Correlations between the histopathological alterations in minor salivary glands and the clinically suspected Sjögren's syndrome.

In sicca syndrome patients the xerostomia, xerophthalmia and the serological findings may strongly suggest the autoimmune Sjögren's syndrome, but the histological findings in the labial salivary gland biopsies do not always justify the suspected diagnosis. The aim of this study was to compare the histomorphological changes and the clinical findings in patients with pathologically established Sjögren's syndrome and in cases with negative histology. A total of 133 labial biopsies have been retrospectively evaluated from 2015 to May 2022, and the characteristic Sjögren's lesions were found in 67 cases. According to the clinical data, 34 cases proved to be primary, and 33 were associated ("secondary") forms. In 66 cases, the histology did not justify Sjögren's syndrome; a significant acinar loss, fibrolipomatous infiltration, and mild sialadenitis had led to the clinical symptoms. In Sjögren's histologies, the acinar loss was detected in just 31.8% of cases, which might indicate that the diminished saliva production represents immune-mediated hypofunction rather than direct damage of the acini. This is the first systemic study in Hungary investigating the correlation between pathological alterations and clinical findings.

Prevalence of Sjögren's syndrome in patients with dry mouth in the region of Central Hungary.

OBJECTIVE: One-third of the Hungarian population suffers from xerostomia. Since there is no evidence of the actual prevalence of Sjögren's syndrome (SS) in Hungary, this study aimed to evaluate the same. MATERIALS AND METHODS: Data were collected from the Faculty of Dentistry, Semmelweis University from 2008 to 2015. A diagnosis of SS was established based on the American College of Rheumatology and European League Against Rheumatism criteria. RESULTS: Of the 1076 patients examined with sicca symptoms, 188 patients had confirmed SS. Primary SS (pSS) was diagnosed in 135 patients and secondary SS (sSS) was confirmed in 53 patients. According to the available statistical records of the public health service of Hungary, there were an average of 16 (0.0014%, 5-26) newly diagnosed SS cases in the entire population and 141 SS patient-practitioner consultations (49-232) per 100,000 inhabitants in the country over the past 10 years (based on the past 10 years: 2011-2020). CONCLUSION: Results revealed that approximately 1/5th-1/6th of patients with sicca symptoms have SS, among whom 72% and 285 have pSS and sSS, respectively. Global Hungarian records simultaneously revealed that the number of both new diagnoses and doctor-SS patient encounters has significantly decreased (by 50%) yearly over the last decade.

Pancreatic myxoglobulosis - a real pearl? / Igazgyöngy pancreasban? Myxoglobulosis különleges esete

The authors present a pancreatic head carcinoma and an independently coexistent simple mucinous cyst, in which myxoglobulosis has developed. This lesion is a rare, peculiar entity, mainly occurring in the appendix or in oral mu-coceles, but in pancreas this is the first case in the literature.

Academic relationships between Hungarian professors and the Second Vienna Medical School.

This article discusses the impact of the 'second' Vienna Medical School, hallmarked by Karl Rokitansky, Joseph Skoda and Ferdinand Hebra, on the study and practice of medicine in Hungary. Six medical doctors' lives and achievements are outlined, who formed a bridge between Vienna and Budapest through their studies and work. Four of them returned to Hungary and promoted the cause of medicine and medical education there. Lajos Arányi (1812-1877) founded in 1844 the Institute of Pathology at the University of Pest. János Balassa (1814-1868) took the Chair of the Surgical Department. Ignaz Philip Semmelweis (1818-1865), the 'Saviour of Mothers', received a position at the Department of Obstetrics and Gynaecology in Vienna in 1846. Gustav Scheuthauer (1832-1894) became Arányi's successor. Each of them continued to keep contact with their tutors in Vienna, especially with Karl Rokitansky, and followed the clinicopathological conception pioneered by the Vienna Medical School regarding diagnostics, treatment and prevention of diseases. Two physicians remained in Vienna: Mór Kaposi (1837-1902), who became known worldwide posthumously due to the connection between Kaposi's sarcoma and AIDS, was the director of the Department of Dermatology of the Vienna University in 1878. Salomon Stricker (1837-1898) undertook the leadership of the Department of General and Experimental Pathology in 1872.

A peculiar pancreatic lesion: nodular foci of trilineage differentiation and diffuse islet cell hyperplasia / Egy különleges pancreaselváltozás: kevert differenciációjú nodularitás és diffúz szigetsejtes hyperplasia.

Összefoglaló. A szerzok egy különleges pancreaselváltozás esetét ismertetik, melyben az acinusok neuroendokrin jellegu transzformációja diffúz, atípusos megjelenésu szigetsejtes hyperplasiával társult, valamint a pancreas mindhárom sejtvonalát (acinaris, ductalis, insularis) tartalmazó nodulusok képzodtek. A komplex megjelenés ellenére a kórfolyamat nem járt endokrin tünetekkel. Esetünkben a kiváltó ok hátterében a struktúrák kóros progenitorsejt-differenciációja állhatott. Az irodalomban ilyen közlés eddig nem ismert. Orv Hetil. 2021; 162(6): 227-232. Summary. The authors present a case of a peculiar pancreatic lesion, in which the neuroendocrine transformation of the acini was associated with a diffuse, atypical insular hyperplasia, and micronodules exhibiting trilineage differentiation. Despite the complex alteration, no endocrine symptoms were noted. The case may represent the result of an abnormal pancreatic differentiation raising the possibility of reprogramming of the progenitor cells. To the best of our knowledge, this is the first report of such a lesion in the literature. Orv Hetil. 2021; 162(6): 227-232.

A Study of Prognostic Factors in Young Patients With Non-HPV Oral Cancer in Central Europe.

The etiological factors of squamous cell carcinomas of the head and neck have been well known for a long time. It is also well known that the incidence of oral cancer diagnosed in younger patients is on the rise. Due to the young age of these patients, the increase in the number of these cases and the fact that many of them neither smoke nor drink alcohol it has been suggested that other factors might be at play in the carcinogenesis of oral cancer. Thus, along the classic etiological factors of smoking and alcohol abuse certain molecular marker anomalies and the human papilloma virus (HPV) have emerged as potential factors. The aim of the present study is to verify the potential prognostic factors and to map the differences in biomarker expression between the young and the old patient groups. In the present study the immunohistochemical profile of samples obtained from oral squamous cell carcinomas was studied and compared with various clinico-pathological parameters. In 88 samples the expressions of p16, p53, Ki67, EGFR were studied with a tissue microarray technique under standard reaction conditions as well as the detection and typing of HPV infection with the Full Spectrum HPV DNA method. The biomarker expression profile of young patients with oral squamous cell carcinoma was compared to that of older patients (above 50). A significant difference was found between the immunohistochemical profile of the young and old patient groups in p16, Ki67 expression. The overall survival and progression free survival were influenced by p16 expression in young age.

Modulated Electro-Hyperthermia Resolves Radioresistance of Panc1 Pancreas Adenocarcinoma and Promotes DNA Damage and Apoptosis In Vitro.

The poor outcome of pancreas ductal adenocarcinomas (PDAC) is frequently linked to therapy resistance. Modulated electro-hyperthermia (mEHT) generated by 13.56 MHz capacitive radiofrequency can induce direct tumor damage and promote chemo- and radiotherapy. Here, we tested the effect of mEHT either alone or in combination with radiotherapy using an in vivo model of Panc1, a KRAS and TP53 mutant, radioresistant PDAC cell line. A single mEHT shot of 60 min induced ~50% loss of viable cells and morphological signs of apoptosis including chromatin condensation, nuclear shrinkage and apoptotic bodies. Most mEHT treatment related effects exceeded those of radiotherapy, and these were further amplified after combining the two modalities. Treatment related apoptosis was confirmed by a significantly elevated number of annexin V single-positive and cleaved/activated caspase-3 positive tumor cells, as well as sub-G1-phase tumor cell fractions. mEHT and mEHT+radioterapy caused the moderate accumulation of γH2AX positive nuclear foci, indicating DNA double-strand breaks and upregulation of the cyclin dependent kinase inhibitor p21waf1 besides the downregulation of Akt signaling. A clonogenic assay revealed that both mono- and combined treatments affected the tumor progenitor/stem cell populations too. In conclusion, mEHT treatment can contribute to tumor growth inhibition and apoptosis induction and resolve radioresistance of Panc1 PDAC cells.

Solid-pseudopapillary Neoplasms of the Pancreas is still an Enigma: a Clinicopathological Review.

The solid-pseudopapillary neoplasm of the pancreas is a rare but enigmatic entity occurring mainly in young women. Since the first description by V. Frantz in 1959 the terminology of this tumor has continuously changed but it has remained simply descriptive, because the exact histogenesis is still obscure. Although in majority of cases the survival is excellent, nevertheless, the expected prognosis is not exactly predictable. In this review the authors aim to summarize its clinico-pathological features, the expected biological behavior, the molecular alterations, the immune phenotype and discuss the putative histogenesis. From diagnostic point of view, the salient histological characteristic findings are analyzed that would help to differentiate it from other, look-alike pancreatic tumors, and suggestions are made about the desirable content of the histological report.

Difficulties in the diagnosis of periapical translucencies and in the classification of cemento-osseous dysplasia.

BACKGROUND: Cemento-osseous dysplasia is a benign fibro-osseous lesion of the tooth-bearing region of the jaws with a periodontal ligament origin. It appears predominantly in Black and Asian middle-aged females. Its importance is that it could mimic a periapical lesion in the early, translucent stage. CASE PRESENTATION: In this report a rare case of familial cemento-osseous dysplasia is presented: a 50-years old Caucasian woman with labial paraesthesia and radiological translucency around the roots of the mandibular incisors and the first molar teeth. The lesion around the first molar was diagnosed as periapical granuloma and a root canal treatment was carried out. The diagnosis of florid cemento-osseous dysplasia and the treatment plan based on two- and three-dimensional radiographic examinations were certified histologically after surgical removal of the lesion. We screened the family members - including the patient's mother, daughter and son - and identified a periapical version of cemento-osseous dysplasia in the daughter. Our case highlights the difficulties of differential diagnosis of cemento-osseous dysplasia and other periapical pathologies. The inconsistencies in the present classification of cemento-osseous dysplasia are also discussed with a proposal for a different classification based on new aspects that would be very helpful in setting up a correct treatment plan. CONCLUSION: Differentiation of endodontic and non-endodontic origin of radiolucency and distinguishing it from anatomical landmarks by appropriate clinical evaluation and using vitality testing can give an opportunity to prevent unnecessary endodontic treatment. The current categories of cemento-osseous dysplasia classification do not cover the early stage of a hereditary florid form of cemento-osseous dysplasia. Instead of anatomical location of the lesion, clinical and genetic features may be recommended as parameters of cemento-osseous dysplasia classification.

Importance of Immunohistochemical Detection of Somatostatin Receptors.

The long-acting somatostatin analogs represent important weapons in treatment protocols of patients with neuroendocrine tumors. Because these peptides preferentially bind to the specific somatostatin receptors, the targeted therapy requires detection of them. As one of the national consulting centers, here we present the results of the immunohistochemically positive neuroendocrine neoplasms diagnosed between 2010 and 2014. Twenty-four paraffin-embedded cases (14 females 10 men, 21-79 years) from different localizations were found to express somatostatin-receptor type 2 (SSTR2). None of the patients has received previous hormonal therapy. The immune reactions have shown membranous, cytoplasmic or mixed patterns. There was no correlation between the expression and the chromogranin A levels, the grades or the hormonal activity/inactivity of the given neoplasms. Our results show that the immunohistochemical detection of SSTR2 is a quick, reliable and effective tool that provides useful information to the oncologists for the therapeutic decision. Because the incidence of the neuroendocrine tumors is still low, centralized pathological units are needed to perform such technique.

Much More than Trousseau Syndrome. The Broad Spectrum of the Pancreatic Paraneoplastic Syndromes.

When 150 years ago Armand Trousseau proposed that some thrombotic events might be the first sign of concealed visceral malignancies, these findings seemed to be just of anecdotal interest. Since then, however, we have learned that adenocarcinomas, including pancreatic cancers could be associated with a wide spectrum of paraneoplastic syndromes. They may precede the detection of the tumor, may occur simultaneously or may develop during its progression. Due to various hematologic, endocrine, cutaneous, articular, neuromuscular, renal or even psychiatric syndromes, their correct interpretation is intriguing, and because their early signs are not necessarily recognized first by oncologists, the paraneoplastic syndromes pose a diagnostic challenge. Unfortunately, we cannot generalize about their mechanisms, because the molecular backgrounds are far-reaching. In most of the cases, the pancreatic cancer cells release various factors into the bloodstream triggering the coagulation cascade. These patients frequently present with venous thromboembolism, and sometimes they are resistant to anticoagulation. The simultaneous thrombotic and bleeding evens do reflect the abnormal hemostasis. In other instances autoantibodies are formed against cutaneous, renal, neuromuscular or nervous tissues, but the mechanism of some syndromes remains unclear. Clinicians should be aware that pancreatic carcinoma may be associated with not just the Trousseau-syndrome.

Ecdysteroids sensitize MDR and non-MDR cancer cell lines to doxorubicin, paclitaxel, and vincristine but tend to protect them from cisplatin.

Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR) mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-hydroxyecdysone (1) and its mono- (2) and diacetonide (3) derivatives to sensitize various MDR and non-MDR cancer cell lines towards doxorubicin, paclitaxel, vincristine, or cisplatin. Drug IC50 values with or without ecdysteroid were determined by MTT assay. Compound 3 significantly sensitized all cell lines to each chemotherapeutic except for cisplatin, whose activity was decreased. In order to overcome solubility and stability issues for the future in vivo administration of compound 3, liposomal formulations were developed. By means of their combination index values obtained via checkerboard microplate method, a formulation showed superior activity to that of compound 3 alone. Because ecdysteroids act also on non-ABCB1 expressing (sensitive) cell lines, our results demonstrate that they do not or not exclusively exert their adjuvant anticancer activity as ABCB1 inhibitors, but other mechanisms must be involved, and they opened the way towards their in vivo bioactivity testing against various cancer xenografts.

Chronic hyperglycemia induces trans-differentiation of human pancreatic stellate cells and enhances the malignant molecular communication with human pancreatic cancer cells.

BACKGROUND: Diabetes mellitus is linked to pancreatic cancer. We hypothesized a role for pancreatic stellate cells (PSC) in the hyperglycemia induced deterioration of pancreatic cancer and therefore studied two human cell lines (RLT-PSC, T3M4) in hyperglycemic environment. METHODOLOGY/PRINCIPAL FINDINGS: The effect of chronic hyperglycemia (CHG) on PSCs was studied using mRNA expression array with real-time PCR validation and bioinformatic pathway analysis, and confirmatory protein studies. The stress fiber formation (IC: αSMA) indicated that PSCs tend to transdifferentiate to a myofibroblast-like state after exposure to CHG. The phosphorylation of p38 and ERK1/2 was increased with a consecutive upregulation of CDC25, SP1, cFOS and p21, and with downregulation of PPARγ after PSCs were exposed to chronic hyperglycemia. CXCL12 levels increased significantly in PSC supernatant after CHG exposure independently from TGF-ß1 treatment (3.09-fold with a 2.73-fold without TGF-ß1, p<0.05). The upregualtion of the SP1 transcription factor in PSCs after CHG exposure may be implicated in the increased CXCL12 and IGFBP2 production. In cancer cells, hyperglycemia induced an increased expression of CXCR4, a CXCL12 receptor that was also induced by PSC's conditioned medium. The receptor-ligand interaction increased the phosphorylation of ERK1/2 and p38 resulting in activation of MAP kinase pathway, one of the most powerful stimuli for cell proliferation. Certainly, conditioned medium of PSC increased pancreatic cancer cell proliferation and this effect could be partially inhibited by a CXCR4 inhibitor. As the PSC conditioned medium (normal glucose concentration) increased the ERK1/2 and p38 phosphorylation, we concluded that PSCs produce other factor(s) that influence(s) pancreatic cancer behaviour. CONCLUSIONS: Hyperglycemia induces increased CXCL12 production by the PSCs, and its receptor, CXCR4 on cancer cells. The ligand-receptor interaction activates MAP kinase signaling that causes increased cancer cell proliferation and migration.

[Insulin-like growth factor-II secreting prostate tumour causing severe hypoglycaemi]. / Inzulinszeru növekedési faktor-2-t termelo prosztatatumor okozta súlyos hypoglykaemia.

The authors present a case of an 82-year-old male patient who presented with frequent hypoglycaemia. Four years prior to the current evaluation the patient had been diagnosed with prostate carcinoma; however, he refused surgical treatment. Initial diagnostic tests indicated organic hypoglycaemia with low serum insulin levels. Insulinoma was excluded and further laboratory tests showed reduced serum insulin-like growth factor-II and normal serum chromogranin A levels as well as normal hypophysis and peripheral hormone values. The authors hypothesised that the severe hypoglycaemia might be the consequence of synthesis and secretion of insulin-like growth factor-II (or its prohormone) by the previously diagnosed prostate tumour. Insulin-like growth factor-II and its prohormone directly increases glucose uptake of the tumour, muscle and adipose tissue, decreases glucose release from the liver and downregulates insulin synthesis due to inhibition of the pancreatic beta cells. The patient required continuous intravenous glucose substitution initially with 5%, subsequently with 20% glucose infusion. Administration of other agents resulted only in temporary improvement. Prostatectomy was again considered but then excluded because of the recurrent hypoglycaemia and the poor general condition of the patient. Hypoglycaemia was finally controlled with glucose and diazoxide therapy, but no improvement in the general condition of the patients was observed and the patient deceased. Immunohistochemistry of the prostate sections showed a carcinoma with strong insulin-like growth factor-II staining, suggesting that insulin-like growth factor-II-secreting prostate tumour caused the severe hypoglycaemia.

Validation of diagnostic accuracy using digital slides in routine histopathology.

BACKGROUND: Robust hardware and software tools have been developed in digital microscopy during the past years for pathologists. Reports have been advocated the reliability of digital slides in routine diagnostics. We have designed a retrospective, comparative study to evaluate the scanning properties and digital slide based diagnostic accuracy. METHODS: 8 pathologists reevaluated 306 randomly selected cases from our archives. The slides were scanned with a 20× Plan-Apochromat objective, using a 3-chip Hitachi camera, resulting 0.465 µm/pixel resolution. Slide management was supported with dedicated Data Base and Viewer software tools. Pathologists used their office PCs for evaluation and reached the digital slides via intranet connection. The diagnostic coherency and uncertainty related to digital slides and scanning quality were analyzed. RESULTS: Good to excellent image quality of slides was recorded in 96%. In half of the critical 61 digital slides, poor image quality was related to section folds or floatings. In 88.2% of the studied cases the digital diagnoses were in full agreement with the consensus. Out of the overall 36 incoherent cases, 7 (2.3%) were graded relevant without any recorded uncertainty by the pathologist. Excluding the non-field specific cases from each pathologist's record this ratio was 1.76% of all cases. CONCLUSIONS: Our results revealed that: 1) digital slide based histopathological diagnoses can be highly coherent with those using optical microscopy; 2) the competency of pathologists is a factor more important than the quality of digital slide; 3) poor digital slide quality do not endanger patient safety as these errors are recognizable by the pathologist and further actions for correction could be taken. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1913324336747310.

Anticancer effects of the organosilicon multidrug resistance modulator SILA 421.

1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 µM for GLC14 small cell lung cancer and 34.00±4.75 µM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, cellular repair mechanisms and growth factor-related signaling cascades eventually resulted in induction of apoptosis in this cell line. In addition to the well established P-gp inhibitory effect of SILA compounds, reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409, may be linked to downregulation of gene expression of kinesins. Interference with DNA replication and transcription seems to be the common denominator of antimicrobial activity and plasmid curing, as well as anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated.

Putative supramolecular complexes formed by carotenoids and xanthophylls with ascorbic acid to reverse multidrug resistance in cancer cells.

BACKGROUND: The molecular basis of interaction of selected carotenoids and xanthophylls with ascorbic acid on cancer cells was studied to determine their anticancer effects. MATERIALS AND METHODS: Drug accumulation was measured in a human ABCB1 gene-transfected mouse lymphoma cell line and in a human lung cancer cell line by flow cytometry; furthermore, their anticancer effects were determined in mice in vivo. RESULTS: Several carotenoids inhibited the multidrug resistance of cancer cells. Ascorbic acid improved the effect of certain xanthophylls, but the effect of capsanthin was not modified. Capsanthin had weak (12%) but capsorubin (85%) had a remarkable antiproliferative effect on A549 lung cancer cells. Capsorubin reduced immediate-early tumor antigen expression, while capsanthin was not effective. Capsorubin accumulates selectively in the nuclei of cancer cells. CONCLUSION: The Authors suggest a special complex formation between membrane-bound capsorubin and ascorbic acid, which can be exploited in experimental chemotherapy.

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas.

MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n=33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffin-embedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch- and G-protein-coupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffin-embedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas.