Aim Lung adenocarcinoma (ADC) is a leading subtype of lung cancer, histologically defined with five different architectural growth patterns: lepidic, acinar, papillary, solid and micropapillary. The aim of this study was to explore the prevalence of epidermal growth factor receptor (EGFR) mutation and a relationship between the specific histological patterns of lung ADC in the population of Bosnia and Herzegovina. Methods The study included tumour tissue from 102 patients with completely resected lung ADC from 2015 to 2020. Molecular testing for the presence of EGFR mutations was performed by real-time PCR method. The relationship between EGFR mutation status and clinicopathological parameters was analysed. Results The EGFR mutation was detected in 12 (11.8%) cases of ADC, more often in non-smokers (p=0.007). A higher percentage of solid growth pattern presented in ADC may be an indicator of EGFR negativity (p=0.039), while a higher percentage of micropapillary growth pattern more common in the presence of EGFR mutation (p=0.047). Conclusion The prevalence of EGFR mutation is in accordance with the expected prevalence considering our studied population, Caucasians from South Europe. Better understanding of the relationship between histological patterns and molecular characteristics of lung ADC will enable earlier diagnosis and optimal treatment for patients.

PURPOSE The aim of this retrospective study was to evaluate and compare diagnostic accuracy and complication rates of percutaneous computed tomography (CT)-guided biopsies of pulmonary lesions 10-35 mm, 35-50 mm, and >50 mm, using the coaxial biopsy technique. METHODS Over a 4-year period, 235 lung biopsies were performed using the coaxial biopsy technique with 18G semi-automated true-cut needle. There were 163 (69.4%) male and 72 (30.6%) female patients, with a mean age of 64.01±9.18 years (18-85 years). The mean lesion size was 59.6±29.3 mm. The lesions were stratified into three groups according to size: lesions <35 mm (n=42, 17.9%), lesions 35-50 mm (n=53, 22.5%), and lesions >50 mm (n=140, 59.6%). Diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for all biopsies, and for each group separately, as well as the incidence of complications. RESULTS The overall diagnostic accuracy was 95.4%, with 95.52% sensitivity, 100% specificity, 100% PPV, and 47.37% NPV. For lesions <35 mm, diagnostic accuracy, sensitivity, and PPV were 100%. The lowest diagnostic accuracy was 93.9% in lesions >50 mm, with 93.65% sensitivity, 100% specificity, 100% PPV, and 42.86% NPV. An adequate sample was obtained in 219 core biopsies (93.2%), while 16 biopsies (6.8%) were nondiagnostic due to necrosis (4.25%) and insufficient biopsy material (2.55%). The most frequent complication was minor pneumothorax, which was seen at a rate of 19.1%; pneumothorax requiring chest tube placement occurred in 3 patients (1.3%). CONCLUSION Diagnostic accuracy decreased with increasing lesion size. On the other hand, complication rates were higher in smaller lesions, more distanced from the pleura.

The identification of numerous gene alterations in the past decade had a major impact on the treatment of Non Small Cell Lung Cancer (NSCLC). These driver mutations lead to specific biochemical pathways, which further promote growth and survival of cancer cells. There are several important mutations which represent well establish targets in the treatment of NSCLC. The first discovered drug-sensitive mutation in NSCLC was Epidermal Growth Factor Receptor (EGFR). The inhibition of EGFR has led the way for targeted therapy in the treatment of NSCLC. Erlotinib, the first anti-EGFR antibody was first approved in 2004. At first, the approval was referred to unselected patients after failure of chemotherapy, but was later proven to be superior in comparison with chemotherapy as first-line treatment of metastatic NSCLC with sensitizing EGFR mutations. Today, there are a variety of other anti-EGFR antibodies, such as gefitinib, afatinib, osimertinib or dacomitinib. The analyzes of phase 3 randomized trial FLAURA, showed superiority of osimertinib in first-line therapy with osimertinib in metastatic NSCLC with EGFR mutations regardless of T790M status. Antoher dirver mutation, found in approximately 5% of patients with NSCLC is ALK gene rearrangemet, also known as ALK fusion. This mutation is not routinely found in patients with squamous cell carcinoma, and therefore it is recommended to test for ALK fusions in patients with metastatic non-squamous NSCLC, based on the data showing efficacy of different kinase inhibitors, such as alectinib, brigatinib, ceritinib and crizotinib. ROS1 gene rearrangements (also known as ROS1 fusions) occur in about 1% to 2% of patients with NSCLC. There are different fusion partners that can be detected in NSCLC: CD74, SLC34A2, CCDC6 and FIG. The benefit of crizotinib, ceritinib and entrectinib for patients with ROS1 fusions was shown in different trials. Aditionally, there are others gene alterations, such as BRAF V600E mutation. These patients have a significant benefit in the treatment with combination of BRAF and MEK inhibitors dabrafenib and trametinib. Detection of RET rearrangements is predictive for the treatment with TKIs selpercatinib and pralsetinib. Furthermore, NTRK, METex14, KRAS mutations are proven to be very efficacious molecular biomarkers in the treatment of NSCLC. Testing for the expression of immune biomarker PD-L1 is crucial predictive biomarker for the treatment with immune checkpoint inhibitors. IHC testing for PD-L1 expression should be performed before first-line treatment in all patients with metastatic NSCLC. There are different checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, ipilimumab, cemiplimab), which showed efficacy alone or in combination with other treatment regimens. Testing of lung cancer specimens for these alterations is important for identification of potentially efficacious targeted therapies, as well as avoidance of therapies unlikely to provide clinical benefit. With the invention of targeted therapies and antibodies directed against tyrosine kinases and other specific driver mutations, the treatment options in lung cancer changed from histology-based to molecular and biomarker-based treatment. These changes in the treatment of NSCLC put in spotlight the significance of the cooperation between oncology and pathology. Brain metastases occur in about 30- 50% of patients with HER2 positive and 40% of patients with triple negative breast cancer. Occurrence of CNS metastases is a marker of aggressive disease. Median overall survival of patients with brain metastases is 13 – 19 months in patients with HER2 positive disease and 4.4 months in patients with triple negative disease. Regarding radiotherapy, breast cancer brain metastases are treated the same as metastases from all other tumor sites. When setting up an indication for local treatment, crucial is to have information about the control of extracranial disease, possibility of further systemic therapy lines and patient’s performance status. Local therapy consists of surgical treatment, with or without consolidation stereotactic radiotherapy and radiotherapy as a sole modality. Preferred method of radiotherapy would be stereotactic radiotherapy (SRT), in patients with up to 10-15 metastases, limiting factor being the volume of the disease (up to 15 mL). With STR local control can be achieved in up to 60% of patients. Fractionated stereotactic radiotherapy (FSRT), delivered in 3 to 12 fractions provides 1- year local control rate in up to 80% of patients. In case stereotactic radiotherapy is not available or possible, patients with good performance status and extracranial disease control could be referred to whole brain radiotherapy (WBRT), which palliates symptoms in about 60% of patients. Both stereotactic and whole brain radiotherapy are connected with cognitive impairment, which is more often after WBRT. WBRT induced cognitive toxicity can be lowered by using hippocampal sparing radiation techniques. WBRT after SRT or neurosurgical procedure improves local control but has no effect on overall survival and can also lead to cognitive impairment. Therefore, WBRT is not indicated after these procedures. Upon neurosurgical operation, SRT of resection cavity should be performed, as it lowers the risk if intracranial relapse of the disease. There are several ongoing trials exploring different radiotherapy techniques (SRT or WBRT), and their timing and combination with various systemic agents in breast cancer patients with brain metastases, such as lapatinib, trastuzumab emtansine, pembrolizumab. In patients with low performance status, loss of extracranial disease control and short life expectancy, it would be reasonable to omit whole brain radiotherapy since it has no effect on survival or quality of life and the same palliative effect can be achieved with corticosteroids use only. Immunotherapy has evolved recently as very promising and possibly effective treatment of several tumor types. Immunotherapy has dramatically changed treatment landscape of some entities, but benefit in colorectal cancer was so far very modest due to fact that only up to 5% of patients with mCRC have high microsatelite instability and mismatch-repair deficient genes. These features are considered as biologic markers for tumors which we expect to respond to immunotherapy. According to data obtained from early clinical studies (phase II) and last year presented phase III study, KEYNOTE-177, led to FDA-approval of pembrolizumab in first line treatment of metastatic colorectal cancer in June 2020. KEY-NOTE-177 was a randomized, open-label study enrolling 307 treatment-naive patients with microsatelite instability-high/mismatch repair-deficient (MSI-H/dMMR) mCRC. Randomization was 1:1 to treatment with pembrolizumab or investigator’s choice of doublet chemotherapy (n=154) meaning standard of care. Dual primary endpoint were PFS and OS, and crossover was permitted at disease progression. This is very important trial, since it was the first randomized- trial evaluating first-line pembrolizumab in patients with metastatic colorectal cancer. This was especially critical for Europe, because pembrolizumab was not approved. It is worth to mention that about 25% of patients had BRAF V600E-mutant tumor sin the trial. Median PFS2 was not reached in the pembrolizumab group and was 23.5 months in the chemotherapy group (HR:0.63)(ASCO GI 2021). The 12-month rate was PFS2 76% for pembrolizumab and 67% for chemotherapy. The same tendency was at 24-month PFS2. The rate of adverse events (AEs) and treatment-related AEs was similar in both treatment arms. Grade ≥ 3 treatment-related AEs were much more common in the chemotherapy group, affecting 66% of the patients compared with 22% of the patients receiving pembrolizumab. Grade ≥ 3 diarrhea, fatigue, and neutropenia also were significantly higher in the chemotherapy group. These results were expected, as pembrolizumab is generally well-tolerated. Generally, quality of life did not decrease in pembrolizumab group (QoL scores), and pain and appetite loss also improved with pembrolizum vs chemotherapy. So, there was a clear benefit in both PFS and QoL for the use of pembrolizumab over chemotherapy. The rate of adverse events (AEs) and treatment-related AEs was similar in both treatment arms. Grade ≥ 3 treatment-related AEs were much more common in the chemotherapy group, affecting 66% of the patients compared with 22% of the patients receiving pembrolizumab. Grade ≥ 3 diarrhea, fatigue, and neutropenia also were significantly higher in the chemotherapy group. These results were expected, as pembrolizumab is generally well-tolerated. Although this results put immunotherapy as very attractive treatment modality, there are many questions still to be answered in the future. We still don’t know the relationship between KRAS-mutant phenotype and immunotherapy, as well as the meaning of other biomarkers. After all, some patients do not respond to immunotherapy, so in the near future we should define which patients would be optimal for immunotherapy in first line setting and which would benefit from chemotherapy, nevertheless. Bacground : Hepatocellular carcinoma is fourth leading cause of death among cancer patients. This cancer is four to eight times more common in the male population and is usually associated with chronic liver damage (hepatitis B (HBV), hepatitis C (HCV) and alcoholic cirrhosis). Cirrhosis, regardless of the cause, is present in 70-80% of HCC cases. Chronic infection with HBV and cirrhosis increases the possibility of HCC up to 100 times. 5-30% of patients with HCV infection develop chronic liver disease, > 30% progress to cirrhosis, and in that population, 1-2% of them develop HCC annually. Co-infection with HBV further increases the risk of developing the disease. Other risk factors are: alcohol abuse, autoimmune diseases (autoimmune hepatitis and primary biliary cirrhos

Aim To examine whether preoperative tumour size may serve as a biomarker for the occurrence of lymphovascular invasion (LVI) in centrally and peripherally located lung adenocarcinoma. Method The study included 261 patients surgically treated for diagnosed lung adenocarcinoma. A ROC curve was used to determine the biomarker potential of tumour size relative to the occurrence of LVI. Binary logistic regression was used to show changes of tumour size impact on the status of LVI. Result Tumour prevalence according to localization had no statistical significance (p=0.464), while the presence of LVI in central, as well as peripheral positions, was statistically significantly different (p<0.001). The area under the curve of 0.978 highlights the fact that tumour size is an excellent marker of the presence of LVI in centrally located adenocarcinomas of the lung. A similar finding was confirmed in peripherally located lung adenocarcinomas with an area below the curve of 0.943. Binary logistical regression showed that in centrally localized adenocarcinomas of the lung, each additional centimetre of tumour growth represents an increase in the likelihood of LVI+ by 17.14 times. In peripherally located adenocarcinomas of the lung, this increase in likelihood of LVI for each centimetre of growth was 5.46 times. Conclusion With a high degree of sensitivity and specificity, preoperative tumour size may serve as an important biomarker and positive predictor of the presence of LVI in lung adenocarcinoma of any location.

A questionnaire on biomarker testing previously used in central European countries was extended and distributed in Western and Central European countries to the pathologists participating at the Pulmonary Pathology Society meeting 26–28 June 2019 in Dubrovnik, Croatia. Each country was represented by one responder. For recent biomarkers the availability and reimbursement of diagnoses of molecular alterations in non-small cell lung carcinoma varies widely between different, also western European, countries. Reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. The support for testing from alternative sources, such as the pharmaceutical industry, is no doubt partly compensating for the lack of public health system support, but it is not a viable or long‐term solution. Ideally, a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. As biomarker enabled therapies deliver a 50% better probability of outcome success, improved and unbiased reimbursement remains a major challenge for the future.

Introduction: Transverse colon volvulus is an uncommon cause of bowel obstruction. Predisposing factors are mental retardation, dysmotility disorders, chronic constipation, and congenital megacolon. Case report: We presented a transverse colon volvulus in a 14-year-old girl with mental retardation. Chronic constipation in neurologically impaired patients was a risk factor predisposing to volvulus. The girl was admitted to our Clinic because of problems that last 4-5 days and was followed by abdominal pain, vomiting and lack of stool. Vomiting was once a day. She was sub febrile up to 37.6°C. On examination, the abdomen was distended, tense, diffusely painful. During the surgery, a 360° clockwise volvulus of the transverse colon was found. After the reduction of volvulus, an enormous transverse colon was resected and protective ileostomy was formed. In the postoperative period, ileostoma functioned a good. The definitive surgical treatment was done on the 20th postoperative day when the occlusion of the ileostomy and transanal biopsy of the rectum was done, which showed the presence of ganglia cells. The patient was discharged from our institution after 1 month. Conclusion: Pediatric patients with neurological conditions and mental retardation present an increased risk of colon transversum volvulus due to chronic obstruction.

The odontogenic keratocyst (OKC) may occur at any age. However, it mostly occurs during the second and third decades of life. Compared to other odontogenic cysts, this type occurs with a frequency of 5-15%. It is more common in the mandible region and in the male sex. Histologically, odontogenic keratocysts are characterized by the presence of an external connective tissue capsule, with keratinizing lining of the epithelium consisting of 5-8 cell layers with marked palisadisation of polarized basal cells and a corrugated parakeratin layer. The objective of this study is to present cases of odontogenic keratocysts, with reference to the latest classification and dilemmas in therapeutic doctrine. This project was realized in the form of descriptive studies, specifically in a series of cases. A collection of four individual cases was found at the Department of Oral Surgery. Due to the proper approach towards diagnosis, adequate and detailed histopathological analysis, and suitable therapeutic procedures, all cases of odontogenic keratocysts were successfully treated without complications. Enucleation of OKC, with a regular follow-up, proved to be the effective therapeutic choice for the patients described in this paper. Only in the case of recurrence would we consider other therapeutic options, primarily enucleation in combination with Carnoy's solution.

In the early stages of cutaneous malignant melanoma (MM), it is extremely difficult to predict adequately the risk from hematogenic and lymphatic metastasis. We investigate whether the immunohistochemical expression of Ki-67 and estrogen receptor beta (ER&bgr;) in cells of MM could predict the status of regional lymph nodes. A total of 55 tissue samples of primary cutaneous melanomas with known status of regional lymph nodes were retrospectively evaluated for Ki-67 and ER&bgr; expression by quantitative immunohistochemistry and then correlated with the status of regional lymph nodes and relevant clinicopathologic parameters. The ER&bgr;-positive expression was detected in 38 of 55 tumors (69.09%). The Clark level showed a strong correlation with ER&bgr; expression, as well as pT stage. All cases of MM showed Ki-67-positive expression and an elevated Ki-67 expression was strongly associated with increased Breslow thickness, Clark level, ulceration, lymphovascular invasion, number of mitosis, and pT stage. Logistic regression analysis showed that when ER&bgr; levels increase by 1%, the risk of positive lymph nodes decreases by 7% (odds ratio=0.930; 95% confidence interval, 0.87-0.99; P=0.036), and, when the Ki-67 expression increases by 1%, the risk of lymph nodes’ positivity increases by 10% (odds ratio=1.108; 95% confidence interval, 1.02-1.19; P=0.009). Correlation between expression of Ki-67 and ER&bgr; and the status of lymph nodes has better prognostic significance than the relationship between melanoma thickness and the status of lymph nodes. Our study showed a significant prognostic value of Ki-67 expression in predicting the behavior of MM and the potential prognostic significance of ER&bgr;.

Background: Malignant melanoma (MM) is one of the tumors with fastest-growing incidence, also deadliest form of skin cancer. In the early stages of the disease it is extremely difficult to adequately predict risk from hematogenic and lymphatic metastasis. We assumed that the determination of Ki-67 and estrogen receptor beta (ER beta) in cells of MM could predict their biological behavior. Objectives: To examine whether the level of expression of Ki-67 and ER beta in cells of MM are in correlation with status of regional lymph nodes (LN), and compare the relationship between melanoma thickness (pT) and status of LN. Methods: Expression of Ki-67 and ER beta was examined by immunohistochemistry, and then staining positivity assessed and correlated with relevant clinical and pathological parameters. Results: Logistic regression analysis showed that when ER beta levels increase by 1% the risk of positive LN decreases by 7% (OR = 0.930, 95%CI 0.87–0.99, p = 0.036), and when the Ki67 expression increases by 1% that the risk of LN positivity increases by 10% (OR = 1.108, 95%CI 1.02 to 1.19, p = 0.009). Conclusions: Correlation between melanoma thickness and the status of LN has less prognostic significance than the relationship between expression of Ki-67 and ER beta and the status of LN. Our study showed a significant prognostic value of Ki67 expression in predicting the behavior of MM, and potential prognostic significance of ER beta.