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Semir Vranić

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Abstract Malignant peritoneal mesothelioma is an extremely rare and poorly recognized neoplasm in children. A 5-year-old boy presented with a 1-year history of progressive painless abdominal distension. A CT revealed a 19 × 19 × 11 cm3 cystic mass in the right hemiabdomen, without infiltrating the surrounding structures. The tumor was completely removed by surgery. The microscopic and immunohistochemical analyses confirmed peritoneal mesothelioma. Comprehensive genomic profiling revealed no major driving mutations including BAP1, no fusions, but with amplifications of AURKA, AURKC, HLA-1B, ZNF-217, OR5F1 and MEN1 genes. Imaging follow-up 3 months after surgery revealed metastatic disease. The patient died of pneumonia at another hospital shortly after the last follow-up examination at our institution. Pediatric peritoneal mesothelioma is an extremely rare malignancy with limited targeted options and a poor prognosis. Some of the identified molecular genomic biomarkers require further exploration and validation in this cancer.

S. Vranić, Zoran Gatalica

Oncologic treatment has recently undergone substantial therapeutic paradigm shifts, from classical tumor-specific and biomarker-agnostic approaches to more molecular, biomarker-specific, and tumor-agnostic. Tumor-type (histology) agnostic drugs work across cancer types and present a novel shift in precision oncology. Compared with traditional cancer therapies, this novel approach implies molecularly informed treatment strategies and enables targeted treatment regardless of tumor histology (type). Such drugs are usually utilized in small clinical cohorts with diverse tumor types sharing a common genomic event (molecular biomarker). One of the key elements of this approach is the presence of a common biomarker across many tumor types. Biomarker predicts response to the targeted drugs, as well as deciphers potential resistance mechanisms. Read more in the PDF.

OBJECTIVE Finding a reliable preoperative predictor of complicated acute appendicitis (AA) has been a challenging diagnostic problem. The present study aimed to identify potential factors that may predict complicated AA in the pediatric emergency department (ED) based on routine, widely available laboratory tests on admission to the ED, including plasma sodium concentration. METHODS We retrospectively reviewed clinical and laboratory data of pediatric patients with AA who underwent emergency surgery at our department between January 2020 and December 2022. The patients were divided into two groups: histopathologically proven complicated AA (n = 80), and non-complicated AA (n = 155). RESULTS Complicated AA was associated with reduced plasma sodium and chloride concentrations (p < 0.001, both), decreased values of lymphocytes (p = 0.002), elevated C-reactive protein (CRP) ( p < 0.001), elevated values of white blood cells (WBC) and neutrophils (p = 0.012 and 0.001, respectively). In binomial logistic regression, increased levels of CRP and WBC, and decreased levels of sodium were predictors of complicated AA. The area under the ROC curve was 0.825 (95% CI 0.764, 0.886). CONCLUSION We identified mild hyponatremia and elevated CRP and WBC values as potential markers for distinguishing complicated from uncomplicated pediatric AA with implications for surgical approaches for treating complicated AA and conservative approaches for treating uncomplicated AA.

Kreso Tomic, K. Krpina, Lara Batičić, Miroslav Samarzija, S. Vranić

Histologic transformation to small cell lung cancer (tSCLC) is a rare but increasingly recognized mechanism of acquired resistance to tyrosine kinase inhibitors (TKI) in patients with epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). Beyond its acknowledged role in TKI resistance, histologic transformation to SCLC might be an important, yet under-recognized, mechanism of resistance in NSCLC treated with immunotherapy. Our review identified 32 studies that investigated tSCLC development in patients with EGFR-mutated NSCLC treated with TKI therapy and 16 case reports of patients treated with immunotherapy. It revealed the rarity of tSCLC, with a predominance of EGFR exon 19 mutations and limited therapeutic options and outcomes. Across all analyzed studies in EGFR-mutated NSCLC treated with TKI therapy, the median time to tSCLC development was ∼17 months, with a median overall survival of 10 months. Histologic transformation of EGFR-mutated NSCLC to SCLC is a rare, but challenging clinical problem with a poor prognosis. A small number of documented cases of tSCLC after immunotherapy highlight the need for rebiopsies at progression to diagnose this potential resistance mechanism. Further research is needed to better understand the mechanisms underlying this phenomenon and to develop more effective treatment strategies for patients with tSCLC.

Z. Zvizdic, Emin Zaimovic, E. Milisic, A. Jonuzi, Una Glamoclija, S. Vranić

OBJECTIVE This study aimed to identify the frequency, severity, and risk factors associated with Hickman catheter-related complications in children with hemato-oncological malignancies at the largest pediatric tertiary care unit in Bosnia and Herzegovina. MATERIALS AND METHODS A cross-sectional study was conducted on a cohort of pediatric cancer patients who underwent Hickman central venous catheters (CVCs) between January 2019 and December 2022. Mechanical, infectious, and thrombotic Hickman catheter-related complications were evaluated and analyzed. We also investigated possible risk factors associated with these complications. RESULTS Seventy-one Hickman CVCs were inserted in 68 children (44 boys and 24 girls) at a mean age of 6.9 ± 4.6. Forty (58.8%) children had hematological malignancies and 28 (41.2%) solid cancers. The median follow-up after Hickman CVC insertion was 190 days (95% CI [160-212]) for 12 644 catheter days. During follow-up, 10 (14.1%) mechanical, 7 (9.9%) infectious, and 1 (1.4%) thrombotic complications were recorded (0.8, 0.48, and 0.08 for mechanical, infectious, and thrombotic complications per 1000 catheter days, respectively). A slightly higher incidence of complications was recorded in children with hematological malignancies (1.59 per 1000 catheter days) compared with children with solid cancers (1.22 complications per 1000 catheter days). CONCLUSION Using Hickman CVCs for long-term venous access in infusional chemotherapy for pediatric cancer patients is safe but is associated with significant morbidity.

N. Ibisevic, Krešimir Tomić, Alen Humačkić, Zlatko Guzin, Blanka Lukić, S. Vranić

Uterine leiomyosarcoma (uLMS) is a rare but aggressive cancer with a high metastatic potential and an unfavorable prognosis. A 54-year-old woman with a history of uterine fibroids clinically presented with a painless, palpable left breast mass measuring 20 mm. A core biopsy of the breast mass demonstrated a cellular spindle cell neoplasm (a potentially malignant smooth muscle neoplasm; B4). A wide local breast-mass excision was performed, revealing grade-2 leiomyosarcoma. A re-review of the uterine fibroids revealed that the largest one (200 × 130 mm), initially diagnosed as symplastic leiomyoma, was morphologically identical to the breast lesion. Additional diagnostic work-up revealed multiple liver and pulmonary metastases with a suspected metastatic sclerotic lesion in the L3 projection. The patient was subsequently treated with chemotherapy protocol for metastatic uLMS. The latest follow-up in September 2023 confirmed stable disease. This case highlights the importance of considering unusual metastatic patterns when evaluating breast masses, particularly in patients with a history of non-specific uterine conditions. Comprehensive diagnostic work-up, including imaging and histopathologic examinations, is crucial for an accurate diagnosis of uLMS and appropriate treatment selection. Further studies are needed to better understand the underlying mechanisms and optimal management strategies for metastatic uLMS.

Tanya Kane, Jason Ford, Rafif Mahmood Al Saady, S. Vranić, O. Musa, Shireen Suliman

Purpose There have been several studies into medical student career decision making in occidental countries (eg US, UK), but medical career selection in a Middle Eastern context has not been as well studied. This study aims to explore determinants underpinning medical students’ residency choice in Qatar. Patients and methods During the Fall semester of the 2022–2023 academic year, all (n=358) medical students from the College of Medicine at Qatar University were invited to participate in an online explorative questionnaire about students’ career choices and the factors determining their selection. Results Of the 358 students, 184 responded (51%). Respondents had a mean age of 20 years; the majority were female (73.9%), Qatari (54.3%), unmarried (97.3%), and enrolled in a pre-clerkship year (55.0%). The most important career determinant was specialty-specific factors. The relative importance of other determinants differed by gender and stage of training. Among our respondents, male students were more likely to rate role models and influencers as being important to their choice, while female students and Qatari students overall were more likely to cite societal obligation. Medical students in Qatar seemed to have career preferences in mind upon entry into medical education. Later-year students were more likely to identify the importance of work-life balance and place of practice, but were less likely to rank prestige and income as an important determinant. Conclusion The results of this baseline study suggest that socioeconomic and cultural context influence medical student career decisions.

Abstract Lipofibromatosis (LF) is a rare benign fibrofatty tumor of infancy and childhood with a predilection for distal extremities, poor margination, and a high local recurrence rate. We report a toddler who presented with an LF involving her right labiocrural fold. Imaging showed a soft tissue mass extending through the right labiocrural fold with possible infiltration into the underlying muscles. The mass was excised entirely, preserving adjacent structures. The histopathologic report revealed the mass to be LF. A 3-year follow-up revealed no disease recurrence. No other cases of LF in this localization have been presented in the literature. Despite its rarity, LF should be considered in diagnosing soft tissue neoplasms in children. Accurate diagnosis and proper surgical management with complete resection are essential to reduce the postoperative recurrence risk.

Hadeel Kheraldine, Arij Fouzat Hassan, Hashim Alhussain, Hamda A. Al-Thawadi, S. Vranić, A. Al Moustafa

Angiogenesis is the process of forming new blood capillaries from pre-existing vessels. Even though it is essential during normal development, it plays a major role in cancer progression. Neratinib is a pan-human epidermal growth factor receptor (HER) inhibitor that has recently been approved for the treatment of HER2-positive breast cancer. However, its effects on angiogenesis and embryogenesis remain unknown. This study examined the antiangiogenic effects of neratinib using the chorioallantoic membrane (CAM) of chicken embryos. We also evaluated neratinib’s toxicity during the early stages of normal development using the chicken embryos, primary embryonic fibroblasts (EFBs), and human umbilical vein endothelial cells (HUVEC). Our findings revealed that neratinib significantly inhibited the CAM angiogenesis compared to controls by reducing vessel percentage area and the average vessel length. Furthermore, neratinib downregulated vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. At lower concentrations, neratinib was well-tolerated during early stages of normal development. Additionally, EFBs treated with neratinib showed no morphological or viability changes when compared to controls. However, at the highest concentration tested, neratinib treatment reduced HUVEC cell viability. This effect may be associated with the dysregulation of key apoptotic genes, including caspase-3, caspase-8, caspase-9, and the B-cell lymphoma 2 (Bcl2) gene. Our findings indicate a novel potential application of neratinib as an antiangiogenic agent, exhibiting tolerable toxicity in the early stages of embryogenesis.

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