Prelude to malignancy: A gene expression signature in normal mammary gland from breast cancer patients suggests pre-tumorous alterations and is associated with adverse outcomes.

Despite advances in early detection and treatment strategies, breast cancer recurrence and mortality remain a significant health issue. Recent insights suggest the prognostic potential of microscopically healthy mammary gland, in the vicinity of the breast lesion. Nonetheless, a comprehensive understanding of the gene expression profiles in these tissues and their relationship to patient outcomes remain missing. Furthermore, the increasing trend towards breast-conserving surgery may inadvertently lead to the retention of existing cancer-predisposing mutations within the normal mammary gland. This study assessed the transcriptomic profiles of 242 samples from 83 breast cancer patients with unfavorable outcomes, including paired uninvolved mammary gland samples collected at varying distances from primary lesions. As a reference, control samples from 53 mammoplasty individuals without cancer history were studied. A custom panel of 634 genes linked to breast cancer progression and metastasis was employed for expression profiling, followed by whole-transcriptome verification experiments and statistical analyses to discern molecular signatures and their clinical relevance. A distinct gene expression signature was identified in uninvolved mammary gland samples, featuring key cellular components encoding keratins, CDH1, CDH3, EPCAM cell adhesion proteins, matrix metallopeptidases, oncogenes, tumor suppressors, along with crucial genes (FOXA1, RAB25, NRG1, SPDEF, TRIM29, and GABRP) having dual roles in cancer. Enrichment analyses revealed disruptions in epithelial integrity, cell adhesion, and estrogen signaling. This signature, named KAOS for Keratin-Adhesion-Oncogenes-Suppressors, was significantly associated with reduced tumor size but increased mortality rates. Integrating molecular assessment of non-malignant mammary tissue into disease management could enhance survival prediction and facilitate personalized patient care.

Assessment of immunomodulation and regulation of cell cycle in epithelium and stroma after Cidofovir injection in patients with recurrent respiratory papillomatosis-Pilot study.

Recurrent respiratory papillomatosis is strictly connected with human papillomavirus (HPV) infection of the epithelium of the upper respiratory tract. The main treatment of lesions located in the larynx or lower pharynx includes microsurgical excision by using a CO2 laser. To decrease the amount of surgical procedures gain in importance combined therapy with antiviral agents. The aim of this study was to investigate the effect of the intralesional application of Cidofovir on the tissue of laryngeal papillomas. We have shown that simultaneous microsurgery with adjuvant therapy of Cidofovir reduces chronic inflammation (by measuring the expression of CD4 and CD8 in tissue samples), cell proliferation, and regulates the cell cycle of HPV-infected cells by reducing the expression of p53 and p63 proteins. In addition, this strategy reduces the multiple surgical procedures and regrowth of the pathology.

Dural sinus thrombosis after resection of vestibular schwannoma using suboccipital retrosigmoid approach-thrombosis classification and management proposal.

Dural sinus thrombosis is one of the complications after posterior fossa surgery. However, that topic is not described well with regard to vestibular schwannoma surgery using the unique suboccipital retrosigmoid approach. We analyzed retrospectively medical records and radiological investigations of 116 patients. The including criteria were histopathologically confirmed vestibular schwannoma operated on using the retrosigmoid approach, preoperative and postoperative contrast-enhanced MRI, and at least 1-year follow-up. The patient group included 36% males and 64% females. The average age was 47.3 ± 13.9 years. Sixty percent of the tumors were classified as T4b according to the Hannover scale and their mean volume was 13.73 ± 10.28 cm3. There were no signs of thrombosis preoperatively. Postoperative changes in the dural sinuses were found in 26 (22%) cases. In 7 (27%) cases, there was an external compression by the hemostatic agent, and in 19 (73%) cases, a thrombus was visualized in the sinus lumen. The size of the sinus, age, and the tumor size were not risk factors for thrombosis, whereas an intraoperative sinus injury was a statistically significant risk factor (p = 0.0012). All of the patients diagnosed with thrombosis were in good clinical condition in long-term follow-up, except one fatal case. Complete recanalization was observed in 58% of cases after 1-year follow-up. Postoperative changes in the dural venous sinuses are a frequent finding after vestibular schwannoma surgery using the suboccipital retrosigmoid approach. Intraoperative dural injury is a risk factor for thrombosis. Thrombosis in that group of patients is usually asymptomatic and does not influence the prognosis.

Overexpression of kif11 is a poor prognostic factor in clear cell renal cell carcinoma.

INTRODUCTION: Unresectable renal cell carcinoma continues to be a great challenge due to our limited understanding of its underlying pathophysiology. We explored the relationship between KIF11 protein expression and the clinical courses of clear cell renal cell carcinoma (ccRCC) using a tissue microarray. MATERIAL AND METHODS: The tissue microarray contained specimens derived from 90 patients, cancer and matched adjacent non-cancerous tissue (2 cores per case), followed up for 7 years. Tumour samples were evaluated for KIF11 expression using the H-score, and their correlations with clinicopathological data and survival data were analysed. RESULTS: 72.7% of ccRCC tissues presented KIF11 cytoplasmic expression with a median value of 20 (interquartile range 0-200). The nuclear staining was positive in 36.36% of ccRCC tissues. Among controls, nuclear KIF11 expression was absent, but cytoplasmic expression was identified in all cases, with a median value of 230 (interquartile range 45-290). Cytoplasmic KIF11 expression in ccRCC tissues was lower than in the control tissues and was positively correlated with tumour grade and mortality (p < 0.05). KIF11 nuclear expression did not correlate with overall survival. CONCLUSIONS: Elevated expression of KIF11 predicts poor clinical outcome in ccRCC patients. Downregulation of KIF11 may provide a new therapeutic strategy for ccRCC.

TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma.

Resistance to systemic therapy is one of the hallmarks of renal cell carcinoma (RCC). Recently, TOLLIP has emerged as a possible driver of autophagy and chemoresistance. We explored the relationship between primary and metastatic RCC tumor characteristics, patient survival, and TOLLIP expression. The tissue microarrays cohort contained 95 cores of the primary tumor, matched metastases, and matched adjacent tissues derived from 32 RCC patients. TOLLIP expression in tumor samples was evaluated using the H-score. All examined samples showed cytoplasmic TOLLIP expression, with a median value of 100 in primary tumors, 107.5 in metastases, and 220 in the control group. The expression was significantly higher in the normal adjacent tissues compared to primary or metastatic RCC (p < 0.05). We found a positive correlation between expressions of TOLLIP in the primary tumor and its metastases (p < 0.05; k = 0.48). TOLLIP expression significantly correlates with a lower overall survival rate (p = 0.047). TOLLIP functions as a ubiquitin-LC3 adaptor in the intracellular pathway associated with autophagy. Relative TOLLIP overexpression may augment autophagy-related signaling, limiting susceptibility to therapy. The blockade of TOLLIP physiological function seems to be a promising approach to overcoming resistance to systemic therapy.

Endoscopic versus stereotactic biopsies of intracranial lesions involving the ventricles.

Stereotactic biopsies of ventricular lesions may be less safe and less accurate than biopsies of superficial lesions. Accordingly, endoscopic biopsies have been increasingly used for these lesions. Except for pineal tumors, the literature lacks clear, reliable comparisons of these two methods. All 1581 adults undergoing brain tumor biopsy from 2007 to 2018 were retrospectively assessed. We selected 119 patients with intraventricular or paraventricular lesions considered suitable for both stereotactic and endoscopic biopsies. A total of 85 stereotactic and 38 endoscopic biopsies were performed. Extra procedures, including endoscopic third ventriculostomy and tumor cyst aspiration, were performed simultaneously in 5 stereotactic and 35 endoscopic cases. In 9 cases (5 stereotactic, 4 endoscopic), the biopsies were nondiagnostic (samples were nondiagnostic or the results differed from those obtained from the resected lesions). Three people died: 2 (1 stereotactic, 1 endoscopic) from delayed intraventricular bleeding and 1 (stereotactic) from brain edema. No permanent morbidity occurred. In 6 cases (all stereotactic), additional surgery was required for hydrocephalus within the first month postbiopsy. Rates of nondiagnostic biopsies, serious complications, and additional operations were not significantly different between groups. Mortality was higher after biopsy of lesions involving the ventricles, compared with intracranial lesions in any location (2.4% vs 0.3%, p = 0.016). Rates of nondiagnostic biopsies and complications were similar after endoscopic or stereotactic biopsies. Ventricular area biopsies were associated with higher mortality than biopsies in any brain area.

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications.

Pancreatic cancer (PC) is the fourth most common cause of death among all cancers. Poor prognosis of PC may be caused by a prevalence of cancer stem cells (CSCs). CSCs are a population of cancer cells showing stem cell-like characteristics. CSCs have the ability to self-renew and may initiate tumorigenesis. PC CSCs express markers such as CD133, CD24, CD44, DCLK1, CXCR4, ESA, Oct4 and ABCB1. There is a wide complexity of interaction and relationships between CSC markers in PC. These markers are negative prognostic factors and are connected with tumor recurrence and clinical progression. Additionally, PC CSCs are resistant to treatment with gemcitabine. Thus, most current therapies for PC are ineffective. Numerous studies have shown, that targeting of these proteins may increase both disease-free and overall survival in PC.

Diagnostic difficulties in cases of papillary urothelial neoplasm of low malignant potential, urothelial proliferation of uncertain malignant potential, urothelial dysplasia and urothelial papilloma: A review of current literature.

Tumours of the urinary tract are the fifth most frequent type of cancer. The most common types are urothelial tumours, among which, non-invasive urothelial neoplasms represent 45% of all cases. The 2016 WHO classification of urinary tract tumours introduced new classifications of non-invasive lesions. Besides urothelial papilloma (UP) and papillary urothelial neoplasm of low malignant potential (PUNLMP), as described in the former classification, the new classification also includes new entities such as urothelial proliferation of uncertain malignant potential (UPUMP) and urothelial dysplasia (UD). Of the aforementioned, UPUMP is the lesion that most commonly progresses, but solely to non-invasive carcinomas. UD is associated with a high risk of progression to invasive carcinoma. Understanding the biological character, and establishing the correct differential diagnosis in cases of non-invasive, non-cancerous lesions of the urinary bladder, will be of importance in establishing outcome predictions for future patients. A systematic review of the current literature allows us to systematize genetic, morphologic and prognostic factors of such lesions. Moreover, the collected data provide the basis for a proposed diagnostic algorithm which facilitates quick and effective differential diagnoses in cases of non-invasive non-cancerous urinary bladder lesions.

Recurrent transcriptional loss of the PCDH17 tumor suppressor in laryngeal squamous cell carcinoma is partially mediated by aberrant promoter DNA methylation.

Protocadherins are cell-cell adhesion molecules encoded by a large family of genes. Recent reports demonstrate recurrent silencing of protocadherin genes in tumors and provide strong arguments for their tumor supresor functionality. Loss of protocadherins may contribute to cancer development not only by altering cell-cell adhesion, that is a hallmark of cancer, but also by enhancing proliferation and epithelial mesenchymal transition of cells via deregulation of the WNT signaling pathway. In this study we have further corroborated our previous findings on the involvement of PCDH17 in laryngeal squamous cell carcinoma (LSCC). We used bisulfite pyrosequencing to analyze a cohort of primary LSCC tumors for alterations in PCDH17 promoter DNA methylation as an alternative gene inactivation mechanism to the homozygous deletions reported earlier. Moreover, we analyzed primary LSCC samples by immunohistochemistry for PCDH17 protein loss. We identified recurrent elevation of PCDH17 promoter DNA methylation in 32/81 (40%) primary tumors (P < 0.001) and therein hypermethylation of 12 (15%) cases in contrast to no tumor controls (n = 24) that were all unmethylated. Importantly, DNA demethylation by decitabine has restored low level PCDH17 expression in LSCC cell lines. In conclusion, we provide a mechanistic explanation of recurrently observed PCDH17 silencing in LSCC by demonstrating the role of promoter methylation in this process. In light of these findings and recent reports showing that PCDH17 methylation is detectable in serum of cancer patients we suggest that testing PCDH17 DNA methylation might serve as a potential biomarker in LSCC.

HPV-Related Head and Neck Squamous Cell Carcinomas.

Since more than 5 years, it becomes evident that there is a new group of patients with squamous cell carcinomas of the head and neck area, namely human papillomavirus (HPV)-related (caused) tumors. As clinical statistics indicate, those patients have better prognosis, even despite more advanced stage compared to those with HPV-negative tumors. In fact, as a surrogate of HPV infection for clinical studies, an immunohistochemical expression of p16 protein is used. In the following chapter, the spectrum of squamous cell carcinomas variants with indication of the percentage cases with proved HPV infection will be presented.

The diagnosis and management of congenital and adult-onset hyperinsulinism (nesidioblastosis) - literature review.

Congenital and adult-onset hyperinsulinism (CHI) must be taken under consideration in the differential diagnosis of hypoglycaemia symptoms with endogenous hyperinsulinism, especially in cases in which there was failure to find an insulinoma. Histological examination is necessary for a definitive diagnosis. CHI is a disorder with three histopathological variants: focal CHI, diffuse CHI, and atypical CHI. These variants are clinically indistinguishable. According to published statistics, 0.5 to 5% of nesidioblastosis cases occur in adults. Clinical manifestation ranges from mildly symptomatic up to life-threatening hypoglycaemia. Early diagnosis and treatment are important in young and very young patients because early treatment accounts for favourable mental outcomes.

Proteomic profiling identifies the inorganic pyrophosphatase (PPA1) protein as a potential biomarker of metastasis in laryngeal squamous cell carcinoma.

Relapse and metastasis are the main causes of unfavorable outcome in head and neck cancers. Whereas, understanding of the molecular background of these processes is far from being complete. Therefore, in this study we aimed to identify potential biomarker candidates of relapse and metastasis in laryngeal squamous cell carcinoma (LSCC) by combining the 2D electrophoresis based protein screen and immunohistochemical analysis of candidate proteins. We screened three groups of LSCC cell lines derived from primary tumors, recurrent tumors and metastases and identified seven proteins that differed significantly in relative abundance between the analyzed groups. Among the identified proteins were the heat shock proteins HSP60 and HSP70 that were significantly downregulated both in recurrences- and metastases-derived cell lines but not in primary tumor-derived cell lines. Moreover, we identified significant upregulation of the annexin V, calreticulin and the inorganic pyrophosphatase (PPA1) exclusively in the metastases-derived cell lines. As these upregulated proteins could potentially become novel biomarkers of metastasis, we have compared their abundance in primary tumor LSCC N(0) cases, primary tumor LSCC N(+) cases as well as in LSCC metastases N(+). Our results show an intense increase of cytoplasmic PPA1 abundance in the N(+) (p = 0.000042) compared to the N(0) group. In summary, we show a group of proteins deregulated in recurrences and metastases of LSCC. Moreover, we suggest the PPA1 protein as a potential new biomarker for metastasis in this cancer.

Pathologic aspects of skull base tumors.

Skull base tumors form a highly heterogeneous group. As there are several structures in this anatomical site, a large number of different primary malignancies might develop, as well as a variety of secondary (metastatic) tumors. In this article, the most common malignancies are presented, along with a short histopathologic description. For some entities, an immunohistochemical profile is also given that should be helpful in proper diagnosis. As many pathologic diagnoses nowadays also include genetic studies, the most common genetic abnormalities in skull base tumors are presented.

Tumor progression driven by pathways activating matrix metalloproteinases and their inhibitors.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is still a problem worldwide. In some publications interactions between the expression of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, and their tissue inhibitors (TIMPs) implicated during cancer progression were suggested. METHODS: The immunohistochemical staining using primary antibody against MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-3 were performed. The research group consists of primary N(0) LSCC (20 cases), primary N(+) LSCC (17 cases), and 18 cases of normal mucosa. RESULTS: Studied MMPs and TIMPs were localized in tumor cells and tumor stroma compartment. MMP-2 expression was higher in stroma compared to tumor cells. MMP-9, TIMP-1, TIMP-2, and TIMP-3 expression was higher in tumor cells than in tumor stroma (P < 0.05). In tumor stroma MMP-2, MMP-9, TIMP-1, and TIMP-3 expression, in LSCC N(0) vs. LSCC N(+) was significantly higher (P < 0.05). The ratios between MMP-2 and TIMP-3 expression were statistically significant (N(0) vs. N(+); P = 0.012). The analyses using classification trees predicted the probability of metastases according to TIMP-3/MMP-14/MMP-2 and MMP-9/TIMP-1 expression levels. CONCLUSIONS: The presence of MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-3 expression in tumor cells and in tumor stroma, and additionally different expression according to lymph node involvement suggested of their impact during cancer progression. The significant correlation between TIMP-3 expression and the presence of lymph node metastases and MMP-2 expression might suggest the importance of TIMP-3 as a prognostic factor during tumor progression. The evaluation of molecular markers which participate in MMP-2 activation pathway have a major impact during metastasis.

[Tobacco smoking as a cofactor for the development of cervical cancer]. / Palenie tytoniu jako kofaktor rozwoju nowotworów szyjki macicy.

UNLABELLED: Etiopathogenesis of cervical cancer is mainly related to persistent HPV infection. However in neoplastic transformation participate additional factors, one of the main is tobacco smoking. Nowadays, in Poland is conduced prophylactic program with the target to decrease incidence and mortality according to cervical cancer. The basis of this program is Pap smears, histological diagnostics and colposcopy. AIM OF STUDY: The aim of this paper was evaluation of correlation between histopatological changes uterin cervix in respect of tobacco smoking and immunohistochemistry LI capsid protein test. MATERIAL AND METHODS: From 3520 patients with incorrect Pap smears selected 36 cases (medium age 36) with incorrect Pap smears and histology. Used immunohistochemical methods (with HRP system) for evaluation of L1 protein. RESULTS: In group with positive L1 test significant part were smokers and those who quite smoking. The results revealed directly relate between cigarette.

Osteosarcoma of the larynx.

Malignant neoplasms of the larynx are divided into epithelial and non-epithelial. Non-epithelial neoplasms include, among others, mesenchymal chondrosarcomas and osteosarcomas. Few cases of laryngeal osteosarcomas described in the literature were usually treated by surgery without the need to use adjuvant radio- or chemotherapy. Few authors propose the initial application of radiotherapy or high-dose chemotherapy. Our study presents a very rare case of a woman treated due to laryngeal osteosarcoma. We have also presented diagnostic difficulties preceding a decision to perform radical surgery. The patient had been eligible for radical surgical treatment, even though there were no features of malignancy in a histopathological examination of the biopsy material. Complete laryngectomy was carried out without the surgery of the cervical lymphatic system. Laryngeal osteosarcoma was diagnosed based on the postoperative histopathological examination using vimentin and Ki67. The patient remains under the care of the Otolaryngology and Laryngological Oncology Department and Oncology Centre in Bydgoszcz. There were no reports on local recurrence or distant metastases during regular check-ups.

Expression of FoxP3 protein plays a key role in thyroid tumors in children.

The expression of FoxP3 in tumor cells might play an important role in cancer progression. We evaluated the immunoexpression of FoxP3 in thyroid tumors in children. Studies revealed high nuclear FoxP3 expression in follicular adenoma, papillary carcinoma, follicular carcinoma and low in goiter. Malignant tumors and adenomas, revealed a statistically significant higher expression of FoxP3 compared with the thyroid goiter. High FoxP3 expression in malignant lesions compared with low expression in goiter, may be indirect evidence of its role in carcinogenesis. Revealed high expression of FoxP3 in benign tumor, may suggest a strong activation of oncogenic processes in this lesion.

Atypical Presentation of Bronchogenic Cyst in the Retroperitoneal Space.

Bronchogenic cysts, benign congenital malformations resulting from abnormal tracheobronchial tree budding, primarily manifest in the mediastinum, with retroperitoneal occurrence being exceedingly rare. Typically incidental findings on imaging, and their diagnosis pose challenges, particularly when malignancy is suspected. We present a case involving a 55-year-old woman diagnosed with chronic back pain. Physical examination revealed a painful mass in the left renal region. Subsequent MRI identified a smooth mass in the left adrenal gland without infiltration of surrounding structures. Laparoscopic surgery successfully removed the lesion without complications. Pathomorphological examination confirmed a gelatinous-filled cyst, identified as a retroperitoneal bronchogenic cyst in the left adrenal gland. Increasing reports of retroperitoneal bronchogenic cysts contribute to a better understanding of their characteristics, aiding preoperative diagnosis. However, given potential malignancy and definitive diagnosis through histopathological examination, surgical resection remains the preferred method.

The role of IL-17 in the pathogenesis and treatment of glioblastoma-an update on the state of the art and future perspectives.

Glioblastoma (GBM) is the most common malignant brain tumor, which, despite significant progress made in the last years in the field of neuro-oncology, remains an incurable disease. GBM has a poor prognosis with a median survival of 12-15 months, and its aggressive clinical course is related to rapid growth, extensive infiltration of adjacent tissues, resistance to chemotherapy, radiotherapy and immunotherapy, and frequent relapse. Currently, several molecular biomarkers are used in clinical practice to predict patient prognosis and response to treatment. However, due to the overall unsatisfactory efficacy of standard multimodal treatment and the remaining poor prognosis, there is an urgent need for new biomarkers and therapeutic strategies for GBM. Recent evidence suggests that GBM tumorigenesis is associated with crosstalk between cancer, immune and stromal cells mediated by various cytokines. One of the key factors involved in this process appears to be interleukin-17 (IL-17), a pro-inflammatory cytokine that is significantly upregulated in the serum and tissue of GBM patients. IL-17 plays a key role in tumorigenesis, angiogenesis, and recurrence of GBM by activating pro-oncogenic signaling pathways and promoting cell survival, proliferation, and invasion. IL-17 facilitates the immunomodulation of the tumor microenvironment by promoting immune cells infiltration and cytokine secretion. In this article we review the latest scientific reports to provide an update on the role of IL-17 role in tumorigenesis, tumor microenvironment, diagnosis, prognosis, and treatment of GBM.