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Wassen",authors:[{id:"27166",title:"Dr",name:"Ignacy",middleName:null,surname:"Kardel",fullName:"Ignacy Kardel",slug:"ignacy-kardel"},{id:"36371",title:"Dr",name:"Jaroslaw",middleName:null,surname:"Chormanski",fullName:"Jaroslaw Chormanski",slug:"jaroslaw-chormanski"},{id:"36372",title:"Dr",name:"Dorota",middleName:null,surname:"Miroslaw-Swiatek",fullName:"Dorota Miroslaw-Swiatek",slug:"dorota-miroslaw-swiatek"},{id:"36373",title:"Prof.",name:"Tomasz",middleName:null,surname:"Okruszko",fullName:"Tomasz Okruszko",slug:"tomasz-okruszko"},{id:"36375",title:"Prof.",name:"Martin",middleName:null,surname:"Wassen",fullName:"Martin Wassen",slug:"martin-wassen"},{id:"74060",title:"MSc",name:"Mateusz",middleName:null,surname:"Grygoruk",fullName:"Mateusz Grygoruk",slug:"mateusz-grygoruk"}]},{id:"19353",title:"Interactive Localisation System for Urban Planning Issues",slug:"interactive-localisation-system-for-urban-planning-issues",signatures:"Roberto De Lotto",authors:[{id:"26791",title:"Prof.",name:"Roberto",middleName:null,surname:"De Lotto",fullName:"Roberto De Lotto",slug:"roberto-de-lotto"}]},{id:"19354",title:"Design and Development of a Compound DSS for Laboratory Research",slug:"design-and-development-of-a-compound-dss-for-laboratory-research",signatures:"Tomáš Hujer",authors:[{id:"26130",title:"Mr.",name:"Tomas",middleName:null,surname:"Hujer",fullName:"Tomas Hujer",slug:"tomas-hujer"}]},{id:"19355",title:"Decision Support System for Designing with Polymer Materials – Current Challenges and Future Expectations",slug:"decision-support-system-for-designing-with-polymer-materials-current-challenges-and-future-expectati",signatures:"Urška Sancin and Bojan Dolšak",authors:[{id:"30703",title:"BSc",name:"Urška",middleName:null,surname:"Sancin",fullName:"Urška Sancin",slug:"urska-sancin"},{id:"36031",title:"Prof.",name:"Bojan",middleName:null,surname:"Dolšak",fullName:"Bojan Dolšak",slug:"bojan-dolsak"}]},{id:"19356",title:"Decision Support System for Sustainability Assessment of Power Generation Technologies",slug:"decision-support-system-for-sustainability-assessment-of-power-generation-technologies",signatures:"Jūratė Šliogerienė, Dalia Štreimikienė and Artūras Kaklauskas",authors:[{id:"25148",title:"Prof.",name:"Arturas",middleName:null,surname:"Kaklauskas",fullName:"Arturas Kaklauskas",slug:"arturas-kaklauskas"},{id:"25626",title:"Dr.",name:"Jūrate",middleName:null,surname:"Šliogeriene",fullName:"Jūrate Šliogeriene",slug:"jurate-sliogeriene"},{id:"32341",title:"Prof.",name:"Dalia",middleName:null,surname:"Štreimikienė",fullName:"Dalia Štreimikienė",slug:"dalia-streimikiene"}]}]}],publishedBooks:[{type:"book",id:"1933",title:"Business Intelligence",subtitle:"Solution for Business Development",isOpenForSubmission:!1,hash:"d72273576047c478fac4567db9e7b649",slug:"business-intelligence-solution-for-business-development",bookSignature:"Marinela Mircea",coverURL:"https://cdn.intechopen.com/books/images_new/1933.jpg",editedByType:"Edited by",editors:[{id:"104617",title:"Prof.",name:"Marinela",surname:"Mircea",slug:"marinela-mircea",fullName:"Marinela Mircea"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7646",title:"Scientometrics Recent Advances",subtitle:null,isOpenForSubmission:!1,hash:"86bbdd04d7e80be14283d44969d1cc32",slug:"scientometrics-recent-advances",bookSignature:"Suad Kunosic and Enver Zerem",coverURL:"https://cdn.intechopen.com/books/images_new/7646.jpg",editedByType:"Edited by",editors:[{id:"88678",title:"Prof.",name:"Suad",surname:"Kunosic",slug:"suad-kunosic",fullName:"Suad Kunosic"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"80227",title:"Recent Advances in Systemic Therapy for Malignant Pleural Mesothelioma: Focus on Anti-Angiogenic Inhibitors and Immune Checkpoint Inhibitors",doi:"10.5772/intechopen.102511",slug:"recent-advances-in-systemic-therapy-for-malignant-pleural-mesothelioma-focus-on-anti-angiogenic-inhi",body:'Malignant pleural mesothelioma (MPM) is a rare neoplasm with a poor prognosis. MPM is strongly associated with past exposure to asbestos [1]. Radical surgeries, such as an extrapleural pneumonectomy or pleural decortication, have been performed for treating patients with MPM previously, but favorable results have been observed in only a limited number of patients [2, 3]. Most patients that present with advanced, non-resectable MPM at diagnosis are candidates for systemic treatments. However, systemic chemotherapy can only be administered to patients with good performance status (PS) [4].
In 2003, Vogelzang et al. reported that the combination of pemetrexed and cisplatin (pemetrexed/cisplatin) improved the response rate (RR), progression-free survival (PFS), and overall survival (OS), compared to cisplatin alone [5]. Since then, systemic chemotherapy with platinum and pemetrexed combination has been considered standard therapy for advanced MPM. However, even with this treatment, the PFS and OS have been estimated at 5.7 months and 12.1 months, respectively [5, 6]. A second-line treatment has not been established. According to the US Surveillance, Epidemiology, and End Results Medicare investigation, the most common second-line treatments are pemetrexed-based retreatment or gemcitabine [6].
There is strong evidence that angiogenesis is an important determinant in the development and progression of MPM. There are two main targets for inhibiting angiogenesis. One is the potent mitogen for endothelial cells, vascular endothelial growth factor (VEGF), which transduces signals by binding to two receptors, VEGF receptors −1 and 2. The other is platelet-derived growth factor (PDGF), which functions as an autocrine growth stimulator in the pathogenesis of MPM [7, 8]. With the introduction of angiogenesis inhibitors, several clinical studies have investigated treatments for MPM.
An alternative approach is to target the complex interaction between cancer and host immunity: cancer cells can acquire the ability to evade the host immune system, which curtails their growth [9, 10]. Cancer cells can also actively subvert the immunosuppressive function of T cells and immune checkpoint molecules, such as cytotoxic T lymphocyte antigen (CTLA)-4, programmed cell death (PD)-1, and PD-ligand (PD-L)-1. In recent years, immune checkpoint inhibitors (ICIs) have shown remarkable results in treating multiple types of neoplasms. The etiology and pathogenesis of MPM are mostly attributed to the generation of an immune microenvironment favorable to tumor growth, caused by asbestos-induced damage [11]. There is evidence that ICIs might play an important role in the treatment of MPM; in fact, some encouraging results have emerged in recent years.
Here, we discuss the results of recent trials on systemic therapies against MPM, with a focus on anti-angiogenic inhibitors and ICIs.
Most early studies on anti-angiogenic agents explored their clinical efficacy as single drugs for treating cancer in the relapsed or recurrent setting. However, the outcome of those studies was generally disappointing. Later, anti-angiogenic agents were combined with cytotoxic agents, mainly pemetrexed/cisplatin.
Bevacizumab is a monoclonal antibody that binds VEGF-A. Bevacizumab was tested in combination with the standard-of-care, cisplatin and pemetrexed, as a first-line treatment. An open-label, randomized phase 2/3 study that added bevacizumab to cisplatin and pemetrexed in chemotherapy-naïve patients showed a beneficial effect [12]. In that study, 448 patients were randomized to either pemetrexed/cisplatin with bevacizumab or chemotherapy alone. Patients were treated for up to 6 cycles. OS was statistically prolonged in the bevacizumab arm; the median OS was 18.8 months, versus 16.1 months for chemotherapy alone (HR: 0.77, 95% CI: 0.62–0.95).
Nintedanib is a multi-target angiokinase inhibitor, with activity against the receptors for VEGF (receptors 1, 2, and 3), PDGF, and fibroblast growth factor. A phase II study on patients with MPM showed that the addition of nintedanib to pemetrexed/cisplatin improved PFS (median 9.4 vs. 5.7 months; hazard ratio [HR]: 0.54; 95% CI: 0.33–0.87; p = 0.010). Moreover, the nintedanib arm showed a trend toward improved OS (median 18.3 vs. 14.2 months; HR: 0.77; 95% CI: 0.46–1.29; p = 0.319), compared to placebo. These positive effects were observed in patients with epithelioid histology. However, the findings were not confirmed in the subsequent phase 3 study [13].
Recently, ramucirumab, an anti-VEGF receptor-2 antibody, was tested in a double-blind, placebo-controlled, phase 2 trial for patients with pretreated MPM. In that trial, 161 patients were randomly assigned to gemcitabine (1000 mg/m2 intravenously, on days 1 and 8 every 3 weeks) or gemcitabine plus ramucirumab (10 mg/kg, intravenously, on day 1 every 3 weeks) [14]. The OS was prolonged in the ramucirumab arm (HR: 0·71, 70% CI: 0·59–0·85; p = 0·028); the median OS was 13·8 months (70% CI: 12·7–14·4) with gemcitabine plus ramucirumab and 7·5 months (70% CI: 6·9–8·9) with gemcitabine plus placebo. Hypertension was more common in the gemcitabine plus ramucirumab group, but no events were related to bleeding.
Anti-CTLA-4 antibodies include tremelimumab and ipilimumab. Drugs that block PD-(L)-1 include pembrolizumab, nivolumab, durvalumab, and avelumab.
The MERIT trial was a phase 2, single-phase study that evaluated the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent MPM, who were refractory or intolerant to 1–2 regimens of therapy [15]. In that study, 34 patients received nivolumab (240 mg intravenously) every 2 weeks, until they displayed progressive disease or unacceptable toxicity. The primary endpoint was the objective RR, which was 29.4% (10/34). The median OS and PFS times were 17.3 and 6.1 months, respectively. Among the 34 patients, 11 (32%) experienced grades ≥3 treatment-related adverse events, including 4 patients (12%) with adverse events that led to study treatment discontinuation (2 events of interstitial pneumonia, and 2 events of pneumonitis). Based on those results, nivolumab was approved for patients with MPM that were refractory or intolerant to prior chemotherapy.
The therapeutic efficacy of nivolumab was confirmed in a phase III trial, which demonstrated that single-agent nivolumab provided a significant improvement in both OS and PFS [16]. In that study, 332 adult patients with previously treated, unresectable, histologically confirmed malignant mesothelioma were randomized to nivolumab or placebo. The median OS was immature, but it was significantly prolonged with nivolumab (9.2 vs. 6.6 months; HR: 0.72; 95% CI: 0.55–0.94; p = 0.02). The median PFS was also prolonged with nivolumab compared to placebo (3.0 vs. 1.8 months; HR: 0.62; 95% CI: 0.49–0.78; p < 0.001). Grades 3–4 treatment-related adverse events occurred in 19% of the nivolumab arm and 6.3% of the placebo arm. Treatment discontinuation due to toxicity occurred in 13.1% of the nivolumab arm, versus 2.7% of the placebo arm.
The MAPS2 trial was a multicenter randomized, open-label, phase 2 trial that investigated nivolumab plus ipilimumab versus single-agent nivolumab, as a salvage treatment [17]. In the intention-to-treat population, 12-week disease control was achieved by 32 of 62 patients (52%; 95% CI: 39–64) in the nivolumab plus ipilimumab group and 25 of 63 patients (40%; 95% CI: 28–52) in the nivolumab group. Asthenia was among the most frequent grade 3 adverse events (n = 3 [5%] in the combination arm and n = 1 [2%] in the nivolumab arm).
The CheckMate 743 trial was a global, open-label, randomized, phase 3 study that investigated first-line nivolumab plus ipilimumab versus the standard platinum plus pemetrexed chemotherapy [18]. In that study, 605 patients with previously untreated, unresectable MPM were randomly assigned to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks), administered for up to 2 years, or platinum (cisplatin or carboplatin) plus pemetrexed chemotherapy, administered once every 3 weeks for up to 6 cycles. The primary endpoint was OS. The OS was significantly extended in the nivolumab plus ipilimumab arm, with a median of 18.1 months (95% CI: 16.8–21.4), compared to 14.1 months (95% CI: 12.4–16.2) in the chemotherapy arm. The HR was 0.74 (96.6% CI: 0.60–0.91). The 1-year and 2-year OS rates were, respectively, 68% (95% CI: 62.3–72.8) and 41% (95% CI: 35.1–46.5) in the nivolumab plus ipilimumab arm, and 58% (95% CI: 51.7–63.2) and 27% (95% CI: 21.9–32.4) in the chemotherapy arm. Across most subgroups, OS was more favorable with nivolumab plus ipilimumab compared to chemotherapy. The most frequently reported grade 3 or higher serious treatment-related adverse events were colitis (3%), in the nivolumab plus ipilimumab arm, and anemia (2%) in the chemotherapy arm.
The DREAM trial was a multicenter, single-arm, open-label, phase 2 trial conducted in 9 institutions in Australia [19]. In that study, 54 patients received cisplatin, pemetrexed, and durvalumab, in 3-week cycles, for up to 6 cycles. Durvalumab was continued for maintenance for up to 12 months. The primary endpoint was PFS at 6 months. Among 54 patients, 31 (57%; 95% CI: 44–70) were alive and progression-free at 6 months. The most frequent grade 3–4 adverse events were neutropenia (13%), nausea (11%), and anemia (7%). Five patients died during the study treatment, but none of the deaths were attributed to the study treatment.
The efficacy and safety of cisplatin, pemetrexed, and nivolumab were tested as first-line therapy for MPM in a phase II study, called JME-001 [20]. Cisplatin, pemetrexed, and nivolumab were administered intravenously every 3 weeks, for a total of 4 to 6 cycles. Patients that did not progress during the combination phase received maintenance therapy with nivolumab until disease progression or unacceptable toxicity. Among 18 enrolled patients, 14 (77·8%; 95% CI: 52·4–93·6) showed an objective response. Ten (55·6%) patients experienced grade 3 or worse adverse events, including disorders of metabolism or nutrition (33·3%), loss of appetite (27·8%), anemia (16·7%), and hyponatremia (11·1%). No treatment-related deaths occurred.
The efficacy and safety of pembrolizumab in combination with standard pemetrexed and platinum-based chemotherapy is currently being tested as a first-line treatment for MPM in phase II/III randomized study (NCT02784171) and in multicenter, open-label, non-randomized study (NCT04153565). Those results will be disclosed within a couple of years.
Cisplatin plus pemetrexed has been the mainstay of systemic treatment for MPM. A phase III trial of platinum, pemetrexed plus the anti-VEGF inhibitor, bevacizumab, showed favorable results, with prolonged PFS and OS. The National Comprehensive Cancer Network (NCCN) guidelines advocate adding bevacizumab as an option; however, that regimen has not been approved in most countries. In recent years, ICIs have shown remarkable progress in treating MPM. Summaries of the major trials, with a focus on recent trials, are shown in Table 1. They include both salvage treatments and first-line treatments. Based on the CheckMate 743 trial results, the ICI-ICI combination of ipilimumab plus nivolumab could be considered a new standard front-line treatment.
Trial (Reference) | Phase | Primary endpoint | Drug | Number of patients | Histology | ORR (%) (CI) | median PFS (months) (CI) | median OS (months) (CI) |
---|---|---|---|---|---|---|---|---|
First-line | ||||||||
MAPS [12] | III | OS | cisplatin + pemetrexed + bevacizumab | 223 | Epi: 179/223 (80%) non-Epi:44/223 (20%) | N.A. | 9.2 (8.5–10.5) | 18.8 (15.9–22.6) |
cisplatin + pemetrexed | 225 | Epi: 182/335 (81%) non-Epi:43/335(19%) | N.A. | 7.3 (6.7–8.0) | 16.1 (14.0–17.9) | |||
Checkmate 743 [18] | III | OS | pembrolizumab | 303 | Epi: 229/303 (76%) non-Epi: 74/303 (24%) | 40 (34.1–45.4) | 6.8 (5.6–7.4) | 18.1 (16.8–21.4) |
cisplatin + pemetrexed | 302 | Epi: 227/302 (75%) non-Epi: 75/302 (25%) | 43 (37.1–48.5) | 7.2 (6.9–8.0) | 14.1 (12.4–16.2) | |||
DREAM [19] | IIb | PFS | platinum + pemetrexed + durvalmab | 54 | Epi: 45/54 (83%) non-Epi: 9/54 (17%) | 48 (35–6) | 6.9 (5.5–9.0) | 18.4 (13.1–24.8) |
JME-001 [20] | II | ORR | cisplatin + pemetrexed + nivolumab | 18 | Epi: 14/18 (78%) non-Epi: 4/18 (22%) | 78 (52.4–93.6) | 8.0 (5.6–14.1) | 20.8 |
Second-line or later | ||||||||
MERIT [15] | IIb | ORR | nivolumab | 34 | Epi: 27 (79%) non-Epi: 7 (21%) | 29 (17–46) | 6.1 (2.9–9.9) | 17.3 (11.5–N.R.) |
MAPS2 [17] | III | If disease control was achieved in at least 40% | nivolumab + ipilimumab | 62 | Epi: 52 (83%) non-Epi: 11 (17%) | 28 (16–40) | 5.6 (3.1–8.3) | 15.9 (10.7–N.R.) |
placebo | 63 | Epi: 53 (85%) non-Epi:9(15%) | 19 (8–29) | 4.0 (2.8–5.7) | 11.9 (6.7–11.7) | |||
RAMES [14] | II | OS | gemcitabine + ramcirumab | 80 | Epi: 68/80 (85%) non-Epi: 12 (15%) | 6.3 (2–14) | 6.4 (5.5–7.6) | 13.8 (12.7–14.4) |
gemcitabine | 81 | Epi: 70/81 (86%) non-Epi:11/81(14%) | 10 (4–19) | 7.5 (6.9–8.9) | 7.5 (6.9–8.9) | |||
CONFIRM [16] | III | PFS OS | nivolumab | 221 | Epi: 195/221 (88%) non-Epi: 26/221 (12%) | 11 (N.A.) | 3.0 (2.8–4.1) | 10.2 (8.5–12.1) |
placebo | 111 | Epi: 98/111 (88%) non-Epi: 13/111 (12%) | 1 (N.A.) | 1.8 (1.4–2.6) | 6.9 (5.0–8.0) |
Recent clinical studies of systemic treatment in malignant pleural mesothelioma.
ORR: objective response rate; CI: confidence interval; PFS: progression-free survival; OS: overall survival; Epi: epithelioid; N.A.: not available; and DCR: disease control rate.
Some unresolved problems should be investigated to make further improvements in the outcome of patients with MPM. One is the rapid drop-off in PFS observed among patients that receive ICIs. A recent study on patients with non-small cell lung cancer showed that ipilimumab plus nivolumab combined with 2 cycles of cytotoxic chemotherapy could reduce the rapid drop-offs in both PFS and OS [21]. Those results supported the notion that the ICI-chemotherapy combination should undergo further clinical development. Results are also anticipated from an ongoing trial that is testing a more aggressive strategy, with a combination of platinum, pemetrexed, atezolizumab, and bevacizumab (BEAT-meso, NCT03762018).
The results of various clinical trials that examined ICIs and angiogenesis inhibitors have been published in recent years. These trials have demonstrated better treatment options for MPM, but personalized medicine remains in the distant future. Although, MPM is a rare disease, the prognosis remains extremely poor. Therefore, it is necessary to conduct more clinical trials and translational investigations to establish personalized treatment options that can provide the most benefit to individual patients.
This study was supported by grants-in-aid from the Ministry of Health, Labor, and Welfare, Japan.
Dr. Fujimoto received consultancy fees from Boehringer Ingelheim, Ono, and Bristol-Myers Squibb, and honoraria or research funding from Chugai, Ono, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and MSD.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
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\\n\\nOAI-PMH
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\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
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\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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Since the regulatory requirements and management strategies are required to be established and complied, sources of impurities shall be carefully classified prior to take subsequent steps such as development of analytical methods and acceptance criteria. Current international regulatory requirements for the management of impurities in pharmaceuticals were reviewed. Procedures for the identification of DPIs in pharmaceuticals, i.e., ethyl cysteinate dimer, (R)-N-methyl-3-(2-bromophenoxy)-3-phenylpropanamine, sestamibi, etc., using high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) were studied. Scheme for the establishment of analytical methods and acceptance criteria of process-related impurities (PRIs) and DRIs in accordance with the requirements of International Council for Harmonization (ICH) and algorithm to perform the identification of DPIs by using LC-MS/MS has been proposed. Practice of kinetic study to distinguish PRIs and DRIs, determination of the potential core fragments coupled with a predicted list of relevant transformations for conducting MS/MS scans, applications of stable isotope distribution patterns or natural abundances, practice of mass balance, etc., have been well demonstrated to justify the reliabilities of identification results.",book:{id:"7710",slug:"quality-management-and-quality-control-new-trends-and-developments",title:"Quality Management and Quality Control",fullTitle:"Quality Management and Quality Control - New Trends and Developments"},signatures:"Kung-Tien Liu and Chien-Hsin Chen",authors:[{id:"36122",title:"PhD.",name:"Kung-Tien",middleName:null,surname:"Liu",slug:"kung-tien-liu",fullName:"Kung-Tien Liu"},{id:"153497",title:"Dr.",name:"Chien-Hsin",middleName:null,surname:"Chen",slug:"chien-hsin-chen",fullName:"Chien-Hsin Chen"}]},{id:"58966",title:"Quality Management Systems for Laboratories and External Quality Assurance Programs",slug:"quality-management-systems-for-laboratories-and-external-quality-assurance-programs",totalDownloads:4617,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"A quality management system (QMS) plans, controls, and improves the elements that impact on the achievement of the desired results by the laboratory and on the satisfaction of the users. There are different standards that establish requirements for the implementation of a quality management system for laboratories, and a cross comparison between them is shown. Additionally, external quality assurance or assessment (EQA) programs offer multiple benefits to laboratories: method validation, comparing of results with other laboratories, testing problem identification, accreditation requirement compliance, and credibility. In order to control the quality of the procedures, these programs are a tool to keep the laboratory procedures and every variable involved in (staff, equipment, and method) well controlled. In the frame of a quality management system, benefits from external quality assurance programs are discussed, and different available designs are reviewed. On the other hand, previous benefits will be real only if reported results for each program are analyzed in detail. Because additional advantages are achieved when the EQA results are integrated in the quality management system of the laboratory, a procedure is proposed. In addition, results from external quality assurance programs corroborate the usefulness of internal controls implemented by the laboratory as part of its quality management system.",book:{id:"6325",slug:"quality-control-in-laboratory",title:"Quality Control in Laboratory",fullTitle:"Quality Control in Laboratory"},signatures:"Verónica Valdivieso-Gómez and Rocío Aguilar-Quesada",authors:[{id:"217457",title:"Ph.D.",name:"Rocio",middleName:null,surname:"Aguilar-Quesada",slug:"rocio-aguilar-quesada",fullName:"Rocio Aguilar-Quesada"},{id:"217467",title:"Ms.",name:"Veronica",middleName:null,surname:"Valdivieso-Gomez",slug:"veronica-valdivieso-gomez",fullName:"Veronica Valdivieso-Gomez"}]},{id:"41063",title:"Cosmetics’ Quality Control",slug:"cosmetics-quality-control",totalDownloads:12664,totalCrossrefCites:2,totalDimensionsCites:12,abstract:null,book:{id:"3276",slug:"latest-research-into-quality-control",title:"Latest Research into Quality Control",fullTitle:"Latest Research into Quality Control"},signatures:"Bruna Galdorfini Chiari, Maria Gabriela José de Almeida, Marcos Antonio Corrêa and Vera Lucia Borges Isaac",authors:[{id:"35801",title:"Dr.",name:"Vera",middleName:null,surname:"Isaac",slug:"vera-isaac",fullName:"Vera Isaac"},{id:"56070",title:"MSc.",name:"Bruna",middleName:null,surname:"Chiari",slug:"bruna-chiari",fullName:"Bruna Chiari"},{id:"56072",title:"Dr.",name:"Marcos Antonio",middleName:null,surname:"Corręa",slug:"marcos-antonio-correa",fullName:"Marcos Antonio Corręa"},{id:"154324",title:"BSc.",name:"Maria Gabriela José De",middleName:null,surname:"Almeida",slug:"maria-gabriela-jose-de-almeida",fullName:"Maria Gabriela José De Almeida"}]},{id:"58071",title:"Systematic Error Detection in Laboratory Medicine",slug:"systematic-error-detection-in-laboratory-medicine",totalDownloads:1752,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Measurements in laboratory medicine have a degree of uncertainty; this uncertainty is often called “error” and refers to imprecisions and inaccuracies in measurement. This measurement error refers to the difference between the true value of the measured sample and the measured value. One of the types of error is systematic error, also called bias, because these errors errors are reproducible and skew the results consistently in the same direction. A common approach to identify systematic error is to use control samples with a method comparison approach. An alternative is use of statistical methods that analyze actual patient values either as an “Average of Normals” or a “Moving Patient Averages.” Fundamental questions should be decided before a quality control method is used: how are weights assigned to the results? Is preference given to more recent samples or to the older samples? How sensitive should the model be? In this chapter, we will expand the fundamental notion of systematic error and explain why it is difficult to identify and measure and current statistical methods that are used to detect systematic error or bias.",book:{id:"6325",slug:"quality-control-in-laboratory",title:"Quality Control in Laboratory",fullTitle:"Quality Control in Laboratory"},signatures:"Amir Momeni-Boroujeni and Matthew R. 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Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"38",title:"Pollution",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",isOpenForSubmission:!0,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null},{id:"39",title:"Environmental Resilience and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",isOpenForSubmission:!0,editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",slug:"jose-navarro-pedreno",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",biography:"Full professor at University Miguel Hernández of Elche, Spain, previously working at the University of Alicante, Autonomous University of Madrid and Polytechnic University of Valencia. Graduate in Sciences (Chemist), graduate in Geography and History (Geography), master in Water Management, Treatment, master in Fertilizers and Environment and master in Environmental Management; Ph.D. in Environmental Sciences. His research is focused on soil-water and waste-environment relations, mainly on soil-water and soil-waste interactions under different management and waste reuse. His work is reflected in more than 230 communications presented in national and international conferences and congresses, 29 invited lectures from universities, associations and government agencies. Prof. Navarro-Pedreño is also a director of the Ph.D. Program Environment and Sustainability (2012-present) and a member of several societies among which are the Spanish Society of Soil Science, International Union of Soil Sciences, European Society for Soil Conservation, DessertNet and the Spanish Royal Society of Chemistry.",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null},{id:"40",title:"Ecosystems and Biodiversity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",isOpenForSubmission:!0,editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",slug:"salustiano-mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",biography:"Salustiano Mato de la Iglesia (Santiago de Compostela, 1960) is a doctor in biology from the University of Santiago and a Professor of zoology at the Department of Ecology and Animal Biology at the University of Vigo. He has developed his research activity in the fields of fauna and soil ecology, and in the treatment of organic waste, having been the founder and principal investigator of the Environmental Biotechnology Group of the University of Vigo.\r\nHis research activity in the field of Environmental Biotechnology has been focused on the development of novel organic waste treatment systems through composting. 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She has focused her research activity on the taxonomy, fauna and ecology of aquatic beetles, in addition to other lines of research such as the conservation of biodiversity in freshwater ecosystems; conservation of protected areas (Red Natura 2000) and assessment of the effectiveness of wetlands as priority areas for the conservation of aquatic invertebrates; studies of water quality in freshwater ecosystems through biological indicators and physicochemical parameters; surveillance and research of vector arthropods and invasive alien species.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",slug:"francisco-ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",biography:"Fran Ramil Blanco (Porto de Espasante, A Coruña, 1960), is a doctor in biology from the University of Santiago de Compostela and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. His research activity is linked to the taxonomy, fauna and ecology of marine benthic invertebrates and especially the Cnidarian group. Since 2004, he has been part of the EcoAfrik project, aimed at the study, protection and conservation of biodiversity and benthic habitats in West Africa. He also participated in the study of vulnerable marine ecosystems associated with seamounts in the South Atlantic and is involved in training young African researchers in the field of marine research.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}}},{id:"41",title:"Water Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",isOpenForSubmission:!0,editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",slug:"yizi-shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",biography:"Prof. Dr. Yizi Shang is a pioneering researcher in hydrology and water resources who has devoted his research career to promoting the conservation and protection of water resources for sustainable development. He is presently associate editor of Water International (official journal of the International Water Resources Association). He was also invited to serve as an associate editor for special issues of the Journal of the American Water Resources Association. He has served as an editorial member for international journals such as Hydrology, Journal of Ecology & Natural Resources, and Hydro Science & Marine Engineering, among others. He has chaired or acted as a technical committee member for twenty-five international forums (conferences). Dr. Shang graduated from Tsinghua University, China, in 2010 with a Ph.D. in Engineering. Prior to that, he worked as a research fellow at Harvard University from 2008 to 2009. 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He received his Ph.D. in Environmental Analytical Chemistry from Assiut University, Egypt, in 1989. His research interest is in analytical and environmental chemistry with special emphasis on: (1) monitoring and assessing biological trace elements and toxic metals in human blood, urine, water, crops, vegetables, and medicinal plants; (2) relationships between environmental heavy metals and human diseases; (3) uses of biological indicators for monitoring water pollution; (4) environmental chemistry of lakes, rivers, and well water; (5) water and wastewater treatment by adsorption and photocatalysis techniques; (6) soil and water pollution monitoring, control, and treatment; and (7) advanced oxidation treatment. Prof. Rashed has supervised several MSc and Ph.D. theses in the field of analytical and environmental chemistry. He served as an examiner for several Ph.D. theses in analytical chemistry in India, Kazakhstan, and Botswana. He has published about ninety scientific papers in peer-reviewed international journals and several papers in national and international conferences. He participated as an invited speaker at thirty international conferences. Prof. Rashed is the editor-in-chief and an editorial board member for several international journals in the fields of chemistry and environment. He is a member of several national and international societies. He received the Egyptian State Award for Environmental Research in 2001 and the Aswan University Merit Award for Basic Science in 2020. 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