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Recurrent Multifocal Langerhans Cell Histiocytosis With Orbital Manifestation 2 2 Background: Langerhans Cell Histiocytosis (LCH) is a rare disease and is more common in children than adults. The incidence is estimated to be approximately 5–10 cases per million children annually. LCH has a wide range of clinical manifestations with rare orbital involvement. Case Presentation: Here, we report a six year-old-girl with recurrent multifocal LCH a year after chemotherapy accompanied by orbital manifestation, present as proptosis of left eye, lagophthalmos, and left superior palpebral abscess with fistula. She had a history of occipital brain LCH with bone involvement, which was surgically removed four years before admission. Ocular examination showed limitations on ocular motility, proptosis, inferonasal displacement of the globe, lagophthalmos, eyelid edema, and hyperemia. In contrast, Head Magnetic Resonance Imaging (MRI) revealed a mass in the left superior orbit and the right occipital condyle. Histopathological examination reveals pathological Langerhans cells with eosinophils and giant cells. The patient was treated with symptomatic drugs while chemotherapy and eyelid reconstruction were planned. Conclusion: LCH is a disorder with highly diverse clinical manifestations. Orbital involvement is one of the uncommon presentations of LCH and necessitates a comprehensive clinical assessment. Early and accurate diagnosis is crucial. Although LCH can lead to serious complications if not promptly treated, recurrence of the disease is relatively rare. Nevertheless, long-term follow-up is recommended to ensure early detection of any potential recurrence and to maintain optimal patient outcomes.   1 12 2025/01/22 1403/11/3 2025/03/8 1403/12/18 Venansya Maulina Praba Venansya Maulina Praba Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Hospital, Surabaya, Indonesia. Maimanah Zumaro Ummi Faiqoh Maimanah Zumaro Ummi Faiqoh Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Hospital, Surabaya, Indonesia. maimanahzumaroo18@gmail.com Ronik Harsono Kamal Ronik Harsono Kamal Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Hospital, Surabaya, Indonesia. Susy Fatmariyanti Susy Fatmariyanti Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Hospital, Surabaya, Indonesia. 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Emerging Evidence of BRAFV600E in LCH: The Iranian Experience 2 2 Introduction: Langerhans cell histiocytosis (LCH) is an inflammatory neoplasm of myeloid origin. The pathologic CD1a+/CD207+ cells are characterized when mutations in the mitogen-activated protein kinase (MAPK) pathway (particularly in BRAFV600E) are activated and involvement of pulmonary, skeletal, pituitary, and cutaneous is seen. we aimed to evaluate a cohort of pediatric LCH patients regarding BRAFV600E mutations. Methods: Three referral centers between 2009-2020 collected definite LCH patients. The patients classified by the detection of BRAFV600E mutations by real-time polymerase chain reaction (RT-PCR) assay, and comparison was done in demographic and clinical manifestations, response to therapy, and outcome. Results: Among 50 LCH patients, 17 (34%) female and 33 (66%) male, somatic mutations in the BRAFV600E gene were detected in 30 (60%) patients and wild-type genotype was seen in 20 (40%) patients. There was remarkable higher frequency of mutation in young children (less than 8 years old particularly < 2 years, p= 0.024). In this study, 21 patients (42%) had multi-system involvement, with no significant difference between the BRAFV600E positive group (14 out of 21, 66.7%) and the BRAFV600E negative group (7 out of 21, 33.3%, p = 0.380). Among patients with risk organ involvement, the BRAFV600E mutation was present in most cases (7 out of 8), and all four patients with central nervous system involvement had this mutation. Patients with the BRAFV600E mutation showed a lower response to treatment, while those without the mutation responded significantly better to first-line therapies. Notably, 6 out of 7 patients who died had the BRAFV600E mutation. Conclusions: In LCH patients, BRAFV600E mutation may influence the onset age, sort and intensity of clinical symptoms, level of the response to therapy, and prognosis. 13 19 2025/01/222025/01/11 1403/10/22 2025/03/82025/03/26 1404/1/6 Bibi Shahin Shamsian Bibi Shahin Shamsian Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Nader Momtazmanesh Nader Momtazmanesh Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Parastoo Molaei Tavana Parastoo Molaei Tavana Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Maryam Kazemi Aghdam Maryam Kazemi Aghdam Pediatric Pathology Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran. Iran.. m_kazemi_aghdam@yahoo.com Fatemeh Malek Fatemeh Malek Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. fmalek7721@gmail.com Armin Shirvani Armin Shirvani Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran. Iran. arminsh2001@yahoo.com Hossein Najmabadi Hossein Najmabadi Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran. hnajm12@yahoo.com Parvin Rostami Parvin Rostami Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran. ah.sa42@gmail.com Mozhgan Hashemieh Mozhgan Hashemieh Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. mozhganhashemieh@gmail.com Mahnaz Jamee Mahnaz Jamee Pediatric Nephrology Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. mahnaz.jamee@gmail.com Langerhans cell histiocytosis BRAFV600E Mortality Treatment Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood, The Journal of the American Society of Hematology. 2020 Apr 16;135(16):1319-31.##Baumgartner I, von Hochstetter A, Baumert B, Luetolf U, Follath F. Langerhans'‐cell histiocytosis in adults. 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DNA Methylation-Dependent Regulation of Lipoprotein Lipase Expression During Human Mesenchymal Stem Cell Differentiation into Adipocytes 2 2 Background: Lipoprotein lipase (LPL) is a critical enzyme in lipid metabolism that hydrolyzes triglyceride-rich lipoproteins. While its role in mature adipose tissue is well understood, the epigenetic regulation of LPL during mesenchymal stem cell (MSC) differentiation into adipocytes remains poorly characterized. This study aimed to investigate the temporal expression pattern of LPL and its relationship with DNA methylation during adipogenic differentiation of human bone marrow-derived MSCs. Methods: Human bone marrow MSCs were isolated and characterized using flow cytometry for specific surface markers (CD34, CD31, CD90, and CD105). Cells were differentiated into adipocytes over 14 days and osteoblasts over 21 days using specific differentiation media. Differentiation was confirmed through Oil Red O and Alizarin Red staining respectively. LPL gene expression was analyzed using both qualitative RT-PCR and quantitative real-time PCR at day 0 (undifferentiated) and day 14 (differentiated) timepoints. DNA methylation patterns were assessed using methylation-specific PCR (MSP) following bisulfite conversion, with collagen gene serving as an internal control. Results: Flow cytometry confirmed MSC identity through positive expression of CD166, CD13, CD105, and CD44. Successful adipogenic differentiation was demonstrated by Oil Red O-positive lipid droplet accumulation, while osteogenic differentiation was confirmed by Alizarin Red S staining of calcium deposits. LPL gene expression was absent in undifferentiated MSCs but showed significant expression in differentiated adipocytes at day 14, coinciding with morphological changes and lipid accumulation. Conclusion: This study demonstrates that LPL expression is epigenetically regulated during MSC differentiation into adipocytes, with significant changes in both gene expression and DNA methylation patterns. The temporal correlation between LPL expression, methylation status, and adipogenic differentiation suggests that LPL serves as a key molecular switch in this process. 20 28 2025/01/222025/01/112025/01/19 1403/10/30 2025/03/82025/03/262025/03/17 1403/12/27 Seied Rasoul Razavi Babaheidari Seied Rasoul Razavi Babaheidari Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. Aryan Salahi-Niri Aryan Salahi-Niri Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Mohammad Hossein Mohammadi Mohammad Hossein Mohammadi Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mohsen Hamidpour Mohsen Hamidpour Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Shadi Esmaeili Shadi Esmaeili Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Lipoprotein lipase DNA methylation Mesenchymal stem cells Adipogenic differentiation Epigenetic regulation Gene expression Geldenhuys WJ, Lin L, Darvesh AS, Sadana P. Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases. Drug Discov Today. 2017;22(2):352-65.##Wang H, Eckel RH. Lipoprotein lipase: from gene to obesity. American Journal of Physiology-Endocrinology and Metabolism. 2009;297(2):E271-E88.##Kockx M, Kritharides L. Triglyceride-Rich Lipoproteins. Cardiology Clinics. 2018;36(2):265-75.##Liu SS, Fang X, Wen X, Liu JS, Alip M, Sun T, et al. How mesenchymal stem cells transform into adipocytes: Overview of the current understanding of adipogenic differentiation. World J Stem Cells. 2024;16(3):245-56.##Pamplona JH, Zoehler B, Shigunov P, Barisón MJ, Severo VR, Erich NM, et al. Alternative Methods as Tools for Obesity Research: In Vitro and In Silico Approaches. Life (Basel). 2022;13(1).##Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. npj Regenerative Medicine. 2019;4(1):22.##Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells: Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Research & Therapy. 2007;9(1):204.##Ahmad B, Serpell CJ, Fong IL, Wong EH. Molecular Mechanisms of Adipogenesis: The Anti-adipogenic Role of AMP-Activated Protein Kinase. Frontiers in Molecular Biosciences. 2020;7.##Feng P, Pang P, Sun Z, Xie Z, Chen T, Wang S, et al. Enhancer-mediated FOXO3 expression promotes MSC adipogenic differentiation by activating autophagy. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2024;1870(2):166975.##Gonzales AM, Orlando RA. Role of adipocyte-derived lipoprotein lipase in adipocyte hypertrophy. Nutr Metab (Lond). 2007;4:22.##Enerbäck S, Ohlsson BG, Samuelsson L, Bjursell G. Characterization of the human lipoprotein lipase (LPL) promoter: evidence of two cis-regulatory regions, LP-alpha and LP-beta, of importance for the differentiation-linked induction of the LPL gene during adipogenesis. Mol Cell Biol. 1992;12(10):4622-33.##Kuryłowicz A. Estrogens in Adipose Tissue Physiology and Obesity-Related Dysfunction. Biomedicines [Internet]. 2023; 11(3).##Lorzadeh A, Romero-Wolf M, Goel A, Jadhav U. Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation. Gastroenterology. 2021;160(7):2267-82.##Fagnocchi L, Mazzoleni S, Zippo A. Integration of Signaling Pathways with the Epigenetic Machinery in the Maintenance of Stem Cells. Stem Cells Int. 2016;2016:8652748.##Li X, Jiang O, Wang S. Molecular mechanisms of cellular metabolic homeostasis in stem cells. International Journal of Oral Science. 2023;15(1):52.##Pereira B, Correia FP, Alves IA, Costa M, Gameiro M, Martins AP, et al. Epigenetic reprogramming as a key to reverse ageing and increase longevity. Ageing Research Reviews. 2024;95:102204.##Castellano-Castillo D, Moreno-Indias I, Fernández-García JC, Alcaide-Torres J, Moreno-Santos I, Ocaña L, et al. Adipose Tissue LPL Methylation is Associated with Triglyceride Concentrations in the Metabolic Syndrome. Clin Chem. 2018;64(1):210-8.##Heindel JJ, Blumberg B, Cave M, Machtinger R, Mantovani A, Mendez MA, et al. Metabolism disrupting chemicals and metabolic disorders. Reproductive Toxicology. 2017;68:3-33.##Choi MR, In Y-H, Park J, Park T, Jung KH, Chai JC, et al. Genome-scale DNA methylation pattern profiling of human bone marrow mesenchymal stem cells in long-term culture. Experimental & Molecular Medicine. 2012;44(8):503-12.##Chinn CA, Ren H, Morival JLP, Nie Q, Wood MA, Downing TL. Examining age-dependent DNA methylation patterns and gene expression in the male and female mouse hippocampus. Neurobiol Aging. 2021;108:223-35.##Guay SP, Brisson D, Lamarche B, Marceau P, Vohl MC, Gaudet D, et al. DNA methylation variations at CETP and LPL gene promoter loci: new molecular biomarkers associated with blood lipid profile variability. Atherosclerosis. 2013;228(2):413-20.##Shi Y, Zhang H, Huang S, Yin L, Wang F, Luo P, et al. Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy. 2022;7(1):200.## ##

Evaluation of Complications and Treatment Outcomes Following Intraluminal Brachytherapy after Definitive Chemoradiation in Patients with Esophageal Cancer 2 2 Background: Limited data exist on complications and treatment outcomes following brachytherapy after chemoradiation in esophageal cancer. This study aimed to assess complications and treatment outcomes after intraluminal brachytherapy post-definitive chemoradiation. Methods and Materials: This retrospective cohort study included esophageal cancer patients treated at Imam Reza Radiotherapy Center, Mashhad, Iran (2016-2023). Patients received chemoradiotherapy with paclitaxel-carboplatin, cisplatin-irinotecan, or cisplatin-5-FU (5-6 weeks), with a total radiation dose of ≥45 Gray. After a two-week rest, they underwent HDR brachytherapy with cobalt-60 and were followed monthly for one year. Results: A total of 125 patients (mean age: 71.08±10.67 years) were evaluated. The overall survival (OS) and disease-free interval (DFI) were 47.26 and 22.62 months, respectively. The most common tumor location was the middle esophagus, and the most common grade was G2. An ECOG score <2 was observed in 96 patients. No significant association was found between OS and DFI with tumor location, grade, dysphagia level, or functional index. However, brachytherapy dose, radiotherapy dose, and chemotherapy regimen were significantly associated with OS, but not with DFI. Post-treatment complications occurred in 98 patients, including local recurrence in 39 cases. Patients without complications had a mean DFI and OS of 54 and 55 months, respectively, while those with complications had 37 and 50 months. Complications were significantly associated with DFI but not with OS. Complete response was seen in 106 patients, significantly correlating with OS (P=0.003) and DFI (P<0.001). Patients with local and distant recurrence had an 11-fold higher mortality risk. Conclusion: Intraluminal brachytherapy after definitive chemoradiation plays a crucial role in treatment management for esophageal cancer. It should be considered as a treatment option, but further studies with larger sample sizes are needed for routine implementation. 29 39 2025/01/222025/01/112025/01/192025/02/2 1403/11/14 2025/03/82025/03/262025/03/172025/03/5 1403/12/15 Azadeh Taghizadeh Azadeh Taghizadeh Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Roham Salek Roham Salek Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Brachytherapy Esophageal Cancer Definitive Chemoradiation Overall survival Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. The Lancet. 2013;381(9864):400-12.##Safaei AM, Ghalehtaki R, Khanjani N, Farazmand B, Babaei M, Esmati E. High-dose-rate intraluminal brachytherapy prior to external radiochemotherapy in locally advanced esophageal cancer: preliminary results. Journal of Contemporary Brachytherapy. 2017;9(1):30-5.##Jayaprakash S, Hegde M, Girisa S, Alqahtani MS, Abbas M, Lee EH, Yap KC, Sethi G, Kumar AP, Kunnumakkara AB. Demystifying the functional role of nuclear receptors in esophageal cancer. International Journal of Molecular Sciences. 2022 Sep 19;23(18):10952.##https://www.cancerresearchuk.org/about-cancer/oesophageal-cancer/survival##Bhatt L, Tirmazy S, Sothi S. Intraluminal High Dose Rate Brachytherapy for Palliation of Dysphagia in Cancer of the Oesophagus. Clinical Oncology. 2011;23(3):S30.##Sjödahl K, Lu Y, Nilsen TI, Ye W, Hveem K, Vatten L, et al. Smoking and alcohol drinking in relation to risk of gastric cancer: a population‐based, prospective cohort study. International journal of cancer. 2007;120(1):128-32.##Lagergren J, Bergström R, Nyrén O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Annals of internal medicine. 1999;130(11):883-90.##Ding G-C, Ren J-L, Chang F-B, Li J-L, Yuan L, Song X, et al. Human papillomavirus DNA and P16INK4A expression in concurrent esophageal and gastric cardia cancers. World journal of gastroenterology: WJG. 2010;16(46):5901.##Kamath A, Wu T-T, Heitmiller R, Daniel R, Shah K. Investigation of the association of esophageal carcinoma with human papillomaviruses. Diseases of the Esophagus. 2000;13(2):122-4.##Ponvilawan B, Rittiphairoj T, Charoenngam N, Rujirachun P, Wattanachayakul P, Tornsatitkul S, et al. Association between Chronic Hepatitis C Virus Infection and Esophageal Cancer: A Systematic Review and Meta-Analysis. Journal of Clinical Gastroenterology. 2022;56(1):55-63.##Chen T, Cheng H, Chen X, Yuan Z, Yang X, Zhuang M, et al. Family history of esophageal cancer increases the risk of esophageal squamous cell carcinoma. Scientific reports. 2015;5(1):1-9.##Sharma P, Jain S, Karunanithi S, Pal S, Julka PK, Thulkar S, et al. Diagnostic accuracy of 18 F-FDG PET/CT for detection of suspected recurrence in patients with oesophageal carcinoma. European journal of nuclear medicine and molecular imaging. 2014;41:1084-92.##Surasi DS, Bhambhvani P, Baldwin JA, Almodovar SE, O'Malley JP. 18F-FDG PET and PET/CT patient preparation: a review of the literature. Journal of nuclear medicine technology. 2014;42(1):5-13.##Kleinberg L, Brock M, Gibson M. Management of locally advanced adenocarcinoma of the esophagus and gastroesophageal junction: finally a consensus. Current treatment options in oncology. 2015;16:1-16.##Yorozu A, Dokiya T. Brachytherapy for esophageal cancer: optimum dose and indications in the modern era. Brachytherapy: Techniques and Evidences. 2019:283-300.##Scarpa M, Valente S, Alfieri R, Cagol M, Diamantis G, Ancona E, et al. Systematic review of health-related quality of life after esophagectomy for esophageal cancer. World journal of gastroenterology: WJG. 2011;17(42):4660.##Folkert MR, Gil'ad NC, Wu AJ, Gerdes H, Schattner MA, Markowitz AJ, et al. Endoluminal high-dose-rate brachytherapy for early stage and recurrent esophageal cancer in medically inoperable patients. Brachytherapy. 2013;12(5):463-70.##Okamoto H, Taniyama Y, Sato C, Fukutomi T, Ozawa Y, Ando R, et al. Definitive Chemoradiotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil for Advanced Cervical Esophageal Cancer: A Medium-Term Outcome. Asian Pacific Journal of Cancer Prevention. 2022;23(2):495-9.##Nishimura Y, Okuno Y, Ono K, Mitsumori M, Nagata Y, Hiraoka M. External beam radiation therapy with or without high‐dose‐rate intraluminal brachytherapy for patients with superficial esophageal carcinoma. Cancer: Interdisciplinary International Journal of the American Cancer Society. 1999 Jul 15;86(2):220-8.##https://doi.org/10.1002/(SICI)1097-0142(19990715)86:23.0.CO;2-O##Gaspar LE, Nag S, Herskovic A, Mantravadi R, Speiser B. American Brachytherapy Society (ABS) consensus guidelines for brachytherapy of esophageal cancer. Clinical Research Committee, American Brachytherapy Society, Philadelphia, PA. International journal of radiation oncology, biology, physics. 1997;38(1):127-32.##Sharan K, Fernandes DJ, Prakash Saxena PU, Banerjee S, Sathian B. Treatment outcomes after intraluminal brachytherapy following definitive chemoradiotherapy in patients with esophageal cancer. J Cancer Res Ther. 2014;10(2):337-41.##Mangesius J, Hörmandinger K, Jäger R, Skvortsov S, Plankensteiner M, Maffei M, Seppi T, Dejaco D, Santer M, Sarcletti M, Ganswindt U. Chemoradiotherapy Combined with Brachytherapy for the Definitive Treatment of Esophageal Carcinoma. Cancers. 2023 Jul 12;15(14):3594.##Tai P, Yu E. Esophageal cancer management controversies: Radiation oncology point of view. World journal of gastrointestinal oncology. 2014;6(8):263.##Murakami Y, Nagata Y, Nishibuchi I, Kimura T, Kenjo M, Kaneyasu Y, Okabe T, Hashimoto Y, Akagi Y. Long-term outcomes of intraluminal brachytherapy in combination with external beam radiotherapy for superficial esophageal cancer. International journal of clinical oncology. 2012 Jun;17:263-71.##Ye M, Han D, Mao Z, Cheng G. A prospective study of radical external beam radiotherapy versus external beam radiotherapy combined with intraluminal brachytherapy for primary esophageal cancer. Brachytherapy. 2022 Sep 1;21(5):703-11.##Gaspar LE, Winter K, Kocha WI, Pinover WH, Graham M, Gunderson L. Swallowing function and weight change observed in a phase I/II study of external-beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 9207). Cancer Journal (Sudbury, Mass). 2001;7(5):388-94.##Fuccio L, Mandolesi D, Farioli A, Hassan C, Frazzoni L, Guido A, et al. 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EGFR Mutations, ROS1, and ALK Rearrangements in Iranian Non-Small Cell Lung Cancer Patients 2 2 Background: Driver mutations, particularly in the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1 genes, are prevalent in non-small cell lung cancer (NSCLC) and significantly influence patient outcomes. These mutations have become crucial biomarkers for targeted therapy, guiding treatment decisions and improving patient survival. Our study aims to evaluate the prevalence of EGFR mutations, ALK, and ROS1 gene rearrangements in a cohort of Iranian NSCLC patients and to investigate their association with patient characteristics. Materials and Methods: Tissue samples from patients diagnosed with non-small cell lung cancer (NSCLC) were subjected to molecular analysis. EGFR mutations, ALK, and ROS1 gene rearrangements were assessed. Additionally, the correlation between these genetic alterations and patient demographics, including age and gender, was explored. Results: Driver mutations or rearrangements were detected in approximately one-third of NSCLC cases. EGFR mutations were the most common, occurring in 22.44% of patients. ALK and ROS1 rearrangements were identified in 8.18% and 2.11% of patients, respectively. The EGFR mutation frequency in patients younger than 36 years was 16%. In contrast, the mutation frequency in older patient cohorts ranged from 11% to 15%. Among EGFR mutations, exon 19 deletions (13.35%) and L858R point mutations (6.81%) were the most prevalent. Notably, exon 19 deletions were more frequent in female patients (27.92%) compared to male patients (9.90%). Conclusion: EGFR mutations were more prevalent than ALK and ROS1 rearrangements in our cohort. Exon 19 deletions and L858R point mutations were the most common EGFR mutations, with a higher frequency observed in female patients. These mutations are frequently associated with lung adenocarcinoma. 40 46 2025/01/222025/01/112025/01/192025/02/22025/01/3 1403/10/14 2025/03/82025/03/262025/03/172025/03/52025/03/6 1403/12/16 Babak Salimi Babak Salimi Research Center of Thoracic Oncology (RCTO), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Maryam Mabani Maryam Mabani Research Center of Thoracic Oncology (RCTO), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Sharareh Seifi Sharareh Seifi Research Center of Thoracic Oncology (RCTO), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Parsa Rostami Parsa Rostami Research Center of Thoracic Oncology (RCTO), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Ali Dehghanifard Ali Dehghanifard Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Negin Khosravi Negin Khosravi Department of Genetic, Ahar Branch, Islamic Azad University, Ahar, Iran. Marziye Madadkar Borna Marziye Madadkar Borna Department of Biology, East Tehran Islamic azad university,Tehran, Iran. Elaheh Sadat Jamali Elaheh Sadat Jamali Immunology Department, Pasteur Institue of Iran, Tehran, Iran. Sarah Shiari Sarah Shiari Research Center of Thoracic Oncology (RCTO), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Hanieh Sattari Hanieh Sattari Research Center of Thoracic Oncology (RCTO), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Adnan Khosravi Adnan Khosravi Research Center of Thoracic Oncology (RCTO), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. adkhosravi@yahoo.com ALK ROS1 EGFR Non-small cell lung carcinoma Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA: a cancer journal for clinicians, 2018. 68(1): p. 7-30.##Rothschild, S.I., Targeted therapies in non-small cell lung cancer-beyond EGFR and ALK. Cancers, 2015. 7(2): p. 930-949.##Lynch, T.J., et al., Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 2004. 350(21): p. 2129-2139.##Paez, J.G., et al., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science, 2004. 304(5676): p. 1497-1500.##Doval, D., et al., Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. OncoTargets and therapy, 2015: p. 117-123.##Lin, J.J. and A.T. Shaw, Recent advances in targeting ROS1 in lung cancer. Journal of thoracic oncology, 2017. 12(11): p. 1611-1625.##Shi, Y., et al., A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). Journal of thoracic oncology, 2014. 9(2): p. 154-162.##Yu, X., et al., The effect of EGFR‐TKIs on survival in advanced non‐small‐cell lung cancer with EGFR mutations: A real‐world study. Cancer Medicine, 2023. 12(5): p. 5630-5638.##Howlader, N., et al., The effect of advances in lung-cancer treatment on population mortality. New England Journal of Medicine, 2020. 383(7): p. 640-649.##Zhou, C., et al., BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. Journal of clinical oncology, 2015. 33(19): p. 2197-2204.##Marinelli, D., et al., Non-small-cell lung cancer: how to manage ALK-, ROS1-and NTRK-rearranged disease. Drugs in Context, 2022. 11.##Araki, T., et al., Current treatment strategies for EGFR-mutated non-small cell lung cancer: from first line to beyond osimertinib resistance. Japanese Journal of Clinical Oncology, 2023. 53(7): p. 547-561.##Hsieh, R.-K., et al., Female sex and bronchioloalveolar pathologic subtype predict EGFR mutations in non-small cell lung cancer. 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Nature, 2007. 448(7153): p. 561-566.##Johnson, B.E., et al., A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC). 2013, American Society of Clinical Oncology.##Kwak, E.L., et al., Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine, 2010. 363(18): p. 1693-1703.##Desai, S., et al., A year of anaplastic large cell kinase testing for lung carcinoma: Pathological and technical perspectives. Indian journal of cancer, 2013. 50(2): p. 80-86.##Bergethon, K., et al., ROS1 rearrangements define a unique molecular class of lung cancers. Journal of clinical oncology, 2012. 30(8): p. 863-870.## ##

Exploring the Intersection of Artificial Intelligence and Oral Cancer: Diagnostic Advances, Genetic Insights, and Precision Medicine 2 2 Background: Oral cancer poses a serious global health challenge due to its high morbidity and mortality rates, largely stemming from late-stage diagnosis and limited treatment success. Recent technological advances, particularly in artificial intelligence (AI), have opened new avenues for early detection and personalized treatment approaches. Objectives: This review aims to explore the role of AI, including machine learning (ML) and deep learning (DL), in the diagnosis, prognosis, and management of oral cancer. It also examines the systemic effects of oral cancer, underlying genetic and hormonal influences, and the impact of oxidative stress and chronic inflammation on disease progression. Methodology: A systematic literature review was conducted covering publications from 1997 to 2024, using PubMed, Scopus, and the Cochrane Library. Studies involving AI, ML, and DL in oral cancer detection and treatment were selected based on predefined inclusion and exclusion criteria. Bibliometric and trend analyses were also performed to assess global research output and collaborative networks. Results: AI techniques such as convolutional neural networks and support vector machines have demonstrated significant utility in early detection, histopathological analysis, and survival prediction. The review also highlights key genetic mutations (e.g., TP53, CDKN2A) and hormonal imbalances (e.g., estrogen, androgen receptors) linked to oral cancer pathogenesis. Furthermore, systemic involvement of organs like the liver, brain, and bone is discussed. Bibliometric data indicate increasing global collaboration and the emergence of AI as a dominant research focus in oral oncology. Conclusion: AI-based diagnostic tools and predictive models offer promising pathways for early detection and personalized treatment in oral cancer. Understanding the molecular, systemic, and epidemiological dimensions of the disease, alongside leveraging computational advancements, can significantly enhance patient outcomes and support the development of precision medicine in oral oncology. 47 63 2025/01/222025/01/112025/01/192025/02/22025/01/32025/02/2 1403/11/14 2025/03/82025/03/262025/03/172025/03/52025/03/62025/03/3 1403/12/13 Rakhi Issrani Rakhi Issrani Department of Preventive Dentistry, College of Dentistry, Jouf University, Sakaka, Kingdom of Saudi Arabia. dr.rakhi.issrani@jodent.org Hafiz Muhammad Zeeshan Hafiz Muhammad Zeeshan Department of Computer Science, Superior University, Lahore, Pakistan. f193037@leads.edu.pk Nosheen Qamar Nosheen Qamar Department of Software Engineering, School of Systems and Technology, University of Management and Technology, Lahore, Pakistan nosheen.qamar@umt.edu.pk Abid Iqbal Abid Iqbal Central Library, Prince Sultan University, Rafha Street, Riyadh, Kingdom of Saudi Arabia iabid@psu.edu.sa Oral Cancer Artificial Intelligence Machine Learning Deep Learning Convolutional Neural Networks Personalized Medicine Chi, A.C., T.A. Day, and B.W. Neville, Oral cavity and oropharyngeal squamous cell carcinoma--an update. CA Cancer J Clin, 2015. 65(5): p. 401-21.##Marur, S. and A.A. Forastiere, Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc, 2008. 83(4): p. 489-501.##Liao, D.Z., et al., Association of Delayed Time to Treatment Initiation With Overall Survival and Recurrence Among Patients With Head and Neck Squamous Cell Carcinoma in an Underserved Urban Population. JAMA Otolaryngol Head Neck Surg, 2019. 145(11): p. 1001-1009.##van der Waal, I., et al., Early diagnosis in primary oral cancer: is it possible? Med Oral Patol Oral Cir Bucal, 2011. 16(3): p. e300-5.##Bagan, J., G. Sarrion, and Y. Jimenez, Oral cancer: clinical features. Oral Oncol, 2010. 46(6): p. 414-7.##Toporcov, T.N., et al., Risk factors for head and neck cancer in young adults: a pooled analysis in the INHANCE consortium. Int J Epidemiol, 2015. 44(1): p. 169-85.##Patel, S.C., et al., Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol, 2011. 29(11): p. 1488-94.##Neville, B.W. and T.A. Day, Oral cancer and precancerous lesions. CA Cancer J Clin, 2002. 52(4): p. 195-215.##Müller, S., et al., Changing trends in oral squamous cell carcinoma with particular reference to young patients: 1971-2006. The Emory University experience. Head Neck Pathol, 2008. 2(2): p. 60-6.##Scully, C. and J. Bagan, Oral squamous cell carcinoma: overview of current understanding of aetiopathogenesis and clinical implications. Oral Diseases, 2009. 15(6): p. 388-399.##Walvekar, R.R., et al., Verrucous carcinoma of the oral cavity: A clinical and pathological study of 101 cases. Oral Oncol, 2009. 45(1): p. 47-51.##Khan, A.J., et al., Adenoid cystic carcinoma: a retrospective clinical review. 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The Role of Food containing Nitrosamine in the Development of Nasopharyngeal Carcinoma: A Literature Review 2 2 Nasopharyngeal carcinoma (NPC) is a rare malignancy originating from epithelial cells in the nasopharynx, with an incidence rate of fewer than 1–2 cases per 100,000 people annually but exceeding 20 cases in endemic regions. Its development is influenced by multiple factors, including nitrosamines found in preserved foods, beer, cigarettes, and drinking water. This review explores the role of nitrosamines in food and the mechanism that caused NPC development by analyzing relevant literature from major databases such as Google Scholar, Web of Science, and PubMed. In addition, nitrosamines, such as N-nitrosodimethylamine (NDMA), form through nitrosation, a process involving nitrites and nitrogen oxides interacting with amino compounds. Although the World Health Organization (WHO) sets a daily nitrosamine intake limit of 10 μg/kg body weight, excessive or prolonged exposure may contribute to cancer development. Once metabolized by cytochrome P450, nitrosamines can cause DNA damage, potentially leading to carcinogenesis. However, NPC results from a complex interplay of factors, and nitrosamines alone do not directly cause cancer. Their carcinogenic potential increases when combined with other risk factors. Additionally, chemopreventive agents such as curcumin and vitamin C may help reduce cancer risk. 64 70 2025/01/222025/01/112025/01/192025/02/22025/01/32025/02/22025/01/28 1403/11/9 2025/03/82025/03/262025/03/172025/03/52025/03/62025/03/32025/03/26 1404/1/6 Achmad Chusnu Romdhoni Achmad Chusnu Romdhoni Department of Otorhinolaryngology-Head & Neck Surgery, Faculty of Medicine, Universitas Airlangga/Dr. Soetomo General Academic Hospital Surabaya, Surabaya, East Java, Indonesia romdhoni-a-c@fk.unair.ac.id Ali Mustofa Ali Mustofa Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, Indonesia alimustofa210203@gmail.com Pandit Bagus Tri Saputra Pandit Bagus Tri Saputra Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, Indonesia panditbagusts@gmail.com Mohd. Razif Mohamad Yunus Mohd. Razif Mohamad Yunus Department of Otorhinolaryngology-Head & Neck Surgery, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia razif72@gmail.com Nasopharyngeal carcinoma Nitrosamine Food Cancer DNA damage Song Y, Cheng W, Li H, Liu X. The global, regional, national burden of nasopharyngeal cancer and its attributable risk factors (1990-2019) and predictions to 2035. Cancer Med [Internet]. 2022 Nov 1 [cited 2023 Nov 30];11(22):4310. Available from: /pmc/articles/PMC9678109/##Chua MLK, Wee JTS, Hui EP, Chan ATC. Nasopharyngeal carcinoma. Lancet [Internet]. 2016 Mar 5 [cited 2023 Nov 30];387(10022):1012-24. Available from: https://pubmed.ncbi.nlm.nih.gov/26321262/##Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet [Internet]. 2019 Jul 6 [cited 2023 Nov 30];394(10192):64-80. Available from: https://pubmed.ncbi.nlm.nih.gov/31178151/##Cao SM, Simons MJ, Qian CN. The prevalence and prevention of nasopharyngeal carcinoma in China. Chin J Cancer [Internet]. 2011 [cited 2023 Nov 30];30(2):114. Available from: /pmc/articles/PMC4013340/##Lijinsky W. N-Nitroso compounds in the diet. Mutat Res Genet Toxicol Environ Mutagen [Internet]. 1999 Jul 15 [cited 2023 Nov 23];443(1-2):129-38. Available from: https://pubmed.ncbi.nlm.nih.gov/10415436/##Tsao SW, Yip YL, Tsang CM, Pang PS, Lau VMY, Zhang G, et al. Etiological factors of nasopharyngeal carcinoma. Oral Oncol [Internet]. 2014 [cited 2023 Dec 1];50(5):330-8. Available from: https://pubmed.ncbi.nlm.nih.gov/24630258/##Tricker AR, Preussmann R. Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential. Mutat Res [Internet]. 1991 [cited 2023 Nov 22];259(3-4):277-89. Available from: https://pubmed.ncbi.nlm.nih.gov/2017213/##Gushgari AJ, Halden RU. Critical review of major sources of human exposure to N-nitrosamines. Chemosphere [Internet]. 2018 Nov 1 [cited 2023 Nov 27];210:1124-36. Available from: https://pubmed.ncbi.nlm.nih.gov/30208538/##Tricker A, Kubacki S. Review of the occurrence and formation of non-volatile N-nitroso compounds in foods. Food Addit Contam [Internet]. 1992 [cited 2023 Nov 23];9(1):39-69. Available from: https://pubmed.ncbi.nlm.nih.gov/1397391/##De Mey E, De Klerck K, De Maere H, Dewulf L, Derdelinckx G, Peeters MC, et al. The occurrence of N-nitrosamines, residual nitrite and biogenic amines in commercial dry fermented sausages and evaluation of their occasional relation. Meat Sci. 2014 Feb 1;96(2):821-8.##Breider F, Gachet Aquillon C, von Gunten U. A survey of industrial N-nitrosamine discharges in Switzerland. J Hazard Mater. 2023 May 15;450:131094.##Xie Y, Geng Y, Yao J, Ji J, Chen F, Xiao J, et al. N-nitrosamines in processed meats: Exposure, formation and mitigation strategies. J Agric Food Res. 2023 Sep 1;13:100645.##Basria R, Mydin SMN, Okekpa SI. Molecular Pathways for Nasopharyngeal Carcinoma focused on Acetaldehyde, Nitrosamines and Nicotine Exposures. Malaysian Journal of Medicine and Health Sciences. 2019;15(SP2):2636-9346.##Li Y, Hecht SS. Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed. Int J Mol Sci [Internet]. 2022 May 1 [cited 2025 Apr 3];23(9):4559. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9105260/##Handoko, Adham M, Rachmadi L, Tobing DL, Asmarinah, Fadilah, et al. First Indonesian Nasopharyngeal Cancer Whole Epigenome Sequencing Identify Tumour Suppressor CpG Methylation. Biologics [Internet]. 2025 [cited 2025 Apr 3];19:1. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11721153/##Liao LJ, Hsu WL, Chen CJ, Chiu YL. Feature Reviews of the Molecular Mechanisms of Nasopharyngeal Carcinoma. Biomedicines [Internet]. 2023 Jun 1 [cited 2025 Apr 3];11(6):1528. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10295754/##Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med [Internet]. 2010 Dec 1 [cited 2025 Apr 3];49(11):1603. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC2990475/##Feng H, Zhou Y, Wang L, Wang Y, Zhou S, Tian F. Consumption of processed food and risk of nasopharyngeal carcinoma: a systematic review and meta-analysis. Transl Cancer Res [Internet]. 2022 Apr 1 [cited 2023 Nov 23];11(4):872-9. Available from: /pmc/articles/PMC9091027/##Johnson GE, Dobo K, Gollapudi B, Harvey J, Kenny J, Kenyon M, et al. Permitted daily exposure limits for noteworthy N-nitrosamines. Environ Mol Mutagen [Internet]. 2021 Jun 1 [cited 2023 Nov 28];62(5):293-305. Available from: https://pubmed.ncbi.nlm.nih.gov/34089278/##Elder DP, Johnson GE, Snodin DJ. Tolerability of risk: A commentary on the nitrosamine contamination issue. J Pharm Sci [Internet]. 2021 Jun 1 [cited 2023 Nov 28];110(6):2311-28. Available from: https://pubmed.ncbi.nlm.nih.gov/33705731/##Abdullah ATM, Khan TA, Sharif M, Mazumdar RM, Rahman MM. Determination of dietary exposure and extraction efficiency of nitrosamine from cooked meat. Curr Res Food Sci. 2022 Jan 1;5:491-7.##Schrenk D, Bignami M, Bodin L, Chipman JK, del Mazo J, Hogstrand C, et al. Risk assessment of N-nitrosamines in food. EFSA Journal [Internet]. 2023 Mar 1 [cited 2025 Apr 4];21(3):e07884. Available from: https://onlinelibrary.wiley.com/doi/full/10.2903/j.efsa.2023.7884##Bercu JP, Masuda-Herrera M, Trejo-Martin A, Sura P, Jolly R, Kenyon M, et al. Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs). Regulatory Toxicology and Pharmacology. 2023 Aug 1;142:105415.##Beard JC, Swager TM. An Organic Chemist's Guide to N-Nitrosamines: Their Structure, Reactivity, and Role as Contaminants. Journal of Organic Chemistry [Internet]. 2021 Feb 5 [cited 2023 Nov 22];86(3):2037-57. Available from: https://pubs.acs.org/doi/full/10.1021/acs.joc.0c02774##Barnes JL, Zubair M, John K, Poirier MC, Martin FL. Carcinogens and DNA damage. Biochem Soc Trans [Internet]. 2018 Oct 10 [cited 2023 Dec 11];46(5):1213. Available from: /pmc/articles/PMC6195640/##Huang YG, Ji JD, Hou QN. A study on carcinogenesis of endogenous nitrite and nitrosamine, and prevention of cancer. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis [Internet]. 1996 Oct 28 [cited 2023 Dec 2];358(1):7-14. Available from: https://pubmed.ncbi.nlm.nih.gov/8921972/##Carlström M, Moretti CH, Weitzberg E, Lundberg JO. Microbiota, diet and the generation of reactive nitrogen compounds. Free Radic Biol Med. 2020 Dec 1;161:321-5.##Lian M. Salted fish and processed foods intake and nasopharyngeal carcinoma risk: a dose-response meta-analysis of observational studies. Eur Arch Otorhinolaryngol [Internet]. 2022 May 1 [cited 2023 Nov 22];279(5):2501-9. Available from: https://pubmed.ncbi.nlm.nih.gov/35094122/##Linton RE, Daker M, Khoo ASB, Choo DCY, Viljoen M, Neilsen PM. Nasopharyngeal carcinoma among the Bidayuh of Sarawak, Malaysia: History and risk factors. Oncol Lett [Internet]. 2021 Jul 1 [cited 2023 Nov 22];22(1). Available from: /pmc/articles/PMC8114476/##Konstantinou E, Fotopoulou F, Drosos A, Dimakopoulou N, Zagoriti Z, Niarchos A, et al. Tobacco-specific nitrosamines: A literature review. Food and Chemical Toxicology. 2018 Aug 1;118:198-203.##Waly MI, Al-Bulushi IM, Al-Hinai S, Guizani N, Al-Malki RN, Rahman MS. The Protective Effect of Curcumin against Nitrosamine-Induced Gastric Oxidative Stress in Rats. Prev Nutr Food Sci [Internet]. 2018 [cited 2023 Dec 11];23(4):288. Available from: /pmc/articles/PMC6342541/##Erkekoglu P, Baydar T. Evaluation of the protective effect of ascorbic acid on nitrite- and nitrosamine-induced cytotoxicity and genotoxicity in human hepatoma line. Toxicol Mech Methods [Internet]. 2010 Feb [cited 2023 Dec 11];20(2):45-52. Available from: https://pubmed.ncbi.nlm.nih.gov/20100056/##Chow CK, Hong CB. Dietary vitamin E and selenium and toxicity of nitrite and nitrate. Toxicology [Internet]. 2002 Nov 15 [cited 2023 Dec 11];180(2):195-207. Available from: https://pubmed.ncbi.nlm.nih.gov/12324194/## ##

Investigating the Refractory Platelet Transfusion: Understanding the Underlying Factors, Diagnosis, and Effective Treatment Strategies 2 2 This review article provides a comprehensive overview of platelet transfusion-refractory (PTR), a condition in which patients do not respond well to platelet transfusions, leading to increased bleeding and complications. It discusses various aspects of PTR such as its causes, prevention, diagnosis, management, and potential complications. While immune-mediated reactions are the primary cause, non-immunologic, patient-related, and donor-related factors can also contribute. Preventing PTR involves methods such as HLA matching, platelet count monitoring, and prophylactic transfusions; however, alternative approaches require further research. Accurate diagnosis is crucial, with treatment strategies depending on the cause often requiring platelet transfusions from HLA-matched donors or immunosuppressive therapies. Complications included bleeding, infection, and adverse drug reactions, highlighting the need for proper management and monitoring. Future research should focus on patient-specific risk factors, alternative prevention methods, and blood product safety. Understanding immune-mediated reactions and other causes, prevention, diagnosis, management, and potential complications can improve outcomes in patients needing platelet transfusions. In conclusion, PTR is a complex condition that healthcare professionals must handle carefully. Ongoing research is crucial to advancing knowledge, enhancing care, and improving patient outcomes. 71 90 2025/01/222025/01/112025/01/192025/02/22025/01/32025/02/22025/01/282025/01/2 1403/10/13 2025/03/82025/03/262025/03/172025/03/52025/03/62025/03/32025/03/262025/03/26 1404/1/6 Elham Razani Elham Razani Department of Hematology and Transfusion Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran Elham.razani.mls@gmail.com Maryam Maryam Khiabani Rad Maryam Maryam Khiabani Rad Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran maria.rad.71@gmail.com Ehsan Larki Tork Ehsan Larki Tork Department of Hematology and Transfusion Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran larki1377@gmail.com Fourozan Bahmani Fourozan Bahmani Abadan Faculty of medical sciences, Abadan, Iran 4- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran bahmani.forouzan@gmail.com Platelet Platelet immunology Transfusion medicine Platelet transfusion refractory Friedman MT, Avadhani V, Gilmore S, Madrigal E. 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A Comprehensive Review of the Role of Viruses in the Onset and Progression of Lung Cancer 2 2 A number of variables may influence the development and spread of lung cancer (LC), one of the most prevalent and fatal cancers in the world. In this context, viruses are important, especially the human papillomavirus (HPV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), influenza virus (IV), and cytomegalovirus (CMV). These viruses can influence the development of LC through metabolic alterations, immune response suppression, and disruption of the tumor microenvironment (TME). Specifically, HPV may contribute to LC through genetic effects, while EBV can induce molecular changes in cells. HIV, by suppressing the immune system and increasing the risk of secondary infections, may create conditions conducive to the development of lung tumors. IV and CMV can also play a role in accelerating tumorigenic processes by impacting the immune system and promoting inflammation. This review article examines the various mechanisms by which viruses are involved in LC and their association with the progression of lung tumors. Additionally, the role of vaccination in preventing LC, particularly in individuals infected with specific viruses, is explored. 91 97 2025/01/222025/01/112025/01/192025/02/22025/01/32025/02/22025/01/282025/01/22025/03/13 1403/12/23 2025/03/82025/03/262025/03/172025/03/52025/03/62025/03/32025/03/262025/03/262025/03/28 1404/1/8 Abolfazl Jafari-Sales Abolfazl Jafari-Sales Department of Microbiology, Kaz.C., Islamic Azad University, Kazerun, Iran. a.jafari_1392@yahoo.com Elham Nozohour-Leilabadi Elham Nozohour-Leilabadi Infectious Diseases Research Center, TaMS.C., Islamic Azad University, Tabriz, Iran. elhamnozohour80@gmail.com Maryam Safari Maryam Safari Infectious Diseases Research Center, TaMS.C., Islamic Azad University, Tabriz, Iran. maryamsafari1381@gmail.com Maryam Farahnaki-Sadabadi Maryam Farahnaki-Sadabadi Infectious Diseases Research Center, TaMS.C., Islamic Azad University, Tabriz, Iran. maryamfarahnaki.2004@gmail.com Negin Yaghoubi-Azar Negin Yaghoubi-Azar Infectious Diseases Research Center, TaMS.C., Islamic Azad University, Tabriz, Iran. 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Effectiveness of Photobiomodulation Therapy for Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Systematic Review and Meta-Analysis 2 2 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and common side effect of cancer therapy, severely impacting cancer therapy compliance and the quality of life of cancer patients. Low-level laser or light-emitting diode (LED) photobiomodulation therapy (PBMT) provides a new, non-invasive therapeutic option. The purpose of the present systematic review and meta-analysis is to evaluate the efficacy of PBMT in the treatment of CIPN during cancer therapy in patients. Methodology: A systematic electronic database search was conducted using randomized controlled trials and clinical studies comparing the impact of PBMT on the symptom of CIPN in the form of modified Total Neuropathy Scores (mTNS), FACT/GOG-NTX scores, and Visual Analogue Scale (VAS) pain scores. Meta-analyses were done using RevMan 5.4.1, producing forest plots, mean differences (MD), 95% confidence intervals (CI), and heterogeneity indices (I²). Results: The review included six trials with a total of 273 patients. The meta-analysis of mTNS revealed the significant reduction of neuropathy severity in the PBMT group compared to the control group (MD = −2.10; 95% CI: −3.94 to −0.26; I²=99%, p<0.0001). Furthermore, the FACT/GOG-NTX neuropathy subscale at follow-up completion, combined in four trials, illustrated the advantage in favor of PBMT as statistically significant (MD = −1.85; 95% CI: −2.70 to −0.99; I²=0%, p=0.80). In addition, four studies that reported the VAS scores of pain showed that the intensity of pain was reduced significantly by PBMT (MD = −1.36; 95% CI: −2.00 to −0.73; I²=87%, p<0.0001). Conclusion: PBMT exhibited statistically significant differences in neuropathy severity, neuropathy symptom, and pain intensity in cancer patients with CIPN, with considerable heterogeneity in some of the outcomes. PBMT was therefore a promising adjuvant treatment to CIPN management. 98 107 2025/01/222025/01/112025/01/192025/02/22025/01/32025/02/22025/01/282025/01/22025/03/132025/01/25 1403/11/6 2025/03/82025/03/262025/03/172025/03/52025/03/62025/03/32025/03/262025/03/262025/03/282025/03/25 1404/1/5 Jigar Haria Jigar Haria Department of Community Medicine, Teerthanker Mahaveer Medical college & research centre, Moradabad, Uttar Pradesh India. drjigar.medical@tmu.ac.in Vinod kumar Vinod kumar Department of Community Medicine, Teerthanker Mahaveer Medical college & research centre, Moradabad, Uttar Pradesh India. drvinodkumarsingh85@gmail.com Sanjeev Jain Sanjeev Jain Department of Community Medicine, Teerthanker Mahaveer Medical college & research centre, Moradabad, Uttar Pradesh India. jainsanjeevkumar77@gmail.com Ajay Kumar Ajay Kumar Department of Community Medicine, Teerthanker Mahaveer Medical college & research centre, Moradabad, Uttar Pradesh India. drajaymedicine.medical@tmu.ac.in Chemotherapy-induced peripheral neuropathy Photobiomodulation therapy. 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