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Objectives Hamartomas are non-neoplastic developmental anomalies, mostly congenital, characterized by uncontrolled, disorganized proliferation of local endogenous tissue, which can normally be found at the site of origin and are very often mesodermally derived. It is well known that hamartoma can be associated with congenital midline cervical cleft and therefore cause a variety of symptoms. In general, they are benign and indolent, but they can be the cause of complex morbidity if they are localized within specific regions, such as the head and neck, which represent highly sensitive and vulnerable areas. Case presentation The reported case is unusual because of the presence of a congenital mesenchymal hamartoma along with the median cervical cleft, in a 1-day-old neonate, without the presence of any respiratory symptoms or associated congenital features. Although extremely rare, hamartomas should be included in the differential diagnosis of congenital neck masses, with emphasis on diagnostic approach, to avoid overly aggressive treatment and possible complications, such as infection, further mass growth, malignant transformation and compression of the adjacent neck structures. Conclusions Appropriate and timely treatment of the hamartoma of the neck in neonates, with further follow-up is necessary to avoid an overly aggressive treatment and to distinguish benign from malignant lesions, which is necessary for successful curative outcome.

Simple Summary The process of HPV-mediated oncogenesis in HNSCCs is not fully understood. DLG1 and SCRIB protein expression levels and localization changes were evaluated in a number of HPV16-positive and HPV-negative OPSCCs and seem to be associated with malignant transformation. Moreover, loss of SCRIB expression inversely correlates with higher grade tumors, and this is much more evident in the presence of HPV16 E6. This could serve as a potential marker in predicting development of OPSCCs. Abstract The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell–cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell–cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs.

Major findings of the pilot study involving 21 critically ill patients during the week after admission to the critical care unit specialized for COVID-19 are presented. Fourteen patients have recovered, while seven passed away. There were no differences between them in respect to clinical or laboratory parameters monitored. However, protein adducts of the lipid peroxidation product 4-hydroxynonenal (HNE) were higher in the plasma of the deceased patients, while total antioxidant capacity was below the detection limit for the majority of sera samples in both groups. Moreover, levels of the HNE-protein adducts were constant in the plasma of the deceased patients, while in survivors, they have shown prominent and dynamic variations, suggesting that survivors had active oxidative stress response mechanisms reacting to COVID-19 aggression, which were not efficient in patients who died. Immunohistochemistry revealed the abundant presence of HNE-protein adducts in the lungs of deceased patients indicating that HNE is associated with the lethal outcome. It seems that HNE was spreading from the blood vessels more than being a consequence of pneumonia. Due to the limitations of the relatively small number of patients involved in this study, further research on HNE and antioxidants is needed. This might allow a better understanding of COVID-19 and options for utilizing antioxidants by personalized, integrative biomedicine approach to prevent the onset of HNE-mediated vitious circle of lipid peroxidation in patients with aggressive inflammatory diseases.

Ectopic adrenal cortical neoplasms of the spinal cord are extremely rare. To date only 10 such cases have been described. We present a case of a 46-year-old woman with lower back pain radiating to the right gluteal and posterior femoral regions, without a history of traumatic injury. Magnetic resonance imaging (MRI) of the thoracic and lumbar spine showed an intradural, extramedullary, well-circumscribed, contrast-enhancing lesion located in the T12–L1 region, hypo- to isointense on T2-weighted imaging, and isointense on T1. Complete surgical removal of the lesion, measuring 3 × 2.5 × 1 cm, was performed. The histopathologic findings revealed the lesion was an ectopic adrenal cortical adenoma, with sheets and nests of round and polygonal cells, mostly round regular nuclei, abundant eosinophilic cytoplasm, 1 mitosis per 10 high-power fields, and without necrosis. These tumors have nonspecific MRI features and therefore can be easily confused with other common spinal tumor types such as ependymoma, schwannoma, meningioma, and metastasis. Although rare, ectopic adrenal spinal cord adenomas should be taken into account in the differential diagnosis of spinal canal intradural neoplasms.

There is a lot of evidence showing that lipid peroxidation plays very important role in development of various diseases, including neurodegenerative diseases and brain tumors. Lipid peroxidation is achieved by two main pathways, by enzymatic or by non-enzymatic oxidation, respectively. In this paper, we focus on non-enzymatic, self-catalyzed chain reaction of poly-unsaturated fatty acid (PUFA) peroxidation generating reactive aldehydes, notably 4-hydroxynonenal (4-HNE), which acts as second messenger of free radicals and as growth regulating factor. It might originate from astrocytes as well as from blood vessels, even within the blood-brain barrier (BBB), which is in case of brain tumors transformed into the blood-brain-tumor barrier (BBTB). The functionality of the BBB is strongly affected by 4-HNE because it forms relatively stable protein adducts thus allowing the persistence and the spread of lipid peroxidation, as revealed by immunohistochemical findings. Because 4-HNE can act as a regulator of vital functions of normal and of malignant cells acting in the cell type- and concentration-dependent manners, the bioactivities of this product of lipid peroxidation be should further studied to reveal if it acts as a co-factor of carcinogenesis or as natural factor of defense against primary brain tumors and metastatic cancer.

Patologija tumora sinonazalnog trakta (nosna šupljina i paranazalni sinusi) izrazito je izazovna zbog različitih histoloških tipova tumora koji se mogu razviti u toj regiji. Usprkos relativno maloj anatomskoj veličini u tom području, mogu se razviti različiti tipovi tumora, od primarnih karcinoma, limfoma, melanoma, sarkoma, koštanih i hrskavičnih tumora, neuralnih/neuroektodermalnih tumora i odontogenih tumora, sve do metastatskih tumora. Tumori nosa i paranazalnih sinusa najčešće potječu od epitela koji oblaže te šupljine. Najčešći su tumori papilomi, zatim karcinomi, dok su svi ostali tumori rijetkost. U zadnjem, četvrtom izdanju SZO (Svjetska Zdravstvena organizacij) klasifikacije tumora glave i vrata iz 2017 godine uključene su glavne promjene u definiciji već postojećih entiteta, opisane su nove lezije i biologija rasta različitih tipova tumora. Na osnovi novih imunohistokemijskih markera i genetike opisani su novi dijagnostički entiteti koji su uključeni u novu klasifikaciju SZO. Novi entiteti u području nosne šupljine i paranazalnih sinusa uključuju NUT karcinom, HPV-povezani sinonazalni karcinom sa značajkama adenoidnog cističnog karcinoma, SMARCB1 (INI-1) deficijentni sinonazalni karcinom, bifenotipski sinonazalni sarkom i adenokarcinom nalik na karcinom bubrežnih stanica. Opisani novi tumorski entiteti mogu se međusobno razlikovati na osnovi širokog spektra imunohistokemijskog bojanja, te molekularne analize.

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology., info:eu-repo/semantics/published

Tumor growth is associated with oxidative stress, which causes lipid peroxidation. The most intensively studied product of lipid peroxidation is 4-hydroxy-2-nonenal (HNE), which is considered as a &ldquo, second messenger of free radicals&rdquo, that binds to proteins and acts as a growth-regulating signaling factor. The incidence of squamous cell carcinoma of the oropharynx is associated with smoking, alcohol and infection of human papilloma virus (HPV), with increasing incidence world-wide. The aim of this retrospective study involving 102 patients was to determine the immunohistochemical appearance of HNE-protein adducts as a potential biomarker of lipid peroxidation in squamous cell carcinoma of the oropharynx. The HNE-protein adducts were detected in almost all tumor samples and in the surrounding non-tumorous tissue, while we found that HNE is differentially distributed in squamous cell carcinomas in dependence of clinical stage and histological grading of these tumors. Namely, the level of HNE-immunopositivity was increased in comparison to the normal oropharyngeal epithelium in well- and in moderately-differentiated squamous cell carcinoma, while it was decreasing in poorly differentiated carcinomas and in advanced stages of cancer. However, more malignant and advanced cancer was associated with the increase of HNE in surrounding, normal tissue. This study confirmed the onset of lipid peroxidation, generating HNE-protein adducts that can be used as a valuable bioactive marker of carcinogenesis in squamous cell carcinoma of the oropharynx, as well as indicating involvement of HNE in pathophysiological changes of the non-malignant tissue in the vicinity of cancer.

Aim: To identify the involvement of Secreted Frizzled Related Protein 1 (SFRP1) promoter hypermethylation in different malignancy grades of astrocytoma and assess its association with beta- catenin, lymphoid-enhancer factor 1, and T-cell factor 1. Methods: Twenty-six astrocytoma samples were collected from 2008-2015. Promoter hypermethylation was evaluated by methylation- specific polymerase-chain-reaction and protein expression by immunohistochemistry and stereological analysis. The staining intensity was scored by comparing immunoreactivity with normal tissue and by using 10% and 50% cut-offs. Results: SFRP1 promoter methylation was found in 32% of astrocytomas. The number of hypermethylated samples increased in higher astrocytoma grades and was the highest in glioblastoma (P = 0.042 compared to other astrocytoma grades). There was 45.8% of samples with the lack of or weak expression of SFRP1 protein and 29.2% with strong expression. Samples with methylated promoter expressed significantly less SFRP1 than samples with unmethylated promoter (P = 0.031). Beta- catenin expression levels were elevated. Yet, glioblastomas with unmethylated SFRP1 promoter had significantly less beta-catenin (P = 0.033). Strong expression of lymphoid-enhancer factor 1 was associated to higher astrocytoma grades (P = 0.006). Conclusion: SFRP1 gene was epigenetically silenced in glioblastomas when compared to low astrocytoma grades, which may suggest that the lack of its protein is involved in astrocytoma progression.

The purpose of our research is to prove that elastic biomechanical characteristics of the temporalis muscle fascia are comparable to those of the fascia lata, which makes the temporalis muscle fascia adequate material for dural reconstruction in the region of the anterior cranial fossa. Fifteen fresh human cadavers, with age range from 33 to 83 years (median age: 64 years; mean age: 64.28 years), were included in the biomechanical study. Biomechanical stretching test with the comparison of elasticity among the tissues of the temporalis muscle fascia, the fascia lata, and the dura was performed. The samples were stretched up to the value of 6% of the total sample length and subsequently were further stretched to the maximum value of force. The value of extension at its elastic limit for the each sample was extrapolated from the force–extension curve and was 6.3% of the total sample length for the fascia lata (stress value of 14.61 MPa), 7.4% for the dura (stress value of 6.91 MPa), and 8% for the temporalis muscle fascia (stress value of 2.09 MPa). The dura and temporalis muscle fascia shared the same biomechanical behavior pattern up to the value of their elastic limit, just opposite to that of the fascia lata, which proved to be the stiffest among the three investigated tissues. There was a statistically significant difference in the extension of the samples at the value of the elastic limit for the fascia lata in comparison to the temporalis muscle fascia and the dura (p = 0.002; Kruskal–Wallis test). Beyond the value of elastic limit, the temporalis muscle fascia proved to be by far the most elastic tissue in comparison to the fascia lata and the dura. The value of extension at its maximum value of force for the each sample was extrapolated from the force–extension curve and was 9.9% of the sample's total length for the dura (stress value of 10.02 MPa), 11.2% for the fascia lata (stress value of 23.03 MPa), and 18.5% (stress value of 3.88 MPa) for the temporalis muscle fascia. There was a statistically significant difference in stress values at the maximum value of force between the dura and the temporalis muscle fascia (p = 0.001; Mann–Whitney U test) and between the dura and the fascia lata (p

Background: Astrocytomas are the most common primary brain tumors that are on the basis of their histology, molecular characteristics and prognosis classified into 4 different malignancy grades. As one of the key oncogenic pathways in human malignancies that has been associated to many human cancers the Wnt signaling pathway has also been implicated in gliomagenesis. In the present study we aimed to identify the status of SFRP1 promoter hypermethylation in different malignancy grades of astrocytoma and assess its parallel expression levels in search for their connection with clinical data. Methods: Promoter hypermethylation of critical molecular component of Wnt signaling – SFRP1 was studied in 24 astrocytomas of different malignancy grades by using methylation-specific PCR (MSP). In order to examine the consequence of hypermethylation, the SFRP1 protein was investigated by immunohistochemistry and analyzed by quantitative stereological analysis. Results: SFRP1 promoter hypermethylation was found in 32% of astrocytomas. Hypermethylation of SFRP1 promoter was progressively rising in higher astrocytoma grades with the highest significant distribution in glioblastoma (P=0.042). The expression of SFRP1 protein showed 45.8% of cases with weak or lack of expression, 25% with moderate and 29.2% with strong expression levels. Our study showed that cases with methylated SFRP1 promoter expressed significantly less SFRP1 protein than unmethylated ones (P=0.031). Furthermore, we have shown that the levels of beta-catenin, pathways indicator of oncogenic activity, were elevated with often nuclear localization. Statistical analysis showed that glioblastoma samples with unmethylated SFRP1 promoter had significantly less beta-catenin (P=0.033). The activation of Wnt signaling was further confirmed by the expression of its transcriptional activators. Strong expression of LEF1 was significantly associated to higher grades (P=0.006). Conclusions: Our findings showed that SFRP1 acts as an antagonist in the evolution of astrocytoma which will contribute to better understanding of astrocytoma molecular profile and offer methylation biomarker of progression.

Oxidative stress is thought to play a major role in etiology of many cancers, including breast cancer. 8-hydroxy- 2'deoxyguanosine (8- OHdG) is the most abundant marker of oxidative DNA damage. The aim of this study was to assess the extent of oxidative DNA damage in different breast cancer molecular surrogate subtypes to investigate the prognostic relevance and role of oxidative base lesion (8-OHdG) in the etiology of breast cancer. 8-OHdG expression was immunohistochemicaly studied on tissue microarrays constructed from 152 patients with invasive breast cancer. Expression was correlated with other prognostic factors, as well as different breast cancer molecular surrogate subtypes such as luminal A, luminal B [human epidermal growth factor receptor 2 (HER2) negative], luminal B (HER2 positive), HER2-enriched ad triple-negative tumors. Triple-negative breast carcinomas (TNBCs) were more frequently 8-OHdG negative compared with non-TNBCs (P=0.036). There was no statistically significant difference between 8-OHdG expression and other breast cancer molecular subtypes.In univariate analysis, there was no significant difference between 8-OHdG expression and breast cancer- specific death, although in multivariate analysis 8-OHdG overexpression was associated with better breast cancer-specific survival (BCSS) (odds ratio=0.04, 95% confidence interval, 0.002- 0.62). In Cox regression analysis, patients with moderate and strong 8- OHdG expression had 0.9 times smaller breast cancer death hazard ratio than patients with negative 8-OHdG expression. Oxidative stress may have less impact in the pathogenesis of TNBCs compared with other surrogate breast cancer molecular subtypes. 8- OHdG may be a promising biomarker in the prediction of prognosis for breast cancer patients.

Excessive production of reactive oxygen species can induce peroxidation of the polyunsaturated fatty acids thus generating reactive aldehydes like 4-hydroxy-2-nonenal (HNE), denoted as "the second messenger of free radicals". Because HNE has high binding affinity for cysteine, histidine and lysine it forms relatively stable and hardly metabolized protein adducts. By changing structure and function of diverse structural and regulatory proteins, HNE achieves not only cytotoxic, but also regulatory functions in various pathophysiological processes. Numerous animal model studies and clinical trials confirmed HNE as one of the crucial factors in development and progression of many disorders, in particular of cancer, (neuro)degenerative, metabolic and inflammatory diseases. Since HNE has multiple biological effects and is in the living system usually bound to proteins and peptides, many research groups work on development of specific immunochemical methods targeting the HNE-histidine adducts as major bioactive marker of lipid peroxidation, following the research pathway initiated by Hermann Esterbauer, who discovered HNE in 60's. Such immunohistochemical studies did not only prove the high biomedical importance of HNE, but have also given new insights into major diseases of the modern man. Immunohistochemical studies have shown reversibility of formation of the HNE-protein adducts, as well as differential onset of the HNE-mediated lipid peroxidation between age- associated atherosclerosis and photoaging, revealing eventually selective anti-cancer effects of HNE produced by non-malignant cells in vicinity of cancer. This review summarizes some of the HNE-histidine immunohistochemistry findings we believe are of broad biomedical interest and could inspire new studies in the field.

Oxidative stress (OS) is the condition that occurs when the anti-oxidative capacity of tissues and cells is overcome. The oxidative damage of cells is caused by free radicals which are products of OS. Lipid peroxidation is an autocatalitic process caused by OS which damages lipids and causes production of highly reactive species such as 4-hyroxynonenal (HNE). Recent findings have shown an increase in HNE-immunopositivity when compared to grade of astrocytic tumors. The cancer stem cell hypothesis suggests that not all cells in the tumor have the same ability to proliferate and maintain the growth of the tumor. Only a relatively small fraction of cells in the tumor, termed cancer stem cells, posses the ability to proliferate and self-renew extensively and expresses the surface marker CD133 (prominin-1). CNS tissue damage via trauma, viruses and ishaemia, increases the amount of OS production, which damages endothelial cells and consequently results in excess production of bone marrow-derived endothelial progenitor cells (EPCs). EPCs are immunoreactive for CD133 and CD34 and are thus important in the process of angiogenesis. Results of our study confirmed the main hypothesis, i.e.the proportional expression and distribution of CD133 and HNE in tumor cells, mesenchymal stroma, blood vessels and in the areas of necrosis, probably due to permanent OS in tumors, whose products continue to damage the endothelial cells and cause an excess production of EPCs. Identification of coexpression HNE and CD133 in GBM has important implication for the understanding of propagation of tumors into higher grade.

U ovom radu prikazali smo slučaj bolesnice hospitalizirane zbog vrućice nepoznatog porijekla u koje je biopsijom temporalne arterije potvrđena dijagnoza temporalnog arteritisa. Bolest se klinički prezentirala vrućicom, glavoboljom i polimijalgijom reumatikom. Patološki laboratorijski nalazi uključivali su ubrzanu sedimentaciju eritrocita, trombocitozu, leukocitozu, povišene vrijednosti CRP i jetrenih transaminaza. Na liječenje kortikosteroidima došlo je do dobre regresije bolesti, a komplikacije nisu zabilježene iako je od početka bolesti do postavljanja dijagnoze i odgovarajućeg liječenja prošlo više od mjesec dana. Ovaj prikaz nas upozorava da infektolozi moraju pomišljati na dijagnozu temporalnog arteritisa u diferencijalno-dijagnostičkom razmatranju febrilnih bolesnika starijih od 50 godina koji se prezentiraju spomenutim tegobama., We report a case of hospitalized patient with fever of unknown origin in whom the diagnosis of temporal arteritis was confirmed by temporal artery biopsy. The disease clinicaly presented with fever, headache and polymyalgia rheumatica. The pathological laboratory findings showed accelerated erythrocyte sedimentation rate, thrombocytosis, leukocytosis, increased levels of C-reactive protein and liver transaminases. The disease regressed after corticosteroid therapy, and no complications were detected although more than one month passed from the beginning of disease until the diagnosis was established and appropriate treatment applied. This case warns us that infectious disease specialists have to consider temporal arteritis in differential-diagnostics in patients older than 50 years of age with fever and described difficulties.

This paper reports a case of sudden bilateral deafness as the first symptom of gastric cancer, an extremely rare and atypical clinical situation. Because common signs of stomach cancer were absent, the patient was first evaluated in the Department of Otolaryngology, University Hospital Center, Zagreb. Only after expanded diagnostic evaluation and rapid progression of the disease in such a case is a malignant tumor suspected. Treatment is mostly ineffective. The unusual presentation of the disease and the rapid course may indicate a hereditary predisposition. Inactivation of tumor suppressor gene DFNA5 was found in 50% of gastric cancers, but of a non-metastasized phenotype. Inactivated DFNA5, otherwise described in hereditary bilateral deafness, perhaps favors the development of deafness in patients with gastric cancer. Our patient had a positive multiple viral antibody titer in serum, inactivated DFNA5 in both gastric cancer tissues and cerebellar metastases, and a metastatic form of the disease. If sudden deafness occurs in elderly patients, the possibility of malignant tumor should be taken into consideration. The link between gastric cancer and the DFNA5 gene is unclear and requires further research.