Pediatric Crohn's Disease in the Upper Gastrointestinal Tract: Clinical, Laboratory, Endoscopic, and Histopathological Analysis.

Crohn's disease (CD) is a progressive, multifactorial, immune-mediated disease characterized by chronic inflammation of any part of the gastrointestinal (GI) tract. Pediatric patients present with a more extensive form of the disease, especially in the upper GI tract with various histopathological inflammatory patterns. Our study aims to analyze the clinical, laboratory, endoscopic, and histopathological findings in children with diagnosed CD and compare results on the initial and follow-up tests. We have included 100 children and adolescents with CD, with performed endoscopic and histopathological (HP) procedures. The results of multiple biopsies executed in these 8 years were matched and compared. We found a statistically significant frequency reduction in stool changes (65.52% to 18.18%), weight loss (35.24% to 4%), and abdominal pain (41.86% to 6.67%) as presenting symptoms. There was an improvement in all laboratory values: fecal calprotectin (1000 to 60,8 µg/g), C-reactive protein (12.2 to 1.9 mg/L), and albumin (36 to 41 g/L). On esophagogastroduodenoscopy and ileo-colonoscopy 36.59% and 64.86% patients had specific findings, respectively. A total of 32 patients had evidence of Crohn's disease in the upper GI tract. Non-caseating granulomas were found on 9% of oesophageal, 18% of gastric, and 12% of duodenal biopsies. In the lower GI tract, we have observed a disease progression in the rectum (72.29 to 82.22%) and descending colon (73.49 to 80%). There was no registered disease progression in the upper GI tract. Our study demonstrated a significant decline in the frequency of symptoms and an improvement in laboratory values on the follow-up examinations. More than a third of our patients had specific endoscopic and HP findings in the upper GI tract, and an additional 23% had HP findings highly suggestive of CD. We demonstrated the importance of regular clinical, laboratory, endoscopic, and histopathological assessments of pediatric CD patients.

Performance and Dimensionality of Pretreatment MRI Radiomics in Rectal Carcinoma Chemoradiotherapy Prediction.

(1) Background: This study aimed to develop a machine learning model based on radiomics of pretreatment magnetic resonance imaging (MRI) 3D T2W contrast sequence scans combined with clinical parameters (CP) to predict neoadjuvant chemoradiotherapy (nCRT) response in patients with locally advanced rectal carcinoma (LARC). The study also assessed the impact of radiomics dimensionality on predictive performance. (2) Methods: Seventy-five patients were prospectively enrolled with clinicopathologically confirmed LARC and nCRT before surgery. Tumor properties were assessed by calculating 2141 radiomics features. Least absolute shrinkage selection operator (LASSO) and multivariate regression were used for feature selection. (3) Results: Two predictive models were constructed, one starting from 72 CP and 107 radiomics features, and the other from 72 CP and 1862 radiomics features. The models revealed moderately advantageous impact of increased dimensionality, with their predictive respective AUCs of 0.86 and 0.90 in the entire cohort and 0.84 within validation folds. Both models outperformed the CP-only model (AUC = 0.80) which served as the benchmark for predictive performance without radiomics. (4) Conclusions: Predictive models developed in this study combining pretreatment MRI radiomics and clinicopathological features may potentially provide a routine clinical predictor of chemoradiotherapy responders, enabling clinicians to personalize treatment strategies for rectal carcinoma.

The Usefulness of the Eosinophilic Esophagitis Histology Scoring System in Predicting Response to Proton Pump Inhibitor Monotherapy in Children with Eosinophilic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is an immune-mediated esophageal disease with rising incidence. While proton pump inhibitors (PPIs) are the first-line treatment, a significant proportion of patients do not respond. This study aimed to determine if the EoE Histology Scoring System (EoEHSS) can predict PPI responsiveness. METHODS: A cross-sectional study was conducted on 89 pediatric patients diagnosed with EoE between 2016 and 2022. Patients were categorized into PPI responders (PPIREoE) and non-responders (PPINREoE) based on post-treatment biopsies. EoEHSS values from biopsies of the esophagus (distal, middle, and proximal segments) were compared between the two groups. RESULTS: No significant differences in EoEHSS scores were observed for the distal and proximal esophagus between the groups. However, the middle esophagus showed a significantly higher EoEHSS grade score in the PPINREoE group, indicating a more pronounced disease severity. Specific histological features, particularly eosinophilic abscesses and surface layering of the middle segment of the esophagus, were significantly different between the groups. CONCLUSIONS: Performing a biopsy of each esophageal segment, particularly the middle, is crucial for diagnostic precision and predicting PPI responsiveness. The EoEHSS can serve as a valuable tool in predicting therapy response, emphasizing the need for personalized therapeutic approaches in EoE management.

Data-Independent Acquisition Mass Spectrometry Analysis of FFPE Rectal Cancer Samples Offers In-Depth Proteomics Characterization of the Response to Neoadjuvant Chemoradiotherapy.

Locally advanced rectal cancer (LARC) presents a challenge in identifying molecular markers linked to the response to neoadjuvant chemoradiotherapy (nCRT). This study aimed to utilize a sensitive proteomic method, data-independent mass spectrometry (DIA-MS), to extensively analyze the LARC proteome, seeking individuals with favorable initial responses suitable for a watch-and-wait approach. This research addresses the unmet need to understand the response to treatment, potentially guiding personalized strategies for LARC patients. Post-treatment assessment included MRI scans and proctoscopy. This research involved 97 LARC patients treated with intense chemoradiotherapy, comprising radiation and chemotherapy. Out of 97 LARC included in this study, we selected 20 samples with the most different responses to nCRT for proteome profiling (responders vs. non-responders). This proteomic approach shows extensive proteome coverage in LARC samples. The analysis identified a significant number of proteins compared to a prior study. A total of 915 proteins exhibited differential expression between the two groups, with certain signaling pathways associated with response mechanisms, while top candidates had good predictive potential. Proteins encoded by genes SMPDL3A, PCTP, LGMN, SYNJ2, NHLRC3, GLB1, and RAB43 showed high predictive potential of unfavorable treatment outcome, while RPA2, SARNP, PCBP2, SF3B2, HNRNPF, RBBP4, MAGOHB, DUT, ERG28, and BUB3 were good predictive biomarkers of favorable treatment outcome. The identified proteins and related biological processes provide promising insights that could enhance the management and care of LARC patients.

Pediatric appendicular actinomycosis: a case report and literature review.

BACKGROUND: Actinomycosis (ACM) is a rare infectious granulomatous disease caused by Actinomyces, a Grampositive, filamentous, saprophytic bacteria. There are several types of pediatric ACM, such as orocervicofacial (55%) and other less common forms: abdominopelvic and thoracic. We report a case of a 16-year-old who presented with abdominal ACM in the setting of acute appendicitis. After the case report, we provide a short literature review of pediatric appendicular ACM cases published. CASE: A 16-year-old boy presented with nausea, vomiting, pain in the upper part of the abdomen and fever (37.5°C) lasting for 24 hours. On physical examination, the patient`s epigastrium and lower right abdominal quadrant were tender. White cell count and C-reactive protein (CRP) were elevated at 16,300/µL and 48.6mg/L respectively. Ultrasonography (US) showed appendicolith and edema of the appendiceal wall, focally with stratification as well as periappendiceal inflammation. The patient underwent a classic appendectomy, and the postoperative course was without complications. Histopathological analysis showed diffuse transmural neutrophilic infiltration of the appendix, focally with areas of necrosis and abscesses. There were numerous brightly eosinophilic colonies made of filamentous bacteria, located predominantly in submucosa. Special stains Grocott-Gomori`s Methenamine Silver and Gram were positive and a diagnosis of ACM was made. CONCLUSIONS: Although appendicitis is very common in the general population, appendicitis associated with ACM is very rare, accounting for 0.02% - 0.06%, especially in the pediatric population. Diagnosis can be very challenging because they usually present with non-specific symptoms, and can form masses that mimic malignancies. Although rare, clinicians and pathologists should be aware of this entity. Satisfactory results and complete cure are achieved with adequate antibiotic therapy and surgery. In most cases, if there are no associated diseases, early and accurate diagnosis ensure an excellent prognosis.

Exploring novel genetic and hematological predictors of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Introduction: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT). To select patients who would benefit the most from nCRT, there is a need for predictive biomarkers. The aim of this study was to evaluate the role of clinical, pathological, radiological, inflammation-related genetic, and hematological parameters in the prediction of post-nCRT response. Materials and methods: In silico analysis of published transcriptomics datasets was conducted to identify candidate genes, whose expression will be measured using quantitative Real Time PCR (qRT-PCR) in pretreatment formaline-fixed paraffin-embedded (FFPE) samples. In this study, 75 patients with LARC were prospectively included between June 2020-January 2022. Patients were assessed for tumor response in week 8 post-nCRT with pelvic MRI scan and rigid proctoscopy. For patients with a clinical complete response (cCR) and initially distant located tumor no immediate surgery was suggested ("watch and wait" approach). The response after surgery was assessed using histopathological tumor regression grading (TRG) categories from postoperative specimens by Mandard. Responders (R) were defined as patients with cCR without operative treatment, and those with TRG 1 and TRG 2 postoperative categories. Non-responders (NR) were patients classified as TRG 3-5. Results: Responders group comprised 35 patients (46.6%) and NR group 53.4% of patients. Analysis of published transcriptomics data identified genes that could predict response to treatment and their significance was assessed in our cohort by qRT-PCR. When comparison was made in the subgroup of patients who were operated (TRG1 vs. TRG4), the expression of IDO1 was significantly deregulated (p < 0.05). Among hematological parameters between R and NR a significant difference in the response was detected for neutrophil-to-monocyte ratio (NMR), initial basophil, eosinophil and monocyte counts (p < 0.01). According to MRI findings, non-responders more often presented with extramural vascular invasion (p < 0.05). Conclusion: Based on logistic regression model, factors associated with favorable response to nCRT were tumor morphology and hematological parameters which can be easily and routinely derived from initial laboratory results (NMR, eosinophil, basophil and monocyte counts) in a minimally invasive manner. Using various metrics, an aggregated score of the initial eosinophil, basophil, and monocyte counts demonstrated the best predictive performance.

EGFR mutation testing from pleural effusions of non-small cell lung cancer patients at the institute for oncology and radiology of Serbia.

BACKGROUND: The use tumor-derived cell-free DNA extracted from body fluids is being evaluated for genetic testing in lung cancer. The aim of this study was to explore the feasibility and utility of implementation of EGFR molecular testing from pleural effusions in non-small cell lung cancer in the clinical diagnostics workflow. PATIENTS AND METHODS: This study included patients diagnosed with primary lung adenocarcinoma in the period July 2016 to June 2023. EGFR mutation testing was performed by qPCR (Cobas®) and dPCR. Testing was performed from 211 plasma samples when tissue was unavailable at diagnosis, and from 301 plasma samples and 18 pleural effusions at progression on first/second generation of EGFR TKIs. Descriptive methods of statistical analysis were used to summarize the sample data. Fisher's exact test, McNemar's test, Cohen's kappa tests were used for statistical analyses. Two-sided p-values <0.05 were considered statistically significant. RESULTS: A significantly higher detection rate of the T790M mutation in pleural effusion was obtained compared to blood (50% and 20%, p=0.047). When comparing the detection success rate of the resistant T790M mutation in pleural effusion and blood, a statistically significant difference was obtained in favor of pleural effusion (50% vs. 21.87%, p=0.01). CONCLUSIONS: Superior performance of pleural effusions compared to blood plasma was shown both in the analysis of success rate and in the detection of the resistant T790M mutation, at progression on EGFR TKIs. Pleural effusion should be considered in this setting whenever available, especially in countries with limited health resources.

Methylenetetrahydrofolate reductase polymorphic variants C677T and A1298C in rectal cancer in Slavic population: significance for cancer risk and response to chemoradiotherapy.

Background: Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to examine the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5-FU)/leucovorin (LV) in the locally advanced setting. Patients and methods: This case-control study included 119 healthy controls and 97 patients with locally advanced rectal cancer (LARC). For MTHFR genotyping, restriction fragment length polymorphism analysis (PCR-RFLP) was employed. Results: In silico analysis highlighted that SNPs C677T and A1298T correlate with MTHFR gene expression, and that gene expression profile correlates with cancer risk and stage. Using dominant and recessive models, it was found that the MTHFR 677CC vs. 677CT+677TT have increased risk of cancer development (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.30-3.95, p = 0.002) as well as 677CC+677CT compared to 677TT (OR: 4.18, 95% CI: 1.16-14.99, p = 0.014). MTHFR 1298AA also shown increased risk for cancer development compared to 1298AC+1298CC (OR:2.0, 95% CI: 1.20-3.59, p = 0.035) Statistical analysis of combined genotypes highlighted the protective role of CT/AC combined genotype (OR: 3.15 95% CI: 1.576-6.279, p = 0.002) while the CC/AA genotype showed an increased risk for rectal cancer development (OR: 2.499, 95% CI: 1.246-5.081, p = 0.016) The carriers of the 677C/1298A haplotype had the highest risk for developing rectal cancer (OR: 1.74; 95% CI: 1.198-2.530, p = 0.002) while the 677T/1298C haplotype seems to provide a protective effect. (OR: 0.44; 95%CI 0.248-0.795, p = 0.003). No significant association with response to chemoradiotherapy was found. Conclusion: Our data point to MTHFR 667C allele and 1298A alleles as low-penetrance risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan, as various population-based factors might also be significant our findings can be used for future meta-analyses and the construction of genetic cancer risk prediction panels.

Prognostic relevance of autophagy-related markers p62, LC3, and Beclin1 in ovarian cancer.

AIM: To analyze the expression of autophagy markers p62, LC3, and Beclin1 in ovarian cancer tissue and evaluate the prognostic potential of these markers. METHODS: The study enrolled 328 patients: 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. The expression of p62, LC3, and Beclin1 was analyzed in central and invasive tumor segments with immunohistochemistry combined with tissue microarray. The expression levels of the analyzed markers were correlated with relevant histopathology parameters. RESULTS: The expression of all analyzed markers was most remarkable in epithelial ovarian carcinoma. There was a strong positive correlation between the expressions of p62 and LC3, while these two markers negatively correlated with Beclin1. High-grade serous carcinoma had higher p62 and LC3 levels, and lower Beclin1 levels than other tumor types. This expression profile was also observed in more advanced tumor stages. CONCLUSION: Prominent p62 and LC3 expression in combination with weak Beclin1 expression in high-grade serous carcinoma indicates potential for the application of autophagy inhibitors in patients with this tumor subtype.

PD-L1 Expression in Different Segments and Histological Types of Ovarian Cancer According to Lymphocytic Infiltrate.

Background and Objectives: Ovarian cancer is the leading cause of death among gynecological tumors. PD-1/PD-L1 immunoregulatory mechanism is activated in ovarian cancers. Lymphocyte infiltration is a significant factor that affects its expression. We analyzed the correlation between localization of lymphocytic infiltrate and PD-L1 expression in epithelial ovarian tumors. Materials and Methods: PD-L1 expression was analyzed in 328 subjects, 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. Expression in central and invasive tumor parts in epithelial ovarian carcinoma was combined with the most pronounced lymphocyte reaction. Immunohistochemical analysis was performed using the tissue microarray and correlated with a set of histopathology parameters. Results: PD-L1 expression was most prominent in epithelial ovarian carcinoma with different levels of expression observed between invasive and central tumor segments. A high level of PD-L1 expression on tumor cells was more frequently present in the invasive than in the central tumor parts (p < 0.001) only in high-grade serous ovarian carcinoma (HGSC). There was no significant correlation between peritumoral lymphocytic infiltrate and PD-L1 expression regardless of tumor segment. In the central tumor parts of HGSC, there was a correlation of intratumoral lymphocytic infiltrate with a higher level of PD-L1 expression (p = 0.003). Conclusions: The most prominent PD-L1 expression was observed in the invasive tumor parts of HGSC. Only the central parts of the HGSC exhibited significant PD-L1 expression in association with considerable intratumoral lymphocytic infiltrate.

The role of haematological parameters in predicting the response to radical chemoradiotherapy in patients with anal squamous cell cancer.

BACKGROUND: Historically, the treatment of choice for anal cancer had been abdominoperineal resection (APR). Radical radiotherapy with concurrent 5-fluorouracil plus mitomycin C chemotherapy was later established as standard therapy, although with a failure rate of 20-30%. The aim of this study was to evaluate the outcomes after radical chemoradiotherapy (CRT), prognostic and predictive factors and patterns of failure. PATIENTS AND METHODS: This study included 47 patients treated with radical CRT for patohistologicaly confirmed anal squamous cell carcinoma. Analysed haematological parameters included: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and haemoglobin level. The final logistic regression model included treatment break period. Tumour response was assessed at 24 weeks from CRT completion. Follow-up was performed every 3 months during the first two years, and every 6 months thereafter. RESULTS: A complete clinical response (CR) was detected in 30 patients (63.8%). Patients who did not achieve a 6-months CR and those who had a CR after 6 months but then relapsed were referred to surgical treatment. With combined CRT and surgical salvage treatment the CR rate was 80.9%. Patients with CR after 6 months had significantly longer disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). A significant effect on the 6-month response was confirmed for PLR (p = 0.03). CONCLUSIONS: Important prognostic factors associated with CR were baseline haemoglobin level and period of treatment interruptions. Potential haematological prognostic factors could be PLR and NLR, which can be routinely determined by low-cost and minimally invasive methods.

Exploring the real-world effect of the SARS-CoV-2 pandemic on the molecular diagnostics for cancer patients and high-risk individuals.

Background: The SARS-CoV-2 pandemic introduced a global distraction effect in cancer patients' care. The aim of this study was to explore the effect of the pandemic on the largest molecular diagnostics center for cancer patients and high-risk individuals in Serbia.Research design and methods: EGFR, KRAS/NRAS, BRAF, and BRCA1/2 mutation testing were performed by qPCR and NGS. NGS was used for panel testing of hereditary breast/ovarian cancer and cancers associated with Lynch syndrome. The analytical output during the state of emergency (SoE) was compared to the period before and after the outbreak using one-way ANOVA. Statistical significance was set at p < 0.05.Results: A 38% reduction in the number of analysis was detected during the SoE. After the SoE, a 19% reduction was noted compared to SoE and 50% compared to the period before the SoE (p = 0.038). Three of the 48 scheduled appointments for pretest genetic counseling were carried out during the SoE, but the number of NGS tests increased by 50%.Conclusions: The SARS-CoV-2 pandemic had a profound negative effect on the diagnostic output of our centralized molecular diagnostics center. The only positive effect was shortening of waiting lists for hereditary cancer patients and high-risk individuals.

Mahonia aquifolium Extracts Promote Doxorubicin Effects against Lung Adenocarcinoma Cells In Vitro.

Mahonia aquifolium and its secondary metabolites have been shown to have anticancer potential. We performed MTT, scratch, and colony formation assays; analyzed cell cycle phase distribution and doxorubicin uptake and retention with flow cytometry; and detected alterations in the expression of genes involved in the formation of cell-cell interactions and migration using quantitative real-time PCR following treatment of lung adenocarcinoma cells with doxorubicin, M. aquifolium extracts, or their combination. MTT assay results suggested strong synergistic effects of the combined treatments, and their application led to an increase in cell numbers in the subG1 phase of the cell cycle. Both extracts were shown to prolong doxorubicin retention time in cancer cells, while the application of doxorubicin/extract combination led to a decrease in MMP9 expression. Furthermore, cells treated with doxorubicin/extract combinations were shown to have lower migratory and colony formation potentials than untreated cells or cells treated with doxorubicin alone. The obtained results suggest that nontoxic M. aquifolium extracts can enhance the activity of doxorubicin, thus potentially allowing the application of lower doxorubicin doses in vivo, which may decrease its toxic effects in normal tissues.

Expression levels of genes involved in cell adhesion and motility correlate with poor clinicopathological features of epithelial ovarian cancer.

PURPOSE: Changes in the expression levels of genes involved in cancer cell adhesion and motility have been reported to have an important role in tumor progression. In this study, we aimed to investigate the clinical significance of ITGAV and CALD1 gene expression in epithelial ovarian cancer (EOC), the most lethal gynecological malignancy. METHODS: Reverse transcription quantitative polymerase chain reaction was used to evaluate ITGAV and CALD1 expression levels in 47 EOC and 19 benign formalin-fixed paraffin-embedded samples. We used Spearman's test to determine the association between ITGAV and CALD1 expression and Wilcoxon test to compare expression levels between malignant and benign ovarian tumor specimens as well as to determine their association with clinicopathological characteristics of EOC. Survival analysis was done by the Kaplan-Meier method and the log-rank test. P ≤ 0.05 was considered statistically significant. RESULTS: CALD1 and ITGAV showed significantly lower expression in EOC than in benign ovarian samples (p<0.001). Furthermore, CALD1 was significantly lower expressed in high-grade tumors (p=0.037) while there was a trend for a lower expression of ITGAV in tumors with high histological grade (p=0.043), in tumors with ascites (p=0.055), and in tumors of patients who relapsed (p=0.083). We also found a significant positive association between ITGAV and CALD1 expression (ρ=0.640, p<0.001) in EOC samples. Kaplan-Meier analysis showed no significant impact of ITGAV and CALD1 expression levels on overall survival of EOC patients (p=0.149 and p=0.430, respectively). CONCLUSION: Our findings indicate that CALD1 and ITGAV gene expression levels correlate with poor clinicopathological features of the EOC.

EGFR mutation testing from liquid biopsy of non-small cell lung cancer at the Institute for Oncology and Radiology of Serbia.

PURPOSE: Resistance to tyrosine kinase inhibitors (TKIs) in lung cancer often occurs, so mutation testing from liquid biopsy is the method of choice as a minimally invasive approach that quickly provides information for additional therapeutic options. The purpose of this study was to assess the success rate and usefulness of EGFR testing from liquid biopsy at the Institute for Oncology and Radiology of Serbia (IORS). METHODS: EGFR mutation testing was performed by real-time qPCR in 4750 tumor samples using the Cobas® EGFR Mutation Test v2. EGFR testing from 104 liquid biopsy samples was used to track the resistance on first-line EGFR-TKIs as well as for initial testing of 124 patients without tissue biopsies. RESULTS: Liquid biopsy samples were tested in cases with inadequate material for DNA isolation or without tissue biopsy at diagnosis. Nine mutated samples were detected (7.3 %) with a 99.2 % testing success rate. Testing liquid biopsy samples of patients who progressed on EGFR-TKIs showed an accordance rate of 67% with driver mutations, and 49% of mutated patients had the T790M mutation which rendered them eligible for third-generation EGFR-TKIs. An additional 5 patients tested EGFR wild type from plasma after progression were rebiopsied and 3 of them had the T790M mutation. CONCLUSIONS: EGFR mutation testing from liquid biopsy has been successfully implemented in Serbia and has proven invaluable for detecting molecular resistance mechanisms to EGFR-TKIs and as an alternative sample source for patients with scarce biopsy material or without any at all.

LungCARD - Report on worldwide research and clinical practices related to lung cancer.

PURPOSE: The management of advanced lung cancer has evolved tremendously over the past two decades. Increasing understanding of the molecular changes that drive tumor progression has transformed the treatment of this disease. Nevertheless, various countries differ in the degree of implementation of genetic tests and the availability of innovative drugs. The LungCARD consortium created a questionnaire to collect information about the local research and clinical practices related to lung cancer diagnosis and therapy. METHODS: A survey composed of 37 questions related to specific lung cancer pharmacogenomics and therapy, was distributed among 18 countries. RESULTS: All together 36 responses were gathered, answered mainly by clinicians. The majority attends 50-200 cancer cases per month, 20-50% of all cancer cases are lung cancer patients, and more than 80% are with non-small-cell lung cancer (NSCLC). Targeted therapy is applied to 50% on average of all NSCLC patients. Forty five percent of participating medical oncologists are treating their patients with immunotherapy. More than 90% of the respondents are guided by results of genetic tests in introducing targeted treatment. As expected, the majority orders EGFR gene testing (85%), followed by ALK (58%) and KRAS testing (32%). Almost all (96%) agreed that more biomarkers should be included in routine genetic testing (ROS1, anti-PDL1, KRAS, MET, HER2, BRAF...), and that blood test is useful in pharmacogenomic testing. CONCLUSION: There is a great variation between countries with respect to all discussed topics. However, the majority recognized a necessity of introducing next generation sequencing (NGS)-based diagnostics and potential of testing from blood. The biggest problem in the treatment of NSCLC is still an access to innovative drugs.

Tumor characteristics, expressions of ERCC1, Bax, p53, IGF1R, Bcl2, Bcl2/Bax and prognostic factors for overall survival in patients with lung carcinoid.

PURPOSE: Neuroendocrine lung tumors (NET) include typical carcinoids (TC), atypical carcinoids (AC), large cell NE carcinoma (LCNEC) and small-cell carcinoma (SCLC), with different clinicopathological profiles and relative grades of malignancy. Although differences between carcinoids and high grade carcinomas are recognized, precise differences and behavior of TC and AC have not been clearly defined. The aim of this study was to better define the differences in the clinical behavior of TC and AC, and to establish new prognostic factors of overall survival (OS), by determining the levels of genetic expression of IGF1R, ERCC1, Bax, p53, Bcl2 and Bcl2/Bax ratio. METHODS: The histopathological diagnosis of 52 surgically resected pulmonary carcinoid tumors was made according to the WHO classification. Gene expressions were evaluated by quantitative real-time PCR. RESULTS: The confirmed prognostic factors for overall survival (OS) were pTNM T (p<0.01), pTNM N (p<0.05), clinical stage (p<0.05), type of surgery (p<0.01) and histopathological (HP) tumor type (p<0.05). Bcl2 mRNA level and Bcl2/Bax ratio were found to have a potential for discrimination of the HP type of tumor (AC vs TC, Receiver Operating Characteristics (ROC) cut-off values 0.1451 and 0.3015, respectively), but without statistically significant impact on OS. CONCLUSIONS: In patients with NETs, smaller primary tumor, absence of positive lymph nodes, and TC type of tumor predicted longer OS. Type of resection has influence on OS. Bcl2 expression and Bcl2/Bax ratio might be valuable as independent diagnostic parametars in lung carcinoids. Therapeutic approaches using attenuation of Bcl2 or upregulation of Bax might prove useful in lung NETs.

Effects of hydroxyapatite@poly-lactide-co-glycolide nanoparticles combined with Pb and Cd on liver and kidney parenchyma after the reconstruction of mandibular bone defects.

Reconstruction of bone defects with the use of biomaterials based on hydroxyapatite (HAp) has been a popular approach in medicine and dentistry. Most often the process of new bone formation is analyzed with the focus only on the region of the reconstructed defect. The effects of the therapy on distant organs have been rarely reported in the literature, especially not in synergy with the exposure to other bioactive chemicals. In this study, reconstruction of the mandibular bone in vivo using poly-lactide-co-glycolide-coated HAp (HAp/PLGA) nanoparticles was monitored with a simultaneous histopathological analysis of distant organs, specifically kidney and liver parenchyma. Heavy metals are among the most prominent environmental pollutants and have a high affinity for the crystal lattice of HAp, where they get incorporated by replacing calcium ions. Lead (Pb) and cadmium (Cd) are two such metals that can be found in food, water and air, but are most commonly present in cigarette smoke, the frequent contaminant of hospital settings in the developing world. The influence of their presence in the repaired bone on the content of calcium (Ca) in the reconstructed bone defect was analyzed, along with the histopathological changes in liver and kidneys. A study performed on 24 female Wistar rats demonstrated that the reconstruction of mandibular bone defects using HAp/PLGA particles induced an increase in the content of Ca in the newly created bone without causing any pathological changes to the liver and the kidneys. The presence of Pb and Cd in the defects reconstructed with HAp/PLGA nanoparticles impeded the regenerative process and led to a severe and irreversible damage to the liver and kidney parenchyma.

Diagnosis of Eosinophilic Esophagitis in Children: A Serbian Single-Center Experience from 2010 to 2017.

OBJECTIVES: The aim of this study was to assess the epidemiological, clinical, endoscopic, and pathohistological characteristics of pediatric eosinophilic esophagitis (EoE) in Serbia. METHOD: All children aged 0-18 years diagnosed with EoE in the period between 2010 and 2017 at the University Children's Hospital in Belgrade, Serbia, were retrospectively enrolled. RESULTS: EoE was diagnosed in 35 children (12.45 ± 3.77 years) with a male predominance (74%). The median incidence rate was estimated to be 0.85 per 100,000 children per year with the highest rate estimated at 3.17 per 100,000 children in 2017. Dysphagia (71.4%) and food impaction (40%) were dominant symptoms. Inflammatory endoscopic changes were found in 74.3% and fibrostenotic changes in 62.9% of the children. The esophageal biopsy rate was low (6.8%), especially in children with reflux and nonspecific symptoms. Subepithelial fibrosis was found in only 20% of the patients. Since 2016, the number of biopsy samples has increased, but the sampling rate of lamina propria is still low (<50%). The correlation between the number of biopsies and lamina propria acquisition was strong (rs = 0.773, p < 0.05). In 2 immunocompetent adolescents, EoE was diagnosed after successful treatment of infectious esophagitis. CONCLUSIONS: An increase in the incidence of EoE in Serbian children is evident. The biopsy rate in children with nonspecific and reflux symptoms should be increased, as well as the number of biopsy samples for the detection of subepithelial fibrosis. In immunocompetent children with infectious esophagitis, EoE should be suspected and endoscopy may be recommended after successful treatment of infection.