Importance of PET/CT examination in patients with malignant uveal melanoma.

INTRODUCTION: Diagnostic and therapeutic management of the patient with malignant uveal melanoma (MMU) is subject to ongoing efforts to innovate. PET/CT (Positron Emission Tomography / Computed Tomography) examination is important in both diagnosis and metastases. MATERIAL AND METHODS: Evaluation of the importance of PET/CT examination in the group of patients diagnosed with MMU in the period 12.1.2016 to 6.12.2018. All patients with a diagnosis of secondary retinal detachment, suspected uveal melanoma, underwent standard examinations to detect possible metastases (liver ultrasound, chest X-ray). Patients for whom a stereotactic radiosurgery solution was planned due to the stage of the disease this examination was to exclude metastasis in the liver or lungs. PET/CT examination is part of the protocol within the exclusion criteria for treatment with stereotactic radiosurgery in one day session surgery. RESULTS: In the group of 84 patients, 47 women (56 %) and 37 men (44 %) were aged between 26 and 90 years. Their average age was 61.4 years. The median group was 64 years, modus 65 years. Of 84 patients, 79 (94 % of cases) had a diagnosis of C69.3 (choroidal melanoma) and 5 patients (6 % of cases) had a diagnosis of C69.4 (ciliary body melanoma). Subsequent PET/CT examination in many patients did not reveal hypermetabolic manifestations that could involve various pathological processes, in others the radiopharmaceutical was captured in the primary tumor area of the uveal tract. Hypermetabolism in eye globe was only found in melanomas with a volume of more than 0.5 cm3. PET/CT examinations were 85, with one patient undergoing examination twice. However, in 25 patients (26 examinations), the radiopharmaceutical was taken up in places that subsequently required closer attention. The initial aim of the examination was to locate possible metastases of MMU. In the others, 3 incidents have been reported: increased metabolism in the lung and liver, thyroid and mediastinal lymph nodes. Of the 85 examinations, 26 (30.6 %) resulted in a hypermetabolic manifestation of accumulation, which was not located in the eye tract, resp. right in the eye. Two malignancies (prostatic carcinoma and rectosigmal carcinoma) have occurred in two patients. Very important was the discovery of MMU metastasis in the liver, which confirmed the important role of PET/CT examination in the management of MMU patients. The metastasis was discovered after repeated PET/CT examination. CONCLUSION: PET/CT examination is a technically demanding examination and is one of the possibilities of imaging intraocular melanoma in tumors with volume more than 0.5 cm3. It is important in determining the grading and staging of the disease before radiosurgical treatment and also in detecting possible metastases after MMU treatment in cases where ultrasound or MRI examinations do not give a definite result. However, our study confirmed the significance of this examination for randomly detected 2 duplex malignancies (2.4%) and 3 incidentalomas (3.6%) in patients whose ophthalmologist diagnosed uveal melanoma and sent patients for full-body PET/CT examination.

Secondary glaucoma in small versus large uveal melanoma patients treated with stereotactic radiosurgery on linear accelerator.

AIM: Secondary radiation-related side effects like secondary glaucoma (SG) of different modalities of treatment in uveal melanoma patients can appear in certain interval after therapy. This study describes the incidence of SG in patients after stereotactic radiosurgery (SRS). METHOD: The data of 230 patients treated by SRS were reviewed for SG. Group of 83 patients who were observed 5 years after treatment in one center with follow-up regularly at least 4 times per year were analyzed. RESULTS: In group of 83 patients with the median age 59 years, the median tumor volume at baseline was 0.41 cm3. The survival without SG after single dose SRS was 94 % in 1.5 year, 77 % in 2 years, 57 % in 3 years, 43 % in 3.5 years, and 18 % in 4.5 year after irradiation. In 6 patients (7.2 %) secondary enucleation was necessary due to SG. Both predictors (tumor volume and age of patient) at the time of SRS were not statistically significant by Cox proportional-hazards regression. CONCLUSIONS: Complications like SG in 5 year interval after irradiation can lead to secondary enucleation of the eye globe (Fig. 3, Ref. 44).

Dosing interval and diagnosis predict infliximab levels in patients with inflammatory bowel disease on maintenance treatment.

OBJECTIVE: The aim of the study was to identify factors influencing infliximab (IFX) trough levels (TL) in patients with inflammatory bowel disease (IBD). METHODS: This was a multicentre cross-sectional study performed at 5 large IBD centres in Slovakia. The cohort consisted of IBD patients, treated either with original IFX or CT-P13 biosimilar, who were examined for the IFX TL and antidrug antibodies (ADA) in a central laboratory. RESULTS: The patient cohort consisted of 116 consecutive IBD patients, 68 with Crohn's disease (CD) and 48 with ulcerative colitis (UC). CD patients had significantly lower IFX TL compared to UC, 2.41 (0.998-5.56) mg/L vs. 4.49 (1.76-8.41) mg/L, p = 0.017. During maintenance treatment, significantly higher mean IFX TL were observed in patients with a 4 week dosing interval than in patients with a 6 or 8 (7.44±3.6 µg/mL vs. 4.19±4.2 vs. 3.30±3.1 µg/mL, p = 0.011 and p< 0.0001, respectively). There was no difference in median TL IFX between original IFX and biosimilar CT-P13 (3.25 (1.24-6.52) mg/L vs. 3.03 (1.30-7.10)). IFX TL correlated with ADA (p=0.005). Multiple regression analysis revealed two independent factors for IFX TL: dosing interval (p<0.0001) and diagnosis (p=0.02). CONCLUSION: In the present study we observed that IBD patients assigned to an intensified dosing interval during maintenance therapy have significantly higher IFX TL than patients receiving conventional 8 week interval. Patients with UC had significantly higher IFX TL.

Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoietic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in population suffering from particular inflammatory bowel disease (IBD). AIMS: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients. METHODS: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplified using PCR and consequently genotyped with genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far. RESULTS: Three hundred and thirty IBD patients were included; 196/132/2 cases of Crohn´s disease/ulcerative colitis/unclassified colitis; 180 (55 %) males. Ninety-three percent of patients were homozygous for wild-type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients while only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was that of TPMT*3A (3.2 %). The distribution of most common allelic variants of TPMT gene among Slovak IBD patients was in accordance with previously reported prevalence in Caucasian populations. CONCLUSION: This study shows the prevalence of TPMT genetic polymorphisms in population of Slovak IBD patients. As in other Caucasian populations, the most common mutant allelic variant is that of TPMT*3A while the prevalence of homozygosity is relatively low (Tab. 3, Ref. 22).

The impact of thiopurine-S-methyltransferase genotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases.

BACKGROUND AND AIMS: The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of inflammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA. METHODS: The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status. RESULTS: Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no significant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed. CONCLUSION: The incidence of leukopenia in TPMT mutant patients was significantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).

Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoetic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in the particular inflammatory bowel disease (IBD) population. AIMS: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients. METHODS: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplified using PCR and consequently genotyped on genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far. RESULTS: Three hundred and thirty IBD patients were included; 196/132/2 Crohn´s disease/ulcerative colitis/unclassified colitis, 180 (55 %) males. Ninety-three percent of patients were homozygous for wild type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients, only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was TPMT*3A (3.2 %). The distribution of the most common allelic variants of TPMT gene among Slovak IBD patients were in accordance with previously reported prevalence in Caucasian populations. CONCLUSION: This study shows the prevalence of TPMT genetic polymorphisms in the Slovak IBD patient`s population. As in other Caucasian populations, the most common mutant allelic variant is TPMT*3A, and the prevalence of homozygosity is relatively low (Tab. 3, Ref. 16).

[Positive tests for serum anti-endomysium antibodies (AEA) and anti-jejunal antibodies (JAB) and histopathological diagnosis of celiac disease in children]. / Pozitivita sérových protilátok proti endomýziu, jejunu a histopatologická diagnostika celiakie u detí.

Non-invasive examination methods are increasingly important in diagnosing celiac disease. New options for diagnosing celiac disease have been discovered in addition to the established biochemical, hematological and other methods as a result expansive progress ofclinical genetics and immunology. At the same time, detection of circulating auto-antibodies is becoming ever more frequent in clinical practice. As a result, many new, clinically highly heterogeneous cases of the disease have been diagnosed and consequently the prevalence of the disease in both child and adult population has grown. Detection of anti-endomysial antibodies (AEA), characteristic for their high sensitivity and specificity, plays an important role in diagnosing and monitoring celiac disease in pediatric practice. Nevertheless, histopathological diagnosis remains the critical tool for definitive diagnosis of the disease. The article refers to relations between the degree of positivity of AEA and JAB antibodies in the IgA class and the respective grade in the Marsh grading system. The objective of the study was to examine AEA and JAB antibodies and the histological picture of the duodenal mucosa in 20 children and adolescents with celiac disease aged from 2 to 18 years. The authors developed a semiquantitative scale of positivity of both the antibodies, which they compared trying to find a correlation between these and the histopathological picture of the duodenal mucosa. The authors point out the need of timely determination of AEA and t-TG (tissue transglutaminase) in patients whose anamnesis, clinical picture or laboratory results may be indicative of celiac disease.

[Histopathological diagnosis of celiac disease in adults with functional dyspeptic syndrome]. / Histopatologická diagnostika celiakie u dospelých s funkcným dyspeptickým syndrómom.

Celiac disease is associated with permanent intolerance to gluten, which is found in some cereals. The symptoms of the disease are often nonconspicuous and the course of the disease is atypical. With the introduction of serological markers as a sensitive method of testing new cases of the disease were identified. Despite of the increased screening intensity among children and adults celiac disease in our region is still underdiagnosed. The article deals with the diagnostics of celiac disease in adults with functional dyspeptic syndrome. It is based on the laboratory and pathological correlation of 25 patients. Our aim was to identify the group at risk with functional dyspeptic syndrome and celiac disease. This disease can show symptoms from the onset all the way to relapse. Each person was examined by a gastroenterologist while hospitalized in the relevant department. In addition to the routine serological testing, blood samples were taken and sent for antiendomyzial antibody testing for positive reaction verification. A subsequent gastrointestinal examination was done and samples taken from the duodenum were sent for histology. Light microscopy analysis showed mucous damage typical for celiac disease, which is expressed with the levels of the Marsh histological grading. In closing, we recommend a three-step approach to goal-oriented screening of celiac disease. Determination of autoantibody against tissue transglutaminase, if positive, then biopsy from the aboral duodenum, and consequently follow-up by testing for antiendomyzial antibody.