Staging by TNM.
\r\n\tIn sum, the book presents a reflective analysis of the pedagogical hubs for a changing world, considering the most fundamental areas of the current contingencies in education.
",isbn:"978-1-83968-793-8",printIsbn:"978-1-83968-792-1",pdfIsbn:"978-1-83968-794-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"b01f9136149277b7e4cbc1e52bce78ec",bookSignature:"Dr. María Jose Hernandez-Serrano",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10229.jpg",keywords:"Teacher Digital Competences, Flipped Learning, Online Resources Design, Neuroscientific Literacy (Myths), Emotions and Learning, Multisensory Stimulation, Citizen Skills, Violence Prevention, Moral Development, Universal Design for Learning, Sensitizing on Diversity, Supportive Strategies",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 14th 2020",dateEndSecondStepPublish:"October 12th 2020",dateEndThirdStepPublish:"December 11th 2020",dateEndFourthStepPublish:"March 1st 2021",dateEndFifthStepPublish:"April 30th 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Phil. Maria Jose Hernandez Serrano is a tenured lecturer in the Department of Theory and History of Education at the University of Salamanca, where she currently teaches on Teacher Education. She graduated in Social Education (2000) and Psycho-Pedagogy (2003) at the University of Salamanca. Then, she obtained her European Ph.D. in Education and Training in Virtual Environments by research with the University of Manchester, UK (2009).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"187893",title:"Dr.",name:"María Jose",middleName:null,surname:"Hernandez-Serrano",slug:"maria-jose-hernandez-serrano",fullName:"María Jose Hernandez-Serrano",profilePictureURL:"https://mts.intechopen.com/storage/users/187893/images/system/187893.jpg",biography:"DPhil Maria Jose Hernandez Serrano is a tenured Lecturer in the Department of Theory and History of Education at the University of Salamanca (Spain), where she currently teaches on Teacher Education. She graduated in Social Education (2000) and Psycho-Pedagogy (2003) at the University of Salamanca. Then, she obtained her European Ph.D. on Education and Training in Virtual Environments by research with the University of Manchester, UK (2009). She obtained a Visiting Scholar Postdoctoral Grant (of the British Academy, UK) at the Oxford Internet Institute of the University of Oxford (2011) and was granted with a postdoctoral research (in 2021) at London Birbeck University.\n \nShe is author of more than 20 research papers, and more than 35 book chapters (H Index 10). She is interested in the study of the educational process and the analysis of cognitive and affective processes in the context of neuroeducation and neurotechnologies, along with the study of social contingencies affecting the educational institutions and requiring new skills for educators.\n\nHer publications are mainly of the educational process mediated by technologies and digital competences. Currently, her new research interests are: the transdisciplinary application of the brain-based research to the educational context and virtual environments, and the neuropedagogical implications of the technologies on the development of the brain in younger students. Also, she is interested in the promotion of creative and critical uses of digital technologies, the emerging uses of social media and transmedia, and the informal learning through technologies.\n\nShe is a member of several research Networks and Scientific Committees in international journals on Educational Technologies and Educommunication, and collaborates as a reviewer in several prestigious journals (see public profile in Publons).\n\nUntil March 2010 she was in charge of the Adult University of Salamanca, by coordinating teaching activities of more than a thousand adult students. She currently is, since 2014, the Secretary of the Department of Theory and History of Education. Since 2015 she collaborates with the Council Educational Program by training teachers and families in the translation of advances from educational neuroscience.",institutionString:"University of Salamanca",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Salamanca",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6942",title:"Global Social Work",subtitle:"Cutting Edge Issues and Critical Reflections",isOpenForSubmission:!1,hash:"222c8a66edfc7a4a6537af7565bcb3de",slug:"global-social-work-cutting-edge-issues-and-critical-reflections",bookSignature:"Bala Raju Nikku",coverURL:"https://cdn.intechopen.com/books/images_new/6942.jpg",editedByType:"Edited by",editors:[{id:"263576",title:"Dr.",name:"Bala",surname:"Nikku",slug:"bala-nikku",fullName:"Bala Nikku"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"65846",title:"Treatment of Children with Osteosarcoma",doi:"10.5772/intechopen.83756",slug:"treatment-of-children-with-osteosarcoma",body:'\nOsteosarcoma is a primary malignant bone tumor that develops from primitive mesenchymal stem cells capable of differentiating into bone, cartilage, or fibrous tissue [1].
\nOsteosarcoma accounts for 3% of all malignant tumors, 35–50% of all malignant bone tumors in pediatric patients. The frequency of occurrence is 4 cases per 1 million children and adolescents per year. About 60% of cases of osteosarcoma detection are recorded at the age of 10–20 years (mainly in the prepubertal and pubertal periods). The gender ratio (boys/girls) is 1.3–1.6:1 [2].In 50% of cases, the tumor is located in the projection of the knee joint (distal femur, proximal tibial bone). The third place in terms of frequency of occurrence is the lesion of the proximal metadiaphysis of the humerus. The defeat of the axial skeleton (pelvis, spinal column) is detected in 12% of cases [3, 4, 5].
\nIn the treatment of children with osteosarcoma, chemotherapy is the main method. Nonadjuvant and adjuvant chemotherapy courses are important. In the middle of the twentieth century, when the main treatment was surgical, the frequency of relapse and metastasis was extremely high. Increased patient survival is due precisely to the intensification of chemotherapeutic treatment, which has reduced the frequency of relapses and metastasis.
\nA localized (locally advanced) variant of osteosarcoma, which occurs in 80% of cases and a disseminated (primary metastatic) variant, which occurs in 20% of cases, are distinguished [3, 6].
\n\n
low grade, central osteosarcoma
classic (conventional) version of osteosarcoma:
chondroblastic osteosarcoma
fibroblastic osteosarcoma
osteoblastic osteosarcoma
osteosarcoma, unspecified accuracy
telangiectatic osteosarcoma
small cell osteosarcoma
high degree of malignancy, superficial osteosarcoma.
\n
T—primary tumor
Tx—the primary tumor cannot be determined [7].
T0—no signs of primary tumor.
T1—the largest tumor size ≤8 cm.
T2—the largest tumor size>8 cm.
T3—several unrelated tumors in the primary zone of bone damage.
N—regional lymph nodes:
Nx—the presence of metastatic lesions in the regional lymph nodes cannot be determined.
N0—no regional metastases in the lymph nodes.
N1—regional lymph node metastases.
M—distant metastases:
Mx—the presence of distant metastases could not be determined or the study was not conducted.
M0—distant metastases are absent.
M1—there are distant metastases.
M1a—in the lungs.
M1b—another localization.
G—degree of differentiation:
Gx—the degree of differentiation could not be determined or the study was not conducted.
G1—well differentiated.
G2—moderately differentiated.
G3—poorly differentiated.
G4—undifferentiated.
G1–2—low degree of malignancy.
G3–4—a high degree of malignancy.
TX | \nPrimary tumor cannot be assessed | \n
T0 | \nNo evidence of primary tumor | \n
T1 | \nTumor confined to one pelvic segment with no extraosseous extension | \n
T1a | \nTumor ≤8 cm in greatest dimension | \n
T1b | \nTumor >8 cm in greatest dimension | \n
T2 | \nTumor confined to one pelvic segment with extraosseous extension or two segments without extraosseous extension | \n
T2a | \nTumor ≤8 cm in greatest dimension | \n
T2b | \nTumor >8 cm in greatest dimension | \n
T3 | \nTumor spanning two pelvic segments with extraosseous extension | \n
T3a | \nTumor ≤8 cm in greatest dimension | \n
T3b | \nTumor >8 cm in greatest dimension | \n
T4 | \nTumor spanning three pelvic segments or crossing the sacroiliac joint | \n
T4a | \nTumor involves sacroiliac joint and extends medial to the sacral neuroforamen | \n
T4b | \nTumor encasement of external iliac vessels or presence of gross tumor thrombus in major pelvic vessels | \n
NX | \nRegional lymph nodes cannot be assessed. Because of the rarity of lymph node involvement in bone sarcomas, the designation NX may not be appropriate, and cases should be considered N0 unless clinical node involvement clearly is evident | \n
N0 | \nNo regional lymph node metastasis | \n
N1 | \nRegional lymph node metastasis | \n
cM0 | \nNo distant metastasis | \n
cM1 | \nDistant metastasis | \n
cM1a | \nLung | \n
cM1b | \nBone or other distant sites | \n
pM1 | \nDistant metastasis, microscopically confirmed | \n
cM1a | \nLung, microscopically confirmed | \n
cM1b | \nBone or other distant sites. Microscopically confirmed | \n
Staging according to the TNM classification is presented in Table 1.
\nStage | \nTNM | \nDegree of malignancy | \n
---|---|---|
IA | \nT1 N0 M0 | \nLow | \n
IB | \nT2 N0 M0 | \nLow | \n
IIA | \nT1 N0 M0 | \nHigh | \n
IIB | \nT2 N0 M0 | \nHigh | \n
III | \nT3 N0 M0 | \nAny | \n
IVA | \nAny Т N0 M1a | \nAny | \n
IVB | \nAny Т N1 Any М Any Т Any N М1b | \nAny Any | \n
Staging by TNM.
The methods of treatment of osteosarcoma over the past 30 years have not changed. There are five main drugs (cisplatin, adriamycin, methotrexate, ifosfamide, and etoposide) that have been used in various combinations and doses [8, 9, 10, 11, 12, 13].
\nThe rates of treatment outcome in the world remain at about the same level. In patients with a localized variant of osteosarcoma, 5-year overall survival (OS) does not exceed 75% and 5-year event-free survival (EFS)—62% (Table 2).
\nTherapy program | \n5-year overall survival, % | \n5-year event-free survival, % | \n
---|---|---|
IOR/OS2 the Istituto Ortopedico Rizzoli [14] | \n75 | \n63 | \n
ISG/OS1 (Italian Sarcoma Group) [15] | \n74 | \n64 | \n
ISG/SSG1 (Italian and Scandinavian Sarcoma Group) [16] | \n77 | \n64 | \n
COSS 88/96 (Cooperative Osteosarcoma Study Group) [17] | \n79 | \n\n |
SSG XIV (Scandinavian Sarcoma Group) [18] | \n\n | 65 | \n
NECO93J/95J (Neoadjuvant Chemotherapy for Osteosarcoma) [19] | \n78 | \n65 | \n
BOTG III/IV (Brazilian Osteosarcoma Treatment Group) [20] | \n61 | \n45 | \n
POG8651 (Pediatric Oncology Group) [21] | \n78 | \n65 | \n
SFOP94 (Société Française d’Oncologie Pédiatrique) [22] | \n76 | \n62 | \n
St.Jude CRH OS91 (Children Research Hospital) [23] | \n74 | \n65 | \n
St.Jude CRH OS99 (Children Research Hospital) [24] | \n79 | \n67 | \n
INT0133-COG (+MTP/-MTP) Children’s Oncology Group [25] | \n78/70 | \n67/61 | \n
MSKC NY (+PAM) Memorial Sloan-Kettering Cancer Center, NY [26] | \n94 | \n72 | \n
COG INT0133, CCG7943, AOST0121 [27] | \n47 | \n22 | \n
ISG/SSG II (Italian and Scandinavian Sarcoma Group) [28] | \n55 | \n46 | \n
EURAMOS1 [29, 30] | \n75 | \n59 | \n
The results of the treatment of pediatric patients with localized osteosarcoma.
In patients with primary metastatic osteosarcoma, the results are much worse, despite attempts to use high doses of drugs, including high-dose polychemotherapy with transplantation of autologous hematopoietic stem cells. At the same time, the 5-year OS does not exceed 35% on average and the 5-year EFS–25% (Table 2).
\nThe most significant interest in the treatment of children with a localized version of osteosarcoma are the studies of the Italian and Scandinavian groups (Italian and Scandinavian sarcoma group–ISG/SSGI, SSG XIV), the French Pediatric Oncological Group (Societe Francaise d’Oncologie Pediatrique–SFOP OS94), and EURAMOS1.
\nFerrari et al. showed the data of the joint study of the Italian and Scandinavian groups (ISG/SSG I), which was conducted from 1997 to 2000. The study included 182 patients.
\nA special feature of neoadjuvant chemotherapy was the use of two courses of monotherapy with high-dose ifosfamide (in a course dose of 15 g/m2) and two courses of MAR (methotrexate (M) 12 g/m2, adriamycin (A) 75 mg/m2, and cisplatin (P) 120 mg/m2) in alternating mode. Adjuvant chemotherapy started at week 14. In this case, the course dose of adriamycin was increased to 90 mg/m2, the dose of cisplatin to 150 mg/m2, and a high-dose ifosfamide was administered in PIM chemotherapy courses (cisplatin, ifosfamide, and methotrexate) and PAI (cisplatin, adriamycin, and ifosfamide).
\nAfter removal of the primary tumor focus, a good histological response (therapeutic pathomorphism of grade 3–4) was achieved in 63% of patients, a poor histological response (treatment pathomorphism of grade 1–2) in 37%. At the same time, the 5-year OV and EFS accounted for 77 and 64%. Consequently, the use of high-dose ifosfamide in an alternating mode with the MAP scheme led to an increase in the frequency of achieving a good histological response, but did not affect the rates of OS and EFS [15, 16, 31].
\nSmeland et al. presented the data of the study of the Scandinavian Group (SSG XIV), which was conducted from 2001 to 2005. The study included 63 patients.
\nNeoadjuvant chemotherapy consisted of two courses of IDA. High-dose ifosfamide (in the course dose of 10 g/m2) was used in monotherapy in patients with a poor histological response to treatment, only after five courses of MAP.
\nAfter removal of the primary tumor lesion, a good histological response was achieved in 45% of patients and a poor histological response in 55%. At the same time, the 5-year OV and BSV accounted for 76–65% and the 5-year EFS in the group with a good histological response for 89%, with a poor histological response 48%. Consequently, the use of ifosfamide after MAP courses in the adjuvant mode did not lead to an increase in OS and EFS, and the frequency of achieving a good histological response was lower than in studies in which the MAP scheme was used in alternating mode with ifosfamide [18].
\nLe Deley et al. presented the results of the randomized SFOP OS94 study, which was conducted from 1994 to 2001. The study included 239 patients (120 in group A and 119 in group B).
\nNeoadjuvant therapy included seven courses of high-dose methotrexate and two courses of monotherapy with adriamycin (in a course dose of 70 mg/m2) in group A or seven courses of high-dose methotrexate and two courses of IE (ifosfamide (I) 12 g/m2 and etoposide (E) 300 mg/m2) in group B. In the adjuvant mode, chemotherapy was replaced with IE courses in group A, and AP in group B for patients with a poor histological response detected after removal of the primary focus. The operative stage of treatment was carried out at 12 and 14 weeks in groups A and B, respectively.
\nA good histological response was achieved in group A in 43% of patients, in group B in 64%, poor histological response in group A in 57%, and in group B in 36% (p = 0.009). The 5-year OS in group A was 75%, in group B—76%, the 5-year EFS in group A—58%, and in group B—66%. A 3-year EFS in group A in patients showed a good histological response for 82%, with a poor histological response for 49%, in group B—77 and 60%, respectively.
\nConsequently, the use of methotrexate, ifosfamide and etoposide in neoadjuvant chemotherapy led to a statistically significant increase in the frequency of achieving a good histological response, but not to an increase in OS and EFS [22].
\nOf particular interest in the treatment of children with primary metastatic osteosarcoma are the Pediatric Oncology Group (POG) IE and ISG/SSG II studies.
\nGoorin et al. presented the results of a phase II/III nonrandomized clinical trial of high-dose ifosfamide and etoposide in patients with primary metastatic osteosarcoma. The study included 43 patients.
\nNeoadjuvant chemotherapy was represented by two courses of IE (ifosfamide (I) 17.5 g/m2 and etoposide (E) 500 mg/m2). Removal of the primary tumor lesion was performed after two courses of IE at 7–8 weeks of therapy. The timing of the removal of metastatic foci was chosen individually during adjuvant chemotherapy, which included four courses of MAP chemotherapy and three courses of iE (with a course dose of ifosfamide (i) 12 g/m2) in an alternating mode.
\nA good histological response was achieved in 65% of patients and poor in 35%. However, the 2-year OS and EFS were 55 and 45%, respectively. Consequently, the use of high-dose ifosfamide in combination with etoposide therapy led to an increase in the frequency of achieving a good histological response, but not indicators of OS and EFS [32].
\nBoye et al. showed the results of the nonrandomized study ISG/SSG II, which was conducted from 1996 to 2004. The study included 57 patients with primary metastatic osteosarcoma.
\nNeoadjuvant chemotherapy included two courses of MAPI. Surgical removal of the primary tumor lesion was performed at week 14.
\nIn the adjuvant mode, two courses of ACyVP (adriamycin (A) 90 mg/m2, cyclophosphamide (Cy) 4 g/m2, and vepesid (VP) 600 mg/m2) and two courses of high-dose chemotherapy VPCarbo (vepesid (VP) 600 mg/m2 and carboplatin (Carbo) 1.5 g/m2) with the support of autologous hematopoietic stem cells. Surgical removal of the primary tumor lesion was performed at week 14.
\nA good histological response was achieved in 29% of patients and poor in 71%. The 5-year OM and BSV were 31 and 27%, respectively [28].
\nMarina et al. presented the results of the EURAMOS1 study in patients with a poor histological response after neoadjuvant MAP chemotherapy. Within the protocol, patients are randomly assigned to the MAP treatment lines (methotrexate (M) 12 g/m2, adriamycin (A) 75 mg/m2, and cisplatin (P) 120 mg/m2) and MAPIE (ifosfamide (I) 14 g/m2 and etoposide 500 mg/m2). In the age group up to 30 years, the MAPIE line of therapy was carried out in 310 patients, the MAPIE line in 308 patients, in the age group up to 20 years—259 (84%) and 271 (88%) patients. Groups of patients are statistically significantly comparable by sex, age, localization of the primary tumor lesion, the presence of metastatic lesions, and the histological variant of the tumor.
\nIn the group of 541 patients with a localized version of osteosarcoma, 247 events were identified, 118 in patients who received the MAP therapy line and 129 in patients who received the MAPIE therapy line. At the same time, the 3-year EFS was 60 and 57%. In the group of patients with primary metastatic osteosarcoma, 3-year EFS was 24 and 18%, for MAP and MAPIE, respectively. Therefore, this study showed that the use of alternating chemotherapy courses for MAP, IE, and Ai in an adjuvant regimen did not lead to an increase in EFS indices [33].
\nTreatment outcomes for children with primary metastatic osteosarcoma remain extremely low and the optimal therapeutic strategy is unknown.
\nNew programs are being developed around the world taking into account the molecular biological features of tumor cells that determine sensitivity to chemotherapy (ERCC1 to cisplatin, TOPO2α to anthracyclines and etoposide, MGMT to epigenetic therapy and cisplatin, RFC1 to methotrexate) [34, 35, 36, 37, 38, 39] and invasive and metastatic potential of a tumor (stem cell markers—CD133, OCT4; transcription factors—p-STAT3, C-MYC; cytokine-associated signaling pathways—ErbB2, VEGFR1, VEGFR2, PDGFRα, and PDGFRβ) [40, 41, 42, 43].
\nCui et al. presented the results of a study to determine the expression of MGMT protein (methylguanine–DNA–methyltransferase) and MGMT gene methylation in patients with osteosarcoma in the age group up to 40 years (mean age 17 years) who were treated with cisplatin in single mode, in a course dose of 120 mg/m2 Determination of MGMT protein expression in immunohistochemical (IHC) study was performed in biopsy tumor material in 76 patients and MGMT gene methylation in 51 patients. The result of IHC was considered positive with a high level of expression—more than 30% (3+), with an average level of expression—20–30% (2+), and with a low level of expression—10–20% (1+). MGMT protein expression was detected in 52 (68%) patients, low expression level in 27 (35%), medium level in 18 (24%), and high level in 7 (9%).
\nA statistically significant relationship was established between the presence of MGMT protein expression and an increase in the frequency of a poor histological response (p = 0.004). The expression level above 20% was detected in 22 out of 43 (51%) patients in the group of patients with 1–2°of therapeutic pathomorphosis and only in 3 out of 33 (9%) patients in the group with 3–4° of therapeutic pathomorphosis.
\nMethylation of the promoter portion of the MGMT gene was observed in 12 of 51 (23.5%) patients and the lack of expression of MGMT protein in 14 of 51 (27.5%) patients. A statistically significant relationship between the absence of methylation and the presence of MGMT protein expression (p < 0.001) was established. In the group of patients with 1–2 degrees of therapeutic pathomorphosis, the absence of MGMT gene methylation was detected in 36 of 38 (94.7%) patients and with 3–4 degrees of therapeutic pathomorphosis in 3 of 13 (23%) patients (p < 0.001).
\nConsequently, the data obtained indicate the formation of tumor resistance to treatment with an alkylating agent—cisplatin in patients whose biopsy material revealed the absence of methylation of the promoter portion of the MGMT gene and the presence of expression of the MGMT protein [34, 35].
\nPitano-Garcia et al. (Spain sarcoma group) conducted a study to determine the expression of RFC1 micro-RNA (reduced folate carrier 1, a transmembrane protein that provides folate and methotrexate transport to the cell) by real-time polymerase chain reaction (PCR) in a tumor substrate in children with osteosarcoma.
\nIn 34 samples, biopsy tumor material in 14 children and metastatic foci tumor material in 20 children were analyzed. In 13 of 14 (92.9%) biopsy specimens and in 11 of 20 (68.8%) metastatic specimens, a low level of RFC1 expression was detected.
\nA poor histological response after neoadjuvant chemotherapy (three courses of intravenous administration of doxorubicin at a dose of 75 mg/m2, three courses of intraarterial administration of cisplatin at a dose of 105 mg/m2, four courses of intravenous administration of methotrexate at a dose of 14 g/m2) in 45% of cases. The biopsy tumor substrate in this group of patients was characterized by a low level of expression of RFC1 micro-RNA in 90% of cases compared to 60% in patients with a good histological response (p = 0.053). The average level of expression was statistically significantly lower in the biopsy material than in the metastatic tumor foci (p = 0.024) [38, 44].
\nTherefore, in this study, there was a tendency to an increase in the frequency of detection of low expression levels of RFC1 micro-RNA in patients with a poor histological response.
\nHattinger et al. (Italian sarcoma group) presented the results of the study, the purpose of which was to determine the prognostic significance of ERCC1 protein expression (excision repair crosscomplementation group 1) in biopsy tumor material in patients with localized osteosarcoma, who underwent programmed treatment of ISG/OS-oss and ISG/SSG1. A tumor sample was considered positive in the presence of a score of 2–3: score 1 (1–10% of positive nuclei), score 2 (11–50% of positive nuclei), and score 3 (more than 50% of positive nuclei).
\nERCC1-positive tumor (score 2–3) was detected in 30 patients (30%). During the ISG/OS-oss program in groups of patients with ERCC1-negative/score 1 and ERCC1-positive (score 2–3), the 5-year-old OS and BSV tumor variants were 91, 38, and 57, 25% (p = 0.001; p = 0.042), with the ISG/SSG1 program–82, 64, and 69, 36% (p = 0.022; p = 0.028), and with both therapy programs–82, 50 and 62, 34% (p < 0.001; p = 0.006). Consequently, a statistically significant relationship has been established between the ERCC1-positive variant of the tumor and lower rates of 5-year OS and BSV [36].
\nNguyen et al. (SFOP) presented the results of a study to determine the prognostic significance of TOP2A protein expression (topoisomerase DNA 2 alfa) and the presence of rearrangement of the TOP2A gene in biopsy tumor material in 105 children with osteosarcoma treated with the SFOP protocol OS94. Patients with a primary metastatic osteosarcoma variant accounted for 17%. After neoadjuvant chemotherapy, a good histological response was detected in 56 patients (53%) and a poor histological response in 49 (47%). Real-time PCR amplification of the TOP2A gene and the TOP2A gene deletion were detected in 21 (21.2%) and 25 (25.3%) patients. In 53 children (53.5%), rearrangements of the TOP2A gene were not detected. A statistically significant relationship was established between the presence of the TOP2A gene rearrangement (amplification and deletion) and the presence of a good histological response after neoadjuvant polychemotherapy (p = 0.004). There was also a tendency to achieve lower rates of 5-year OM and BSV in patients whose tumor cells had amplified the TOP2A gene (p = 0.09 and 0.06). The expression of the TOR2A protein was determined in 17 patients by immunohistochemistry. Medium (2+) and high (3+) levels of expression were detected in all patients; expression was above 30% in 12 of 17 children (70.5%). There is no statistically significant relationship between the expression of the TOR2A protein above 30% and the presence of amplification or deletion of the TOP2A gene (p > 0.05) due to an insufficient number of observations [37].
\nXiao et al. presented the results of a study of a personalized approach to the prescription of chemotherapy depending on the presence or absence of markers of drug resistance in 28 patients with localized osteosarcoma. The average age in the patient group was 20.1 g. To determine the sensitivity to chemotherapy, the following markers were used: for doxorubicin–expression of TOP2A micro-RNA, mutation of the ABCB1 gene, and mutation of the GSTP1 gene; for cisplatin–expression of microcryptal ERCC1, BRCA1, and mutation of genes XRCC1-exon6 and XRCC1-exon10, and for ifosfamide–mutation of CYP2C9 * 3.
\nAt the same time, a high level of sensitivity to ifosfamide was detected in all patients (100%), to cisplatin in 11 out of 28 (39.2%), to doxorubicin in 6 out of 28 (21.4%); medium and high levels of sensitivity to cisplatin in 17 of 28 (60.7%), to doxorubicin in 20 of 28 (71.4%). Chemotherapy, taking into account the sensitivity of the tumor to drugs, was performed in 8 of 28 patients (28.5%). In this group, only one relapse of the disease was detected, while in the rest of the 20 patients, four relapses of the disease were detected: in one case, progression during neoadjuvant chemotherapy and in another case, fatal outcome from toxicity of therapy. The average duration of observation for groups was not indicated, and no statistically significant difference was obtained due to the insufficient number of observations [39].
\nIn addition, the study of markers of stem tumor cells CD133 (Prominin 1) and Octamer-binding transcription factor 4 (OCT4), as well as the transcription factors signal transducer and activator of transcription 3 (STAT3), and myelocytomatosis viral oncogene homolog (C-MYC), which determines the invasive and metastatic potential of a tumor [45, 46, 47].
\nSo in the work of He et al., there was a significant correlation between the expression of CD133 in tumor cells and a higher frequency of metastatic lesions, a lower median of overall survival. A CD133-positive variant was detected in 46 of 70 (65.7%) patients, in 6 out of 16 (37.5%) in the group with a localized osteosarcoma variant, and in 40 out of 54 (74%) in the group with the primary metastatic osteosarcoma (p = 0.002). The median overall survival rate was statistically significantly lower in the group with CD133-positive tumor (p = 0.000). When conducting the study “Transwell invasion,” a significantly higher invasive potential of the CD133-positive variant of the tumor was established (p < 0.05). Real-time PCR established a higher level of expression of micro-RNA OCT4 in a CD133-positive variant of the tumor (p < 0.05) [41].
\nLi et al. in an experimental model on cell lines showed that about 80% of cells in a CD133-positive variant of the tumor are in the G0/G1 phases of the cell cycle (p < 0.01). Also, real-time PCR revealed a significantly higher level of expression of the multidrug-resistant gene (MDR1) in the CD133-positive variant of the tumor (p < 0.05) [48].
\nIn the studies presented, He and Li et al., the mechanisms of drug resistance, invasion, and metastasis in case of CD133-positive variant of the tumor were established.
\nIn the works of Tu et al., the significance of activation of the IL6R/STAT3/p-STAT3tyr705 mesenchymal stem cell signaling pathway to increase the metastatic potential of tumor cells was exemplified by the example of cell lines (Saos 2 and U2-OS). The relationship between the increased expression of p-STAT3tyr705 and increased expression of the drug resistance markers multidrug resistance protein (MRP) and MDR1 has been established. An increase in sensitivity to doxorubicin, but not to cisplatin, was also noted with inhibition of this signaling pathway [43, 49].
\nHan et al. using cell lines (MG63 and SAOS2) as an example showed that an increase in C-MYC expression leads to activation of the MEK–ERK signaling pathway and an increase in the expression of MMP2 and MMP9, which enhance the invasive and metastatic potential of a tumor [50].
\nWu et al. investigated the prognostic significance of C-MYC expression in biopsy tumor material in 56 children with osteosarcoma who were treated with methotrexate, cisplatin, and adriamycin. Expression of the C-MYC protein was detected in 48 of 56 (85.7%) patients. A statistically significant relationship was established between the presence of C-MYC expression and a decrease in the apoptotic index (p < 0.05). In addition, in the group of patients with C-MYC-positive variant of the tumor and the intensity of expression, at 2+ and 3+, a significantly lower 3-year-old OM was established (p < 0.05) [51].
\nConsequently, in the works of Tu, Han, and Wu et al., the significance of transcription factors in the development of drug resistance, invasion, and metastasis of the tumor has been established.
\nInnovative therapeutic approaches are used mainly in patients with metastatic osteosarcoma, relapse, and refractory course of the disease. Currently, the following key areas are distinguished: (1) the use of monoclonal antibody preparations, (2) tumor-modifying therapy using nitrogen-containing bisphosphonates, (3) the use of chemotherapeutic drugs that affect various cellular signaling pathways (multikinase inhibitors and mTOR inhibitors), and (4) the use of drugs that promote the activation of tumor-associated macrophages.
\nRossi et al. presented the results of a study aimed at determining the expression of vascular endothelial growth factor (VEGF) in a biopsy tumor substrate and in tumor material after neoadvanting chemotherapy (two courses of MAP) in 16 patients with localized osteosarcoma, who received programmed treatment using the SSG XIV protocol. Four levels of expression were evaluated: negative and low–at an expression level <25%, medium—at 25–50% (1+), high—at 50–75% (2+), and very high—at>75% (3+). Medium and high levels of VEGF expression in biopsy tumor material were detected in 11 (6 in medium and 5 in high) out of 16 patients (68.7%). After neoadjuvant chemotherapy and the removal of the primary tumor site, VEGF expression was established in all samples, and there was an increase in expression in samples that were positive in the initial study.
\nHigh and very high levels of expression, increased expression after neoadjuvant chemotherapy was statistically significantly correlated with the localization of the primary tumor lesion in the femur (p = 0.02), with the appearance of local recurrence (p = 0.04) and/or early metastatic lesions in the lungs (p = 0.04), with a fatal outcome from the refractory course of the disease (p = 0.04).
\nTherefore, the presence of VEGF expression in the biopsy material and an increase in the expression of VEGF after neoadjuvant chemotherapy are factors for poor prognosis of the disease [42]. But this study requires the continuation of the fact that it includes a small number of patients.
\nIn addition, Ohba et al. showed in an in vivo experiment using human osteosarcoma cell lines (TE85 and 143B) the mechanism of autocrine stimulation of tumor transformation and proliferation using the example of the VEGF/VEGFR signaling pathway. In this study, the expression of VEGF-A and VEGFR micro-RNA was evaluated [52].
\nCurrently, little experience has been gained with the use of the drug bevacizumab in children with osteosarcoma.
\nBevacizumab (Avastin) is a partially humanized monoclonal antibody to VEGF-A, IgG1, which realizes its activity through a second type of immunopathological reaction (antibody-mediated complement-dependent cytotoxicity and antibody-mediated cell-dependent cytotoxicity) [53].
\nTurner et al. (St. Jude Children’s research hospital) presented preliminary results of using bevacizumab in combination with neoadjuvant chemotherapy (two courses of IDA) in 27 children with osteosarcoma. The drug was used at a dose of 15 mg/kg. There are three introductions for neoadjuvant chemotherapy. A satisfactory toxicity profile has been established. The study NCT00667342 continues [54, 55].
\nBack in 1999, employees of the Memorial Sloan-Kettering Cancer Center presented the results of a study assessing the effect of ErbB2 expression (Erb-B2 receptor tyrosine kinase 2) on the nature of the histological response after neoadjuvant polychemotherapy and on the rates of OS and BSV. The study included 53 patients. ErbB2 overexpression was detected in 42% of patients in the entire study group, in 50% with metastatic variant and in 76% at the time of detection of relapse or refractory course of the disease, and also statistically significantly correlated with poor histological response (p = 0.02) and BSV (p = 0.05). The 5-year BSV in patients with a localized version of osteosarcoma and ErbB2-positive status was 47%, with ErbB2-negative status—79% [40].
\nConflicting data on the prognostic significance of ErbB2-positive status in patients with localized osteosarcoma were obtained.
\nIn 2002, the Japanese Osteosarcoma Group (Japanese Osteosarcoma Group) published the results of a study that included 155 patients with localized osteosarcoma from 1984 to 1995. At the same time, 5-year BSV in patients with ErbB2-positive status was 45%, with ErbB2-negative status—72% [56].
\nIn 2014, the Children Oncology Group (COG) presented completely different results of the study, which from 1999 to 2002 included 135 patients with localized osteosarcoma. Only 13% of patients showed ErbB2-positive status. The 5-year RR in patients with ErbB2-positive status was 73%, and with the ErbB2-negative status—72%, the 5-year RR was 59 and 69%, respectively. No statistically significant difference in survival was observed [57].
\nThus, it was confirmed that ErbB2 can be considered as a potential target for targeted therapy in metastatic variant, relapse, and refractory course of the disease.
\nCOG presented the results of a phase 2 clinical trial of the drug Trastuzumab (Herceptin) in combination with MAPIE polychemotherapy in 96 patients with primary metastatic osteosarcoma. This study was conducted from 2001 to 2005.
\nTrastuzumab is a partially humanized IgG1κ monoclonal antibody to ErbB2, which also realizes its activity through a second type of immunopathological reaction (antibody-mediated complement-dependent cytotoxicity and antibody-mediated cell-dependent cytotoxicity). The drug was administered at a dose of 4 mg/kg in the first week, and then 2 mg/kg 1 time per week (34 in total) only in patients in whose tumor substrate ErbB2 expression was detected.
\nSurgical removal of the primary tumor lesion was performed at week 11. Adjuvant chemotherapy began at week 13.
\nIn the group with trastuzumab, a good histological response was detected in 56% of patients and without trastuzumab, it was 40%, a poor histological response of 44–60%, respectively. At the same time, the 3-year OS and BSV in the group of patients who received treatment with trastuzumab accounted for 59 and 32%, and in the group of patients who received treatment without trastuzumab for 50 and 32%. Consequently, the use of trastuzumab with polychemotherapy MAPIE led to an increase in the frequency of achieving a good histological response, but not to an increase in the rates of OS and EFS [58].
\nOf particular interest is tumor-modifying therapy using nitrogen-containing bisphosphonates. Currently, the following mechanisms of action of nitrogen-containing bisphosphonates have been identified, which are represented by the activation of tumor cell apoptosis by the caspase mechanism (indirectly through protein Rb and P53) and without the participation of the caspase mechanism (an increase in AIF—apoptosis of the inducing factor); increased expression of TNF-related apoptosis-inducing ligand–death receptor 5 (TRAIL-DR5, TRAIL-induced apoptosis); reduction of receptor activator of nuclear factor kappa-B ligand (RANKL) expression–ligand of nuclear factor activation receptor kB in osteosarcoma cells, which leads to suppression of tumor cell proliferation, osteoclast activity, changes in the tumor microenvironment, bone resorption, and risk of metastasis; γδT activation of cellular cytotoxicity; and tumor activation of associated macrophages [59, 60, 61, 62].
\nIn addition, the potentiating effect of nitrogen-containing bisphosphonates on cisplatin and adriamycin has been confirmed [63].
\nCurrently, a rather small experience has been gained in using these drugs in children with osteosarcoma.
\nMeyers et al. published the results of a study on the combined use of pamidronate with MAP chemotherapy. The study included 40 patients, 32 in the age group under 18, 29 with a localized version of osteosarcoma, and 11 with a primary metastatic option of osteosarcoma.
\nIn accordance with the program, pamidronate was administered once a month at a dose of 2 mg/kg 48–72 h after adriamycin, methotrexate, a total of 12 administrations.
\nSurgical removal of the primary tumor lesion was performed at week 11. Adjuvant chemotherapy began at week 13. Removal of metastatic foci was carried out individually at the stage of adjuvant therapy.
\nThe frequency of achieving a good and poor histological response is not indicated. However, relatively high rates of 5-year OS and EFS were obtained: 93 and 72% in patients with localized osteosarcoma and 64 and 45% in patients with metastatic osteosarcoma [26].
\nCOG presented the results of the pilot protocol AOST06P1 aimed at studying the combined use of zoledronic acid with MAPIE polychemotherapy in children with the primary metastatic osteosarcoma. This study included 24 patients. Zoledronic acid was administered at a dose of 1.2–3.5 mg/m2 in each course of chemotherapy.
\nThe maximum tolerated dose of zoledronic acid was established, which was 2.3 mg/m2. Indicators of a 2-year OV and EFS were 60 and 32%, respectively [63].
\nPiperno-Neumann et al. presented the results of a phase 3 randomized study OS 2006, the purpose of which was to identify the potentiating effect of zoledronic acid when used together with polychemotherapy MIE and MAP.
\nThe study included 217 children, 107 in the control group, and 110 in the group with zoledronic acid. Groups of patients were statistically significantly comparable by sex, age, foci of primary and metastatic lesions, and histological variant of the tumor.
\nZoledronic acid was administered at a dose of 0.05 mg/kg (maximum dose of 4 mg) with each course of chemotherapy (IE and AP).
\nNeoadjuvant chemotherapy consisted of two courses of IE (ifosfamide (I) 12 g/m2, etoposide 300 mg/m2) and seven administrations of high-dose methotrexate ((M) 12 g/m2). Surgical removal of the primary tumor lesion was performed at week 14. Adjuvant chemotherapy included two courses of MIE in the group with a good histological response and five courses of MAP in the group with a poor histological response. A good histological response after neoadjuvant polychemotherapy was achieved in 73% of patients. However, there was no statistically significant difference in achieving a good histological response, in terms of OS and BSV in groups of patients who received programmed treatment with or without zoledronic acid. The number of events in the group with zoledronic acid was 42% (47/110) and in the group without zoledronic acid was 31% (34/107). Consequently, this study shows the high effectiveness of chemotherapy courses with IE in combination with methotrexate in the neoadjuvant regimen. The presence of the potentiating effect of zoledronic acid has not been proven [64].
\nIn the treatment of refractory forms of osteosarcoma, drugs are also used that affect various cellular signaling pathways. Understanding the mechanisms of tumor activation opens up the possibility of using multikinase and mammalian target of rapamycin complex (mTOR) inhibitors.
\nTakagi and Peng et al. in an in vitro experiment on cell lines (SaOS2, MG63, HOS), pathogenetic mechanisms of cytokine-induced tumor transformation and proliferation were shown through the activation of VEGF/VEGFR/PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase)/AKT (protein kinase B) and the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathways [65, 66]. The most studied drugs from this group are currently sorafenib (nexavar) and everolimus (afinitor) [67]. Sorafenib is a nonselective multikinase inhibitor that inhibits the activity of various cellular signaling pathways, in particular VEGFR1, VEGFR2, PDGFRα, and PDGFRβ, while everolimus is an mTOR inhibitor [68].
\nYmera et al. of the Italian Sarcoma Group published the results of a preclinical study (in vitro and in vivo), which noted the mutually potentiating antitumor effect of everolimus and sorafenib on osteosarcoma cell lines (KHOS, MNNG-HOS, and U2OS). The effect of everolimus and sorafenib on mTORC1/mTORC2 is manifested in a decrease in the expression of mTORC1 and an increase in the expression of mTORC2, which provides proapoptotic and antiproliferative effects. With the combined use of everolimus and sorafenib, there is a decrease in the expression of both mTORC1 and mTORC2 [69].
\nFrom 2008 to 2009, Grignani et al. of the Italian Sarcoma Group conducted a second phase of clinical trials of the drug sorafenib in patients with relapse and refractory osteosarcoma. The study included 35 patients with osteosarcoma in the age group over 14 years. Partial response was achieved in 5 (14%) patients and stabilization of the disease in 12 (34%) patients. The overall response rate was 48%. At the same time, 4-month progression-free survival was 45% (15 out of 35) [70].
\nFrom 2011 to 2013, Grignani et al. conducted a second phase of clinical trials of a combination of drugs of everolimus and sorafenib in patients with relapse and refractory osteosarcoma after performing standard polychemotherapy MAP (study NCT01804374). The study included 38 patients over the age of 18 years. Everolimus was administered in a dose of 5 mg once a day and sorafenib 400 mg two times a day. The duration of chemotherapy was 28 days. Partial response was achieved in 4 (10%) patients and stabilization of the disease in 20 (53%) patients. The overall response rate is 63%. This figure is 15% more than in the study, where sorafenib was used in monomode. A 4-month progression-free survival was 58% and for 6-month, it was 45% (17 out of 38) [71].
\nThus, taking into account the data of studies in 2008 (application of sorafenib in mono mode) and 2011 (using a combination of sorafenib with everolimus), it can be said that the combination of sorafenib with everolimus leads to an increase in the overall response rate and an increase in survival rate without disease progression within 6 months. However, by the year, this difference disappears.
\nAt ASCO 2016, preliminary results were presented in a pilot study of the use of everolimus/sorafenib in children with relapse and refractory osteosarcoma, which was carried out at the Institute of Pediatric Oncology and Hematology N.N. Blokhin Medical Research Center of Oncology from 2013 to 2016. This protocol included 14 patients. The first line of therapy is represented by the program “Osteosarcoma 2006” in seven patients and “Osteosarcoma 2014” in seven patients. All patients underwent therapy, which included doxorubicin, cisplatin, high-dose methotrexate, high-dose ifosfamide, and gemcitabine and docetaxel.
\nThe number of courses of therapy for everolimus/sorafenib ranged from 2 to 18. The toxicity of therapy was erythema cutaneous in all patients (100%), palmar and plantar syndrome in 1 (7%), and mucositis 1–2 in 4 (28.5%). Hematologic toxicity did not exceed 1–2 degree in all patients. A transient increase in transaminases up to five norms in all patients (100%) was also noted.
\nPartial response to treatment was achieved in 5 of 14 (35.7%) patients and stabilization of the disease in 9 (64.3%). The overall response rate was 100%. Survival without disease progression for more than 6 months was detected in 6 out of 14 (43%) patients. The mean follow-up was 7 ± 1.2 months. The maximum period without progression of the disease is 18.4 months.
\nThe findings suggest that everolimus/sorafenib combination resulted in a partial response in 35.7% of cases with a satisfactory toxicity profile [72].
\nCompared to international data (Italian sarcoma group) in the presented study, the achievement of a partial response, stabilization of the disease, and the overall response rate were significantly higher.
\nCurrently, a number of studies aimed at studying the role of tumor-associated macrophages. Activation of tumor-associated macrophages can be achieved through the use of preparations of liposomal tripeptides (mifamurtide) and interferon preparations (interferon alpha-2A).
\nMeyers et al. presented the results of the randomized study CCG 7921/POG 9351, which was conducted from 1993 to 1997. The study included 662 patients with a localized version of osteosarcoma.
\nA feature of line A therapy was the use of two courses of neoadjuvant chemotherapy for MAP, and in line B therapy, two courses of neoadjuvant chemotherapy MAi, alternating courses of MAR and MAi at the stage of adjuvant chemotherapy, was used. Surgical removal of the primary tumor lesion was performed at week 10. Mifamurtide (MTP) was administered at a dose of 2 mg/m2 two times a week for 12 weeks, and then once a week for 24 weeks in accordance with randomization.
\nThe mechanism of action of mythamurtide (MTP) is to activate monocytes/macrophages with antitumor activity, which is realized by binding to specific receptors toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 2 receptor (NOD2), followed by altering the activity of cellular signal pathways (ERK1/2—extracellular-signal regulated kinase 1/2), NF-kB—nuclear factor kappa-B, and AP1—adapter protein 1 [73].
\nAfter removal of the primary tumor focus, a good histological response in group A was achieved in 42% of patients and in group B in 48%, and a poor histological response in group A was 58% and in group B was 52%. At the same time, the 6-year-old RH was 74%, without the use of MTP was 70% and with the MTP was 78%; BSV was 64%, without the use of MTR was 61% and with MTP was 67%. In group A: OS without the use of MTR was 71% and with MTR was 75%; BSV without MTR was 64% and with MTR was 63%. In group B: OS without the use of MTR was 71% and with MTR was 75%; BSV without MTR was 64% and with MTR was 63%. The addition of MTP to polychemotherapy led to a statistically significant increase in the 6-year OS from 70 to 78% (p = 0.03), and there was also a tendency to an increase in BSV, mainly in group B (p = 0.08) [25].
\nKubo et al. published the results of a pilot study that determined the prognostic significance of the expression level of interferon α/β receptors in 40 patients with localized osteosarcoma who received treatment according to the NECO95J program. Expression of interferon α/β receptors was detected in 45% of patients. When conducting multivariate statistical analysis, a significant association was observed between the expression of interferon α/β receptors and 5-year-old OM and survival free of metastatic lesions (VSMP). The 5-year OM, in the presence of expression of the α/β interferon receptor in the tumor substrate, was 81%, with no expression, 47% (p = 0.043), and in the 5-year HSMP, it was 75 and 41% (p = 0.023). This study confirms the possibility of using interferon preparations in the treatment of osteosarcoma in patients with overexpression of α/β interferon receptors [74].
\nBielack et al. presented the results of the EURAMOS1 study in patients with a good histological response after neoadjuvant MAP chemotherapy. In the age group up to 30 years, the MAP line of therapy was carried out to 359 patients, the MAP INF line α–2b—to 357 patients, in the age group up to 20 years—333 (92.7%) and 332 (92.9%) patients. Groups of patients are statistically significantly comparable by sex, age, localization of the primary tumor lesion, the presence of metastatic lesions, and the histological variant of the tumor.
\nIn accordance with the program, pegylated INF–α–2b was administered at a dose of 0.5 mg/kg (at a maximum dose of 50 mg) once a week for 4 weeks, and then 1 mg/kg (at a maximum dose of 100 mg) 1 time per week (from 30 to 104 weeks of programmed treatment).
\nIn a group of 630 patients with a localized version of osteosarcoma, 135 events were detected: 72 in patients who received the MAP therapy line and 63 in patients who received the MAP INF therapy line–2b. At the same time, the 3-year EFS was 77 and 80%, respectively. Therefore, the use of INF–α–2b as maintenance therapy after MAP in patients with a good histological response did not lead to an increase in EFS [75].
\nThe data set out in paragraph 3 are summarized in Table 3.
\nAuthors | \nAgents | \n
---|---|
Ferrari S. | \nIfosfamide, adriamycin, cisplatin | \n
Le Deley M.C. | \nMethotrexate, adriamycin, ifosfamide, etoposide | \n
Cui Q. | \nCisplatin | \n
Pitano-Garcia A. | \nDoxorubicin, cisplatin | \n
Wu X. | \nMethotrexate, cisplatin, adriamycin | \n
Ohba T. | \nBevacizumab (Avastin) | \n
Children Oncology Group | \nTrastuzumab | \n
Trials/authors and agents.
Thus, the results of treatment of children with primary metastatic osteosarcoma, relapse, and refractory course of the disease remain unsatisfactory. Molecular biological factors that determine sensitivity to chemotherapy, invasive, and metastatic potential of the tumor, as well as the prognosis of the disease, among which special attention is deserved are as follows: expression of MGMT protein, methylation of the promoter part of the MGMT gene, expression of ERCC1 proteins, VEGF, CD133, p-STAT3tyr705, C-MYC, expression of RFC1 micro-RNA, and the presence of rearrangement of the TOR2A gene. It is important to note that there was no comprehensive assessment of the value of these markers for the histological response to neoadjuvant chemotherapy and survival rates in patients with osteosarcoma.
\nResearch methodology is the path through which researchers need to conduct their research. It shows the path through which these researchers formulate their problem and objective and present their result from the data obtained during the study period. This research design and methodology chapter also shows how the research outcome at the end will be obtained in line with meeting the objective of the study. This chapter hence discusses the research methods that were used during the research process. It includes the research methodology of the study from the research strategy to the result dissemination. For emphasis, in this chapter, the author outlines the research strategy, research design, research methodology, the study area, data sources such as primary data sources and secondary data, population consideration and sample size determination such as questionnaires sample size determination and workplace site exposure measurement sample determination, data collection methods like primary data collection methods including workplace site observation data collection and data collection through desk review, data collection through questionnaires, data obtained from experts opinion, workplace site exposure measurement, data collection tools pretest, secondary data collection methods, methods of data analysis used such as quantitative data analysis and qualitative data analysis, data analysis software, the reliability and validity analysis of the quantitative data, reliability of data, reliability analysis, validity, data quality management, inclusion criteria, ethical consideration and dissemination of result and its utilization approaches. In order to satisfy the objectives of the study, a qualitative and quantitative research method is apprehended in general. The study used these mixed strategies because the data were obtained from all aspects of the data source during the study time. Therefore, the purpose of this methodology is to satisfy the research plan and target devised by the researcher.
The research design is intended to provide an appropriate framework for a study. A very significant decision in research design process is the choice to be made regarding research approach since it determines how relevant information for a study will be obtained; however, the research design process involves many interrelated decisions [1].
This study employed a mixed type of methods. The first part of the study consisted of a series of well-structured questionnaires (for management, employee’s representatives, and technician of industries) and semi-structured interviews with key stakeholders (government bodies, ministries, and industries) in participating organizations. The other design used is an interview of employees to know how they feel about safety and health of their workplace, and field observation at the selected industrial sites was undertaken.
Hence, this study employs a descriptive research design to agree on the effects of occupational safety and health management system on employee health, safety, and property damage for selected manufacturing industries. Saunders et al. [2] and Miller [3] say that descriptive research portrays an accurate profile of persons, events, or situations. This design offers to the researchers a profile of described relevant aspects of the phenomena of interest from an individual, organizational, and industry-oriented perspective. Therefore, this research design enabled the researchers to gather data from a wide range of respondents on the impact of safety and health on manufacturing industries in Ethiopia. And this helped in analyzing the response obtained on how it affects the manufacturing industries’ workplace safety and health. The research overall design and flow process are depicted in Figure 1.
Research methods and processes (author design).
To address the key research objectives, this research used both qualitative and quantitative methods and combination of primary and secondary sources. The qualitative data supports the quantitative data analysis and results. The result obtained is triangulated since the researcher utilized the qualitative and quantitative data types in the data analysis. The study area, data sources, and sampling techniques were discussed under this section.
According to Fraenkel and Warren [4] studies, population refers to the complete set of individuals (subjects or events) having common characteristics in which the researcher is interested. The population of the study was determined based on random sampling system. This data collection was conducted from March 07, 2015 to December 10, 2016, from selected manufacturing industries found in Addis Ababa city and around. The manufacturing companies were selected based on their employee number, established year, and the potential accidents prevailing and the manufacturing industry type even though all criterions were difficult to satisfy.
It was obtained from the original source of information. The primary data were more reliable and have more confidence level of decision-making with the trusted analysis having direct intact with occurrence of the events. The primary data sources are industries’ working environment (through observation, pictures, and photograph) and industry employees (management and bottom workers) (interview, questionnaires and discussions).
Desk review has been conducted to collect data from various secondary sources. This includes reports and project documents at each manufacturing sectors (more on medium and large level). Secondary data sources have been obtained from literatures regarding OSH, and the remaining data were from the companies’ manuals, reports, and some management documents which were included under the desk review. Reputable journals, books, different articles, periodicals, proceedings, magazines, newsletters, newspapers, websites, and other sources were considered on the manufacturing industrial sectors. The data also obtained from the existing working documents, manuals, procedures, reports, statistical data, policies, regulations, and standards were taken into account for the review.
In general, for this research study, the desk review has been completed to this end, and it had been polished and modified upon manuals and documents obtained from the selected companies.
The study population consisted of manufacturing industries’ employees in Addis Ababa city and around as there are more representative manufacturing industrial clusters found. To select representative manufacturing industrial sector population, the types of the industries expected were more potential to accidents based on random and purposive sampling considered. The population of data was from textile, leather, metal, chemicals, and food manufacturing industries. A total of 189 sample sizes of industries responded to the questionnaire survey from the priority areas of the government. Random sample sizes and disproportionate methods were used, and 80 from wood, metal, and iron works; 30 from food, beverage, and tobacco products; 50 from leather, textile, and garments; 20 from chemical and chemical products; and 9 from other remaining 9 clusters of manufacturing industries responded.
A simple random sampling and purposive sampling methods were used to select the representative manufacturing industries and respondents for the study. The simple random sampling ensures that each member of the population has an equal chance for the selection or the chance of getting a response which can be more than equal to the chance depending on the data analysis justification. Sample size determination procedure was used to get optimum and reasonable information. In this study, both probability (simple random sampling) and nonprobability (convenience, quota, purposive, and judgmental) sampling methods were used as the nature of the industries are varied. This is because of the characteristics of data sources which permitted the researchers to follow the multi-methods. This helps the analysis to triangulate the data obtained and increase the reliability of the research outcome and its decision. The companies’ establishment time and its engagement in operation, the number of employees and the proportion it has, the owner types (government and private), type of manufacturing industry/production, types of resource used at work, and the location it is found in the city and around were some of the criteria for the selections.
The determination of the sample size was adopted from Daniel [5] and Cochran [6] formula. The formula used was for unknown population size Eq. (1) and is given as
where n = sample size, Z = statistic for a level of confidence, P = expected prevalence or proportion (in proportion of one; if 50%, P = 0.5), and d = precision (in proportion of one; if 6%, d = 0.06). Z statistic (Z): for the level of confidence of 95%, which is conventional, Z value is 1.96. In this study, investigators present their results with 95% confidence intervals (CI).
The expected sample number was 267 at the marginal error of 6% for 95% confidence interval of manufacturing industries. However, the collected data indicated that only 189 populations were used for the analysis after rejecting some data having more missing values in the responses from the industries. Hence, the actual data collection resulted in 71% response rate. The 267 population were assumed to be satisfactory and representative for the data analysis.
The sample size for the experimental exposure measurements of physical work environment has been considered based on the physical data prepared for questionnaires and respondents. The response of positive were considered for exposure measurement factors to be considered for the physical environment health and disease causing such as noise intensity, light intensity, pressure/stress, vibration, temperature/coldness, or hotness and dust particles on 20 workplace sites. The selection method was using random sampling in line with purposive method. The measurement of the exposure factors was done in collaboration with Addis Ababa city Administration and Oromia Bureau of Labour and Social Affair (AACBOLSA). Some measuring instruments were obtained from the Addis Ababa city and Oromia Bureau of Labour and Social Affair.
Data collection methods were focused on the followings basic techniques. These included secondary and primary data collections focusing on both qualitative and quantitative data as defined in the previous section. The data collection mechanisms are devised and prepared with their proper procedures.
Primary data sources are qualitative and quantitative. The qualitative sources are field observation, interview, and informal discussions, while that of quantitative data sources are survey questionnaires and interview questions. The next sections elaborate how the data were obtained from the primary sources.
Observation is an important aspect of science. Observation is tightly connected to data collection, and there are different sources for this: documentation, archival records, interviews, direct observations, and participant observations. Observational research findings are considered strong in validity because the researcher is able to collect a depth of information about a particular behavior. In this dissertation, the researchers used observation method as one tool for collecting information and data before questionnaire design and after the start of research too. The researcher made more than 20 specific observations of manufacturing industries in the study areas. During the observations, it found a deeper understanding of the working environment and the different sections in the production system and OSH practices.
Interview is a loosely structured qualitative in-depth interview with people who are considered to be particularly knowledgeable about the topic of interest. The semi-structured interview is usually conducted in a face-to-face setting which permits the researcher to seek new insights, ask questions, and assess phenomena in different perspectives. It let the researcher to know the in-depth of the present working environment influential factors and consequences. It has provided opportunities for refining data collection efforts and examining specialized systems or processes. It was used when the researcher faces written records or published document limitation or wanted to triangulate the data obtained from other primary and secondary data sources.
This dissertation is also conducted with a qualitative approach and conducting interviews. The advantage of using interviews as a method is that it allows respondents to raise issues that the interviewer may not have expected. All interviews with employees, management, and technicians were conducted by the corresponding researcher, on a face-to-face basis at workplace. All interviews were recorded and transcribed.
The main tool for gaining primary information in practical research is questionnaires, due to the fact that the researcher can decide on the sample and the types of questions to be asked [2].
In this dissertation, each respondent is requested to reply to an identical list of questions mixed so that biasness was prevented. Initially the questionnaire design was coded and mixed up from specific topic based on uniform structures. Consequently, the questionnaire produced valuable data which was required to achieve the dissertation objectives.
The questionnaires developed were based on a five-item Likert scale. Responses were given to each statement using a five-point Likert-type scale, for which 1 = “strongly disagree” to 5 = “strongly agree.” The responses were summed up to produce a score for the measures.
The data was also obtained from the expert’s opinion related to the comparison of the knowledge, management, collaboration, and technology utilization including their sub-factors. The data obtained in this way was used for prioritization and decision-making of OSH, improving factor priority. The prioritization of the factors was using Saaty scales (1–9) and then converting to Fuzzy set values obtained from previous researches using triangular fuzzy set [7].
The researcher has measured the workplace environment for dust, vibration, heat, pressure, light, and noise to know how much is the level of each variable. The primary data sources planned and an actual coverage has been compared as shown in Table 1.
Planned versus actual coverage of the survey.
The response rate for the proposed data source was good, and the pilot test also proved the reliability of questionnaires. Interview/discussion resulted in 87% of responses among the respondents; the survey questionnaire response rate obtained was 71%, and the field observation response rate was 90% for the whole data analysis process. Hence, the data organization quality level has not been compromised.
This response rate is considered to be representative of studies of organizations. As the study agrees on the response rate to be 30%, it is considered acceptable [8]. Saunders et al. [2] argued that the questionnaire with a scale response of 20% response rate is acceptable. Low response rate should not discourage the researchers, because a great deal of published research work also achieves low response rate. Hence, the response rate of this study is acceptable and very good for the purpose of meeting the study objectives.
The pretest for questionnaires, interviews, and tools were conducted to validate that the tool content is valid or not in the sense of the respondents’ understanding. Hence, content validity (in which the questions are answered to the target without excluding important points), internal validity (in which the questions raised answer the outcomes of researchers’ target), and external validity (in which the result can generalize to all the population from the survey sample population) were reflected. It has been proved with this pilot test prior to the start of the basic data collections. Following feedback process, a few minor changes were made to the originally designed data collect tools. The pilot test made for the questionnaire test was on 10 sample sizes selected randomly from the target sectors and experts.
The secondary data refers to data that was collected by someone other than the user. This data source gives insights of the research area of the current state-of-the-art method. It also makes some sort of research gap that needs to be filled by the researcher. This secondary data sources could be internal and external data sources of information that may cover a wide range of areas.
Literature/desk review and industry documents and reports: To achieve the dissertation’s objectives, the researcher has conducted excessive document review and reports of the companies in both online and offline modes. From a methodological point of view, literature reviews can be comprehended as content analysis, where quantitative and qualitative aspects are mixed to assess structural (descriptive) as well as content criteria.
A literature search was conducted using the database sources like MEDLINE; Emerald; Taylor and Francis publications; EMBASE (medical literature); PsycINFO (psychological literature); Sociological Abstracts (sociological literature); accident prevention journals; US Statistics of Labor, European Safety and Health database; ABI Inform; Business Source Premier (business/management literature); EconLit (economic literature); Social Service Abstracts (social work and social service literature); and other related materials. The search strategy was focused on articles or reports that measure one or more of the dimensions within the research OSH model framework. This search strategy was based on a framework and measurement filter strategy developed by the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) group. Based on screening, unrelated articles to the research model and objectives were excluded. Prior to screening, researcher (principal investigator) reviewed a sample of more than 2000 articles, websites, reports, and guidelines to determine whether they should be included for further review or reject. Discrepancies were thoroughly identified and resolved before the review of the main group of more than 300 articles commenced. After excluding the articles based on the title, keywords, and abstract, the remaining articles were reviewed in detail, and the information was extracted on the instrument that was used to assess the dimension of research interest. A complete list of items was then collated within each research targets or objectives and reviewed to identify any missing elements.
Data analysis method follows the procedures listed under the following sections. The data analysis part answered the basic questions raised in the problem statement. The detailed analysis of the developed and developing countries’ experiences on OSH regarding manufacturing industries was analyzed, discussed, compared and contrasted, and synthesized.
Quantitative data were obtained from primary and secondary data discussed above in this chapter. This data analysis was based on their data type using Excel, SPSS 20.0, Office Word format, and other tools. This data analysis focuses on numerical/quantitative data analysis.
Before analysis, data coding of responses and analysis were made. In order to analyze the data obtained easily, the data were coded to SPSS 20.0 software as the data obtained from questionnaires. This task involved identifying, classifying, and assigning a numeric or character symbol to data, which was done in only one way pre-coded [9, 10]. In this study, all of the responses were pre-coded. They were taken from the list of responses, a number of corresponding to a particular selection was given. This process was applied to every earlier question that needed this treatment. Upon completion, the data were then entered to a statistical analysis software package, SPSS version 20.0 on Windows 10 for the next steps.
Under the data analysis, exploration of data has been made with descriptive statistics and graphical analysis. The analysis included exploring the relationship between variables and comparing groups how they affect each other. This has been done using cross tabulation/chi square, correlation, and factor analysis and using nonparametric statistic.
Qualitative data analysis used for triangulation of the quantitative data analysis. The interview, observation, and report records were used to support the findings. The analysis has been incorporated with the quantitative discussion results in the data analysis parts.
The data were entered using SPSS 20.0 on Windows 10 and analyzed. The analysis supported with SPSS software much contributed to the finding. It had contributed to the data validation and correctness of the SPSS results. The software analyzed and compared the results of different variables used in the research questionnaires. Excel is also used to draw the pictures and calculate some analytical solutions.
The reliability of measurements specifies the amount to which it is without bias (error free) and hence ensures consistent measurement across time and across the various items in the instrument [8]. In reliability analysis, it has been checked for the stability and consistency of the data. In the case of reliability analysis, the researcher checked the accuracy and precision of the procedure of measurement. Reliability has numerous definitions and approaches, but in several environments, the concept comes to be consistent [8]. The measurement fulfills the requirements of reliability when it produces consistent results during data analysis procedure. The reliability is determined through Cranach’s alpha as shown in Table 2.
Internal consistency and reliability test of questionnaires items.
K stands for knowledge; M, management; T, technology; C, collaboration; P, policy, standards, and regulation; H, hazards and accident conditions; PPE, personal protective equipment.
Cronbach’s alpha is a measure of internal consistency, i.e., how closely related a set of items are as a group [11]. It is considered to be a measure of scale reliability. The reliability of internal consistency most of the time is measured based on the Cronbach’s alpha value. Reliability coefficient of 0.70 and above is considered “acceptable” in most research situations [12]. In this study, reliability analysis for internal consistency of Likert-scale measurement after deleting 13 items was found similar; the reliability coefficients were found for 76 items were 0.964 and for the individual groupings made shown in Table 2. It was also found internally consistent using the Cronbach’s alpha test. Table 2 shows the internal consistency of the seven major instruments in which their reliability falls in the acceptable range for this research.
Face validity used as defined by Babbie [13] is an indicator that makes it seem a reasonable measure of some variables, and it is the subjective judgment that the instrument measures what it intends to measure in terms of relevance [14]. Thus, the researcher ensured, in this study, when developing the instruments that uncertainties were eliminated by using appropriate words and concepts in order to enhance clarity and general suitability [14]. Furthermore, the researcher submitted the instruments to the research supervisor and the joint supervisor who are both occupational health experts, to ensure validity of the measuring instruments and determine whether the instruments could be considered valid on face value.
In this study, the researcher was guided by reviewed literature related to compliance with the occupational health and safety conditions and data collection methods before he could develop the measuring instruments. In addition, the pretest study that was conducted prior to the main study assisted the researcher to avoid uncertainties of the contents in the data collection measuring instruments. A thorough inspection of the measuring instruments by the statistician and the researcher’s supervisor and joint experts, to ensure that all concepts pertaining to the study were included, ensured that the instruments were enriched.
Insight has been given to the data collectors on how to approach companies, and many of the questionnaires were distributed through MSc students at Addis Ababa Institute of Technology (AAiT) and manufacturing industries’ experience experts. This made the data quality reliable as it has been continually discussed with them. Pretesting for questionnaire was done on 10 workers to assure the quality of the data and for improvement of data collection tools. Supervision during data collection was done to understand how the data collectors are handling the questionnaire, and each filled questionnaires was checked for its completeness, accuracy, clarity, and consistency on a daily basis either face-to-face or by phone/email. The data expected in poor quality were rejected out of the acting during the screening time. Among planned 267 questionnaires, 189 were responded back. Finally, it was analyzed by the principal investigator.
The data were collected from the company representative with the knowledge of OSH. Articles written in English and Amharic were included in this study. Database information obtained in relation to articles and those who have OSH area such as interventions method, method of accident identification, impact of occupational accidents, types of occupational injuries/disease, and impact of occupational accidents, and disease on productivity and costs of company and have used at least one form of feedback mechanism. No specific time period was chosen in order to access all available published papers. The questionnaire statements which are similar in the questionnaire have been rejected from the data analysis.
Ethical clearance was obtained from the School of Mechanical and Industrial Engineering, Institute of Technology, Addis Ababa University. Official letters were written from the School of Mechanical and Industrial Engineering to the respective manufacturing industries. The purpose of the study was explained to the study subjects. The study subjects were told that the information they provided was kept confidential and that their identities would not be revealed in association with the information they provided. Informed consent was secured from each participant. For bad working environment assessment findings, feedback will be given to all manufacturing industries involved in the study. There is a plan to give a copy of the result to the respective study manufacturing industries’ and ministries’ offices. The respondents’ privacy and their responses were not individually analyzed and included in the report.
The result of this study will be presented to the Addis Ababa University, AAiT, School of Mechanical and Industrial Engineering. It will also be communicated to the Ethiopian manufacturing industries, Ministry of Labor and Social Affair, Ministry of Industry, and Ministry of Health from where the data was collected. The result will also be availed by publication and online presentation in Google Scholars. To this end, about five articles were published and disseminated to the whole world.
The research methodology and design indicated overall process of the flow of the research for the given study. The data sources and data collection methods were used. The overall research strategies and framework are indicated in this research process from problem formulation to problem validation including all the parameters. It has laid some foundation and how research methodology is devised and framed for researchers. This means, it helps researchers to consider it as one of the samples and models for the research data collection and process from the beginning of the problem statement to the research finding. Especially, this research flow helps new researchers to the research environment and methodology in particular.
There is no “conflict of interest.”
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