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IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
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\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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Research on plant flavonoids has developed rapidly with the realization of the importance of plant flavonoids to plants themselves. Although parts of the biosynthesis pathway, transport, regulation, and function of flavonoids in plants have been evaluated, several genetic and biochemical mechanisms remain unclear due to differences in research strategies. Reverse genetics promoted the elucidation of the flavonoid pathway in the early stages, the forward genetics strategy is better for solving the problems that reverse genetics cannot solve, and this technique has since promoted the analysis of the flavonoid pathway. Breeding flavonoid biofortified crops can be an important strategy to solve the nutrient deficiency issues of people in developing countries, however, the stability and bioavailability of flavonoid contents in biofortified crops need further attention. In the future, the application of forwarding genetics may constitute a major direction of flavonoid research to resolve the stability and bioavailability issues.
\r\n\r\n\tThis book aims to provide a comprehensive overview of flavonoid metabolism and the role of forwarding genetics to uncover the remaining aspects of crop biofortification for the manipulation and enhancement of beneficial nutrients.
",isbn:"978-1-80356-705-1",printIsbn:"978-1-80356-704-4",pdfIsbn:"978-1-80356-706-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"a09c0aef04a5e8af53f1bec55e6ed2a3",bookSignature:"Dr. Hafiz Muhammad Khalid Abbas and Dr. Aqeel Ahmad",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11614.jpg",keywords:"Isoflavonoids, Pathways, Gene Interaction, Stability, Bioavailability, HPLC, mGWAS, mQTL Mapping, Genome Editing, Biofortification, Flavones, Genistein",numberOfDownloads:7,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 23rd 2022",dateEndSecondStepPublish:"May 27th 2022",dateEndThirdStepPublish:"July 26th 2022",dateEndFourthStepPublish:"October 14th 2022",dateEndFifthStepPublish:"December 13th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Abbas is a researcher working on metabolic engineering to enhance the bioavailability of flavonoids in plants. 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In this respect, we present an evolved oncology diagnostic system (http://www.carismolecularintelligence.com/i-o/). First of all, immunotherapy options should be sought through the development of complex immunoregulatory pathways. One of the systems that can be used in immunological diagnosis is Caris Molecular Intelligence. This system provides oncologists with reliable molecular information to make decisions about the use of immunotherapy. The tests are validated for testing PD-L1, MSI, and tumor mutation load (TML). Programmable cell death-ligand 1 (PD-L1) is one of the most important control immune proteins that mediates tumor-induced suppression by T-cell downregulation. Expression of PD-L1 may indicate a more likely response to immunotherapy. Of course, a perfect marker to predict the response to PD-L1 inhibitor therapy has not been validated for the moment, but with these tests, we have an important orientation (Cochrane Collaboration Guidelines).
Microsatellite instability (MSI) is caused by the failure of the mismatch repair (MMR) system. MSI-High correlates with the increase in neoantigenic burden, which is more likely to respond favorably to immunotherapy.
Tumor mutation load (TML) measures the total number of non-sinusoidal somatic mutations identified on the megabase of the genome coding region. High TML supports neoantigens and responds favorably to immunotherapy.
The immune system is capable of recognizing and destroying tumor cells as well as pathogens. However, one of the hallmarks of cancer is its ability to avoid the immune system [1].
There are a lot of complex interactions between the cells presenting the antigen, the lymphocytes, and the tumor cells. The most studied is the cell membrane T-cell receptor binding, called programmed cell death 1 (PD-1), and its ligands 1 or 2 (PD-L1 or PD-L2) expressed by some tumor cells. This interaction results in inactivation of T lymphocytes in an effort to avoid the immune response against tumor cells [2, 3]. Inhibition of this pathway is the target of inhibitors of immune control points. There are two types of agents: anti-PD-1 and anti-PD-L1 monoclonal antibodies.
Among these, anti-PD-1 agents that bind the lymphocyte receptor and block both PD-L1 and PD-L2 bindings are considered to be more toxic than anti-PD-L1 due to their broad spectrum of clinical activity. However, this has not been confirmed by recent clinical trials [4, 5]. Pembrolizumab and nivolumab, two monoclonal antibodies against PD-1, as well as avelumab monoclonal IgG1 anti-PD-L1 antibodies, atezolizumab and MEDI4736, showed consistent antitumor activity against NSCLC [6].
Despite an improvement in overall survival (OS) by platinum-based chemotherapy (NSCLC Meta-analyses Collaborative Group, 2008), prognosis remains unsatisfactory for patients with advanced NSCLC, with a median survival of 8–12 months [7, 8].
In 2006, there was a plateau for chemotherapy in a study that none of the four chemotherapy regimens compared offered a significant advantage over the others in the treatment of advanced non-small cell lung cancer [8].
The development in molecular characterization of NSCLC, especially in histological subtypes of adenocarcinoma, has allowed the identification of key genetic aberrations in NSCLC, which can be addressed with molecular targeted therapy. Genetic aberrations in EGFR, ALK, ROS1, RET, BRAF, and NTRK have a predictive value for susceptibility to receptor tyrosine kinase inhibitors [9, 10, 11]. Despite the success of molecular diagnostics, acquired resistance and disease progression are inevitable [9, 10, 11].
Treatment options for patients with small-cell lung cancer (SCLC) where the disease progressed after platinum-based chemotherapy are even more limited.
Immunotherapy in cancer has been described as any therapy that interacts with immunity. Immunotherapy in cancer can be classified into passive and active types. Passive immunotherapy has been described as administration of an active agent produced or generated outside the patient’s body. Theoretically, such an approach does not depend on the host’s own immune system to have an effect. Examples of passive immunotherapy include the use of monoclonal antibodies, such as trastuzumab [12, 13], and adoptive cell therapy, such as tumor-infiltrating lymphocytes (CAR-T cell) [14]. This new approach of therapy has and specific toxicity: cytokine release syndrome, neurologic toxicity, “on target/off tumor” recognition, and anaphylax [15].
Active immunotherapy involves stimulating or determining the host’s immune system to recognize a tumor as a foreign. Examples of active immunotherapy include vaccination against cancer with tumor antigens and an adjuvant enhancement of immune cell function with cytokines, as well as targeting of immune control regulators with immune control inhibitor control.
Inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) are used in NSCLC and SCLC.
Studies that examine the efficacy of cytokines such as interferon alpha and interleukin-2 (IL-2) in lung cancer patients were negative and will not be discussed [16].
Therapeutically acting vaccines in cancer are designed to eliminate cancer cells by increasing their own immune responses. This type of vaccine contrasts with prophylactic vaccines, which are usually administered to healthy people. Cancer vaccines can be classified into several major types, such as cellular vaccines, peptide vaccines, and genetic vaccines [17].
Vaccines against cancer, despite despite setbacks attempt to harness the patient’s immune system to fight tumor cells and show a promise in clinical trials.
Cellular vaccines may be either autologous or allogeneic. Autologous tumor cell vaccines are developed by isolating tumor cells from an individual (patient), creating a vaccine that is administered back to the same patient, usually in combination with an adjuvant that stimulates the immune system. These vaccines have been among the first types of cancer vaccines tested and have the advantage of provoking an immune response to a wide range of tumors. Antigens expressed by the patient’s own tumor result in tumor destruction. Although similar to autologous vaccines, allogeneic vaccines are obtained by administering tumor cells to a patient, creating a vaccine that is then administered to another patient with the same type of cancer [18].
Unlike cellular vaccines that are made directly from patient tumors, peptide vaccines are often synthesized in vitro to mimic tumor-associated proteins in order to elicit an immune response against tumor cells expressing that protein [19].
Genetic vaccines are composed of DNA molecules or synthetic RNAs encoding tumor-associated proteins and are administered either alone or packaged in a nonpathogenic virus. The genetic material is taken up by the recipient cells, translated into proteins encoded, processed, and presented to the immune system to elicit the immune response against tumor-associated proteins [20].
DNA vaccination has suddenly become a favored strategy for inducing immunity. The molecular precision offered by gene-based vaccines, together with the facility to include additional genes to direct and amplify immunity, has always been attractive. However, the apparent failure to translate operational success in preclinical models to the clinic, for reasons that are now rather obvious, reduced initial enthusiasm. Recently, novel delivery systems, especially electroporation, have overcome this translational block. Here, we assess the development, current performance, and potential of DNA vaccines for the treatment of cancer.
Early studies on Calmette-Guerin adjuvant Calmette-Guerin adjuvant and neoadjuvant bacillus vaccine therapy were negative [21, 22].
In the modern age, multiple-stage, locally advanced, and advanced NSCLC vaccine studies have been conducted. The recombinant protein-associated anti-melanoma-antigen-associated antigen (MAGE)-A3 vaccine has been extensively studied in adjuvant therapy after complete resection. A randomized phase II trial showed that for patients with stage IB–II, MAGE-A3 in NSCLC, who did not receive any adjuvant chemotherapy, there was a tendency toward survival gain. And, survival without signs of disease was positively influenced by the MAGE-A3 vaccine compared to placebo after a median follow-up to 70 months (HR, 0.75; 95% CI, 0.46–1.23; p = 0.254) [23].
However, clinical benefit was not found in the randomized, double-blind, placebo-controlled phase III (MAGRIT) study in fully resected NSCLC IB–IIIA MAGE-A3, with or without adjuvant chemotherapy. Subsequently, for the total population in this study, median disease-free survival was 60.5 months for the MAGE-A3 vaccine group and 57.9 months for the placebo group (HR, 1.02; 95% CI, 0.89–1.18; p = 0.74). In the subgroup that performed adjuvant chemotherapy, median disease-free survival was 58.0 months in the vaccine group and 56.9 months in the placebo group (HR, 0.97; 95% CI, 0.80–1.18; p = 0.76) [24].
Tecemotide (L-BLP25) is a peptide vaccine based on a 25 amino acid sequence of mucin-1 (MUC1), which has shown promising activity in locally advanced NSCLC in a phase II study [25].
Subsequently, the result led to the initiation of two randomized trials. One was a complete phase III trial, START, in which the placebo tecemotide was compared for patients with stage III NSCLC without disease progression after chemoradiation therapy [26].
The second study, INSPIRE, was a randomized phase II study of Asian patients that did not have convincing results after the Asian phase [27].
Analysis of the START study showed that there was no significant difference in median overall survival between the tecemotide arm and placebo arms (25.6 months vs. 22.3 months; HR adjusted, 0.88; 95% CI, 0.75–1.03; p = 0.123). However, following a prespecified subgroup analysis, median overall survival was different between the vaccine arm and the placebo arm for patients receiving concomitant chemoradiation therapy (30.8 months vs. 20.6 months; HR, 0.78; 95% CI, 0.64–0.95; p = 0.016) compared with patients receiving sequential chemoradiation therapy (19.4 months vs. 24.6 months; HR, 1.12; 95% CI, 0.87–1.44; p = 0.38) [28].
In the advanced stage of the disease, the TG4010, another vaccine targeting MUC1, used a viral vector to express both MUC1 and IL-2 (a T-cell stimulus). The results were promising.
In a phase IIb study (TIME) results (part of the randomized, double-blind, placebo-controlled, phase IIb/III study), showed that in the overall population, disease-free survival was 5.9 months for the TG4010 group and 5.1 months for placebo (HR, 0.74; 95% CI, 0.55–0.98; p = 0.019) [29].
Belagenpumatucel-L is an allogeneic tumor cell tumor vaccine derived from four cell lines of NSCLC with different histologies, also express an antisense transgene for transforming beta2 growth factor that reduces the regulation of its immunosuppressive transformation. The results of a phase II study suggested clinical efficacy in patients with advanced NSCLC, and a randomized phase III (STOP) study was initiated. Patients with stage III/IV NSCLC in whom the disease did not progress after platinum-based chemotherapy received either belagenpumatucel-L or placebo [30]. There was no significant difference in overall survival between the two arms (20.3 months vs. 17.8 months; HR, 0.94; p = 0.594); there was also no difference in progression-free survival (PFS) (4.3 months vs. 4.0 months; HR, 0.99; p = 0.947) [30].
The epidermal growth factor receptor (EGFR) is an important signaling pathway in NSCLC, and a vaccine has been developed against its related EGF ligand, using recombinant human EGF coupled to a carrier protein. In a randomized phase II trial, patients with stage IIIB/IV NSCLC were randomly assigned to receive the best supportive treatment or EGF vaccines after first-line chemotherapy [31]. In the global population, there was a trend toward improved overall survival and a significant survival advantage for patients who had a good antibody response to the EGF [31].
A subsequent phase III study included patients with stage IIIB/IV NSCLC who were randomly assigned to the first line of chemotherapy to make the vaccine or the best supportive care. In the safety population, overall survival was 10.83 months for the vaccine arm and 8.86 months for the control arm [32]. For patients who received at least four doses of vaccine, overall survival differed significantly between the vaccine group and the supportive treatment group (12.43 months vs. 9.43 months; HR, 0.77; p = 0.036). In addition, overall survival was longer (14.66 months) for patients vaccinated with high concentrations of EGF at the baseline [32].
Ipilimumab in combination with chemotherapy has been studied in patients with advanced NSCLC who have not received the previous treatment. In this phase II triple-arm study, patients were randomly assigned to chemotherapy (carboplatin plus paclitaxel), sequential chemotherapy with ipilimumab, or chemotherapy with concomitant ipilimumab. The primary endpoint of the study was overall survival and progression-free survival, which was 4.6 months for the chemotherapy arm, 5.7 months for the sequential ipilimumab chemo arm (HR, 0.72; p = 0.05), and 5.5 months for the ipilimumab arm concomitantly with chemotherapy (HR, 0.81; p = 0.13) [33]. Progression-free survival was better in NSCLC patients with squamous histology than patients with nonsquamous NSCLC. To confirm these results, a larger phase III trial (NCT02279732) was initiated for patients with squamous cell NSCLC.
Conclusion of the study was that phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC [33].
In the Govindan study ipilimumab added to chemotherapy (carboplatin plus paclitaxel) did not improve the survival of patients with advanced NSCLC [34].
PD-1 inhibitors include agents such as nivolumab and pembrolizumab. Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that disrupts PD-1-mediated signaling, thus releasing T cells from their inhibitory interaction with PD-L1 and PD-L2. Pembrolizumab is a monoclonal antibody, the humanized IgG4/kappa isotype, which also blocks the binding of PD-L1 and PD-L2 to PD-1 on T cells, resulting in activation of tumor-specific cytotoxic T cells. Cytotoxicity is complement-dependent (CDC) (Alsaab) [35].
Action may be important because cytotoxicity can cause an exhaustion of activated T cells and infiltrating lymphocytes into tumors. PD-1 is expressed on effector T cells and other immune cells [36].
Checkmate 026 did not show a benefit in PFS for nivolumab versus chemotherapy. The authors reveal the fact that nivolumab monotherapy did not result in longer progression-free survival than platinum-based chemotherapy as first-line treatment for stage IV or recurrent NSCLC in a broad population of patients with a PD-L1 expression level of 5% or more. Overall survival with single-agent nivolumab was similar to overall survival with platinum-doublet chemotherapy. Nivolumab had a favorable safety profile as compared with chemotherapy, and no new safety signals were observed [37].
The new data from the phase 1b CA209-003 study were presented at the American Association for Cancer Research annual meeting: “The longest follow-up to date on patients treated with nivolumab for advanced non-small cell lung cancer (NSCLC) shows a 16% 5-year overall survival (OS) rate, according to new results presented here at the American Association for Cancer Research annual meeting.” Suzanne Topalian, from Johns Hopkins University, and a coinvestigator (April 03, 2017): “the 5-year overall survival really quadrupled the survival that we would otherwise expect if these same patients had received chemotherapy” (April 03, 2017) (https://www.medscape.com/viewarticle/878148).
Nivolumab provides a long-term clinical benefit and a favorable tolerability profile compared to docetaxel in previously treated patients with advanced NSCLC [38]. FDA approved of nivolumab for second-line treatment of patients with advanced NSCLC.
In a single-arm phase II study (CheckMate 063) with nivolumab for patients with squamous cell NSCLC who were treated with third-line therapy and beyond, the partial response rate was 14.5, and 26% of patients had a stable disease [4]. Overall survival was 8.2 months, and 1-year survival was about 41%. Noteworthy, the study population was very refractory to treatment, with 65% of patients treated with at least three previous systemic therapy lines. In addition, 61% of patients had disease progression as the best response to the latest therapy [39].
In another phase II trial (CheckMate 153), 824 patients with advanced NSCLC were treated for 1 year with nivolumab. The partial response and stable disease rates were 12 and 44%, respectively. The answers were independent of the PD-L1 expression [40].
The second-line treatment with nivolumab was superior to docetaxel in two subsequent phase III randomized phases in advanced NSCLC patients receiving double-blind platinum chemotherapy.
In a study of 272 patients with squamous NSCLC (CheckMate 017), median overall survival and 1-year survival were better for nivolumab than for docetaxel. The risk for death was 0.59 with nivolumab (p < 0.001) [6].
In the study (CheckMate 057), which included patients with advanced nonsquamous NSCLC histology, nivolumab in line 2 was also associated with better overall survival and survival over 1 year, also better than docetaxel (HR, 0.73) [41]. In subset analysis of subset biomarker values, PD-L1 expression ≥1, ≥5, and ≥10% corresponded to an improvement in PFS with a HR of 0.70, 0.54, and 0.52, respectively, and in OS with a HR of 0.58, 0.43, and 0.40. In contrast, in tumors with a low PD <1, <5, and <10% PD-L1 expression, HR for PFS was 1.19, 1.31, and 1.24, respectively, and for OS was 0.87, 0.96, and 0.96 [41].
The safety and efficacy of single-agent nivolumab in first-line treatment of patients with advanced NSCLC have been reported in CheckMate 012 adverse events occurred in 71% of patients, the most common being fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). The overall confirmed response was 23%, and progression-free survival and overall survival were 3.6 months and 19.4 months. The nonprogression-free survival rate of 24 weeks was 41%. The survival rate at 1 year was 73% [42].
Recently, in a phase III study, first-line nivolumab compared to a platinum-based chemotherapy for tumors with a PD-L1 expression of 5% or greater (CheckMate 026) showed progression-free survival greater for the chemotherapy arm, but overall survival was better for the nivolumab arm [43]. The objective response rate was lower for the nivolumab arm. In conclusion, nivolumab monotherapy did not result in longer progression-free survival than platinum-based chemotherapy as first-line treatment for stage IV or recurrent NSCLC. In this study the PD-L1 expression level was 5% or more [43].
SCLC is most often an extended stage disease at the time of diagnosis. Although the first line of platinum-based chemotherapy has activity, the disease progresses inevitably, and response rates in the second-line treatment are low and are not sustainable. The activity and safety of nivolumab with or without ipilimumab in previously treated SCLCs were evaluated in CheckMate 032. The objective response rate was 10% with nivolumab 3 mg/kg alone, 23% with 1 mg/kg of nivolumab in combination with 3 mg/kg of ipilimumab, and 19% with 3 mg/kg of nivolumab in combination with 1 mg/kg of ipilimumab. PD-L1 expression was not associated with responses [44].
Patients with small-cell lung cancer (SCLC) and a high tumor mutation burden had an important increase in survival (near doubling in response rate and 1-year overall survival) with ipilimumab combined with nivolumab versus nivolumab alone.
The efficacy and safety of pembrolizumab at two different doses in previously untreated patients, advanced NSCLC, were reported in the Keynote-001 study. The objective response rate was 19.4%, and the median response time was 12.5 months. The progression-free survival was 3.7 months, and overall survival was 12.0 months [45]. The objective response rate was 18% in those treated previously and 24.8% of untreated patients. The objective response rate was 45.2%, and no time to progression was 6.3 months. The objective response rate was similar regardless of dose, schedule, and histology subtype. The response rate was higher among smokers than nonsmokers. Treatment-related adverse events of any grade occurred in 70.9% of patients, 9.5% having a grade 3 or higher adverse event [45].
Pembrolizumab was evaluated in a phase II/III study of patients previously treated with advanced NSCLC (Keynote-010). A total of 1034 patients were randomized to receive either 2 mg/kg dose or 10 mg/kg of pembrolizumab or 75 mg/m2 of docetaxel every 3 weeks [46]. All patients had at least 1% tumor cells that were positive for PD-L1. Overall survival was improved with both doses of pembrolizumab compared to docetaxel. Among patients with at least 50% of the tumor cells expressing PD-L1, overall survival rates were 14.9 and 17.3 months with pembrolizumab at doses of 2 mg/kg and 10 mg/kg, respectively, compared to 8.2 months with docetaxel. Any degree of treatment-related adverse events occurred in 63% of pembrolizumab 2 mg/kg and 66% of patients receiving 10 mg/kg. The treatment-related toxicity was higher (81%) in the docetaxel arm.
Grade 3–5 treatment-related adverse events were less common in pembrolizumab-treated patients (2 mg/kg (13%), 10 mg/kg (16%)) versus docetaxel (35%) [46].
The Keynote-024 phase 3 clinical trial was the basis for pembrolizumab approval as a first-line treatment for patients with a diagnosis of metastatic NSCLC for whom PD-L1 expression is in 50% or more of tumor cells. Keynote-024 is a randomized, open-label phase 3 study evaluating pembrolizumab monotherapy at a fixed dose of 200 mg compared to the platinum-based chemotherapy standard for the treatment of patients with metastatic NSCLC with both squamous and unscrupulous histologies.
In phase III trial for first-line therapy of patients with advanced NSCLC (Keynote-024), with a PD-L1 tumor expression of 50% or greater, patients were randomly assigned to pembrolizumab- or platinum-based chemotherapy doublets, and progression-free survival was significantly better for pembrolizumab (HR, 0.50, 95% CI, 0.37–0.68; p < 0.001) median 10.4 months [47].
Overall survival was 0.60 (95% CI, 0.41–0.89; p = 0.005). The estimated percentage of patients in life at 12 months with pembrolizumab was 70%. In addition, the response rate was higher for pembrolizumab than for chemotherapy. Adverse events associated with pembrolizumab therapy were fewer than chemotherapy. The results are innovative because this is the first to demonstrate the superiority of anti-PD-1 therapy to platinum [47].
Preliminary data from a multicohort phase Ib study on pembrolizumab with previously treated PD-L1-positive subjects include a 25% objective response rate and a 31% disease control rate [48].
PD-L1 inhibitors also inhibit PD-1/PD-L1 interactions. PD-L1 inhibitors include atezolizumab, durvalumab, and avelumab. Atezolizumab and durvalumab are human IgG1 anti-PD-L1 antibodies with mutations in their Fc domains to eliminate both antibody-dependent cell-mediated cytotoxicity (ADCC) activity and complement-dependent cytotoxicity (CDC) activity. Avelumab is a fully human IgG1 anti-PD-L1 monoclonal antibody and, unlike another PD-1/PD-L1 inhibitor, has been shown to retain ADCC and CDC activity in preclinical studies [49].
In a single-arm phase II study (IMpower 110 study), the objective response rate for atezolizumab was 16%, regardless of PD-L1 expression in immune cells, and 28% in patients with 5% or more high expression PD-L1 [50]. Atezolizumab (MDPL3280A) clearly is an added value in the treatment of advanced-stage pretreated NSCLC. Its interest in contrast with other immune checkpoint inhibitors relies on its efficacy, even in low or no PD-L1 expression subgroups. Considering that the efficacy of anti-PD-1 such as pembrolizumab or nivolumab is overall higher in PD-L1-positive patients, atezolizumab might be preferable in PD-L1-negative patients. It will be necessary to consider other variant methods of PD-L1 testing used for each therapy to further explore this hypothesis [51].
In a randomized phase II (Poplar) study in patients receiving platinum-based chemotherapy, atezolizumab was associated with a higher overall survival (HR, 0.73; CI 95%, 0.53–0.99; p = 0.04) [52]. In another phase II trial (BIRCH), advanced NSCLC patients who were selected for PD-L1 expression received atezolizumab as first-line or as a subsequent therapy. Response rates ranged from 17 to 27% [53], and median overall survival was 14 months for patients receiving atezolizumab as the first line of therapy. Overall survival has not yet been achieved for patients receiving atezolizumab as a subsequent therapy [53]. In the OAK study, a phase III trial of previously treated NSCLC patients randomly assigned to atezolizumab or docetaxel, the overall survival was significantly better for atezolizumab (13.8 months vs. 9.6 months; HR, 0.73; 95% CI, 0.62–0.87; p = 0.0003) [54]. The OAK study led to the FDA approval of atezolizumab for second-line therapy of advanced NSCLC [54].
In a phase I/II study with durvalumab in 2009 in the first-line treatment in NSCLC patients irrespective of PD-L1 status, the overall response rate was 27 and 29% for PD-L1-positive tumors (defined as ≥25% of tumor cells expressing PD-L1) and 11% in PD-L1-negative tumors [55]. In a phase II trial of patients with advanced NSCLC who received at least two previous systemic therapy lines, the activity was extremely encouraging. The objective response rate and survival rate at 1 year increased according to the PD-L1 expression: 7.5% (PD-L1 expression less than 25%), 16.4% (more than 25% expression), and 30.9% (greater than 90% expression). The corresponding 1-year survival rates were 34.5, 47.7, and 50.8% [56].
The study PACIFIC was presented to the ESMO Congress 2017 and was a randomized, double-blind, international, phase 3 study comparing durvalumab as consolidation therapy with placebo in patients with stage III, locally advanced, unresectable NSCLC that had not progressed after platinum-based chemoradiotherapy. Median progression-free survival as assessed by means of blinded independent central review was 16.8 months (95% confidence interval [CI], 13.0–18.1) with durvalumab versus 5.6 months (95% CI, 4.6–7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42–0.65; two-sided p < 0.001). Authors consider that this study will change the clinical practice [57].
CTLA-4 and PD-1/PD-L1 are combination. CTLA-4 inhibitors are also studied in conjunction with PD-1 and PD-L1 inhibitors. Results of preclinical studies indicate that this combination can work synergistically to produce improved antitumor activity [58].
Nivolumab was combined with ipilimumab for first-stage NSCLC in setting up in a phase I (CheckMate 12) study. The results included objective response rates ranging from 13 to 39%.
In NSCLC, the first-line nivolumab plus ipilimumab had a tolerable safety profile and showed an encouraging clinical activity characterized by a high response rate and durable response. In our study, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further evaluation of this combination in a phase 3 study [59].
Durvalumab was combined with the tremelimumab CTLA-4 inhibitor in a phase Ib study of patients with advanced NSCLC. Although many adverse events occurred during the study dose phase, the antitumor activity (23% objective response rate) was evident regardless of the PD-L1 status in the evaluable patients in the dose study—the expansion phase of the study [60].
In a phase III randomized study, the frontline durvalumab, either in combination with tremelimumab or as a single agent, did not improve progression-free survival (PFS) in patients with stage IV metastatic non-small cell lung cancer (NSCLC) compared with standard platinum-based chemotherapy [61].
Immunotherapy has become one of the most important therapeutic tools in advanced lung cancer. Existing studies have revealed a response rate of between 13 and 39%. It is also important that this therapy, unlike TKI-targeted therapy, also responds to smokers who make up most of the lung cancer patients.
Another important benefit from immunotherapy in advanced lung cancer is that squamous non-small cell lung cancer also responds to this therapy. Some promising results are and in treatment of small-cell lung cancer.
From existing studies, it is trembling that immunotherapy can improve survival compared to chemotherapy in a selected patient population, both in the first line and in the second line.
There is not yet a valid predictive marker that can be used to choose patients who will respond to immunotherapy. Currently, the only marker used is PD-1 expression that does not have a good validity. For the moment, there are not criteria to select patients for treatment with PD-1 or PD-L1 inhibitor because data to compare these two pathways is lacking. Better results were however obtained with a percent of PD-L1more then 50%. More study are needed to define the best combination of immunotherapy with chemotherapy or radiotherapy.
Vaccine therapy is promising but needs additional evaluation. Vaccine in combination with other therapeutic modalities especially checkpoint inhibitors is possible to have some benefits and must be studied.
Many guidelines are developed to treat side effects of immunotherapy. Despite a correct supportive therapy, some side effects are life-threatening. But generally, the quality of life of patients treated with immunotherapy is improved.
Technological advances in the areas of computing, software development, internet, internet of things, cloud computing, and several other areas that encompass the New Information and Communication Technologies (ICT) brought changes in work routines, education, and even in social relationships. The ICT concept refers mainly to processes and products related to knowledge stemming from electronics, microelectronics, and telecommunications. These technologies are characterized by being evolutionary - that is to say, they are in permanent transformation. According to [1, 2], the Information Society or Knowledge Society is a phenomenon in which different instances (social, political, cultural, educational) are mediated by technological means. This new articulation allowed the consolidation of several remote activities such as virtual work, online classes, virtual communities for the development of activities of various kinds, providing new forms of the process of generating, acquiring, retaining, and sharing knowledge, with the emergence of platforms dedicated to formal and informal teaching-learning processes in digital media. Some researchers still believe that the maturity and excellence of remote work and education processes has not yet been reached. The processes of knowledge acquisition and sharing in digital environments still present several barriers. [2] emphasizes that access to technology is not what guarantees access to the digital world, as it is necessary “to be in a position to actively participate in the collective intelligence processes that represent the main interest of cyberspace”.
The concepts of digital literacy and media literacy are also relevant, as they are defined in this work as elements linked to the use of ICT that enable the construction and sharing of knowledge. As defined by Livingstone [3], the concept of media literacy is a set of basic and advanced skills relating individual skills to social practices, crossing the border between formal and informal knowledge. For [4], the literacy is conditioned to the process of access to information, its critical understanding, and the production of new knowledge from this process, since they consider that “the critical dimension of literacy is the basis to ensure that participants can not only act in a practice and build a meaning within it, but can transform and actively produce it in various ways”. Thus, digital literacy is related to different competencies that allow network users to access information on multiplatform, to critically and strategically evaluate it, and to use it for different purposes, from the acquisition process to sharing said knowledge, thus reaching the objectives sought.
Starting from the ICTs, the concepts of digital and media literacy, and the processes of knowledge sharing in LMS, we enter into the contemporary proposals of the use of gamification for the development and consumption of teaching-learning platforms and contents. From this introduction, the chapter structure presents the methodology used, the gamification relationships with accessible LMS, the use of Design Thinking as a model for building the gamification process, the importance of developing accessible LMS, strategies for the development of accessible platforms from gamification and design thinking, and the conclusions and proposals of future works.
The research methodology adopted was qualitative, with an exploratory and descriptive study approach. According to [5, 6], through the qualitative method, one seeks in the process of collecting, analyzing, and interpreting data, paradigms that can validate the observations and considerations regarding the research. [5] also points out that during the process, the researcher immerses themselves in the environment in which the research is being developed to relate their object of research to the study environment, drawing the conclusions in relation to the initial proposal.
The bibliographic review was carried out in books, articles, journals, dissertations, and theses, and with research also supported in scientific databases. The themes cut out for this first filter were the search for works that brought approaches related to objects of learning, gamification, design thinking, and accessibility on the web.
Then, we sought to filter the results of the first research with the scope of developing education platforms, accessibility, and possible gamified approaches. As an exploratory study, we sought to use the collection of information and studies from the bibliographic review, identifying the possibilities of applying gamification and design thinking in the development of accessible LMS, aiming to list steps to develop an accessible LMS with gamified resources for visually and hearing-impaired people, and the proposal to use design thinking and also gamification for organizing the flow of production and development of LMS, exploring gamification with a focus on accessibility tools, stimulating their implementation since the beginning of the project. Combined with the exploratory and descriptive study, Design Science Research - DSR precepts were adopted. The method is based on Design Science and was chosen for bringing an iterative construction proposal according to the prototyping, construction, and product evaluation processes.
The Design Science methodology seeks a scientific or technological gain from a raised problem. Technological research points to the design of an artifact to solve the problem and/or contribute to the area through gains in the field of research. But in addition to building a product, model, artifact, method, instance, it is essential to advance the theory and that the knowledge produced is disseminated in academic bodies and in the area in question, so that it can spread the dissemination of the knowledge produced to researchers, scientists, professionals and/or users in the research area, in order to guide them in solving problems. The choice of DSR is justified because, according to [7] the method “underlies and operationalizes the conduct of research when the objective to be achieved is an object or prescription”.
Under the DSR’s precepts, the path outlined in the research used the following DSR steps:
Problem identification;
Awareness of the problem,
Literature review;
Identification of artifacts and configuration of problem classes;
Proposition of artifacts to solve the problem.
As mentioned, the DSR methodological scope was not applied in full, as the following steps (artifact design and artifact development); evaluation of the artifact; clarification of learning) will be applied in future steps, as we present in this chapter the scope of the research project and artifact proposal.
The initial steps of the research are presented here due to their relevance to the particular discussions regarding the artifact, which according to [8], is the organization of the components of the internal environment to achieve objectives in a given external environment.
Figure 1 shows how the design of an artifact should consider the different layers of the artifact’s development process:
Layers of the artifact development process: Adapted from [
Thus, artifacts are built to seek a solution in a given class of problems. According to [8], before starting the design or development of an artifact, it is necessary to consult what exists about this artifact in the scientific bases as well as its application in real environments. With this, it is possible to ensure greater assertiveness of the researcher when proposing the artifacts that can solve a given problem situation. Once a possible artifact solution is chosen, the researcher must take care of the development of the artifact itself. From the DSR, this research presents the DSR as a basis for the research, development and testing of the artifact, also associating the steps of design thinking with the method.
Gamification is presented in this research as a tool to enhance learning in accessible LMS, as well as to stimulate the development of accessibility tools by developers. For [9], the resource can help in the enrichment of educational experiences, as a way in which the student recognizes and responds through a differentiated use experience, very close to the experience he has in the simple act of playing. The term gamification was used for the first time in the early 2000s, but it was not noticed as something that deserved the attention of the industry. As of 2010, its use began to be observed in a series of conferences and events of great public in the world [10]. According to [9], the use of game design elements outside the context of games is called gamification. [11] see in gamification a possibility of creating “learning spaces mediated by challenge, pleasure, and entertainment”. [12] defend the use of gamification in education, suggesting that the use of game mechanics in the learning process increases the commitment of users, making activities more attractive and captivating. Based on the authors, it is pointed out that in addition to the proven benefits to the target audience, also proposing that the development of software with game elements can bring benefits to the final product, as the developers are also experiencing the user experience process by following a gamified dynamic.
Gamification appears as a possibility of education in which the barriers of time and space can be broken with the use of appropriate technologies. However, changes in the behavior of the subjects involved in the teaching and learning process are necessary so that demotivation does not occur and the main focus, which is education, is not lost. [13] present several characteristics and recommendations for the use of gamification in learning objects, among which we can mention the use of challenges, the possibility of teamwork, self-motivation, and the construction of social bonds. [14] bring other essential characteristics: the goal of the game, the well-defined rules, the feedback system, and voluntary participation.
For [15], gamification is formed by four principles - the basis, mechanics, esthetics, and thinking as in a game:
the foundation of games is the creation of an environment or system in which people want to invest their cognition, time, and energy. Basically, it seeks to favor the engagement of individuals in abstract challenges defined by rules that have interactivity and feedbacks that result in quantifiable responses, culminating emotional reactions;
mechanics are crucial blocks of rules used in the gamification process. Mechanics alone are not enough to transform a given experience into an engaged one, but they contribute to it;
esthetics corresponds to the look and feel of experience, essential elements in the gamification process. It encompasses how the experience is esthetically perceived by the individual;
thinking as in a game is the most important attribute in the gamification process - It corresponds to the idea and thought of converting a boring or monotonous task into a motivating activity, applying elements such as: competition, exploration, cooperation, and narrative. It becomes a virtual facts manager that promotes insights into real-world operations.
The development of platforms, LMS and other content flows related to knowledge has been increasingly developed through gamification. Among the justifications for its use, [16] points out that the challenges present in the games are invitations to the adventure of knowledge and to a dynamic learning experience within the work and education processes.
In relation to the learning mobilized in gamified LMS, for Piaget, errors mobilize learning because they allow reflection to solve problems. The immersion process of students within the LMS is enhanced by the gamification process and the experience can even articulate interactions and collective missions between students, providing the construction of knowledge shared through the Human Computer Interaction – HIC - process. This correlation indicates the associative potential of the gamification process with learning objects in classroom or distance education. The process uses an articulation of knowledge through an initial base, challenges to promote acquisition and sharing, missions that allow and enable learning from mistakes and the achievement of objectives, culminating in performance feedback and the advancement of levels, with benefits and prizes.
According to [17], “the evolution from
Analyzing the use of the Design Thinking approach to education and the gamification process, we can see the possibility of applying some of the concepts proposed by [18] such as empathy, prototyping, and design of experiences. In this perspective, the gamification process based on design thinking must work with the construction of a platform and its contents using steps like discovery, interpretation, ideation, experimentation, and evolution.
As [19] point out, this type of development must be collaborative and integrated, with group-oriented actions, collective participation in decision-making, self-regulating coordination, systemically organized thinking, and by building relationships through empathy.
Design thinking associated with gamification seeks to optimize products by matching human needs with available technical resources and considering the practical constraints of the projects. Thus, in the development of gamified platforms under the precepts of design thinking, the teacher and the team of developers carry out an intense investigation of how the platform and its contents meet the needs of students, as well as how to create added value for students who use it. To [20] the design thinking process is essentially centered on the human being who emphasizes observation, collaboration, rapid learning, visualization of ideas, rapid construction of prototypes, learning from failures, allowing a project to be validated more effectively and with public feedback.
This project model used in gamification in education contributes to the development of platforms closer to the needs of students, since, according to [21], agents are organized based on behaviors derived from mental models, focused on insights, observation and empathy, linked to other concepts of design thinking such as collaboration, creation, experimentation, and prototyping. From the initial ideas, one can use premises and hypotheses developed from the students’ experiences, bringing to their content the insights; the “collaboration” process with the multidisciplinary team; the creation of prototypes in a simplistic and objective way, and experimentation of prototypes with students to collect feedback on inconsistencies and errors, redefining the product.
This process should always be guided by the student’s needs, raised at the beginning of the project and the premises of knowledge construction through game strategies that, according to [22] mobilizes students to interact with the gamified environment receiving immediate feedback of their actions, being able to interpret their choices according to their goals. When they continuously repeat this cycle (action-feedback-interpretation) it allows players to gradually develop their cognitive abilities. Combined with design thinking, gamification allows developers and users to benefit from these processes, allowing LMS to be thought of since its development with triggers to stimulate immersion and the “Flow State”, defined as “an activity carried out without the expectation of any future benefit, but simply because doing it is the reward itself” [22]. Figure 2 shows the flow path:
Diagram showing the path for the flow state (source: Adapted from Csikszentmihalyi for authors, p. 74).
The Theory of Flow by Csikszentmihalyi presents how some experiences can take its participant to a Flow state. Mihaly created the autotelic experience model, considered “a self-sufficient activity, carried out without the expectation of any future benefit, but simply because doing it is the reward itself” [22]. With the proposal to develop an accessible LMS with gamification we intend to promote this flow from A1 to A4, promoting students and developers of different profiles to rise from their challenges occurring according to their ability (A1). When starting the path, the Flow state is suggested, but this soon turns into boredom (A2), as the skills have already increased and no longer correspond to the initial challenge. But as soon as a new challenge is proposed, the feeling becomes anxiety (A3), since now the person intends to overcome this new challenge and reach the Flow state (A4) again. According to [23] the individual reaches their Flow state in two moments: A1 and A4, which are equally pleasant. What differs these times is the level of skill acquired, because upon reaching the full Flow state the individual realizes that his skill corresponds to the level of the challenge proposed, transforming motivation into stimulus.
In the article “Flow in games (and everything else)”, [24] it is pointed out that Csikszentmihalyi’s research and personal observations identified eight major components of Flow that can be associated with the gamification process: challenging activity requiring skill; a merging of action and awareness; clear goals; direct, immediate feedback; concentration on the task at hand; a sense of control; loss of self-consciousness; an altered sense of time. In addition to platforms that allow dynamic knowledge, that encourage and mobilize students to learn, exchange experiences, and share knowledge, it is also important to think about the experience of the different users who can use the platforms. In this context, in addition to the development of the platform and its contents and dynamics, the accessibility of disabled people must also be taken into account, following the accessibility guidelines from the beginning of the project to allow any user to have access to the available content.
People with any type of disability have always lived on the margins of society for centuries. According to [23], the history of prejudice has always been present and many people have been placed on the margins of society because they have some type of disability. The search for inclusion begins to occur mainly in the post-1960s period, as a result of the struggle of organizations working to defend the rights of disabled people. Through innumerable guidelines, regulations and norms carried out, actions emerge that mobilize the path of social inclusion. In the search for rights, a very important motto for disabled people arises: “Nothing About Us Without Us”. According to [25], the motto communicates the idea that no policy or decision regarding the rights of disabled people without the full and direct participation of the members of the group affected by this policy. The author also points out that in the words of the disabled person, there would be the understanding that “no matter how good the intentions of non-disabled people, public agencies, companies, social institutions or society in general, we no longer accept to receive results forged against us, even for our benefit.”
Ref. [25] also points out that inclusion is necessary, as it cannot be seen as a utopia, but a possibility before the eyes against prejudices and masked forms of exclusion. It is not possible to think about inclusion without fighting the processes of exclusion inherent in life in society.
In this research, we propose the development of accessible environments based on the recommendations made by groups such as the World Wide Web Consortium (W3C) and Global Learning Consortium (GLC), including Web Accessibility Initiative - World Wide Web Consortium (WAI-W3C), IMS GLC - Accessibility Guidelines (IMS GLC-ACC) and Web Accessibility Initiative - Accessible Rich Internet Applications (WAI-ARIA) and [26] proposal, in which he proposed based on the web accessibility guidelines, on universal design and their possibilities to promote inclusion in Learning Objects accessible to people with visual impairments and people with hearing impairments. According to the researcher, to promote accessibility in digital content, varied media such as texts, audio, videos, animated images, static images, etc. should be used. The guidelines created provide recommendations for making media elements accessible by making alternative media available.
According to [26] alternative media are alternative content which function as an extension of equivalent content and are provided in different ways, but with the same ultimate learning objective. Alternative texts can be considered alternative texts; textual transcription of the video; extended audio description; audio description synchronized with the video; subtitles or captions for sounds; sign language interpretation for sounds. Equivalent media, on the other hand, are content identical to each other, but provided in a different mode, for example, a text available in the LMS and the same text associated with a file for printing in Braille.
But in addition to the recommendations of the W3C and GLC groups - categorization of menus and submenus and high-contrast, for example, the researcher also proposed as alternative media to ensure accessibility the use of resources that must be available to be activated in digital environments such as printing Braille text, audio description, sign language, subtitles for the deaf and people with hearing loss.
The general organization of the media and the alternatives required to ensure accessibility of the content must be thought of from the initial design of an LMS, promoting the native development of the environment to ensure accessibility. Using the proposed by [26], this research makes an initial cut for the development of accessibility in LMS for people with visual impairment and people with hearing impairment, presenting some peculiarities in the next items.
For educators, the concern with blindness focuses on the necessary and appropriate conditions for satisfactory development and learning. The moment in which blindness occurs is also important. For [27] “the person who is born blind, who establishes his object relations, structures his ego, and organizes all of his cognitive structure from hearing, touch, kinesthesia, smell, and taste, differs from someone who loses their vision after their development has already occurred”. This distinction is made because the perceptions constructed by those who have had visual acuity are imagery.
The references of those who were born blind - or became blind until the age of 5 - are built and centered in other senses, having a different perception of the world in relation to those who have low vision or acquired blindness. Thus, this relationship with the imagery world is compromised but this does not mean the loss of their ability to understand. Researchers start to emphasize the disabled person as a social being in which, their marginalization in relation to the world deprives them of a development of the senses. [28] brought this reflection in relation to the construction of identity, pointing out that blindness is not a defect, a lack, a weakness, but in some sense, it is also the origin of a new manifestation of skills, an additional, a strength - however strange and paradoxical that this idea may seem. The researcher starts to interpret the lack of a sense - the vision - as a means of linking a process of improvement of the other cognitions, in which they start to develop and refine the touch, smell, and hearing to compensate for the loss of vision. In relation to learning, [29] point out that the individuality of each person, in a more latent way for the visually impaired due to their lack or reduced vision, makes the learning processing mode also present specific characteristics, combining remaining sensory information for the mental construction of space. The researchers reinforce the value of language and the social experience it provides among people with sight loss and people with vision. Through language, the visually impaired individual is able to approach the culture and context of the person with vision.
Thus, it is essential that the materials available on the internet and in VLE have alternative media resources (such as text resources with larger sources or audio description, for example) to provide access and mediation to language and knowledge. As previously mentioned, the process of knowing and relating to the world goes through the process of language acquisition and mastery that can be of an oral, written, visual, and gestural nature, mediated by different cognitive senses.
Hearing loss is expressed by the reduction or absence of the ability to perceive sounds. According to [30] it can be understood as a type of sensory deprivation whose common symptom is an abnormal reaction to the sound stimulus, expressing the hearing loss through deafness or low hearing. For [31], deafness is called the decrease in the capacity of normal perception of sounds, and is considered as being deaf the person whose hearing is not functional in ordinary life. Many people develop hearing problems throughout their lives, due to accidents or illness.
By having their capacity for sound perception reduced, the person with hearing loss has difficulty understanding the language used through orality - which has its expressive mark in the sound expression, in synchrony with the gestural. [32], define that it is through language that human beings establish communication with others around them, thus allowing the production of new knowledge. When sensory factors (such as hearing loss, for example) prevent oral language from being established, new forms of linguistic manifestation begin to emerge, such as visual and sign language, which allows the deaf person to have a new possibility of contact with the world, because the insertion of a deaf person in the digital environment faces the same challenges already experienced throughout their history. If, on the one hand, the standards established by WCAG 2.0 favor the accessibility of disabled people in the web environment, on the other hand, the question of language remains the obstacle that separates the deaf from their first language.
It can be seen that although there are different definitions and categorizations for hearing loss, it should be understood here that promoting accessibility on the web and VLE for people with any type of hearing loss, regardless of the language it expresses, is a step to reduce exclusion.
Another important point is the relationship of language built in these environments and their adaptations to promote accessibility. [33] point out that research related to didactic content for people with hearing loss in virtual environments points out the need to adapt short texts, reduce difficult vocabulary, use images to introduce a concept, use -when necessary- video with a Brazilian Sign Language interpreter, videos with sizes suitable for visualization of sign language and lip reading, adequate presentation speed, clear navigation.
When thinking about the precepts of web accessibility, we bring the concept of universal design, which, according to [34], is defined as a product, a physical environment or information, which must be accessed, understood, and used without the need for adaptation, modification or use of specialized solutions by anyone, regardless of their skills or disabilities. For an accessible LMS, the validation of the Universal Design concept only occurs when people with any type of disability or restrictions can have access to a product, physical environment or information.
Regarding the web, some sites are already looking to make adaptations for accessibility, but there is still much to be done. The WCAG guide and the W3C web “Accessibility Booklet” present the main idea contained in the Universal Design that the projected world should adapt as best as possible to all people, instead of requiring a great effort to adapt. However, most websites and LMS available on the Internet do not yet have accessible resources such as audio description, subtitles and sign language translation. Thus, the use of Universal Design means a big step towards an increasingly more inclusive world, which adapts to the different skills and needs of people, with less individual adaptive effort.
For the development of accessible education and learning platforms, let us start with the theoretical framework related to the development of computer systems. According to [35], quality in Software Engineering must be directed taking into account three aspects: product quality, quality of the development process and quality of the development team. [35, 36] consider that the processes used to develop the software are directly linked to the quality of the product. Regarding development standards and quality, [37] considers that it is not uncommon for software development companies to deliver their products with features that were not requested by users, with delays in the schedule and low quality of the final product. Some processes are indicated by the authors, which show that many organizations that have adopted agile methodologies for software development has several benefits as result: more satisfied customers, better rates of return on investment, reduced development costs, faster results, among others.
Associated with agile methodologies, gamification and design thinking can be used to produce environments with accessibility.
For [38], one of the main objectives of agile software development is to develop the software more quickly and with quality through a series of iterations (short periods of time) that are feasible in terms of cost and time. Each iteration produces a version of the software bringing business value to the customer in a way that ensures that the defined requirements have been implemented.
Unlike traditional software development methods, agile methods are marked for being more collaborative and for encouraging team interaction through constant communication [39]. For [40], “We are discovering better ways to develop software by doing it ourselves and helping others to do it. Through this work, we started to value individuals and interaction between them more than processes and tools; Software in operation more than comprehensive documentation; Collaboration with the client more than contract negotiation; Responding to change rather than following a plan.” The ‘Agile Manifesto’ does not reject processes and tools, documentation, contract negotiation, or planning, but it simply shows that they are of secondary importance when compared to individuals and interactions, with the software being executable, with customer collaboration and quick responses to changes and changes.
Based on what was proposed by [41], the use of design thinking for the process of developing accessible platforms is possible through the organization of multidisciplinary teams, with research teams from the design areas; programming; communication and accessibility specialist consultants. Starting from Theory of Flow, it was listed which premises could be followed in the stages of Empath, Definition, and Ideation, correlating to these processes the concepts of gamification and the accessibility guidelines in education platforms, as shown inFigure 3.
Correlation between the theories presented and the empath, definition, and ideation steps. Source: from the authors.
The figure presented in the research “Gamification in Education Through Design Thinking” presents the confluence and the different definitions of the theory of flow, design thinking, gamification, and accessibility in the phases of empathy/discovery; definition, and ideation of design thinking.
In relation to the method, Design Thinking is associated with the Design Science Research method (see Figure 1), with confluent steps in which empathy, definition are associated with “Space of Design” of the DSR, listing requirements and possible solutions to problems and ideation, is associated with the layers of the artifact under construction, presenting the viability, utility and representation of the artifact. The prototype and testing steps are also related to the DSR with the construction of the artifact; and use of the artifact with pilot instantiation and clearance of the artifact.
This research does not include the Prototype and Tests phases, as they are subsequent steps for the construction of the prototype based on the concepts presented.
In software development, it is also possible to use gamification to promote the encouragement of fulfilling the stages in the processes of agile methodologies. It can be organized through groups of hierarchical and partially ordered challenges that must be overcome, with a developer or a team of developers who need to have various skills, different knowledge and organization of workflows. This concept is directly related to the steps of design thinking presented above; the game mechanics present in gamification and the different stages and sprints present in agile methodologies.
This set of characteristics can be organized so that they can learn new skills and knowledge, combine them to overcome challenges during development and be rewarded with effective completion after each stage of the journey, whether they get rewards or not, depending on success or failure, respectively.
The design thinking methodology applied to the project follows the definition of Bootcamp Bootleg by [42]. The approach proposed by [42] is divided into five phases: empathy (user-centered process, to immerse, engage and observe the problem); definition (makes a synthesis, presents a focus of the problem or point of view); ideation (generation of ideas, exploration of solutions); prototyping (producing ideas in a more real context, bringing material character); tests (to redefine solutions and put the prototype in contact with people).
Based on the categorization made by [44], associated with that proposed by [45, 46], we can list similarities between the two approaches. Table 1 shows how the concepts can be related by these categories.
Based on the above, engagement is sought based on the application of the precepts of implementing accessibility for people with vision and hearing disabilities in the programming phases, based on accessibility guidelines, to ensure inclusive access for anyone in online environments through friendly and intuitive interfaces.
This step is already a first challenge, as there are still no recommendations or accessibility guidelines for LMS.
Developers should follow the recommendations made by groups such as the World Wide Web Consortium (W3C) and Global Learning Consortium (GLC), including Web Accessibility Initiative - World Wide Web Consortium (WAI-W3C)1, IMS GLC - Accessibility Guidelines (IMS GLC- ACC)2 and Web Accessibility Initiative - Accessible Rich Internet Applications (WAI-ARIA)3), which are institutions that created parameters of accessibility in websites and virtual environments, of which they are the bases for the development for this research, because currently they are the ones that determine the guidelines of web accessibility, being the basis of the proposal for the recommendations presented for the proposal for the development of accessible LMS.
In relation to the visually impaired person, in order to browse the websites/web systems, these people make use of assistive technologies, categorized as screen reader software, whose function is to interpret the page code and reproduce by audio through a speech synthesizer. However, the interaction of screen readers on websites will only work properly if certain coding standards are applied in the development, established in the International Web Accessibility Guidelines, which were developed by the Web Accessibility Initiative (WAI), an organ created by the W3C (World Wide Web Consortium). Among these initiatives, the WCAG (Web Content Accessibility Guidelines) and the WAI-ARIA (Web Accessibility Initiative - Accessible Rich Internet Applications) guidelines will be highlighted, a standard created to make dynamic content and applications more accessible, which together with HTML, guarantee a navigation with accessibility for screen reader users.
When a website is not developed thinking about the access of people with vision disabilities, users of assistive technologies of screen readers not following the international standards mentioned may present several accessibility barriers that will hinder or even prevent access to the functionalities for a great number of people. Hearing impaired people, on the other hand, need resources such as the interpretation of texts in sign language and the use of subtitles for the deaf and people with hearing loss.
With the use of recommendations, WCAG (Web Content Accessibility Guidelines), and WAI-ARIA, and, with the production of audio description resources, self-contrast, subtitles for the deaf and people with hearing loss and sign language, it is sought that developers are encouraged to develop these steps with gamified strategies.
From what was proposed, it is then presented what are the strategies for the development of an LMS based on gamification strategies. In the case of this study, the use of challenges is suggested, with the availability of a ranking of scores, as well as the use of badges as trophies, for example.
For the application of the elements of gamification in the design steps aligned with design thinking and accessibility, the steps follow the criteria of scoring and badges present in the gamification mechanics. The main strategy of gamification of the developed learning object occurs through the appropriation of the reward system of conventional games where the player earns points for each development task performed in the correct period and with proposals for solving the problems that arose during the execution.
Scoring rewards are awarded after the completion of each sprint or troubleshooting presented. Also, a forum is proposed between the development teams so that doubts can be exposed to the teams and solutions proposals are sent.
It is therefore suggested that gamification from the rewards system be used for planning the development of the platform in all its phases, from presentation and training in the language chosen for the development to the identification of the system requirements, the test scenarios, prototyping, system modeling, implementation, testing and deployment, delimited by the phases of design thinking and Design Science Research.
The scoring system follows that specified in Table 2.
Concepts of [44] | Concepts of [45, 46] | |
---|---|---|
Feedback | Time that the user takes to dominate the game or perform a certain task | Pleasant productivity, the players see applied efforts and energies achieving the desired results |
Social | Socialization- interaction between the system and users; and duty - the system’s and the generated social relations’ capacity of creating and accepting the user’s emotional investment | Generation of the possibility of working cooperatively, in teams and groups in order to solve problems / Construction of stronger social relationships through emotional bonds |
Competition | Self-competition and effort to overcome the results | Pursuit of self-motivation to remain in the activity (intrinsic motivation) |
Progression | The system’s capacity of providing persistence to the user | Activities created with challenges that can be overcome |
Mechanics | Pleasure that the user finds in the game | Epic meaning of achieving something expected |
Context | Context of the system’s actions | _________________________ |
Activity | Points earned |
---|---|
Complete a step or sprint | 100 points |
Solve a problem | 100 points + trophy |
Post a reply on the forum | 50 points |
Scoring system for gamified development.
For [47] this type of strategy is known in the world of conventional games as badges and consists of an element that integrates reward at the same time. For the author, using badges is equivalent to a process of defining, seeking, and achieving goals and objectives, which increases performance in three ways: increasing the level of expectations regarding the result of the process, which leads the participant to increase his performance; defining clear goals which facilitates self-assessment during the process; and increasing satisfaction from meeting the target. Corroborating with this, in an experiment carried out with students through a virtual learning environment, [48] found an improvement in the results of practical activities through the adoption of gamification strategies with the use of badges.
With the adoption of this system of rewards, what is intended is to use gamification, as raised in the literature, to increase motivation and engagement in activities. In addition to these positive reinforcements materialized through points and trophies, the strategies developed also aim to mitigate negative reinforcements and frustration. In the case of scoring, it works as a personal motivation for development teams to seek to beat their records.
Likewise, winning trophies when correctly completing a step or solving problems generates a reward.
The score ranking serves to encourage developers to achieve leadership, as well as direct their efforts from their greatest qualities. The ranking itself is not just a query tool, but an agent that mobilizes engaged developers to seek to be in good positions on the table. In each of the steps, the following types of punctuation are defined:
User score for each week
Final user score for each sprint
Scoring teams for each week
Final team score for each sprint
Punctuation for forum responses
Trophies will be awarded for specific tasks and achievements, which are strategic for the progress of the project. In this project, they are similar to the reward systems of conventional games and are triggers for interaction, collective work and team engagement, and participation in problem solving. The trophies will be made available for:
The team with the highest score in each step
The developer who solves problems during the process
Presentation of the importance of accessibility in LMS - This process is user-centered to immerse, engage, and observe the problem. Regarding the gamification requirements, we have an emphasis on the social and mechanic requirements of the games, presenting the work of the multidisciplinary team being carried out through the concepts of Design Thinking, seeking a direct relationship with the issue of empathy for a product to be closely related to a social issue, in which users can, through the system, promote relationships of socialization and interaction, triggering the phases of competition and progression also in the product development process. Here, the work in cooperation is also directed, in teams and groups, to solve problems, mobilizing the construction of social bonds and stronger relationships through affective bonds. The mechanics, on the other hand, are directed towards the construction of the gamified LMS based on the generated relational situations.
The association with accessibility in this phase, however, occurs with studies directed to dynamics used in gamified LMS that, from the phases of a merging of action and awareness and concentration on the task at hand; Social and Mechanical, and Accessibility Strategies and Universal Design;
Presentation of the concepts of accessibility, the accessibility guidelines, and case studies - This step makes a synthesis and presents a focus of the problem or point of view. For gamification requirements in this step, we have an emphasis on feedback from the empathy step, with a focus on different skills and a framework of prior knowledge. Thus, feedback related to the time when the user performs a certain task is essential, as well as the feedback regarding mistakes and successes. In the validation phase, this process must be mapped so that it continues and manages to feel the satisfaction of meeting the challenges. With this, the process of progression occurs;
Progression: In order for it to remain stimulated to develop accessibility in the LMS, its goals and actions must be clarified and what are the key points for it to be able to fulfill them. It is suggested to work in the team, with personalized progression according to the profile of the developer or the team, in which the goals are set according to the profile presented. Another possibility is for the developer or team to define their tracks and challenges, directing actions and goals according to their abilities and skills.
Competition: It was decided to seek in the definition step the possibility of, in addition to self-competition, also bringing collective challenges. This feature should be explored, but in a very reflective way in learning environments. Promoting competition in gamification is one of the engines that generates the process of immersion and resumption. As previously mentioned, the scores and trophies in the steps can increase engagement.
Accessibility: Emphasized points: sign language, subtitles, environment architecture for screen readers, and audio description. For accessibility, it is the moment, from the studies and the project proposal stimuli that came with gamification, to elaborate the framework of possibilities for the proposal of an LMS following the IMS-GLC and W3C-WCAG and WAI-ARIA guidelines with accessibility features such as sign language, subtitles, environment architecture for screen readers, and audio description.
In the ideation, all the information and data obtained during the immersion are gathered and it is time to sit down with everyone involved and devise the possible solutions. It is essential to take into account the point of view of each of the participants at this time, also realizing the various possibilities for the development of the accessible LMS. In this step, the ideas most voted by the team can be scored, with the score and trophies for developers and teams. It is worth remembering that the concepts presented must be articulated so that people with vision or hearing disabilities can explore them. Thus, it defines the importance of using what [4] defines as alternative media that, with studies for the execution of sign language resources and subtitles for people with hearing impairment, and organization of the Virtual Environment architecture according to with the guidelines of IMS-GLC and W3C-WCAG and WAI-ARIA, to be accessed by screen readers, in addition to the audio description feature of videos and images. It is the phase of generating ideas, exploring solutions to define teams and development steps.
As the proposal places LMS accessibility as the main element, in each step the scores must be articulated in relation to the development of accessibility requirements such as:
Organization of navigation elements on the website with the correct semantic structure of HTML provided by WCAG:
Use of headers hierarchically
Objective description in links
Forms developed with labels, differentiated color, HTML fieldset and legend tags, description of the buttons,
Accessible images
Keyboard access
Page titles
Modal window
Insertion of sign language window in the platform texts, videos, audios, podcasts and audiovisual resources.
Inserting subtitles for deaf people and people with hearing loss in videos, podcasts and music
Description of images, Audio description of videos;
High contrast of images and platform.
It is also important to note that when developing a project that contemplates accessibility, it is worth noting the available options such as CMS, frameworks, and libraries. Many of the aforementioned options already have resources in their code to assist in development in compliance with international accessibility standards, providing guidance and information in the respective documentation. We can mention some as “Bootstrap”, “React”, “Angular”, “Wordpress”, “Moodle”, among others. Based on what was discussed above, it is suggested that the entire production flow of an LMS and its tools have a gamified strategy for product development teams.
As previously presented, the next steps (Prototype and Tests) will not be presented, as they will be the scope for the development of accessible and gamified LMS, and will be described in future works.
The research develops the proposal for software development actions so that gamified LMS can be designed and programmed through design thinking, having gamified resources in the development process, encouraging the use of WCAG (Web Content Accessibility Guidelines) accessibility guidelines and WAI-ARIA (Web Accessibility Initiative - Accessible Rich Internet Applications).
From the bibliographic survey and the steps described in Design Science Research and Design Thinking, and the search for accessible and gamified platforms, requirements were raised for a first gamified development experience of an accessible LMS. With the initial questions of this research, a proposal for prior planning is presented so that these platforms and their media - videos, texts, audios, and games contain accessibility resources and allow the disabled public to experience the same processes as those who do not have deficiency. As a way to streamline the workflow and incorporate game elements from the initial design, gamification and design thinking are used as part of the work methodology of the development teams.
The goal is to promote an immersive and gamified experience from the beginning of an LMS project, placing the development team itself in the midst of UXm stimulated by the theory of Flow for the production of the platform and its accessibility features. Gamified development inserts game elements into the various software engineering practices used by the team, and mainly the focus on project management to assist in the gamification of any software process. It is noteworthy that currently many development teams have used the agile methodologies and practices of software engineering expecting that, when applied during the development, the mechanics of the games allow a broad and analytical vision in the process of aligning the steps and sprints with challenges and exchanges between teams being crucial moments for the prototyping and testing phases - which must also be carried out with the disabled public. Thus, the proposal allows to follow the processes of [Lockwood], with the processes of observation, collaboration, rapid learning, visualization of ideas, rapid construction of prototypes, learning from failures, outlined by gamification strategies, allowing a validation of the project more effective.
Regarding the gamification of the steps of software development, it is expected that the teams will encourage increased dedication in carrying out tasks; the search to face the challenges of each step and to solve the problems autonomously; assisting other employees by stimulating punctuation and team satisfaction in seeking the best results from the gamification processes.
With the steps of empathy, definition, and ideation, and the proposal of gamification in the development of accessible LMS, we seek to initiate a path to stimulate new possibilities for software development, as well as the proposal to design LMS with accessibility since its initial draft. In addition to the use of gamification in the development process, this work seeks to bring reflection to researchers, educators, developers, and instructional designers about the need to advance in research that develop alternatives to foster the inclusion process and the active participation of disabled people in society.
For future steps, it is suggested the development of an LMS with accessibility from the model proposals presented in this research;
To present the requirements of an accessible and gamified LMS for the end user, with tests carried out with disabled people;
It is important to emphasize that it is essential to present the execution and validation of a prototype, showing how the concepts of UX and accessibility applied since the development will benefit the accessibility and the gamification resources in the accessible LMS.
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