37%, respectively. Conclusions: Cellular senescence was detected in both germ cell neoplasia in situ and testicular cancer, but was more prevalent within the premalignant lesions.

Comparative Expression Analysis of TP53 Tumor Suppressor and MDM2 Oncogene in Colorectal Adenocarcinoma.

Background/Aim: The tumor protein 53 (TP53) tumor suppressor protein (17p13.1) acts as a significant regulator for the cell cycle normal function. The gene is frequently mutated in colorectal adenocarcinoma (CRC) patients and is associated to poor prognosis and low response rates to chemo-targeted therapy. Our purpose was to correlate TP53 expression with Mouse Double Minute 2 Homolog (MDM2), a proto-oncogene (12q14.3) and a major negative regulator in the TP53-MDM2 auto-regulatory pathway. Materials and Methods: A total of forty (n=40) colorectal adenocarcinoma (CRC) cases were included in this study. An immunohistochemistry-based assay was implemented by using anti-TP53 and anti-MDM2 antibodies in the corresponding tissue sections. Additionally, a digital image analysis assay was implemented for objectively measuring TP53/MDM2 immunostaining intensity levels. Results: TP53 protein overexpression was detected in 27/40 (67.5%), whereas MDM2 overexpression in 28/40 (70%) cases. Interestingly, in 21/40 (52.5%) cases, a combined TP53/MDM2 co-expression was detected, whereas in 6/40 (15%), a combined loss of expression was identified (overall co-expression: p=0.119). p53 overexpression was significantly correlated to grade of the examined cases (p=0.001), whereas MDM2 to stage and max diameter of the malignancies (p=0.001 and 0.024, respectively). Conclusion: TP53/MDM2 over expression is a frequent and significant genetic event in CRCs associated with an aggressive biological behavior, as a result of increased dedifferentiation grade and advanced stage/elevated tumor volume, respectively. MDM2 oncogene overactivation combined with mutated and overexpressed TP53 is observed in sub-groups of patients leading to specific gene/protein signatures - targets for personalized chemotherapeutic approaches.

Cellular senescence in testicular cancer. Is there a correlation with the preoperative markers and the extent of the tumor? An experimental study.

PURPOSE: The aim of this experimental study is to investigate the correlation between the presence of senescent cells and the tumor size, the lymphovascular invasion (LVI), the invasion of rete testis (RTI), the preoperative tumor markers or pathological stage in patients who underwent orchiectomy for malignant purposes. METHODS: This experimental study included patients with a history of radical orchiectomy performed from January 2011 to January 2019. The testicular tissue specimens underwent an immunohistopathological process for the detection of the presence of cellular senescence. Besides, the tumor size, the histopathological type, the pathological stage of the tumor and the presence of Lymphovascular (LVI) or rete testis (RTI) invasions were also recorded. Additionally, the preoperative serum levels of alpha-fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase were recorded. After the completion of immunohistochemical analysis, the rate of senescent cells in each specimen was also recorded. RESULTS: The mean senescent cell rate was estimated to be 14.11±11.32% and 15.46±10.58% in patients with presence of LVI or absence of LVI, respectively (p=0.46). The mean senescent cell rate was calculated at 18.13±12.26% and 12.56±9.38% (p=0.096) in patients with presence of RTI or absence of RTI, respectively. The mean senescent cell rate in the pT1 group was calculated at 14.58 ± 9.82%, while in T2 and T3 groups the mean senescent cell rate was estimated to be 15.22 ± 12.03% and 15.35 ± 14.21%, respectively (p=0.98). A statistically significant correlation was detected between the senescence rate and the tumor size (Pearson score 0.40, p=0.027) and between the rate of senescent cells and the preoperative level of lactate dehydrogenase (LDH) (Pearson score -0.53, p=0.002). CONCLUSIONS: The presence of cellular senescence was correlated with the extent of the testicular tumor in terms of tumor size as well as the preoperative level of the LDH serum marker.

P53/MDM2 Complex-Based Targeted Strategies in Colon Adenocarcinoma.

In the current molecular review, we describe the mechanisms of TP53/MDM2 deregulation and their impact on the colon adenocarcinoma molecular substrate and phenotype. Among the genes that are critically altered in carcinogenesis, the TP53 tumor suppressor gene is of major importance. The TP53 gene (gene locus: 17p13.1) regulates the cell cycle by controlling the G1/S and G2/M checkpoints securing the normal sequence of cell cycle phases. Furthermore, it is involved in apoptosis programmed cell death. The gene is mutated or epigenetically altered in all epithelial malignancies, including colon adenocarcinoma. Additionally, Mouse Double Minute 2 Homolog (MDM2), a proto-oncogene (12q14.3), acts as a major negative regulator for p53 expression in the p53-MDM2 auto-regulatory pathway. MDM2 binds directly to p53 and represses its transcriptional activity, promoting p53 degradation. CONCLUSION: In colon adenocarcinoma, MDM2 oncogene overexpression directly influences p53 oncoprotein expression levels.

Impact of Immune-Inflammatory Microenvironment Alterations on the Bronchial Lumen of Children With Protracted Bacterial Bronchitis.

Protracted bacterial bronchitis is a syndrome that is among the most common causes of chronic cough. In order to understand its pathogenetic mechanisms, there is an increasing interest in the study of the immune microenvironment in the bronchial lumen. The aim of this retrospective study is the determination of the types and quantity of the inflammatory cells that infiltrate the bronchial epithelium as well as of the thickness of the basement membrane. Ninety-seven endobronchial biopsies, obtained from 77 children (30 males and 47 females) aged between 5 and 14 years, with chronic (>8 weeks) wet/productive cough, were subjected to hematoxylin and eosin staining. Using an appropriate image analysis and processing software, we determined the types and the quantity of the inflammatory cells that infiltrated the bronchial epithelium, and the thickness of the basement membrane. The metric data were then subjected to extensive statistical analysis. According to our results, females had increased levels of eosinophils (p = 0.021) and lymphocytes (p = 0.044) compared to males. Moreover, we found that membrane thickness was negatively correlated with the number of eosinophils (p < 0.0001), neutrophils (p = 0.023), and lymphocytes (p = 0.024). Finally, the pairwise comparisons of the number of eosinophils, neutrophils, lymphocytes, and other cell types revealed significant (p < 0.05) positive correlations. Protracted bacterial bronchitis activates pulmonary innate immune pathways. Also, it is accompanied by basement membrane thickening, which is a typical characteristic of several respiratory diseases, such as asthma.

Metabolic Response of Adult Male Offspring Rats to Prenatal Caffeine Exposure.

Caffeine is the most widely consumed psychoactive substance, with recommendations from health associations and regulatory bodies for limiting caffeine consumption during pregnancy being increasingly common. Prenatal exposure to caffeine has been shown to increase the risk of developing abnormalities in lipid metabolism in adult life. We further investigated the effect of prenatal caffeine exposure (PCE) (20 mg/kg of body weight) on the metabolic "reserve" of male Sprague Dawley offspring fed on a high fructose diet in adult life. Male adult PCE offspring were assigned to four groups; Nw and Nf: offspring of control mothers (N group of mothers), having received tap water or high fructose water respectively; Cw and Cf: offspring exposed to caffeine during gestation (C group of mothers) and receiving tap water or a high fructose water solution, respectively. Cf rats presented increased serum triglyceride level, as well as raised systolic and diastolic blood pressure levels, together with extensive renal tissue oedema in adulthood, compared to the other groups (p<0.05 for all comparisons). These findings show further evidence for potential detrimental metabolic effects of prenatal caffeine exposure during adulthood in this animal model.

A type of neoplasia deadlier than gastric adenocarcinoma? Report of a case of primary gastric squamous cell carcinoma.

BACKGROUND: Primary gastric squamous cell carcinoma is an extremely rare malignancy with few case reports reported so far in the current medical literature. Its incidence varies between 0.04 and 0.07% of all gastric malignancies with a male predominance in the sixth decade of life. It has been found that this type of malignancy has a more aggressive behavior and associated poorer prognosis, when compared to gastric adenocarcinoma. Thus, the most appropriate management of this kind of neoplasia is still debatable due to the small number of reported cases. CASE PRESENTATION: We report the case of a 66-year-old man who underwent total gastrectomy with D2 lymphadenectomy for an ulcerative lesion in the fundus of the stomach that turned out to be primary gastric squamous cell carcinoma. CONCLUSIONS: Upon confirmation of this specific malignancy, the affected patients should be enrolled in strict follow-up protocols after curative surgery, since the risk for metastasis is high. Physicians should maintain high clinical suspicion in order to diagnose these tumors at an early stage, along with the need to rule out any other possible primary sites of squamous malignancy.

A case report on metastatic ileal neuroendocrine neoplasm to the breast masquerading as primary breast cancer: A diagnostic challenge and management dilemma.

RATIONALE: Metastatic neuroendocrine neoplasms (NENs) to the breast are very rare entities comprising only 1% to 2% of all metastatic breast tumors. In this article, we describe a case of a neuroendocrine ileal neoplasm metastatic to breast and liver, with breast metastatic tumor to be the initial manifestation of the disease. PATIENT CONCERNS: We herein report a rare case of a female patient admitted to our department with a palpable painful mass on her left breast. DIAGNOSIS: The surgical and histological investigation revealed a metastatic neuroendocrine neoplasm to the breast originated from terminal ileum. INTERVENTIONS: A left lumpectomy, right hemicolectomy, cholecystectomy, left hepatectomy along with liver metastasectomies (V, VI, VIII) plus radiofrequency ablation of lesions to the right liver lobe plus standard lymphadenectomy was performed. OUTCOMES: Considering the advanced stage of the disease, the patient received an adjuvant therapy of somatostatin analog plus everolimus. Under the guidance of oncological consultation, patients follow-up with CT and MRI scan and clinical re-evaluations in the first 3 and 6 months, substantiates no evidence of recurrence and she presents herself asymptomatic. LESSONS: An appropriate level of suspicion and selective immunohistochemistry in these cases, particularly where no prior history of a known primary neuroendocrine neoplasm occurs, may help to diagnose a previously undetected neuroendocrine tumor elsewhere in the body and provide guidance for the appropriate treatment selection.

The Goodness-of-fit of the Fractal Dimension as a Diagnostic Factor in Breast Cancer.

A large number of studies have found that the fractal dimension increases with the progression towards pathological or more pathological states, but there are also studies that have demonstrated the opposite relationship. In this study, we calculate the nuclear box-counting fractal dimension of 109 malignant, 113 benign, and 80 normal isolated breast cells in order to investigate its possible diagnostic importance. We computed the fractal dimension and its goodness-of-fit (i.e., the r-squared value that describes how well the regression line fits the set of the measurements) for two different sets of box size lengths. The statistical analysis did not confirm an important diagnostic potential of the nuclear fractal dimension of isolated breast cells. However, the goodness-of-fit did display a diagnostic potential. The r-squared value may be able to serve as a complementary diagnostic parameter.

Primary hyperparathyroidism caused by enormous unilateral water-clear cell parathyroid hyperplasia.

BACKGROUND: Parathyroid water-clear cell hyperplasia (WCCH) and water-clear cell adenoma (WCCA) are rare causes of primary hyperparathyroidism. The frequency of WCCH seems to be less than 1% of all primary hyperplasia. CASE PRESENTATION: We report a 53-year-old woman with a large unilateral water clear cell parathyroid hyperplasia associated with primary hyperparathyroidism and severe osteoporosis. Ultrasonography showed a 5.4 cm multilobulated hypoechoic well defined mass localized in the lower half of the left thyroid lobe. Technetium sestamibi scanning showed a persistent very large area of increased activity possibly corresponding to a left inferior double parathyroid adenoma. At surgery, two large merged lobulated parathyroid glands were removed from the left superior and inferior aspects of the adjacent thyroid extending to the sub-clavicular area. Histopathology showed polygonal hyperplastic vacuolated cells with abundant water clear cytoplasm. The lesion had lack of capsule or rim of parathyroid tissue and immunohistochemistry was positive for PTH staining. These findings were consistent with diffused water clear cell hyperplasia. After parathyroidectomy, iPTH and calcium levels dropped immediately. CONCLUSION: The clinical presentation of the patients with water clear cells parathyroid content and hyperparathyroidism is indistinguishable from that of the more common causes of primary hyperparathyroidism of adenoma or hyperplasia and the diagnosis is made only on pathological examination. In conclusion, the distinction of water clear cell hyperplasia from water clear cell adenoma can be challenging in many cases, although clinically significant as far as treatment and follow-up.

Primary Malignant Melanoma of Renal Pelvis with Extensive Clear Cell Change.

Our presentation illustrates a rare case of primary renal pelvis malignant melanoma in a 35-year-old man. The diagnosis of malignant melanoma was based on immunophenotype and the detection of intracellular melanin pigment. The renal origin was proven by the presence of scattered melanocytes within the urothelium of the pelvis. The tumor exhibited extensive clear cell change that closely mimics clear cell renal cell carcinoma. The patient's clinical history did not disclose any signs of previous melanocytic skin or mucosa lesions. Differential diagnosis includes tumors capable of synthesizing melanin or expressing melanocytic markers.