The long-term outcome and efficacy of PR1/BCR-ABL multipeptides vaccination in chronic myeloid leukemia: results of a 7-year longitudinal investigation 2 2 Background: Although Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML), not all patients reach complete remission and a considerable proportion of the patients develop resistance to Imatinib. Material and Methods: In an attempt to increase the tail on the survival curve, we conducted a Phase I/II study of PR1/BCR-ABL multipeptides vaccination trial in CML patients with at least 15 months of Imatinib treatment and 5 months of persistent molecular residual disease. Results: One month after the completion of the vaccinations, 4 patients nearly developed a 1-log fall in their BCR-ABL transcript level, with 4 patients achieving a major molecular response (MMR). Nine patients were followed for more than a period of 7 years. The vaccinations were associated with a MMR in five patients and a complete molecular response (CMR) in one patient. The removal of Imatinib in two patients who achieved MMR after the vaccinations led to a resurgence of the leukemia population and relapse. Conclusion: Our study suggests that a combination of immunotherapy with Imatinib targeted therapy keeps the leukemia population under control, improving the long-lasting clinical and molecular response of CML patients, for at least 7 years. 84 94 2022/09/14 1401/6/23 2022/12/22 1401/10/1 Seyed H. Ghaffari Seyed H. Ghaffari Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran shghaffari200@yahoo.com Ebrahim Osfouri Ebrahim Osfouri Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran Ebrahimosfouri@yahoo.com Mohammad Ahmadvand Mohammad Ahmadvand Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran Davood Bashash Davood Bashash Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran David_5980@yahoo.com Parisa Ghaffari Parisa Ghaffari Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran Ahmadreza Niavarani Ahmadreza Niavarani Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran Iran ahmadreza.niavarani@gmail.com Elham Hossaini Elham Hossaini Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran Marjan Yaghmaie Marjan Yaghmaie Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran marjan_yaghmaie@yahoo.com Roghieh Koohi Roghieh Koohi Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran koohirora@yahoo.com Andisheh ie Ghashgha Andisheh ie Ghashgha Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran a-ghashghaie@farabi.tums.ac.ir Atieh Pourbagheri-Sigaroodi Atieh Pourbagheri-Sigaroodi Department of Biotechnology, faculty of Advanced Sciences and Technology, Pharmaceutical sciences branch, Islamic Azad University (IAUPS), Tehran, Iran Iran atips1991@gmail.com Seyed A. Mousavi Seyed A. Mousavi Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran a_mousavi@tums.ac.ir Kamran Alimoghaddam Kamran Alimoghaddam Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran alimgh@ams.ac.ir Ardeshir Ghavamzadeh Ardeshir Ghavamzadeh Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran Iran ghavamza@sina.tums.ac.ir Multi-peptide vaccination BCR-ABL PR1 peptide Chronic myeloid leukemia ## ##

The evaluation of TLR1, TLR2, TLR4, TLR7, and TLR8 expression levels in the newly-diagnosed acute myeloid leukemia (AML) patients 2 2 Background: Acute myeloid leukemia (AML) is described by the clonal expansion of myeloid blasts with abnormal differentiation. Considering the role of Toll-like receptors (TLRs) in inflammation induction and the effect of chronic inflammation on cancer development, investigating the state of TLRs’ expression in human malignancies has attracted scientists’ attention. Methods: In this study, 36 newly-diagnosed AML patients and 36 control samples were examined. The mRNA expression levels of TLR1/2/4/7/8 were measured in both groups using real-time PCR. The student’s t-test was utilized to compare gene expression levels between the two populations and the one-way ANOVA test was used to compare data among multiple subtypes. Results: All TLR gene expression levels were significantly up-regulated in patients compared to the control group (p<0.05). Positive correlations between different TLRs were observed as well. AML patients under the age of 55 showed significantly higher TLR1/2/4 expression in comparison with healthy individuals of the same age; a similar comparison in people above 55 also showed an elevated expression of TLR1/2/4/8. Male patients overexpressed almost all genes compared to healthy subjects; the levels of TLR1/2/4 were also higher in female patients. No difference was observed comparing blast percentages and FAB subtypes. Conclusion: By considering the results of this experiment, it seems that TLRs up-regulation in AML patients may contribute to the pathogenesis and development of the disease; however, more investigations are required to elucidate the exact roles of these receptors in AML. ./files/site1/files/Supplementary_Fig._1.docx 95 103 2022/09/142022/10/20 1401/7/28 2022/12/222022/12/15 1401/9/24 Kosar Fateh Kosar Fateh Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran k.v.fateh@gmail.com Bahareh Kashani Bahareh Kashani Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Iran bahareh_kashani@yahoo.com Zahra Hasanpour Zahra Hasanpour Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran zahrahasanpoor56@yahoo.com Naser Shagerdi Esmaeli Naser Shagerdi Esmaeli Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran naser.shagerdi.esmaeli@gmail.com Vahid Amiri Vahid Amiri Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran vahid.amiri529@gmail.com Seyed H. غفاری Seyed H. Ghaffari Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Iran shghaffari200@yahoo.com Davood Bashash Davood Bashash Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran david_5980@yahoo.com Acute myeloid leukemia (AML) Toll-like receptor (TLR) Gene expression Pathogenesis Inflammation ## ##

The Mitochondrial DNA 4977-bp Deletion in Patients with Colorectal Cancer: a Case-control Study in Iran 2 2 Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide, and its occurrence can be ascribed to genetic susceptibility. Mitochondrial DNA 4977-bp (mtDNA 4977), as the most described mtDNA deletion, has been long proposed to be involved in various types of cancers. However, a few studies on mtDNA 4977-bp deletion in Iranian patients with CRC have been reported. The current study aimed to determine mtDNA 4977 frequency in CRC and its association with cancer susceptibility. We conducted a case-control study in which a total of 26 patients with CRC, 26 tumor tissues, adjacent normal tissues, peripheral blood samples, and peripheral blood samples from 50 healthy subjects were included. mtDNA 4977 was detected using multiplex PCR technique and direct DNA sequencing. Real-time PCR was also used to determine deletion levels. mtDNA 4977 was observed in six patients (23.07%), four (15.3%) in both tumor and matched surrounding normal tissues, and two (7.69%) in adjacent normal tissues, but not detected in both patients and control samples in peripheral samples. A significant difference was found between mtDNA 4977 deletion in tumoral and adjacent normal tissues (P=0.001). No relation was observed between mtDNA 4977 and categorical variables, including age and gender, and tumor stage. The analysis confirmed no association between the mtDNA 4977-bp deletion and susceptibility to colorectal cancer in Iranian patients. However, more extensive studies are required to confirm or reject these findings. 104 110 2022/09/142022/10/202022/09/16 1401/6/25 2022/12/222022/12/152022/12/16 1401/9/25 Sharareh Kamfar Sharareh Kamfar Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Iran kamfarsharareh@gmail.com Fariba Alaei Fariba Alaei Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Iran alaeifariba52@gmail.com Reza Zaferani Reza Zaferani Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Iran kimiya.zaferani@gmail.com Vahide Zeinali Vahide Zeinali Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Iran vahide.zeynaly4183@gmail.com Colorectal cancer Mitochondrial DNA Multiplex PCR Gene deletion Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68(6):394-424.##Huang Y, Zhao M, Yin J, Lu T, Yang X, Yuan G, Li M, Liu Y, Zhan C, Wang Q. Pulmonary metastasis in newly diagnosed colon-rectal cancer: a population-based nomogram study. International Journal of Colorectal Disease. 2019;34(5):867-78.##Alidoust M, Hamzehzadeh L, Khorshid Shamshiri A, Afzaljavan F, Kerachian MA, Fanipakdel A, Aledavood SA, Allahyari A, Bari A, Moosanen Mozaffari H. Association of SMAD7 genetic markers and haplotypes with colorectal cancer risk. BMC medical genomics. 2022;15(1):1-9.##Dekker E, Tanis PJ, Vleugels JL, Kasi PM, Wallace M. Pure-AMC. Lancet. 2019;394:1467-80.##Cross AJ, Ferrucci LM, Risch A, Graubard BI, Ward MH, Park Y, Hollenbeck AR, Schatzkin A, Sinha R. A Large Prospective Study of Meat Consumption and Colorectal Cancer Risk: An Investigation of Potential Mechanisms Underlying this AssociationMeat and Colorectal Cancer. Cancer research. 2010;70(6):2406-14.##Zygulska AL, Pierzchalski P. Novel diagnostic biomarkers in colorectal cancer. International Journal of Molecular Sciences. 2022;23(2):852.##Kit AH, Nielsen HM, Tost J. DNA methylation based biomarkers: practical considerations and applications. Biochimie. 2012;94(11):2314-37.##Ahlquist DA, Taylor WR, Mahoney DW, Zou H, Domanico M, Thibodeau SN, Boardman LA, Berger BM, Lidgard GP. The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clinical Gastroenterology and Hepatology. 2012;10(3):272-7. e1.##Bohr VA. Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radical Biology and Medicine. 2002;32(9):804-12.##Whitehall JC, Greaves LC. Aberrant mitochondrial function in ageing and cancer. Biogerontology. 2020;21(4):445-59.##Bazzani V, Equisoain Redin M, McHale J, Perrone L, Vascotto C. Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing. International Journal of Molecular Sciences. 2022;23(19):11391.##Shuwen H, Xi Y, Yuefen P. Can mitochondria DNA provide a novel biomarker for evaluating the risk and prognosis of colorectal cancer? Disease markers. 2017;2017.##Dani MAC, Dani SU, Lima SP, Martinez A, Rossi BM, Soares F, Zago MA, Simpson AJ. Less∆ mtDNA4977 than normal in various types of tumors suggests that cancer cells are essentially free of this mutation. Genet Mol Res. 2004;3:395-409.##Dai JG, Xiao YB, Min JX, Zhang GQ, Yao K, Zhou RJ. Mitochondrial DNA 4977 BP deletion mutations in lung carcinoma. Indian journal of cancer. 2006;43(1):20.##Chen T, He J, Shen L, Fang H, Nie H, Jin T, Wei X, Xin Y, Jiang Y, Li H. The mitochondrial DNA 4,977-bp deletion and its implication in copy number alteration in colorectal cancer. BMC medical genetics. 2011;12(1):1-9.##Nie H, Shu H, Vartak R, Milstein AC, Mo Y, Hu X, Fang H, Shen L, Ding Z, Lu J. Mitochondrial common deletion, a potential biomarker for cancer occurrence, is selected against in cancer background: a meta-analysis of 38 studies. PloS one. 2013;8(7):e67953.##Aran V, Victorino AP, Thuler LC, Ferreira CG. Colorectal cancer: epidemiology, disease mechanisms and interventions to reduce onset and mortality. Clinical colorectal cancer. 2016;15(3):195-203.##Alshammari SA, Alenazi HA, Alshammari HS. Knowledge, attitude and practice towards early screening of colorectal cancer in Riyadh. Journal of Family Medicine and Primary Care. 2020;9(5):2273.##Li C, Li Y, Gao L-B, Wang Y-Y, Zhou B, Lv M-L, Lu H-M, Zhang L. Vitamin D receptor gene polymorphisms and the risk of colorectal cancer in a Chinese population. Digestive diseases and sciences. 2009;54(3):634-9.##Zhao B, Zhang J, Zhang J, Luo R, Wang Z, Xu H, Huang B. Assessment of the 8th edition of TNM staging system for gastric cancer: the results from the SEER and a single-institution database. Future Oncology. 2018;14(29):3023-35.##Greaves LC, Nooteboom M, Elson JL, Tuppen HA, Taylor GA, Commane DM, Arasaradnam RP, Khrapko K, Taylor RW, Kirkwood TB. Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. PLoS genetics. 2014;10(9):e1004620.##Damas J, Samuels DC, Carneiro J, Amorim A, Pereira F. Mitochondrial DNA rearrangements in health and disease-a comprehensive study. Human mutation. 2014;35(1):1-14.##Zhang Y, Ma Y, Bu D, Liu H, Xia C, Zhang Y, Zhu S, Pan H, Pei P, Zheng X. Deletion of a 4977-bp fragment in the mitochondrial genome is associated with mitochondrial disease severity. PloS one. 2015;10(5):e0128624.##Nourazarian AR, Kangari P, Salmaninejad A. Roles of oxidative stress in the development and progression of breast cancer. Asian Pacific Journal of Cancer Prevention. 2014;15(12):4745-51.##Blajszczak C, Bonini MG. Mitochondria targeting by environmental stressors: implications for redox cellular signaling. Toxicology. 2017;391:84-9.##Chen T, He J, Huang Y, Zhao W. The generation of mitochondrial DNA large-scale deletions in human cells. Journal of human genetics. 2011;56(10):689-94.##Wei YH, Lee CF, Lee HC, Ma YS, Wang CW, Lu CY, Pang CY. Increases of mitochondrial mass and mitochondrial genome in association with enhanced oxidative stress in human cells harboring 4,977 bp‐deleted mitochondrial DNA. Annals of the New York Academy of Sciences. 2001;928(1):97-112.##Yusoff AAM, Khair SZNM, Abd Radzak SM, Idris Z, Lee H-C. Prevalence of mitochondrial DNA common deletion in patients with gliomas and meningiomas: a first report from a Malaysian study group. Journal of the Chinese Medical Association. 2020;83(9):838.##Zhu W, Qin W, Sauter ER. Large-scale mitochondrial DNA deletion mutations and nuclear genome instability in human breast cancer. Cancer detection and prevention. 2004;28(2):119-26.##Futyma K, Putowski L, Cybulski M, Miotla P, Rechberger T, Semczuk A. The prevalence of mtDNA4977 deletion in primary human endometrial carcinomas and matched control samples. Oncology reports. 2008;20(3):683-8.##Meissner C, Bruse P, Mohamed SA, Schulz A, Warnk H, Storm T, Oehmichen M. The 4977 bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: a useful biomarker or more? Experimental gerontology. 2008;43(7):645-52.##Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Flint Beal M, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature genetics. 1992;2(4):324-9.##Dimberg J, Hong TT, Skarstedt M, Löfgren S, Zar N, Matussek A. Novel and differential accumulation of mitochondrial DNA deletions in Swedish and Vietnamese patients with colorectal cancer. Anticancer Research. 2014;34(1):147-52.##Krishnan KJ, Reeve AK, Samuels DC, Chinnery PF, Blackwood JK, Taylor RW, Wanrooij S, Spelbrink JN, Lightowlers RN, Turnbull DM. What causes mitochondrial DNA deletions in human cells? Nature genetics. 2008;40(3):275-9.##Ericson NG, Kulawiec M, Vermulst M, Sheahan K, O'Sullivan J, Salk JJ, Bielas JH. Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLOS genetics. 2012;8(6):e1002689.## ##

Blood culture-negative infective endocarditis with thalassemia and neurological complication: A dangerous combination 2 2 Background: Infective endocarditis (IE) is a life-threatening systemic disease that mostly affects people with valvular heart disease, prosthetic valves, or intracardiac devices. Infective endocarditis is a dangerous cardiac involvement in thalassemia patients. Thus, a multidisciplinary approach is important to provide efficient and effective therapy. Case presentation: A 31-year-old man came to our tertiary referral hospital complaining of right-side paralysis of the body and slurred speech. Vital signs were normal. There were grade III/VI systolic murmurs from chest examination in midclavicular line intercostal space V sinistra. Head CT scan without contrast showed an embolic event. Peripheral blood smear showed iron deficiency anemia. Further electrophoresis hemoglobin (Hb) examination showed HbE-pathy. Echocardiography showed vegetations on the anterior and posterior mitral leaflet, leading to severe mitral regurgitation (MR). Blood culture examinations showed no bacterial growth. The patient was then diagnosed with severe MR due to possible IE, acute stroke infarction, and HbE thalassemia. The patient was treated with optimal medical therapy because he refused surgery. After six months of follow up, patients were found dead at his house Conclusions: Thalassemia is a risk factor for infective endocarditis. Both are a dangerous combination, and early recognition should be made carefully to prevent worse outcome. 111 115 2022/09/142022/10/202022/09/162022/05/22 1401/3/1 2022/12/222022/12/152022/12/162022/12/2 1401/9/11 Novia Kusumawardhani Novia Kusumawardhani Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University – dr. Soetomo General Hospital, Surabaya, Indonesia Indonesia noviakusumawardhani@gmail.com Ivana Purnama Dewi Ivana Purnama Dewi Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University – dr. Soetomo General Hospital, Surabaya, Indonesia 2Faculty of Medicine Duta Wacana Christian University, Yogyakarta, Indonesia Indonesia 916ivana@gmail.com Louisa Fadjri Kusuma Wardhani Louisa Fadjri Kusuma Wardhani Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University – dr. Soetomo General Hospital, Surabaya, Indonesia Indonesia louisafk@gmail.com Mohammad Budiarto Mohammad Budiarto Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University – dr. Soetomo General Hospital, Surabaya, Indonesia Indonesia raden-m-b@fk.unair.ac.id Infective endocarditis Negative Blood culture Thalassemia Stroke ## ##

“How should we treat older patients with Metastatic Colorectal Cancer, A Review” 2 2 Nearly 50 % of newly diagnosed colorectal cancer, affect people over 70 years of age. Inclusion of older patients in clinical trials has been extremely rare. As a result, there is debate on how to manage these patients because it is still unclear how to balance the therapeutic advantages and toxicities. For patients who do not have comorbid conditions, with performance status (P.S.) 0–1, treatment guidelines are comparable to those for younger ones. Chemotherapy is an option for older patients; however, a full geriatric evaluation is recommended. Bevacizumab, an anti-vascular epithelial growth factor (anti-VEGF), combined with chemotherapy has become a standard of care in older patients. Anti-epidermal growth factor receptor (anti-EGFR) treatment is proposed both as monotherapy in the third-line or with chemotherapy in first or second line. Clinical trials that compared chemotherapy alone versus doublet chemotherapy plus anti-EGFR in older patients found that age is not an absolute contraindication for using anti-EGFR in first or second line. In fit older patients, anti-EGFR monotherapy in the first second or third line has demonstrated feasibility and antitumor efficacy. The major side effect is cutaneous rash which is easily managed. However, treatment in older patients should be carried out and be based on co-morbidities. 116 124 2022/09/142022/10/202022/09/162022/05/222022/11/10 1401/8/19 2022/12/222022/12/152022/12/162022/12/22022/12/12 1401/9/21 Alfredo Colombo Alfredo Colombo Oncology Unit C.D.C Macchiarella - Palermo-Italy Italy alfredocolo63@gmail.com Concetta Maria Porretto Concetta Maria Porretto Oncology Unit C.D.C Macchiarella - Palermo-Italy Italy massimo69cp@libero.it Ivan Fazio Ivan Fazio Radiotherapy Unit CDC Macchiarella - Palermo- Italy Italy ivanfazio27@gmail.com Tommaso Sciacchitano Tommaso Sciacchitano Oncology Unit C.D.C Macchiarella - Palermo-Italy Italy tommaso.sciacchitano@tin.it Antonella Mazzonello Antonella Mazzonello Radiotherapy Unit CDC Macchiarella Italy oncologia@casadicuramacchiarella.it Metastatic colorectal cancer Anti-EGFR Chemotherapy Toxicities Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68:394-424.##Les cancers en France, Les Données, INCa. édition https://www.e-cancer.fr/content/download/255246/3573612/file/Cancers_en_FranceEssentiel_Faits_et_chiffres- 2018.pdf; 2018.##Holleczek B, Rossi S, Domenic A, et al. On-going improvement and persistent differences in the survival for patients with colon and rectumcancer across Europe 1999- 2007 - results from the EUROCARE-5 study. Eur J Cancer 2015; 51:2158-68.##Gouverneur A, Salvo F, Berdai D,Moore N, Fourrier-Reglat A, Noize P. Inclusion of elderly or frail patients in randomized controlled trials of targeted therapies for the treatment of metastatic colorectal cancer: a systematic review. J Geriatr Oncol 2018; 9:15-23.##Papamichael D, Audisio RA, Glimelius B, et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol 2015; 26:463-76.##Jarrett PG, Rockwood K, Carver D, Stolee P, Cosway S. Illness presentation in elderly patients. Arch Intern Med 1995; 155:1060-4.##Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386-422.##Soubeyran P, Bellera C, Goyard J, et al. Validation of the G8 screening tool in geriatric oncology: the ONCODAGE project. J Clin Oncol 2011; 29:9001.##Soubeyran P, Bellera C, Goyard J, et al. Screening for vulnerability in older cancer patients the ONCODAGE prospective multicenter cohort study. PLoS One 2014;9:e115060.##Shafiei M, Yoon R, McLachlan A, Boddy A, Beale P, Blinman P. Pharmacokinetics of anticancer drugs used in treatment of older adults with colorectal Cancer: a systematic review. Ther Drug Monit 2019; 41:553-60.##Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the chemotherapy risk assessment scale for high-age patients (CRASH) score. Cancer 2012; 118:3377-86.##Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and rail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomized factorial trial. Lancet 2011; 377:1749-59.##Aparicio T, Lavau-Denes S, Phelip JM, et al. Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02). Ann Oncol 2016; 27:121-7.##Aparicio T, Jouve JL, Teillet L, et al. Geriatric factors predict chemotherapy feasibility: ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. J Clin Oncol 2013; 31:1464-70.##Aparicio T, Gargot D, Teillet L, et al. Geriatric factors analyses from FFCD 2001-02 phase III study of first-line chemotherapy for elderlymetastatic colorectal cancer patients. Eur J Cancer 2017; 74:98-108.##Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomized phase 3 trial. Lancet Oncol 2013;14: 1077-85.##Aparicio T, Bouche O, Taieb J, et al. Bevacizumab+chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results. Ann Oncol 2018; 29:2270.##https://doi.org/10.1093/annonc/mdx529##Aparicio T, Bouche O, Francois E, et al. Geriatric analysis from PRODIGE 20 randomized phase II trial evaluating bevacizumab + chemotherapy versus chemotherapy alone in older patients with untreated metastatic colorectal cancer. Eur J Cancer 2018; 97:16-24.##Landre T, Uzzan B, Nicolas P, et al. Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. A meta-analysis. Int J Colorectal Dis 2015; 30:1305-10.##Landre T, Maillard E, Taleb C, et al. Impact of the addition of bevacizumab, oxaliplatin, or irinotecan to fluoropyrimidin in the first-line treatment of metastatic colorectal cancer in elderly patients. Int J Colorectal Dis 2018; 33:1125-30.##Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29:2011-9.##Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26:1626-34.##Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28:4697-705.##https://doi.org/10.1200/jco.2010.28.15_suppl.3528##VanderWalde N, Jagsi R, Dotan E, et al. NCCN guidelines insights: older adult oncology, version 2.2016. J Natl Compr Canc Netw 2016; 14:1357-70.##Folprecht G, Köhne C, Bokemeyer C, et al. Cetuximab and 1st-line chemotherapy in elderly and younger patients with metastatic colorectal cancer (MCRC): a pooled analysis of the CRYSTAL and OPUS studies. Ann Oncol 2010; 21:194.##Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomized, open-label, phase 3 trial. Lancet Oncol 2014; 15:1065-75.##Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25:1346-55.##Douillard J, Siena S, Peeters M, Koukakis R, Terwey J, Tabernero J. Impact of baseline age on efficacy and safety of first-line panitumumab + FOLFOX4 vs FOLFOX4 treatment. Ann Oncol 2014;25 iv187.##Jehn CF, Boning L, Kroning H, Possinger K, Luftner D. Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer. Br J Cancer 2012;106: 274-8.##Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28:4706-13.##https://doi.org/10.1200/JCO.2009.27.6055##PeetersM, Price T, Cervantes A, et al. Impact of baseline covariates and prior therapy on the efficacy of second-line panitumumab + FOLFIRI vs FOLFIRI treatment. Ann Oncol 2014;25 (iv187-iv8).##Sastre J, Gravalos C, Rivera F, et al. First-line cetuximab plus capecitabine in elderly patients with advanced colorectal cancer: clinical outcome and subgroup analysis according to KRAS status from a Spanish TTD group study. Oncologist 2012;17: 339-45.##Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomized phase 3 MRC COIN trial. Lancet 2011; 377:2103-14.##MéndezMéndez JC, Ramos M, De la Cámara Gómez JC, et al. First-line panitumumab plus capecitabine for the treatment of elderly patientswith wild-type KRASmetastatic colorectal cancer: preliminary results of the phase II, PANEL GITuD-2011-01 study. Ann Oncol 2017;28.##Kienle DL, Dietrich D, Ribi K, et al. Cetuximab monotherapy and cetuximab plus capecitabine as first-line treatment in older patients with RAS- and BRAF wild-type metastatic colorectal cancer. Results of the multicenter phase II trial SAKK 41/10. J Geriatr Oncol 2019; 10:304-10.##Sastre J, Massuti B, Pulido G, et al. First-line single-agent panitumumab in frail elderly patientswithwild-type KRAS metastatic colorectal cancer and poor prognostic factors: a phase II study of the Spanish cooperative group for the treatment of digestive tumours. Eur J Cancer 2015; 51:1371-80.##Ohta K, Kato T, Goto M, et al. Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, RAS wild-type colorectal cancer: OGSG 1602. ASCO Gastrointestinal Cancers Symposium 2020; 38:106 January 23-25.##Pietrantonio F, Cremolini C, Aprile G, et al. Single-agent Panitumumab in frail elderly patients with advanced RAS and BRAF wild-type colorectal Cancer: challenging drug label to light up new Hope. Oncologist 2015; 20:1261-5.##Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357:2040-8.##Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25: 1658-64.##Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomized, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014; 15:569-79.##Rouyer M, Fourrier-Réglat A, Noize P, et al. Efficacité et sécurité d'emploi du cétuximab en traitement de 1re ligne du cancer colorectal métastatique chez les sujets âgés: résultats de la cohorte EREBUS. Rev Epidemiol Sante Publique 2016; 64 (S271-S2).##Jehn CF, Boning L, Kroning H, Pezzutto A, Luftner D. Influence of comorbidity, age and performance status on treatment efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory elderly patientswithmetastatic colorectal cancer. Eur J Cancer 2014; 50:1269-75.##Rosati G, Pinto C, Di Fabio F, et al. Quality of life, compliance, safety and effectiveness in fit older metastatic colorectal patients with cancer treated in first-line with chemotherapy plus cetuximab: a restrospective analysis from the ObservEr study. J Geriatr Oncol 2018; 9:243-8.##Battaglin F, Schirripa M, Buggin F, et al. The PANDA study: a randomized phase II study of first-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS and BRAF wild-type elderly metastatic colorectal cancer patients. BMC Cancer 2018;18:98.##Feliu J, Salud A, Losada EP, et al. First-line treatment with panitumumab plus FOLFIRI in elderly patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer and good performance status: OPALO trial. J Clin Oncol 2018; 36:3618.##Tebbutt NC, Steer CB, Sjoquist KM, et al. MONARCC: a randomized phase II study of panitumumabmonotherapy and panitumumab plus 5 fluorouracil as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer: an AGITG clinical trial. ASCO Gastrointestinal Cancers Symposium 2020;38: TPS271 January 23-25.##Canoui-Poitrine F, Lievre A, Dayde F, et al. Inclusion of older patients with Cancer in clinical trials: the SAGE prospective multicenter cohort survey. Oncologist 2019;24 (e1351-e9).##Retornaz F, Guillem O, Rousseau F, et al. Predicting chemotherapy toxicity and death in older adults with Colon Cancer: results of MOST study. Oncologist 2020;25(1): e85-93. ##https://doi.org/10.1634/theoncologist.2019-0241## ##

Coagulopathies after vaccination against SARS-CoV-2: The sole solution might lead to another problem 2 2 The common reported adverse impacts of COVID-19 vaccination include the injection site’s local reaction followed by various non-specific flu-like symptoms. Nevertheless, uncommon cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) following viral vector vaccines (ChAdOx1 nCoV-19 vaccine, Ad26.COV2 vaccine) have been reported. This literature review was performed using PubMed and Google Scholar databases using appropriate keywords and their combinations: SARS-CoV-2, adenovirus, spike protein, thrombosis, thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia (VITT), NF-kappaB, adenoviral vector, platelet factor 4 (PF4), COVID-19 Vaccine, AstraZeneca COVID vaccine, ChAdOx1 nCoV-19 COVID vaccine, AZD1222 COVID vaccine, coagulopathy. The abstracts and titles of each article were assessed by authors for screening and inclusion English reports about post-vaccine CVST and VITT in humans were also collected. Some SARS-CoV-2 vaccines based on viral vector, mRNA, or inactivated SARS-CoV-2 virus have been accepted and are being pragmatic global. Nevertheless, the recent augmented statistics of normally very infrequent types of thrombosis associated with thrombocytopenia have been stated, predominantly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The numerical prevalence of these side effects seems to associate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the meticulous molecular mechanisms are still not clear. The present review summarizes the latest data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis demonstrating that coagulopathies, including thromboses, thrombocytopenia, and other associated side effects, are correlated to an interaction of the two components in the COVID-19 vaccine. 125 139 2022/09/142022/10/202022/09/162022/05/222022/11/102022/10/24 1401/8/2 2022/12/222022/12/152022/12/162022/12/22022/12/122022/12/8 1401/9/17 Saeed Hassani Saeed Hassani Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Arak University of Medical Sciences, Arak, Iran Iran Meshkat Mesh Poortavakol Meshkat Mesh Poortavakol Student Research Committee, Arak University of Medical Sciences, Arak, Iran Iran Mohammad Sayyadi Mohammad Sayyadi Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Arak University of Medical Sciences, Arak, Iran Iran SARS-CoV-2 Spike protein Thrombosis Vaccine-induced immune thrombotic thrombocytopenia (VITT) Covid-19 vaccination Platelet factor 4 (PF-4) Mehta OP, Bhandari P, Raut A, Kacimi SEO, Huy NT. Coronavirus disease (COVID-19): comprehensive review of clinical presentation. Front Public Health. 2021;8:582932.##Jernigan DB, COVID C, Team R. Update: public health response to the coronavirus disease 2019 outbreak-United States, February 24, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(8):216.##Al‐Amer R, Maneze D, Everett B, Montayre J, Villarosa AR, Dwekat E, et al. COVID‐19 vaccination intention in the first year of the pandemic: A systematic review. J Clin Nurs. 2022;31(1-2):62-86.##Beatty AL, Peyser ND, Butcher XE, Cocohoba JM, Lin F, Olgin JE, et al. Analysis of COVID-19 vaccine type and adverse effects following vaccination. JAMA Netw Open. 2021;4(12):e2140364-e.##Le TT, Cramer JP, Chen R, Mayhew S. Evolution of the COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(10):667-8.##Delshad M, Sanaei M-J, Pourbagheri-Sigaroodi A, Bashash D. Host genetic diversity and genetic variations of SARS-CoV-2 in COVID-19 pathogenesis and the effectiveness of vaccination. Int Immunopharmacol. 2022:109128.##Belay ED, Cato G, Rao AK, Abrams J, Wilson WW, Lim S, et al. Multisystem Inflammatory Syndrome in Adults after SARS-CoV-2 infection and COVID-19 vaccination. Clin Infect Dis. 2021.##Salzman MB, Huang C-W, O'Brien CM, Castillo RD. Multisystem inflammatory syndrome after SARS-CoV-2 infection and COVID-19 vaccination. J Emerg Infect Dis. 2021;27(7):1944.##Meyers S, Crescente M, Verhamme P, Martinod K. Staphylococcus aureus and neutrophil extracellular traps: The master manipulator meets its match in immunothrombosis. Arterioscler Thromb Vasc Biol. 2022;42(3):261-76.##Tang A, Caballero AR, Bierdeman MA, Marquart ME, Foster TJ, Monk IR, et al. Staphylococcus aureus superantigen-like protein SSL1: A toxic protease. J Pathog. 2019;8(1):2.##Liesenborghs L, Verhamme P, Vanassche T. Staphylococcus aureus, master manipulator of the human hemostatic system. J Thromb Haemost. 2018;16(3):441-54.##Kouo T, Chaisawangwong W. SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children. J Clin Invest. 2021;131(10).##Liu C, Chi K, Yang M, Guo N. Staphylococcal enterotoxin a induces intestinal barrier dysfunction and activates NLRP3 inflammasome via NF-κB/MAPK signaling pathways in mice. Toxins. 2022;14(1):29.##Hariharan A, Hakeem AR, Radhakrishnan S, Reddy MS, Rela M. The role and therapeutic potential of NF-kappa-B pathway in severe COVID-19 patients. Inflammopharmacology. 2021;29(1):91-100.##Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther. 2020;5(1):1-23.##Sun S-C. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17(9):545-58.##Su C-M, Wang L, Yoo D. Activation of NF-κB and induction of proinflammatory cytokine expressions mediated by ORF7a protein of SARS-CoV-2. Sci Rep. 2021;11(1):1-12.##Olajide OA, Iwuanyanwu VU, Lepiarz-Raba I, Al-Hindawi AA. Induction of exaggerated cytokine production in human peripheral blood mononuclear cells by a recombinant SARS-CoV-2 spike glycoprotein S1 and its inhibition by dexamethasone. Inflamm. 2021;44(5):1865-77.##Robles JP, Zamora M, Adan-Castro E, Siqueiros-Marquez L, de la Escalera GM, Clapp C. The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling. J Biol Chem. 2022;298(3).##Hsu AC, Wang G, Reid AT, Veerati PC, Pathinayake PS, Daly K, et al. SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitors in vitro. Biorxiv. 2020.##Khan S, Shafiei MS, Longoria C, Schoggins JW, Savani RC, Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. Elife. 2021;10:e68563.##Petruk G, Puthia M, Petrlova J, Samsudin F, Strömdahl A-C, Cerps S, et al. SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. j Mol Cell Biol. 2020;12(12):916-32.##Barh D, Aljabali AA, Tambuwala MM, Tiwari S, Serrano-Aroca Á, Alzahrani KJ, et al. Predicting COVID-19-comorbidity pathway crosstalk-based targets and drugs: towards personalized COVID-19 management. Biomedicine. 2021;9(5):556.##Shchelkanov MY, Kolobukhina L, Burgasova O, Kruzhkova I, Maleev V. COVID-19: etiology, clinical picture, treatment. Russian Journal of Infection and Immunity. 2020;10(3):421-45.##Sillen M, Declerck PJ. A narrative review on plasminogen activator inhibitor-1 and its (Patho) physiological role: To target or not to target?. Int J Mol Sci. 2021;22(5):2721.##Kubala MH, DeClerck YA. The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding. Cancer Metastasis Rev. 2019;38(3):483-92.##Leitzke M, Schönknecht P. The Viral Accelerated NF-κB Pathway Probably Drives COVID-19-associated Coagulopathy via Excessive Transcription of Tissue Factor and Plasminogen Activator Inhibitor 1-Case Report. Archives of Clinical and Biomedical Research. 2021;5(4):664-80.##Mussbacher M, Salzmann M, Brostjan C, Hoesel B, Schoergenhofer C, Datler H, et al. Cell type-specific roles of NF-κB linking inflammation and thrombosis. Front Immunol. 2019;10:85.##Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, et al. Complement activation and endothelial perturbation parallel COVID-19 severity and activity. J Autoimmun. 2021;116:102560 9.##Kircheis R. Coagulopathies after vaccination against SARS-CoV-2 may be derived from a combined effect of SARS-CoV-2 spike protein and adenovirus vector-triggered signaling pathways. Int J Mol Sci. 2021;22(19):10791.##Kojok K, El-Kadiry AE-H, Merhi Y. Role of NF-κB in platelet function. Int J Mol Sci. 2019;20(17):4185 (PMID: 31461836).##Kumar GB, Zhou M-M. Calming the cytokine storm of COVID-19 through inhibition of JAK2/STAT3 signaling. Drug Discovery Today. 2021.##Luo W, Li Y-X, Jiang L-J, Chen Q, Wang T, Ye D-W. Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19. Trends Pharmacol Sci. 2020;41(8):531-43.##Satarker S, Tom AA, Shaji RA, Alosious A, Luvis M, Nampoothiri M. JAK-STAT pathway inhibition and their implications in COVID-19 therapy. Postgrad Med. 2021;133(5):489-507.##Arepally GM, Padmanabhan A. Heparin-induced thrombocytopenia: a focus on thrombosis. Arteriosclerosis, thrombosis, and vascular biology. Arterioscler Thromb Vasc Biol. 2021;41(1):141-52.##Marchetti M, Zermatten MG, Bertaggia Calderara D, Aliotta A, Alberio L. Heparin-induced thrombocytopenia: a review of new concepts in pathogenesis, diagnosis, and management. J Clin Med. 2021;10(4):683.##Al Rawahi B, BaTaher H, Jaffer Z, Al‐Balushi A, Al‐Mazrouqi A, Al‐Balushi N. Vaccine‐induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCOV19) vaccine-A case report. Res Pract Thromb Haemost. 2021;5(6):e12578.##McGonagle D, De Marco G, Bridgewood C. Mechanisms of immunothrombosis in vaccine-induced thrombotic thrombocytopenia (VITT) compared to natural SARS-CoV-2 infection. J Autoimmun. 2021;121:102662.##Sakurai F, Tachibana M, Mizuguchi H. Adenovirus vector-based vaccine for infectious diseases. Drug Metab Pharmacokinet. 2021:100432.##Vanaparthy R, Mohan G, Vasireddy D, Atluri P. Review of COVID-19 viral vector-based vaccines and COVID-19 variants. Infez Med. 2021;29(3):328.##Alhinai ZA, Elsidig N. Countries with similar COVID-19 vaccination rates yet divergent outcomes: are all vaccines created equal?. Int J Infect Dis. 2021;110:258-60.##Pai M, Chan B, Stall N, Grill A, Ivers N, Maltsev A, et al. Vaccine-induced immune thrombotic thrombocytopenia (VITT) following adenovirus vector COVID-19 vaccination. Science Briefs of the Ontario COVID-19 Science Advisory Table. 2021;2(17):1-7.##Aleem A, Nadeem AJ. Coronavirus (COVID-19) vaccine-induced immune thrombotic thrombocytopenia (VITT). StatPearls [Internet]. 2022.##Rizk JG, Gupta A, Sardar P, Henry BM, Lewin JC, Lippi G, et al. Clinical characteristics and pharmacological management of COVID-19 vaccine-induced immune thrombotic thrombocytopenia with cerebral venous sinus thrombosis: a review. JAMA Cardiol. 2021;6(12):1451-60.##Voulgaridi I, Sarrou S, Dadouli A, Peristeri A-M, Nasika A, Onoufriadis I, et al. Intensity of Humoral Immune Responses, Adverse Reactions, and Post-Vaccination Morbidity after Adenovirus Vector-Based and mRNA Anti-COVID-19 Vaccines. Vaccines. 2022;10(8):1268.##Heinz FX, Stiasny K. Profiles of current COVID-19 vaccines. Wien Klin Wochenschr. 2021;133(7):271-83.##Ruggeri ZM, Ruf W. Is VITT really a HIT. Nat Immunol. 2021;22(11):1352-3.##Kadkhoda K. Post‐adenoviral‐based COVID‐19 vaccines thrombosis: A proposed mechanism. Thromb Haemost. 2021;19(7):1831.##Pitkänen HH, Jouppila A, Helin T, Dulipati V, Kotimaa J, Meri S, et al. COVID-19 adenovirus vaccine triggers antibodies against PF4 complexes to activate complement and platelets. Thromb Res. 2021;208:129-37.##Nazy I, Sachs UJ, Arnold DM, McKenzie SE, Choi P, Althaus K, et al. Recommendations for the clinical and laboratory diagnosis of VITT against COVID‐19: communication from the ISTH SSC Subcommittee on Platelet Immunology. J Thromb Haemost. 2021;19(6):1585-8.##Vercruysse K, Devreese KM. Laboratory testing for post ChAdOx1 nCOV‐19 vaccination VITT: A challenge. Comment on: Recommendations for the clinical and laboratory diagnosis of VITT against COVID‐19: Communication from the ISTH SSC Subcommittee on Platelet Immunology. J Thromb Haemost. 2021;19(9):2355.##Greinacher A, Langer F, Makris M, Pai M, Pavord S, Tran H, et al. Vaccine‐induced immune thrombotic thrombocytopenia (VITT): update on diagnosis and management considering different resources. J Thromb Haemost. 2022;20(1):149-56.##Bissola A-L, Daka M, Arnold DM, Smith JW, Moore JC, Clare R, et al. The clinical and laboratory diagnosis of vaccine-induced immune thrombotic thrombocytopenia. Blood Adv. 2022.##Matar RH, Than CA, Nakanishi H, Daniel RS, Smayra K, Sim BL, et al. Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: a systematic review and meta-analysis. Blood Coagul Fibrinolysis. 2022;33(2):90.##Sayyadi M, Khosravi M, Ghaznavi-Rad E. Contribution value of coagulation abnormalities in COVID-19 prognosis: a bright perspective on the laboratory pattern of patients with coronavirus disease 2019. Eur Rev Med Pharmacol Sci. 2021;25(1):518-22.##Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID‐19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18(7):1738-42.##Al-Samkari H, Gupta S, Leaf RK, Wang W, Rosovsky RP, Brenner SK, et al. Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19. Ann Intern Med. 2021;174(5):622-32.##Ortega-Paz L, Galli M, Capodanno D, Franchi F, Rollini F, Bikdeli B, et al. Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J Cardiovasc Pharmacother. 2021.##Guo Z, Sun L, Li B, Tian R, Zhang X, Zhang Z, et al. Anticoagulation management in severe coronavirus disease 2019 patients on extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth. 2021;35(2):389-97.##Vayne C, Rollin J, Gruel Y, Pouplard C, Galinat H, Huet O, et al. PF4 immunoassays in vaccine-induced thrombotic thrombocytopenia. N Engl J Med. 2021;385(4):376-8.##Singh B, Kanack A, Bayas A, George G, Abou-Ismail M, Kohlhagen M, et al. Anti-PF4 VITT antibodies are oligoclonal and variably inhibited by heparin. medRxiv. 2021.##Khave LJ, Zafari P, Pirsalehi A, Salari S, Baghestani A, Akbari ME, et al. Association between thrombocytopenia and platelet profile with morbidity/mortality of severe and non-severe COVID-19 patients. Rev Assoc Med Bras. 2021;67:1670-5.##Marietta M, Coluccio V, Luppi M. Potential mechanisms of vaccine-induced thrombosis. Eur J Intern Med. 2022.##Wolf ME, Luz B, Niehaus L, Bhogal P, Bäzner H, Henkes H. Thrombocytopenia and intracranial venous sinus thrombosis after "COVID-19 vaccine AstraZeneca" exposure. J Clin Med. 2021;10(8):1599.##Greinacher A, Schönborn L, Siegerist F, Steil L, Palankar R, Handtke S, et al., editors. Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT). Semin Hematol. 2022.##Zinatizadeh MR, Zarandi PK, Zinatizadeh M, Yousefi MH, Amani J, Rezaei N. Efficacy of mRNA, adenoviral vector, and perfusion protein COVID-19 vaccines. Biomed Pharmacother. 2022;146:112527.##Bashash D, Abolghasemi H, Salari S, Olfatifar M, Eshghi P, Akbari ME. Elevation of D-dimer, but not Pt and aPTT, reflects the progression of covid-19 toward an unfavorable outcome: a meta-analysis. IJBC 2020(12).##Gattringer T, Gressenberger P, Gary T, Wölfler A, Kneihsl M, Raggam RB. Successful management of vaccine-induced immune thrombotic thrombocytopenia-related cerebral sinus venous thrombosis after ChAdOx1 nCov-19 vaccination. Stroke Vasc Neurol. 2022;7(1).##Kollias A, Kyriakoulis KG, Lagou S, Kontopantelis E, Stergiou GS, Syrigos K. Venous thromboembolism in COVID-19: A systematic review and meta-analysis. Vas Med. 2021;26(4):415-25.##Franchini M, Liumbruno GM, Pezzo M. COVID‐19 Vaccine‐associated Immune Thrombosis and Thrombocytopenia (VITT): diagnostic and therapeutic recommendations for a new syndrome. Eur J Haematol. 2021;107(2):173-80.##Graf T, Thiele T, Klingebiel R, Greinacher A, Schäbitz W-R, Greeve I. Immediate high-dose intravenous immunoglobulins followed by direct thrombin-inhibitor treatment is crucial for survival in Sars-Covid-19-adenoviral vector vaccine-induced immune thrombotic thrombocytopenia VITT with cerebral sinus venous and portal vein thrombosis. J Neurol. 2021;268(12):4483-5.##Patriquin CJ, Laroche V, Selby R, Pendergrast J, Barth D, Côté B, et al. Therapeutic plasma exchange in vaccine-induced immune thrombotic thrombocytopenia. N Engl J Med. 2021;385(9):857-9.##Kohansal Vajari M, Shirin M, Pourbagheri‐Sigaroodi A, Akbari ME, Abolghasemi H, Bashash D. COVID‐19‐related coagulopathy: A review of pathophysiology and pharmaceutical management. Cell Biol Int. 2021;45(9):1832-50.##Chen P-W, Tsai Z-Y, Chao T-H, Li Y-H, Hou CJ-Y, Liu P-Y. Addressing vaccine-induced immune thrombotic thrombocytopenia (VITT) following COVID-19 vaccination: a mini-review of practical strategies. Acta Cardiol Sin. 2021;37(4):355.##Scutelnic A, Krzywicka K, Mbroh J, van de Munckhof A, van Kammen MS, de Sousa DA, et al. Management of Cerebral Venous Thrombosis Due to Adenoviral COVID‐19 Vaccination. Ann Neurol. 2022.##Rico-Mesa JS, Rosas D, Ahmadian-Tehrani A, White A, Anderson AS, Chilton R. The role of anticoagulation in COVID-19-induced hypercoagulability. Curr Cardiol Rep. 2020;22(7):1-6.##Hadid T, Kafri Z, Al-Katib A. Coagulation and anticoagulation in COVID-19. Blood Rev. 2021;47:100761.##Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID‐19 patients. J Thromb Haemost. 2020;18(7):1743-6.##Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, Syrigos K. Thromboembolic risk and anticoagulant therapy in COVID‐19 patients: emerging evidence and call for action. Br J Haematol. 2020;189(5):846-7.##Bilotta C, Perrone G, Adelfio V, Spatola GF, Uzzo ML, Argo A, et al. COVID-19 vaccine-related thrombosis: A systematic review and exploratory analysis. Front Immunol. 2021;12.##Thiele T, Weisser K, Schönborn L, Funk MB, Weber G, Greinacher A, et al. Laboratory confirmed vaccine-induced immune thrombotic thrombocytopenia: Retrospective analysis of reported cases after vaccination with ChAdOx-1 nCoV-19 in Germany. Lancet Reg Health Eur. 2022;12:100270.##Lacy J, Pavord S, Brown KE. VITT and second doses of Covid-19 vaccine. N Engl J Med. 2022;386(1):95-99.##Casucci G, Acanfora D. DIC-like syndrome following administration of ChAdOx1 nCov-19 vaccination. Viruses. 2021;13(6):1046.##Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag D, Hochman S, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.##Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384(23):2202-11.##Bayas A, Menacher M, Christ M, Behrens L, Rank A, Naumann M. Bilateral superior ophthalmic vein thrombosis, ischaemic stroke, and immune thrombocytopenia after ChAdOx1 nCoV-19 vaccination. The Lancet. 2021;397(10285):e11.##Castelli GP, Pognani C, Sozzi C, Franchini M, Vivona L. Cerebral venous sinus thrombosis associated with thrombocytopenia post-vaccination for COVID-19. Crit Care. 2021;25(1):1-2.##Franchini M, Testa S, Pezzo M, Glingani C, Caruso B, Terenziani I, et al. Cerebral venous thrombosis and thrombocytopenia post-COVID-19 vaccination. Thromb Res. 2021;202:182-3.##Mehta PR, Mangion SA, Benger M, Stanton BR, Czuprynska J, Arya R, et al. Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination-A report of two UK cases. Brain Behav Immun. 2021;95:514-7.##Blauenfeldt RA, Kristensen SR, Ernstsen SL, Kristensen CCH, Simonsen CZ, Hvas AM. Thrombocytopenia with acute ischemic stroke and bleeding in a patient newly vaccinated with an adenoviral vector‐based COVID‐19 vaccine. J Thromb Haemost. 2021;19(7):1771-5.##Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384(22):2124-30.##D'agostino V, Caranci F, Negro A, Piscitelli V, Tuccillo B, Fasano F, et al. A rare case of cerebral venous thrombosis and disseminated intravascular coagulation temporally associated to the COVID-19 vaccine administration. J Pers Med. 2021;11(4):285.##Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021;384(22):2092-101.## ##

Gold nanoparticles in radiation therapy: an old story yet mesmerizing 2 2 Radiotherapy (RT) is generally considered to be one of the most effective cancer treatments. The primary goal of RT is to accurately induce radiation damage to the tumor while limiting radiation toxicity to a level acceptable to normal tissue. This is accomplished by targeting the tumor with radiation. On the other hand, the status of RT procedures as they stand today is not substantial enough to eliminate advanced metastatic and radio-resistant hypoxic tumors. Radiologists and medical physicists all face the same fundamental challenge of improving treatment efficacy while minimizing damage to surrounding healthy tissue. Through a process called radio-sensitization, tumor cells become more sensitive to the damaging effects of radiation. Therefore, radiosensitizers are compounds that are either medicinal or inactive and boost the efficacy of radiation treatment. In the last few years, there has been a surge of interest in the use of formulations to enhance the effectiveness of radiotherapy, especially when employing metallic, primarily gold-based nanoparticles. The aim of combining NPs with radiation therapy is to enhance the differential effect of treatment between normal and malignant cells. Gold nanoparticles (AuNPs) have been the most widely investigated nanoplatforms for use in radiation therapy due to their high X-ray absorption rate and synthetic modifiability, which allows precise control over the physical properties of the particles. We only highlight the radio-sensitization characteristics of gold nanoparticles in cancer treatment in the current review article. 140 149 2022/09/142022/10/202022/09/162022/05/222022/11/102022/10/242022/10/9 1401/7/17 2022/12/222022/12/152022/12/162022/12/22022/12/122022/12/82022/12/14 1401/9/23 Yasamin Kavousi Yasamin Kavousi Non-communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran yasamin.kavousii@gmail.com Mohadeseh Mohammadi Mohammadi Mohadeseh Mohammadi Mohammadi Department of Radiology Technology, Shahid Beheshty University of Medical Sciences ,Tehran, Iran. Iran mohadese.mohamadi14@gmail.com Mahdieh Ahmadikamalabadi Mahdieh Ahmadikamalabadi Non-communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran Iran mkniloo@yahoo.com Fereshteh Koosha Fereshteh Koosha Department of Radiology Technology, Shahid Beheshty University of Medical Sciences ,Tehran, Iran. Iran frshtkoosha@yahoo.com Nanoparticles AuNPs Radiotherapy Cancer treatment ## ##

The Iranian Childhood Cancer Biobank 2 2 Background: Biological resources, along with patient-related clinical data, are basically required for personalized medicine and translational research. In this regard, pediatric cancer biobanks have considerable significance due to their special challenges, which include the need for long-term sample collection (due to high diversity and rare tumors), the difficulty of working with children, as well as the limited volume of samples available in children. Methods: After obtaining all necessary approvals (from the ethics committee, scientific board, and financial support), standard operating procedures (SOPs) were defined for all aspects of the biobank procedures, including equipping the lab, sample collection, processing, storage, as well as clinical data recording. Results: Until July 2022, approximately 8,000 samples from 720 patients have been collected in the biobank. In summary, the samples in the biobank are classified into three categories: leukemia (40.7%), solid tumors (39.44%), and central nervous system tumors (15.56%). The unique activities of the biobank include the collection of various biological samples from patients and their parents, inter-university cooperation, the use of a vacuum system to preserve tissue, the launching of an online database for recording patients' medical data, and the setting up of a bilingual website for announcements at the national and international levels. Conclusion: Iranian Childhood Cancer Biobank (ICCBB) is the first pediatric biobank center in Iran that collects various samples and associated clinical data from patients with a wide range of childhood cancers. The ICCBB aims to advance clinical research in the field of pediatric cancer by providing both the required quantity and quality of biological samples. 150 156 2022/09/142022/10/202022/09/162022/05/222022/11/102022/10/242022/10/92022/09/8 1401/6/17 2022/12/222022/12/152022/12/162022/12/22022/12/122022/12/82022/12/142022/11/19 1401/8/28 Peyman Eshghi Peyman Eshghi Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran peshghi64@gmail.com Nasrin Dehghan-Nayeri Nasrin Dehghan-Nayeri Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran nasrindehghan10@gmail.com Maryam Kazemi Aghdam Maryam Kazemi Aghdam Pediatric Pathology Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran m_kazemi_aghdam@yahoo.com Yalda Nilipour Yalda Nilipour Pediatric Pathology Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran yalnil@yahoo.com Mohsen Rouzrokh Mohsen Rouzrokh Pediatric Surgery Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran mohsen_rouzrokh@yahoo.com Zahra Badiei Zahra Badiei Department of Pediatric Hematology-Oncology, Dr Sheikh Pediatric Hospital, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran Iran badieez@mums.ac.ir Hamid Farhangi Hamid Farhangi Department of Pediatric Hematology-Oncology, Dr Sheikh Pediatric Hospital, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran Iran farhangih@mums.ac.ir Mehran Noroozi Mehran Noroozi Maternal and Childhood Obesity Research Center, Urmia University of Medical Sciences, Urmia, Iran Iran mehranxnoroozi@gmail.com Hasan Reza Mohammadi Hasan Reza Mohammadi Department of Neurosurgery, Mofid children’s hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran hrmohamadi@sbmu.ac.ir Ehsan Moradi Ehsan Moradi Department of Neurosurgery, Mofid children’s hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran moradieh@sbmu.ac.ir Samin Alavi Samin Alavi Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran saminalavi@hotmail.com Leily Mohajerzadeh Leily Mohajerzadeh Pediatric Surgery Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran mohajerzadehl@yahoo.com Shahin Shamsian Shahin Shamsian Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran shahinshamsian@gmail.com Ahmad Khaleghnejad Tabari Ahmad Khaleghnejad Tabari Pediatric Surgery Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran khaleghnejad@gmail.com Javad Ghoroubi Javad Ghoroubi Pediatric Surgery Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran jghoroubi@yahoo.com Nader Momtazmanesh Nader Momtazmanesh Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran nmomtazmanesh@yahoo.com Mehdi Sarafi Mehdi Sarafi Pediatric Surgery Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran mehdicalls@yahoo.com Reza shojaeian Reza shojaeian Department of General Surgery, Mashhad University of Medical Science, Mashhad, Iran Iran kalipoopo@gmail.com Paria Dehghanian Paria Dehghanian Department of Pathology, Akbar children’s hospital, Mashhad, Iran Iran Dehghanianp2@mums.ac.ir Parastoo Molaei Tavana Parastoo Molaei Tavana Department of Pediatrics, Loghman Hakim hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran dr_p1984@yahoo.com Cancer Biobank Children Pediatric cancer biobank ## ##