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.

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.

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.

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.

[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.

miRNA Expression Profiling in G1 and G2 Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine neoplasms pose a growing clinical challenge due to their rising incidence and variable prognosis. The current study aims to investigate microRNAs (miRNA; miR) as potential biomarkers for distinguishing between grade 1 (G1) and grade 2 (G2) pancreatic neuroendocrine tumors (PanNET). A total of 33 formalin-fixed, paraffin-embedded samples were analyzed, comprising 17 G1 and 16 G2 tumors. Initially, literature-based miRNAs were validated via real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), confirming significant downregulation of miR-130b-3p and miR-106b in G2 samples. Through next-generation sequencing, we have identified and selected the top six miRNAs showing the highest difference between G1 and G2 tumors, which were further validated. RT-qPCR validation confirmed the downregulation of miR-30d-5p in G2 tumors. miRNA combinations were created to distinguish between the two PanNET grades. The highest diagnostic performance in distinguishing between G1 and G2 PanNETs by a machine learning algorithm was achieved when using the combination miR-106b + miR-130b-3p + miR-127-3p + miR-129-5p + miR-30d-5p. The ROC analysis resulted in a sensitivity of 83.33% and a specificity of 87.5%. The findings underscore the potential use of miRNAs as biomarkers for stratifying PanNET grades, though further research is warranted to enhance diagnostic accuracy and clinical utility.

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.

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.

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.

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.

[Verner-Morrison syndrome: a case study]. / Verner-Morrison-szindróma egy esete.

Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.

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.

Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas.

BACKGROUND: Glucagon-producing tumors are either solitary neoplasms of the pancreas, occasionally associated with a glucagonoma syndrome, or multiple neoplasms associated with multiple endocrine neoplasia type 1 (MEN1). We observed a previously undescribed multicentric glucagon-producing tumor disease that is not related to MEN1. METHODS: Pancreatic tissue from four patients showing multiple neuroendocrine microadenomas and in two cases also macrotumors were screened for hormones using immunohistochemical and morphometric methods. MEN1, von Hippel-Lindau, and p27 germ line and somatic mutation analysis was performed. Deletion of MEN1 (11q13), von Hippel-Lindau (3p25), and the centromere 11 and 3 gene locus was determined by fluorescence in situ hybridization. DNA copy number changes were studied using array comparative genomic hybridization. RESULTS: The pancreatic tissue from the four patients contained more than 870 microadenomas and 10 macrotumors, all of which expressed exclusively glucagon and none of which showed evidence of malignancy. In addition, many islets were unusually large and showed glucagon cell hyperplasia. There was no clinical or molecular evidence of any hereditary tumor disease, and changes in the MEN1 gene were only seen in individual tumors. Array comparative genomic hybridization of one macrotumor and 20 pooled microadenomas revealed a homogeneous diploid chromosome set. CONCLUSIONS: The findings are sufficiently distinctive to suggest a new neoplastic disease of the endocrine pancreas that we recommend calling glucagon cell adenomatosis. Clinically, this disease may be an incidental finding, or it may lead to a glucagonoma syndrome.

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.

Neuroendocrine carcinoma associated with X-linked hyper-immunoglobulin M syndrome: report of four cases and review of the literature.

X-linked hyper-immunoglobulin M syndrome (XHIGM) is a primary immunodeficiency disorder characterized by severe defects of both cellular and humoral immunity due to impaired expression of CD40 ligand on activated T lymphocytes. Patients with XHIGM usually present with a wide variety of infections caused by common and opportunistic pathogens including Pneumocystis jirovecii. In addition, subjects with XHIGM have an increased risk for hepatocellular and bile duct carcinomas, which are rarely observed in other primary immunodeficiencies. We present here clinical, immunological, and molecular findings of four patients with CD40 ligand deficiency associated with neuroendocrine carcinoma (NEC). NEC developed as a rapidly disseminated solid cancer leading to death in three patients. Data presented here and published previously suggest that CD40 ligand deficiency may predispose patients for the development of NEC. Histochemical findings suggested that CD56, in addition to cytokeratin and chromogranin A, may be a useful marker for early detection of NEC. We conclude that patients with XHIGM should be carefully followed to diagnose and treat NEC, a formidable neuroendocrine cancer.

Vascular activity of two silicon compounds, ALIS 409 and ALIS 421, novel multidrug-resistance reverting agents in cancer cells.

PURPOSE: The aim of this study was to investigate the effects of two novel multidrug-resistance reverting agents, ALIS 409 [1,3-dimethyl-1,3-p-fluorophenyl-1,3(3-morfolinopropyl)-1,3-disiloxan dihydrochloride] and ALIS 421 [1,3-dimethyl-1,3-(4-fluorophenyl)-1,3[3(4-buthyl)-(1-piperazinyl)-propyl]-1,3-disiloxan tetrahydrochloride], on vascular functions in vitro. EXPERIMENTAL DESIGN: A comparison of their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, was performed. RESULTS: In endothelium-denuded rat aorta rings, ALIS 409 and ALIS 421 antagonized 60 mM K(+)-induced contraction in a concentration-dependent manner with IC(50) values of 52.2 and 15.5 microM, respectively. ALIS 409 and ALIS 421 inhibited L-type Ca(2+) current recorded in artery myocytes in a concentration-dependent manner with IC(50) values of 6.4 and 5.6 microM, respectively. In rat aorta, ALIS 409 and ALIS 421 antagonized the sustained tonic contraction induced by phenylephrine with IC(50) values of 58.0 and 13.7 microM (endothelium-denuded rings) and of 73.9 and 31.9 microM (endothelium-intact rings), respectively. In endothelium-denuded rings, ryanodine reduced significantly the response to phenylephrine in the absence of extracellular Ca(2+) whereas nifedipine, ALIS 409 or ALIS 421 did not affect it. Phenylephrine-stimulated influx of extracellular Ca(2+) was markedly reduced when tissues were pretreated with ALIS 409, ALIS 421 or nifedipine, and stimulated when they were pretreated with ryanodine. Application of ALIS 409 (up to 100 microM) to intact rat aorta rings failed to induce mechanical responses. CONCLUSIONS: Our results provide functional evidence that the myorelaxing effect elicited either by ALIS 409 or by ALIS 421 involved mainly the direct blockade of extracellular Ca(2+) influx. This effect, however, took place at concentrations much higher than those effective as modifiers of multidrug resistance in cancer cells.

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.

Review. Molecular background of chemoresistance in pancreatic cancer.

The survival data of patients with ductal pancreatic adenocarcinoma are rather poor, partly because the disease is frequently diagnosed at an advanced stage, partly because it is characterized by a chemoresistant phenotype. Even first-line chemotherapeutic drugs result in a modest objective response. This drug resistance is attributed to many different, unrelated mechanisms, including abnormal membrane receptor transport, ineffective metabolic drug conversion or enhanced metabolite inactivation, increased DNA repair and alterations in the apoptotic pathways. The role of NF-kappaB, cyclin D1 and stromal factors is also emphasized by many groups. The involvement of the ABC-transporters is not a universal feature, their alterations are important only in the resistance against specific cytostatics. Although several well-known molecular mechanisms have been elucidated, our understanding of drug insensitivity is still fragmentary, especially because recent microarray studies revealed that hundreds of genes are up- or down-regulated in resistant tumor cells, but their exact significance is still unclear. The reversal of the drug resistance is an area of intensive investigation, but to date, the compounds investigated are effective mainly in experimental systems and prospective studies are needed to validate their clinical applicability.

Molecular aspects of stromal-parenchymal interactions in malignant neoplasms.

Carcinomas are composed of parenchymal and stromal elements, and the malignant behavior is principally dictated by the cancer cells. However, the malignant tumors not merely grow into a preexisting interstitial tissue, but they actively form a new stroma and modify their composition. Thus, the tumor stroma is significantly different from that of the neighboring tissues. Cancer cells may alter their stroma by cell-to-cell contact, soluble factors or by modification of the extracellular matrix (ECM), they induce myofibroblast differentiation and govern the desmoplastic stroma reaction. On the other hand, the stromal cells (especially the myofibroblasts) are able to modify the phenotype, invasiveness, metastatic capacity of carcinomas, typically promoting the progression. Regarding pancreatic cancer, the pancreatic stellate cells (PSCs) seem to be the key elements in the cross-talk between the parenchymal cells and the desmoplastic stroma. The tumor stroma is also rich in tumor-associated macrophages (TAM), but their role in the malignant process is contradictory and may be different in various tumor types, but most studies suggest a negative impact on the tumor growth. The relationship between the parenchymal and stromal elements is highly complex, they mutually alter their characteristics. Because the neostroma of the carcinomas largely seems to promote the invasiveness of the malignant tumors, novel therapeutic strategies are being evaluated targeting the stromal elements, with some encouraging, but still fragmentary results.