[Successful pregnancy of a patient with primary sclerosing cholangitis awaiting liver transplantation]. / Primer szklerotizáló cholangitisben szenvedo, májtranszplantációra váró beteg sikeres várandóssága.

In women, primary sclerotising cholangitis (PSC) associated with ulcerative colitis and intrahepatic cholestasis is a rare disease. To date, there are no data from Hungary on the fertility and pregnancy outcome of women with this chronic liver disease. Our aim is to present the favorable pregnancy outcome of a woman with PSC associated with ulcerative colitis, intrahepatic cholestasis and postpartum colectomy, and review of the literature. A young nulligravida was first diagnosed with ulcerative colitis. Five years later, PSC developed with progressive fibrosis and cholestasis necessitating liver transplantation. While on waiting list, spontaneous conception occurred. Except for pregnancy-induced hypertension, pregnancy uneventfully progressed until the third trimester when 8 g oral cholestyramine/day was administered to lower high maternal (over 100 µmol/L) total bile acid (TBA) level. In the 36th week of gestation acute exacerbation of ulcerative colitis resulted in maternal fever and chorioamnionitis leading to fetal distress. Elective delivery of the eutrophic neonate followed by emergency cesarean section. In the early puerperium, colitis progressed to septic pancolitis resistant to medical treatment. 12 days after laparoscopic subtotal colectomy, the patient was discharged in good health condition. 3 months later, ileostomy was closed and she got back on the transplantation waiting list. Our data correspond with previous reports and suggest that women with PSC with underlying ulcerative colitis and cholestasis have a good chance for favorable pregnancy outcome. However, both PSC and underlying colitis might progress during pregnancy and puerperium. Oral cholestyramin is an effective and safe treatment for high maternal TBA levels. Orv Hetil. 2023; 164(6): 234-240.

Cutaneous metastases at the sites of pembrolizumab-induced bullous pemphigoid lesions in a patient with melanoma.

The authors report a case of bullous pemphigoid (BP) that occurred during pembrolizumab therapy in a 67-year-old male patient with advanced melanoma. Following regression of BP blisters, they reintroduced anti-PD-1 treatment. Due to the flare-up of BP, immunotherapy was discontinued again and corticosteroid was restarted. As the BP lesions regressed, interestingly, new skin metastases developed, exactly where the blisters were. One year after discontinuation of anti-PD-1 treatment, considering the significant tumor progression, pembrolizumab was restarted. This induced tumor remission, while the added low-dose corticosteroid was able to prevent the recurrence of BP. The patient carries the BP-predisposing HLA-DQB1*03:01 allele. In conclusion, anti-PD-1 rechallenge may be considered in metastatic melanoma, even if restarting anti-PD-1 has previously caused the flare-up of BP symptoms.

Immune checkpoint inhibitors prolong the survival of patients with metastatic melanoma. Bullous pemphigoid (BP) is a rare, cutaneous, immune-related adverse event. The authors report a case of BP that occurred during pembrolizumab therapy in a 67-year-old male patient with advanced melanoma who responded to anti-PD-1 treatment with a partial response. Following the resolution of BP symptoms, pembrolizumab treatment was restarted after discontinuation of systemic corticosteroid therapy. Due to the flare-up of BP, anti-PD-1 treatment was discontinued and steroid therapy was restarted; however, skin metastases soon developed, exactly where the BP blisters were. Pembrolizumab rechallenge was successful in inducing the complete regression of skin metastases, while the added low-dose corticosteroid was able to prevent the recurrence of BP.

The present and the future of medical simulation education in Hungary / Az egészségügyi szimulációs oktatás jelene és jövoje Magyarországon

Simulation-based medical education aims to model clinical situations and tasks using simulators, computers or even human beings. By using this system, the students are able to learn and master technical, also non-technical skills in lifelike situations. This publication contains a historical review of simulation-based education system, and its actualities in Hungary. Simulation has an unquestionable role in medical education. It is beneficial for the students, for the teachers, and for the teaching hospitals as well, since it saves clinical equipment and reduces the human burden. Its main purpose is to establish connection between theoretical and practical competencies, preparing the students for real medical challenges. Simulation has been a known teaching method for centuries, but only the 21st century brought real breakthrough due to the sudden development of technology. As a result of the recent years' innovative development and accepted innovative solutions, the modeling of complex medical procedures turned into more realistic. In Hungary, 3D-printed tools, virtual reality and augmented reality approaches are already adopted for education purposes. The national simulation network contains 3 universities and 16 hospitals. The initial developments are shown to be successful, as simulation-based training is progressively involved in undergraduate and post-graduate education, and the overall feedback is positive from the involved students. The evolvement of comprehensive national methodology for education has started also, by publishing reference books. This review is about the state of the national simulation education and offers development possibilities. Orv Hetil. 2020; 161(26): 1078-1087.

Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy.

AIM OF THE STUDY: Combination of ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3DDA±RBV) therapy is shown to be effective in HCV genotype 1 (GT1) infected patients. However, sparse data exist in patients who failed previous boceprevir or telaprevir based therapies. Real life efficacy and safety of this combination were evaluated in HCV GT1b infected patients (mostly cirrhotics) with compensated liver disease who failed previous boceprevir or telaprevir based therapies more than a year before. MATERIAL AND METHODS: Data of previous protease inhibitor failure patients, treated with 3DAA+RBV for 12 weeks (GT1b and/or non-cirrhotics) or 24 weeks (non-GT1b cirrhotics), were retrospectively collected. RESULTS: Population characteristics: boceprevir/telaprevir-failure: 82/45, GT1b: 117, cirrhotic: 111 (87.4%). SVR12/24 was observed in 103/105 patients (98.1%) of those who reached either time point. Four SAEs reported: one death due to myocardial infarction, another due to recurrent hepatocellular carcinoma after achieving SVR12, two hospitalizations (elevation of transaminases, pneumonia). Grade ≥ 3 AEs or laboratory abnormalities were reported in < 10% of patients; they were transient in all patients. No early discontinuation of drugs due to SAE has been reported. CONCLUSIONS: One year after previous failure of boceprevir or telaprevir based therapy, 12 weeks of 3DAA+RBV combination in HCV GT1b infected patients is similarly effective and safe as in those with no previous HCV therapy, even in the presence of cirrhosis. These findings might be of particular interest in settings where alternative therapies for such patients are not available or not affordable.

An uracil-linked hydroxyflavone probe for the recognition of ATP.

Background: Nucleotides are essential molecules in living systems due to their paramount importance in various physiological processes. In the past years, numerous attempts were made to selectively recognize and detect these analytes, especially ATP using small-molecule fluorescent chemosensors. Despite the various solutions, the selective detection of ATP is still challenging due to the structural similarity of various nucleotides. In this paper, we report the conjugation of a uracil nucleobase to the known 4'-dimethylamino-hydroxyflavone fluorophore. Results: The complexation of this scaffold with ATP is already known. The complex is held together by stacking and electrostatic interactions. To achieve multi-point recognition, we designed the uracil-appended version of this probe to include complementary base-pairing interactions. The theoretical calculations revealed the availability of multiple complex structures. The synthesis was performed using click chemistry and the nucleotide recognition properties of the probe were evaluated using fluorescence spectroscopy. Conclusions: The first, uracil-containing fluorescent ATP probe based on a hydroxyflavone fluorophore was synthesized and evaluated. A selective complexation with ATP was observed and a ratiometric response in the excitation spectrum.

Immunotopographical Differences of Human Skin.

The immunological barrier of the healthy skin is considered to be unified on the whole body surface-however, recent indirect findings have challenged this dogma since microbial and chemical milieu (e.g., sebum, sweat, and pH) exhibit remarkable differences on topographically distinct skin areas. Therefore, in the present study, we performed whole transcriptomic and subsequent pathway analyses to assess differences between sebaceous gland rich (SGR) and sebaceous gland poor (SGP) regions. Here, we provide the first evidence that different skin regions exhibit a characteristic innate and adaptive immune and barrier milieu as we could detect significantly increased chemokine (CCL2, 3, 19, 20, 23, 24) and antimicrobial peptide (S100A7, A8, A9, lipocalin, ß-defensin-2) expression, altered barrier (keratin 17, 79) functions, and a non-inflammatory Th17/IL-17 dominance in SGR skin compared to SGP. Regarding pro-inflammatory molecules (IL-1α, IL-6, IL-8, IL-33, TNF-α), similarly low levels were detected in both regions. Our data may explain the characteristic topographical localization of some immune-mediated and autoimmune skin disorders and we also propose that the term "healthy skin control sample," widely used in experimental Dermatology, should only be accepted if researchers carefully specify the exact region of the healthy skin (along with the site of the diseased sample).

[Screening, diagnosis, treatment, and follow up of hepatitis C virus related liver disease. National consensus guideline in Hungary from 22 September 2017]. / A hepatitis C-vírus-fertozés szurése, diagnosztikája, antivirális terápiája, kezelés utáni gondozása. Magyar konszenzusajánlás. Érvényes: 2017. szeptember 22-tol.

The treatment of hepatitis C is based on a national consensus guideline updated six-monthly according to local availability and affordability of approved therapies through a transparent allocation system in Hungary. This updated guideline incorporates some special new aspects, including recommendations for screening, diagnostics, use and allocation of novel direct acting antiviral agents. The indication of therapy in patients with no contraindication is based on the demonstration of viral replication with consequent inflammation and/or fibrosis in the liver. Non-invasive methods (elastographies and biochemical methods) are preferred for liver fibrosis staging. The budget allocated for these patients is limited. Interferon-based or interferon-free therapies are available for the treatment. Due to their limited success rate as well as to their (sometimes severe) side-effects, the mandatory use of interferon-based therapies as first line treatment can not be accepted from the professional point of view. However, they can be used as optional therapy in treatment-naïve patients with mild disease. As of interferon-free therapies, priority is given to those with urgent need based on a pre-defined scoring system reflecting mainly the stage of the liver disease, but considering also additional factors, i.e., hepatic decompensation, other complications, activity and progression of liver disease, risk of transmission and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained virological response value in different patient categories with consensus amongst treating physicians, the National Health Insurance Fund of Hungary and patients' organizations. Interferon-free treatments and shorter therapy durations are preferred. Orv Hetil. 2018; 159(Suppl 1): 3-23.

[Screening, diagnosis, treatment, and follow up of hepatitis C virus related liver disease. National consensus guideline in Hungary from 15 October 2016]. / A hepatitis C-vírus-fertozés szurése, diagnosztikája, antivirális terápiája, kezelés utáni gondozása. Magyar konszenzusajánlás. Érvényes: 2016. október 15-tol.

Treatment of hepatitis C is based on a national consensus guideline updated six-monthly according to local availability and affordability of approved therapies through a transparent allocation system in Hungary. This updated guideline incorporates some special new aspects, including recommendations for screening, diagnostics, use and allocation of novel direct acting antiviral agents. Indication of therapy in patients with no contraindication is based on demonstration of viral replication with consequent inflammation and/or fibrosis in the liver. Non-invasive methods (elastographies and biochemical methods) are preferred for liver fibrosis staging. The budget allocated for these patients is limited. Therefore, expensive novel direct acting antiviral combinations as first line treatment are reimbursed only, if the freely available, but less effective and more toxic pegylated interferon plus ribavirin dual therapy deemed to prone high chance of adverse events and/or low chance of cure. Priority is given to those with urgent need based on a pre-defined scoring system reflecting mainly the stage of the liver disease, but considering also additional factors, i.e., hepatic decompensation, other complications, activity and progression of liver disease, risk of transmission and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained virological response value in different patient categories with consensus amongst treating physicians, the National Health Insurance Fund and patient's organizations. Interferon-free treatments and shorter therapy durations are preferred. Orv. Hetil., 2017, 158(Suppl. 1), 3-22.

Comprehensive DNA Methylation and Mutation Analyses Reveal a Methylation Signature in Colorectal Sessile Serrated Adenomas.

Colorectal sessile serrated adenomas (SSA) are hypothesized to be precursor lesions of an alternative, serrated pathway of colorectal cancer, abundant in genes with aberrant promoter DNA hypermethylation. In our present pilot study, we explored DNA methylation profiles and examined selected gene mutations in SSA. Biopsy samples from patients undergoing screening colonoscopy were obtained during endoscopic examination. After DNA isolation and quality analysis, SSAs (n = 4) and healthy controls (n = 5) were chosen for further analysis. DNA methylation status of 96 candidate genes was screened by q(RT)PCR using Methyl-Profiler PCR array system. Amplicons for 12 gene mutations were sequenced by GS Junior Instrument using ligated and barcoded adaptors. Analysis of DNA methylation revealed 9 hypermethylated genes in both normal and SSA samples. 12 genes (CALCA, DKK2, GALR2, OPCML, PCDH10, SFRP1, SFRP2, SLIT3, SST, TAC1, VIM, WIF1) were hypermethylated in all SSAs and 2 additional genes (BNC1 and PDLIM4) were hypermethylated in 3 out of 4 SSAs, but in none of the normal samples. 2 SSAs exhibited BRAF mutation and synchronous MLH1 hypermethylation and were microsatellite instable by immunohistochemical analysis. Our combined mutation and DNA methylation analysis revealed that there is a common DNA methylation signature present in pre-neoplastic SSAs. This study advocates for the use of DNA methylation as a potential biomarker for the detection of SSA; however, further investigation is needed to better characterize the molecular background of these newly recognized colorectal lesions.

[Treatment options of non-melanoma skin tumors in organ transplant recipients in relation to a case report]. / Nonmelanoma bortumorok kezelési lehetoségei szervtranszplantált betegeknél egy esetismertetés kapcsán.

The authors present the case of a 59-year-old male patient, whose first kidney transplantation was in 1983 and the second in 2000. The first squamous cell carcinoma appeared on the skin 2 years after the first transplantation. Since 2003, at least two precancerous lesions or non-melanoma skin tumors have been removed surgically yearly. These cancers appeared predominantly on the sun-exposed skin, and were multiple. As these tumors could behave aggressively and prone to recurrence, complex treatment was applied, which included a switch in immunosuppressive drugs and the application of field therapies. The authors give an overview of these treatment options in relation to the case presentation, emphasizing that not only early detection and active treatment of the precancerous lesions and skin cancers are essential, but education of proper sun-protection methods and dermatology care are also important in order to avoid the development of these tumors.

Hepatitis C-vírus-fertozés: diagnosztika, antivirális terápia, kezelés utáni gondozás. Magyar konszenzusajánlás. Érvényes: 2015. szeptember 12-tol.

Approximately 70.000 people are infected with hepatitis C virus in Hungary, more than half of whom are not aware of their infection. From the point of infected individuals early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases and complications (liver cirrhosis, liver failure and liver cancer) and can increase work productivity and life expectancy on one hand. From socioeconomic aspect, this could also prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity. Available since 2003 in Hungary, pegylated interferon + ribavirin dual therapy can clear the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of a direct acting first generation protease inhibitor drug (boceprevir or telaprevir) to the dual therapy increases the chance of sustained virologic response to 63-75% and 59-66%, respectively. These two protease inhibitors are available and financed for a segment of Hungarian patients since May 2013. Between 2013 and February 2015, other direct acting antiviral interferon-free combination therapies have been registered for the treatment of chronic hepatitis C, with a potential efficacy over 90% and typical short duration of 8-12 weeks. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and or fibrosis in the liver. Non-invasive methods (eleastography and biochemical methods) are accepted and preferred for staging liver damage (fibrosis). For initiation of treatment accurate and timely molecular biology tests are mandatory. Eligibility for treatment is a subject of individual central medical review. Due to budget limitations tharpy is covered only for a proportion of patients by the National Health Insurance Fund. Priority is given to those with urgent need based on a Hungarian Priority Index system reflecting primarily the stage of liver disease, and considering also additional factors, i.e., activity and progression of liver disease, predictive factors of treatment and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained virologic response value in different patient categories with consensus between professional organizations, National Health Insurance Fund and patient organizations. More expensive therapies might be available upon co-financing by the patient or a third party. Interferon-free treatments and shorter therapy durations preferred as much as financially feasible. A separate budget is allocated to cover interferon-free treatments for the most-in-need interferon ineligible/intolerant patients, and for those who have no more interferon-based therapy option. Orv. Hetil., 2015, 156(Suppl. 2), 3-24.

Comprehensive DNA Methylation Analysis Reveals a Common Ten-Gene Methylation Signature in Colorectal Adenomas and Carcinomas.

Microarray analysis of promoter hypermethylation provides insight into the role and extent of DNA methylation in the development of colorectal cancer (CRC) and may be co-monitored with the appearance of driver mutations. Colonic biopsy samples were obtained endoscopically from 10 normal, 23 adenoma (17 low-grade (LGD) and 6 high-grade dysplasia (HGD)), and 8 ulcerative colitis (UC) patients (4 active and 4 inactive). CRC samples were obtained from 24 patients (17 primary, 7 metastatic (MCRC)), 7 of them with synchronous LGD. Field effects were analyzed in tissues 1 cm (n = 5) and 10 cm (n = 5) from the margin of CRC. Tissue materials were studied for DNA methylation status using a 96 gene panel and for KRAS and BRAF mutations. Expression levels were assayed using whole genomic mRNA arrays. SFRP1 was further examined by immunohistochemistry. HT29 cells were treated with 5-aza-2' deoxycytidine to analyze the reversal possibility of DNA methylation. More than 85% of tumor samples showed hypermethylation in 10 genes (SFRP1, SST, BNC1, MAL, SLIT2, SFRP2, SLIT3, ALDH1A3, TMEFF2, WIF1), whereas the frequency of examined mutations were below 25%. These genes distinguished precancerous and cancerous lesions from inflamed and healthy tissue. The mRNA alterations that might be caused by systematic methylation could be partly reversed by demethylation treatment. Systematic changes in methylation patterns were observed early in CRC carcinogenesis, occuring in precursor lesions and CRC. Thus we conclude that DNA hypermethylation is an early and systematic event in colorectal carcinogenesis, and it could be potentially reversed by systematic demethylation therapy, but it would need more in vitro and in vivo experiments to support this theory.

[Tomato peel: rare cause of biliary tract obstruction]. / Paradicsomhéj: az epeúti elzáródás ritka oka.

Foreign bodies in the biliary tree are rare causes of obstructive jaundice. Food bezoars are infrequent as well. They can cause biliary obstruction after biliary tract interventions, or in the presence of biliary-bowel fistula or duodenum diverticulum. Food bezoars usually pass the gastrointestinal tract without any symptoms, but they can cause abdominal pain and obstructive jaundice in the case of biliary tract obstruction. Endoscopic retrograde cholangio-pancreatography has the major role in the diagnosis and the treatment of the disease. Authors summarize the medical history of a 91-year-old female patient, who developed vomiting and right subcostal pain due to the presence of tomato peel within the ductus choledochus.

Activation of transient receptor potential vanilloid-3 inhibits human hair growth.

In the current study, we aimed at identifying the functional role of transient receptor potential vanilloid-3 (TRPV3) ion channel in the regulation of human hair growth. Using human organ-cultured hair follicles (HFs) and cultures of human outer root sheath (ORS) keratinocytes, we provide the first evidence that activation of TRPV3 inhibits human hair growth. TRPV3 immunoreactivity was confined to epithelial compartments of the human HF, mainly to the ORS. In organ culture, TRPV3 activation by plant-derived (e.g., eugenol, 10-1,000 µM) or synthetic (e.g., 2-aminoethoxydiphenyl borate, 1-300 µM) agonists resulted in a dose-dependent inhibition of hair shaft elongation, suppression of proliferation, and induction of apoptosis and premature HF regression (catagen). Human ORS keratinocytes also expressed functional TRPV3, whose stimulation induced membrane currents, elevated intracellular calcium concentration, inhibited proliferation, and induced apoptosis. Of great importance, these effects on ORS keratinocytes were all mediated by TRPV3, as small interfering RNA-mediated silencing of TRPV3 effectively abrogated the cellular actions of the above agonists. These findings collectively support the concept that TRPV3 signaling is a significant player in human hair growth control. Therefore, TRPV3 and the related intracellular signaling mechanism might function as a promising target for pharmacological manipulations of clinically relevant hair growth disorders.

[Colonoscopy, the primary tool for colonic screening]. / A kolonoszkópia a vastagbélszurés elsodleges módszere.

Through an overview of the colonic screening methods, the authors study colonoscopy with high emphasis. Taking into consideration its high sensitivity and specificity in the detection of colorectal carcinomas and adenomas, as well as the possibility of adenoma removal through examination, colonoscopy is recommended to be applied as the primary colonic screening within the scope of a national screening program.

The half-and-half nail: a new sign of Crohn's disease? Report of four cases.

Systemic disease can produce changes in the nails. Perhaps the best known example of this is koilonychia as a sequale of iron deficiency anemia. "Half and half nail" is a type of pseudoleuconychia that can be caused by chronic renal disease, Kawasaki's disease, cirrhosis, and zinc deficiency. It has not been described in patients with Crohn's disease yet. Four male patients with Crohn's disease were observed. None of them had extraintestinal manifestations of Crohn's disease. The average duration of the disease was 5.25 (range, 1-10) years. The nail alterations were defined with a portion of the nail being as much as 15 to 40 percent of normal color distally, whereas the rest of the nail was white. The contrast between the two zones remains sharply demarcated even after constricting venous return. Histologic examination was not performed. Every patient had zinc deficiency but not hypalbuminaemia or sideropenia. After review of relevant literature (MEDLINE, PubMed, etc.), we found that half-and-half nail had not been described in Crohn's disease. This study was designed to highlight the fact that the half-and-half nail, which was thought to be a sign of chronic renal failure, also occurs in patients with Crohn's disease. The relationship of this symptom to clinical activity cannot yet be assessed and has only been observed in four cases.

Role of acellular dermal matrix allograft in minimal invasive coverage of deep burn wound with bone exposed--case report and histological evaluation.

A sandwich graft was applied to the debrided cortical bone layer of the tibia in the case of a 72-year-old male patient with full-thickness necrotic burn injury. The combined graft consisted of a dermal template material and autologous split thickness skin graft. After application, the graft was found totally accepted and provided good functionality with acceptable appearance. Histopathologic evaluation revealed a complete take with revascularisation of the implant. Supporting lamellar bony trabecules were also seen in the deep dermal dermis representing a connection to the underlying bone. The use of the dermal matrix in deep burn exposing the bone provides a satisfactory functional result and good cosmetic appearance.

Carcinoma arising in enterocutan fistulae of Crohn's disease patients: description of two cases.

Rarely, carcinoma arises from the fistulous tract of Crohn's disease. Adequate radiological examination often produces misleading pseudonegative findings. We reported two cases of fistula cancers treated with infliximab. The short time-span between the administration of this drug and the diagnosis of cancer makes the correlation between the two unlikely.

[Fungal esophagitis]. / Gombás nyelócsógyulladás.

The gastrointestinal mucosa is one of the principal portal of entry in systemic fungal infections. Esophagitis is the most frequent among the fungal infections of the gastrointestinal tract. The etiologic factors of fungal infections are various Candida species, most frequently Candida albicans. Due to the large number of asymptomatic patients, great attention should be paid to the predisposing factors (AIDS, cancer, antibiotic or steroid therapy). The diagnosis is based on the endoscopic picture, microscopic examination and culture of the mucosal brushings, and histological examination of the esophageal mucosa. The treatment is based on azol derivates, mainly fluconazole. In fluconazole resistant cases amphotericin B is the drug of choice. The rare complications are perforation, bleeding and stricture.