Artificial intelligence (AI) is a new field of science in which computers will provide decisions-supporting tools to help doctors make difficult clinical choices. Recent AI applications in otolaryngology include head and neck oncology, rhinology, neurotology, and laryngology. The aim of this systematic review is to describe the potential uses of AI in head and neck oncology with a special focus on the surgical field.The authors performed a systematic review, in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, in the main medical databases, including PubMed, Scopus, and Cochrane Library, considering all original studies published until February 2023 about the role of AI in head and neck cancer surgery. The search strategy included a combination of the following terms: “artificial intelligence” or “machine learning” and “head and neck cancer”.Overall, 303 papers were identified and after duplicate removal (12 papers) and excluding papers not written in English (1 paper) and off-topic (4 papers), papers were assessed for eligibility; finally, only 12 papers were included. Three main fields of clinical interest were identified: the most widely investigated included the role of AI in surgical margins assessment (7 papers); the second most frequently evaluated topic was complications assessment (4 papers); finally, only one paper dealt with the indication of salvage laryngectomy after primary radiotherapy.The authors report the first systematic review in the literature concerning the role of AI in head and neck cancer surgery. An increasing influx of AI applications to clinical problems in otolaryngology is expected, so specialists should be increasingly prepared to manage the constant changes. It will always remain critical for clinicians to use their skills and knowledge to critically evaluate the additional information provided by AI and make the final decisions on each patient. Artificial intelligence (AI) is a new field of science in which computers will provide decision-supporting tools to help doctors make difficult clinical choices . The achClinical applications of ML include improving cancer diagnosis and prognosis prediction by integrating clinical and genomic data; computer vision algorithms enable for example the delineation of surgical anatomy, quick detection of radiographic abnormalities, or the classification of malignant tissue in pathological specimens such as fine-needle aspirate samples or intraoperative frozen sections –5.Recent ML applications in otolaryngology include head and neck oncology , rhinology (standardization of imaging reporting), neurotology (codification of adult hearing loss types), and laryngology  .In the field of head and neck oncology, AI is showing broad potential for both diagnostic and therapeutic management. Regarding diagnosis, ML methods have been extensively investigated in all imaging modalities including ultrasound (US), computed tomography (CT), magnetic resonance (MR), and nuclear medicine , 8.Interestingly some authors have recently proposed a classification neural network to distinguish normal tissue from cancerous tissue of head and neck using hyperspectral imaging (HSI). HSI is a non-invasive diagnostic modality that provides information about tissue pathology by measuring the reflected, fluorescent, and transmitted light that interacts with tissue .Another promising role of ML in head and neck oncology is for automated radiotherapy planning. In fact, ML applications include several phases of the entire radiotherapy process such as auto-contouring, planning, and delivery (adaptive therapy) both for external beam radiotherapy and interventional radiotherapy (brachytherapy) , 11.So far, one of the topics that have not yet been adequately investigated is the use of AI in head and neck cancer from the surgical perspective. The aim of this systematic review is to describe the potential uses of AI in head and neck oncology with a special focus on the surgical field.The author conducted this systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines  as reporThe search was carried out using a combination of the following keywords: “artificial intelligence” or “machine learning” and “head and neck cancer”. The author considered as inclusion criteria for the research original articles specifically reporting on the role of AI in head and neck cancer surgery, including both prospective and retrospective studies. We excluded articles not in English, letters to the editor, conference papers, reviews, and papers off-topic. Two independent authors (AL and AC) examined titles and abstracts with the aim of finding eligible articles. The identified articles were subsequently retrieved for full-text analysis. In cases of disagreement, a panel discussion among the other authors involved with this task allowed to solve the situation. The data extracted were the authors of the paper, the year of publication, the authors’ country, the patients’ number, and the topic assessed.The search strategy was performed according to the PRISMA guidelines. On the whole, 303 articles were found and after removing duplicate (12 papers) and excluding articles not written in English (1) and off-topic (4), articles were assessed for eligibility; finally, only 12 articles were included and summarized in Three main fields of clinical interest were identified: the most widely investigated included the role of AI in surgical margins assessment (7 articles); the second most frequently evaluated topic was about complications assessment (4 papers); finally, only one paper dealt with the indication of salvage laryngectomy after primary radiotherapy.The papers collected in this systematic review have a publication range from 2017 to 2023; with regard to the number of patients included, the authors could identify a significant variation among the studies, from less than ten to several thousand. The most widely investigated field includes the role of AI in surgical margins assessment.Costantino et al.  developeTighe et al.  proposedOther papers introduce ML HSI as a potential new approach for tumour margins assessment , 16–19. Pertzborn et al.  showed tMoreover, Halicek’s research , 17 demoThe second most frequently evaluated topic was complications assessment. In this regard, Formeister et al.  firstly Subsequently, Tighe et al.  addresseFinally, one paper dealt with the potential role of AI to predict which patients will require salvage total laryngectomy after primary radiotherapy with or without chemotherapy for laryngeal SCC by applying ML techniques to information from more than 16,000 patient experiences and paying particular attention to sociodemographic variability .Head and neck surgery is considered the most ancient subspecialty in medicine and offers great opportunities for ML technology application . RegardiConcerning complications assessment in HNSCC surgery, one of the potential risk factors is comorbidity, as many patients with HNSCC have concomitant diseases. Another factor to consider is the duration of anaesthesia . RegardiTo the very best of our knowledge, this is the first systematic review in the literature concerning the role of AI in head and neck cancer surgery. However, there are some limitations in this systematic review: there are still few manuscripts about the role of AI in head and neck cancer surgery and the fields of application that can be found so far are very scanty. Consequently, the practical role of AI in head and neck cancer surgery has yet to be well-defined and further research is needed. An increasing influx of AI applications to clinical problems in otolaryngology is expected, so specialists should be increasingly prepared to manage the constant changes. It will always remain critical for clinicians to use their skills and knowledge to critically evaluate the additional information provided by AI and make the final decisions on each patient.


Diagnosis and treatment of multiple primary malignancies are becoming a new challenge in clinical practice worldwide. The present study aimed to characterize the clinical and genetic features of multiple primary malignancies in patients with synchronous or metachronous lymphoma and another solid tumor. We retrospectively analyzed 11 cases with lymphoma and another solid tumor. The germline mutations in plasma cell-free DNA samples and somatic mutations in lymphoma and solid tumor tissue samples were identified using targeted next-generation sequencing. In the 11 lymphoma patients, the most common type of concurrent solid tumor was colon adenocarcinoma  followed by papillary thyroid carcinoma . Metachronous lymphoma and solid tumor in 6 patients were treated with corresponding standard therapy asynchronously. Chemotherapy for colon adenocarcinoma during the interval of lymphoma chemotherapy led to excellent outcome in two patients. Immediate chemotherapy for lymphoma plus elective surgery for synchronous papillary thyroid carcinoma also yielded good prognosis in two patients with synchronous double primaries. Interestingly, we found that 10 of 11 patients with lymphoma and another solid tumor harbored germline mutations in Fanconi anemia complementation group (FANC) genes, including FANCI, FANCA, FANCG, FANCL, FANCD1, FANCF, FANCJ, and FANCS. In summary, comprehensive study of the clinical and genetic features of patients with multiple primary malignancies may improve diagnosis and treatment in the future. Mutations in FANC genes might be a predisposition to tumorigenesis of lymphoma patients with a second solid malignancy. During the last three decades, substantial progress has been made in the prevention, early diagnosis, and treatment of malignancies. Advances in early detection and effective treatment have significantly improved overall survival in patients with malignant tumors, such as proteomics used in ovarian cancer . The fivMultiple primary malignancies are defined as more than one synchronous or metachronous cancers in which the second primary malignant tumor is diagnosed within or after 6 months of the primary one, respectively . EpidemiThe present study aimed to characterize the clinical and genetic features of multiple primary malignancies in lymphoma patients. We summarized the diagnosis, treatment, and prognosis of 11 patients with synchronous or metachronous lymphoma and another solid tumor. We also determined and compared the germline and somatic genetic mutations in both tumor tissues/cells.This study enrolled 11 lymphoma patients who were diagnosed with multiple primary malignancies and treated at the China-Japan Union Hospital of Jilin University. The diagnosis of lymphoma and other solid tumors was confirmed by biopsy. Multiple primary malignancies were defined as two or more histologically unrelated, independent primary malignancies in one individual and were diagnosed using the criteria proposed by the Surveillance Epidemiology and End Results (SEER) project and the International Association of Cancer Registries and International Agency for Research on Cancer (IACR/IARC). Synchronous multiple tumors were diagnosed in an interval of less than 6 months, while metachronous tumors were diagnosed in an interval of more than 6 months. Only patients with lymphoma (HL or NHL) and another solid cancer were included in the present study. Patients with more than two primary malignancies were excluded from this study. The demographic and clinical data were obtained by medical record review. The Institutional Review Board of the China-Japan Union Hospital of Jilin University  approved the study protocol (#20220628020), and the project has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2008 (5). All involved patients provided written informed consent.Next-generation sequencing was carried out to detect germline mutations in plasma cell-free DNA samples and somatic mutations in lymphoma tissue and solid tumor tissue samples as previously described . BrieflyAmong the 11 patients with an average age of 57 years old, four of them had a history of heavy smoking or drinking, and only two patients had a family history of cancer. The detailed demographic characteristics and medical history of the patients were summarized in Six of the 11 lymphoma patients suffered diffuse large B cell lymphoma (DLBCL), and all were non-germinal center B-cell (non-GCB) subtype. Five patients had synchronous while six had metachronous multiple primary malignancies. The interval of metachronous multiple primary malignancies ranged from 19 to 96 months. Lymphoma and colon adenocarcinoma are the most common combination of synchronous multiple primary malignancies, which occurred in three patients. Two patients had HL while nine had NHL with the most common type being non-GCB DLBCL in our patients. In the 11 lymphoma patients, the most common type of concurrent solid tumor was colon adenocarcinoma followed by papillary thyroid carcinoma. The diagnosis and staging of lymphoma and the concurrent solid tumor were listed in Patients with HL were treated with ABVD  chemotherapy while the majority of patients with NHL were treated with CHOP -based regimes Table 3.FANCI, FANCA, FANCG, FANCL, FANCD1, FANCF, FANCJ, and FANCS , including nd FANCS Table 4,TET2 and KDR genes were identified in both angioimmunoblastic T-cell lymphoma and her papillary thyroid carcinoma tissues  might be a predisposition to double primary malignancies of thyroid cancer gastric adenocarcinoma , (#20220628020). The patients/participants provided their written informed consent to participate in this study.DZ, LH and CJ collected the data, performed the experiments, analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. LB conceived and designed the experiments, prepared tables, authored or reviewed drafts of the paper, and approved the final draft. All authors contributed to the article and approved the submitted version.


HCC, the most common form of primary liver cancer, is the fastest rising cause of cancer-related death in the United States. HCC disproportionately affects racial and ethnic minorities in the United States. A practical framework is needed to organize the complex patient, provider, health system, and societal factors that drive these racial and ethnic disparities. In this narrative review, we adapted and applied the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to the HCC care continuum, as a step toward better understanding and addressing existing HCC-related disparities. We first summarize the literature on HCC-related disparities by race and ethnicity organized by the framework’s 5 domains  and 4 levels  of influence. We then offer strategies to guide future research initiatives toward promotion of health equity in HCC care. Clinicians and researchers may help mitigate further inequities and better address racial and ethnic disparities in HCC care by prioritizing the following in HCC research: (1) increasing racial and ethnic minority representation, (2) collecting and reporting HCC-related data by racial and ethnic subgroups, (3) assessing the patient experience of HCC care by race and ethnicity, and (4) evaluating HCC-specific social determinants of health by race and ethnicity. These 4 priorities will help inform the development of future programs and interventions that are tailored to the unique experiences of each racial and ethnic group.  HCC-related disparities by race and ethnicity exist along the entire HCC care continuum, from early identification of cirrhosis to HCC-related mortality. These disparities are thought to be multifactorial in origin and are linked to patient, provider, and health system factors. Such factors may include downstream and midstream social determinants of health,4 which include but are not limited to individual health literacy, insurance coverage, and neighborhood poverty. In addition, more upstream factors,4 such as systemic racism and discriminatory US policies  disproportionately affect racial and ethnic minorities, further exacerbating disparities in care.8HCC, the most common form of primary liver cancer, is the fastest growing cause of cancer-related death in the United States10), but it can provide an opportunity for clinicians, researchers, and Tribal Health Organizations to advocate for interventions and policies that may address some of the existing inequities in liver cancer care. In this narrative review, we therefore present an adapted version of the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework11 to summarize the potential drivers of existing disparities in HCC care by race and ethnicity. We then provide potential strategies to guide future research initiatives to address knowledge gaps, mitigate further inequities, and more effectively address existing disparities along the HCC care continuum.Evaluating HCC disparities by race and ethnicity has its limitations  consortium recently proposed a conceptual model to highlight the steps along the HCC screening process, including risk assessment, screening initiation, result follow-up, diagnostic evaluation, and treatment evaluation.11 has been successfully used to promote research on disparities in other settings, including in end-of-life care among Black Americans13 and the inclusion of Arab/Middle East/North African communities in disparity research.14 However, to our knowledge, it has never been applied in liver cancer care. As shown in Table 11 In this review, we combined all factors across racial and ethnic groups into 1 framework for ease of visualization. However, this framework should be further tailored to the experiences of specific racial and ethnic minority groups for it to be most effective. Our goal is for this framework to be used in public health, clinical, and research settings to guide future programs and research initiatives that can effectively address liver cancer disparities.The NIMHD Research Framework9 We recognize that many studies combine the Asian American, Native Hawaiian, and Pacific Islander populations, which may limit the interpretation of findings. As HCC is the most common form of primary liver cancer, the terms “liver cancer” and “HCC” are also used interchangeably.This review focuses on the racial and ethnic minority groups commonly identified by studies in the United States—African American or Black, American Indian and Alaska Native (AI/AN), Asian American or Asian and Pacific Islander (API), and Hispanic or Latinx.To illustrate how the NIMHD framework can be used to describe the potential drivers of HCC-related disparities, we present model examples for each step of the HCC care pathway by framework domain  and level of influence. However, we recognize that factors from multiple domains and levels of influence might affect the same step in the HCC care continuum . As a result, we have also included a table highlighting these associations by race and ethnicity Table .Impact of the biological domain15 Between 2003 and 2011, Hispanic and Asian American people experienced a 35.8% increase and 5.5% decrease in HCC incidence, respectively.16 Between 1992 and 2018, AI/AN populations experienced a 4.3% annual increase in HCC incidence.17 By 2030, Hispanic and Black persons are projected to have the highest HCC incidence rates.18US population–based Surveillance, Epidemiology, and End Results (SEER) data consistently show that AI/AN people have the highest annual HCC incidence rate , followed by Hispanic , API , Black , and White  people.19These differences in HCC incidence may be driven in part by biological factors at the individual level  Table . For exa23 The HBV genotype F1b is a strong risk factor for HCC and is found in Southwest Alaska, Spain, Argentina, and Chile.25 HBV genotype C is another risk factor for HCC and is found in Northwest Alaska, Siberia, and several East Asian countries.26 Among American Indian people, the risk of NAFLD and NASH, a leading cause of cirrhosis,28 may also vary by Tribal group. For example, the Pima Indian population experiences a disproportionately high rate of type 2 diabetes,29 which is a risk factor for NAFLD and NASH, compared with other AI and minority groups. Among Hispanic people, one of the many factors that might contribute to the rising prevalence of NAFLD and NASH, include the PNPLA3 gene polymorphism, which is more common in this population and associated with greater hepatic fat content, more severe liver inflammation, and higher risk of HCC.30 Multiple studies have also shown that Black people experience a higher prevalence of HCV infection,31 which is an independent risk factor for HCC in patients with cirrhosis.32 Finally, despite advances in HBV awareness, vaccination, and treatment,33 Asian American people bear the greatest burden of HBV-related HCC34 due to a large proportion of individuals who emigrated from HBV-hyperendemic countries and high rates of vertical transmission.35 These findings highlight the importance of promoting clinical, translational, and genomic HCC research to better recognize risk factors for cirrhosis and HCC, specific to each racial and ethnic group. These results can then inform tailored efforts to promote early identification of liver disease, access to treatment if applicable , and increase community awareness of HCC risk to reduce existing disparities in HCC incidence.HCC incidence may also vary by race and ethnicity due to biological factors at the community level (community level of influence). The predominant etiology of underlying liver cirrhosis and associated risk of HCC may vary by race and ethnicity due to the high community burden of specific chronic liver diseases  that are present in each minority group. As an example, HCC incidence may be high among Alaska Native people due to the burden of HBV, HCV, and autoimmune hepatitis.Impact of the behavioral domain19 but overall rates of HCC surveillance remain suboptimal.36 Receipt of surveillance further varies by race and ethnicity. SEER-Medicare claims data showed that 59% of Black and 49% of Hispanic patients (vs. 47% of White patients) received no HCC screening in the 3 years before their HCC diagnosis.37 In other studies, Black and Hispanic patients were 60% less likely than White patients to receive consecutive HCC screening tests38 and similarly less likely to be referred to specialty clinics,39 where HCC screening is more likely to occur than in primary care settings.40HCC surveillance with imaging and alpha-fetoprotein testing is recommended every 6 months in patients with cirrhosis or chronic HBV,41 that affect provider behaviors related to HCC screening, provider knowledge of clinical guidelines,42 insufficient clinical time to prioritize HCC screening,42 and varying provider perceptions of screening modalities.43 There is therefore an ongoing need to identify how to implement successful interventions and surveillance programs to optimize patient and provider interactions in the clinical setting and thereby improve HCC surveillance rates. In addition, as novel biomarkers and imaging offer opportunities for individualized and risk-based HCC surveillance, further evaluating the factors that contribute to interpersonal behaviors related to surveillance will be critical to improving adherence to recurrent surveillance events, irrespective of surveillance modality.These differences in the receipt of surveillance may stem from multiple factors that impact the patient and provider interaction . These factors may include implicit racial/ethnic biasesImpact of the health care system domain43 The presence of clear practice guidelines around HCC surveillance (community level of influence) may therefore also impact patient receipt of surveillance. However, current guidelines are not consistent across specialty and primary care associations. For example, while the American Association for the Study of Liver Diseases, which is likely to influence gastroenterology and hepatology providers’ clinical practices, recommends HCC surveillance in at-risk individuals every 6 months,19 the US Preventive Services Task Force,44 which is likely to influence primary care clinicians’ cancer screening practices, has not yet provided recommendations on HCC surveillance. As minority patients are more likely to receive care in primary care settings39 where HCC screening occurs less often than in specialty clinics,40 promoting consistent practice guidelines across specialties may help address disparities in the receipt of HCC surveillance by race and ethnicity.Many providers already believe practice guidelines are essential to their decision-making process related to ordering HCC surveillance for their patients.28 but how to best implement HCC surveillance in this growing patient population remains unclear .45 As a recent study found that the rates of NAFLD-related deaths have disproportionately increased among Black and AI/AN people since the pandemic,46 investing in research that evaluates the effectiveness and cost-effectiveness of various surveillance modalities in NAFLD may also help reduce disparities in care by standardizing clinical practice, especially among minority patient groups disproportionately affected by NAFLD.Similarly, prioritizing multidisciplinary research that can better inform evidence-based practice guidelines (community level of influence) may also promote further equity in the receipt of HCC surveillance. For example, NAFLD is now a leading cause of cirrhosis,Impact of the physical/built environment domain47 This may include home and school environments, neighborhood walkability, and the availability of grocery stores in a community.The physical/built environment refers to the physical space in which individuals live, learn, and work.53 Compared with White patients, Asian American patients are 13% less likely, while Hispanic and Black patients are respectively 20% and 18% more likely, to present with advanced stage HCC.55 Multiple physical/built environment factors, such as county-level and neighborhood-level characteristics (community level of influence), may contribute to these disparities. As an example, people living in rural and suburban areas (vs. urban areas) are more likely to present with late-stage HCC, not receive HCC treatment, and die owing to HCC.56 A greater proportion of Black and Hispanic patients also live in US counties with higher social vulnerability index scores, and individuals from high social vulnerability index counties are more likely to present with larger tumors and receive nonsurgical interventions for HCC.57 Similarly, API and Hispanic people were more likely to develop HCC if they lived in low socioeconomic status (SES) (vs. high SES) neighborhoods.58 These findings highlight the importance of assessing and collecting both individual and neighborhood-level social determinants to health to better address inequities in HCC care stemming from geographical and built environment differences by race and ethnicity.Several studies have already shown that HCC stage at diagnosis varies by race and ethnicity.Impact of the behavioral domain19 but overall rates of HCC surveillance remain suboptimal.36 Receipt of surveillance further varies by race and ethnicity. SEER-Medicare claims data showed that 59% of Black and 49% of Hispanic patients (vs. 47% of White patients) received no HCC screening in the 3 years before their HCC diagnosis.37 In other studies, Black and Hispanic patients were 60% less likely than White patients to receive consecutive HCC screening tests38 and similarly less likely to be referred to specialty clinics,39 where HCC screening is more likely to occur than in primary care settings.40HCC surveillance with imaging and alpha-fetoprotein testing is recommended every 6 months in patients with cirrhosis or chronic HBV,41 that affect provider behaviors related to HCC screening, provider knowledge of clinical guidelines,42 insufficient clinical time to prioritize HCC screening,42 and varying provider perceptions of screening modalities.43 There is therefore an ongoing need to identify how to implement successful interventions and surveillance programs to optimize patient and provider interactions in the clinical setting and thereby improve HCC surveillance rates. In addition, as novel biomarkers and imaging offer opportunities for individualized and risk-based HCC surveillance, further evaluating the factors that contribute to interpersonal behaviors related to surveillance will be critical to improving adherence to recurrent surveillance events, irrespective of surveillance modality.These differences in the receipt of surveillance may stem from multiple factors that impact the patient and provider interaction . These factors may include implicit racial/ethnic biasesImpact of the health care system domain43 The presence of clear practice guidelines around HCC surveillance (community level of influence) may therefore also impact patient receipt of surveillance. However, current guidelines are not consistent across specialty and primary care associations. For example, while the American Association for the Study of Liver Diseases, which is likely to influence gastroenterology and hepatology providers’ clinical practices, recommends HCC surveillance in at-risk individuals every 6 months,19 the US Preventive Services Task Force,44 which is likely to influence primary care clinicians’ cancer screening practices, has not yet provided recommendations on HCC surveillance. As minority patients are more likely to receive care in primary care settings39 where HCC screening occurs less often than in specialty clinics,40 promoting consistent practice guidelines across specialties may help address disparities in the receipt of HCC surveillance by race and ethnicity.Many providers already believe practice guidelines are essential to their decision-making process related to ordering HCC surveillance for their patients.28 but how to best implement HCC surveillance in this growing patient population remains unclear .45 As a recent study found that the rates of NAFLD-related deaths have disproportionately increased among Black and AI/AN people since the pandemic,46 investing in research that evaluates the effectiveness and cost-effectiveness of various surveillance modalities in NAFLD may also help reduce disparities in care by standardizing clinical practice, especially among minority patient groups disproportionately affected by NAFLD.Similarly, prioritizing multidisciplinary research that can better inform evidence-based practice guidelines (community level of influence) may also promote further equity in the receipt of HCC surveillance. For example, NAFLD is now a leading cause of cirrhosis,Impact of the physical/built environment domain47 This may include home and school environments, neighborhood walkability, and the availability of grocery stores in a community.The physical/built environment refers to the physical space in which individuals live, learn, and work.53 Compared with White patients, Asian American patients are 13% less likely, while Hispanic and Black patients are respectively 20% and 18% more likely, to present with advanced stage HCC.55 Multiple physical/built environment factors, such as county-level and neighborhood-level characteristics (community level of influence), may contribute to these disparities. As an example, people living in rural and suburban areas (vs. urban areas) are more likely to present with late-stage HCC, not receive HCC treatment, and die owing to HCC.56 A greater proportion of Black and Hispanic patients also live in US counties with higher social vulnerability index scores, and individuals from high social vulnerability index counties are more likely to present with larger tumors and receive nonsurgical interventions for HCC.57 Similarly, API and Hispanic people were more likely to develop HCC if they lived in low socioeconomic status (SES) (vs. high SES) neighborhoods.58 These findings highlight the importance of assessing and collecting both individual and neighborhood-level social determinants to health to better address inequities in HCC care stemming from geographical and built environment differences by race and ethnicity.Several studies have already shown that HCC stage at diagnosis varies by race and ethnicity.Impact of the sociocultural domain59 but are also less likely to receive curative therapies ,61 even when presenting with early-stage HCC.54 These findings may be related but not limited to individual beliefs about liver cancer and treatment options .Access to HCC treatment is closely linked to HCC stage at diagnosis. However, racial minority patients do not receive the same type of HCC treatment even when presenting at similar disease stages. Black and Hispanic patients are not only the least likely of racial minority groups to receive any HCC treatmentImpact of the biological domain62 and curative therapy in early-stage HCC.54 This may in part be explained by the higher rates of HBV-related HCC, including in noncirrhotic patients, within the Asian American community63 (community level of influence). As many patients with chronic HBV are recommended to undergo regular HCC surveillance irrespective of cirrhosis status,19 Asian American patients may be more likely to be diagnosed with early-stage or noncirrhotic HCC, both of which may be more amenable to curative treatments such as resection.19On the other hand, Asian American patients are more likely than other minority groups to receive resectionImpact of the behavioral domain65 This difference is particularly important, as patients with HCC, if detected early, are usually the most likely to be listed for transplantation.66 One potential explanation for this finding could be that providers and transplant selection committees use varying definitions of “adequate social support,” which is a subjective eligibility criterion for transplant listing ; for example, the intersection of race and SES might make it challenging for minority patients to have a caregiver who can afford to miss work while caring for a transplant recipient. Other reasons may include provider implicit bias affecting referral patterns67 and inconsistent thresholds of financial security68 that may impact the patient and provider interaction and prohibit transplant listing.Hispanic, Black, and Asian American patients are also less likely than White patients to receive liver transplantation for HCC.69 and palliative care.70 Among Medicare beneficiaries, a greater proportion of racial and ethnic minority patients (44% vs. 31% of White patients) received no hospice care in their final year of life.71These disparate findings also extend to end-of-life care; Hispanic and Black patients are again less likely than White patients to receive immunotherapy for advanced HCCThese findings suggest the importance of eliciting both patient and provider beliefs about liver cancer and treatment risks and benefits, to better understand the facilitators and barriers at the interpersonal level to delivering standard-of-care HCC treatments equitably across all racial and ethnic groups. The integration of community-engaged and qualitative research methods  may be one way to systematically collect and report on these topics.Impact of the sociocultural environment domain72 Interestingly, this correlation with SES was not observed among AI/AN patients, but this may be related to the small sample size of AI/AN people included in the study. Such findings suggest that unmeasured or difficult to measure factors such as perceived social stigma, cultural identity, and financial stability may play important roles in the pathway toward HCC-related survival. Additional studies will need to better assess the relationship between these factors, including the possibility of other confounding factors such as individual health literacy and educational attainment and their impact on HCC-related mortality.Individual SES  can also impact HCC-related mortality. Patients with lower SES (vs. higher SES) experience higher HCC mortality irrespective of race and ethnicity; Black patients with low SES have the highest 5-year HCC mortality rate at 11.5%.Impact of the health care system domain76 First, minority patients are more likely than White patients to be uninsured or to receive public insurance .78 In 2021, 18.8% and 47.4% of AI/AN, 17.7% and 37.7% of Hispanic, 9.6% and 45.3% of Black, 5.8% and 28.2% of Asian, and 5.7% and 35.7% of White Americans were uninsured and recipients of public insurance, respectively.79 Second, compared with Medicare or privately insured patients, Medicaid and uninsured patients with HCC have up to a 43% and 88% higher risk of death, respectively.76 In a multicenter study, lack of insurance was independently associated with decreased survival among patients with HCC.74 In another study, HCC mortality was not associated with race and ethnicity among White, Black, and Hispanic patients after adjusting for insurance coverage and health system.73 These findings suggest the importance of increasing individual access to health insurance to improve HCC-related mortality.Multiple studies have shown that an individual’s insurance status  plays an important role in HCC care.80 Furthermore, within the US Veterans Affairs health system, where access to care is less of a concern, we found that generally observed disparities by race and ethnicity were not present, instead Black and Hispanic patients (vs. White) were more likely to receive HCC screening.81 These findings highlight some of the potentially modifiable factors within the health care system domain that currently influence HCC-related disparities. More studies are needed to evaluate the mechanism by which type of insurance coverage may be related to the timely receipt of HCC surveillance and/or access to HCC treatment, which may affect HCC-related mortality. Similarly, the impact of health policy changes on insurance coverage should be more closely assessed to better understand the societal level changes that could improve HCC-related survival both short term and long term.On a larger scale, health policies that impact access to health insurance  can also impact HCC outcomes. In a recent systematic review, Medicaid expansion has been associated with increased access to insurance coverage among patients with cancer and survivors overall and, in particular, among low-income people and minority people.82 It is therefore important to urgently implement and disseminate effective interventions and develop strategies to engage under-represented patient populations to promote health equity in HCC care. Although a variety of interventions have previously aimed to improve outcomes along the HCC care continuum . In particular, there is a paucity of data from AI/AN, Native Hawaiian, and Pacific Islander communities, including information regarding gene polymorphism distribution, despite the high burden of HCC incidence and mortality in these communities. Building collaborations by investing in opportunities to grow clinical and research programs at nontertiary and nonacademic facilities , as racial and ethnic minority patients frequently receive care at these locations, will also help promote sustainable academic-community research relationships and thereby increase minority representation in HCC studies. As an example, the National Cancer Institute’s P20 grant mechanism has enabled us to establish a collaboration among the University of Washington, Fred Hutchinson Cancer Center, Alaska Native Tribal Health Consortium, and Cherokee Nation Health Services to study the use of biomarkers and abbreviated MRI-based HCC surveillance to promote early detection of HCC among AI/AN people.92 In indigenous communities, we have learned that collaborations that incorporate traditional knowledge can be particularly valuable for influencing upstream determinants of health.Collect and report data on HCC risk and incidence, surveillance, stage at diagnosis, treatment, and mortality by racial and ethnic subgroups. HCC incidence and mortality rates differ by country of origin or subgroup, but studies often combine API, Hispanic, and Black patients into large racial and ethnic minority groups. Similarly, the AI/AN population includes many Tribal nations, each with its own distinct health system and community characteristics, which may have profound differences in cirrhosis—or HCC-related risk factors or outcomes. There is also a growing number of individuals who self-identify as a multiracial person. Thus, disaggregation and expansion of existing demographic variables are critical to enhancing the quality of data collection and interpretation in HCC research settings. Specifically, collecting data along the HCC care continuum by subgroup can be especially helpful when trying to assess factors within the physical/built environment, sociocultural, and health care system contexts, as specific subgroups of patients may have varying experiences or outcomes related to HCC care that would otherwise go unnoticed. For example, social stigma and beliefs related to HBV infection may differ by Asian American subgroups, which may affect future intervention targets.Assess the patient experience of HCC care within each racial and ethnic group. At multiple steps along the HCC care continuum, the impact of patient-provider interactions, and their sociocultural environments cannot be overstated. While quantitative metrics related to HCC incidence and mortality are valuable, understanding the lived experiences of patients and providers can be instrumental in identifying key opportunities to address HCC-related disparities. In particular, because these experiences may vary by race and ethnicity, integrating community-based and mixed methods studies that include patient surveys, focus groups, and semistructured interviews will allow investigators to design interventions that are more likely to be successful within each minority group. Future studies would also benefit from including metrics on the implementation of an intervention  to evaluate and identify which approaches would be most successful within specific racial and ethnic minority groups.Evaluate for HCC-specific social determinants of health by race and ethnicity. Studies have increasingly shown how HCC outcomes at the individual level are influenced by upstream factors such as neighborhood poverty, rurality of residence, and proximity to health care facilities. For example, among AI/AN people, HCC incidence varies by location and is highest in the Northern Plains, followed by Southwest, Pacific Coast, Southern Plains, East, and Alaska.93 However, the reasons for these differences are not clear. Thus, simultaneously collecting data on individual-level, neighborhood-level, and community-level characteristics among others may help explain the mechanism by which HCC disparities exist. In addition, evaluating the influence of socioeconomic characteristics and studying the interaction of clinical cofactors such as NAFLD and alcohol use between Tribal Groups may shed light on the variance of incidence rates. These findings can then inform the design and implementation of multilevel interventions, which target multiple factors involved in the HCC care pathway. Multilevel interventions are more likely to improve the impact and sustainability of future interventions.94We therefore propose the following strategies Figure  to guideThese 4 priorities to strategically improve the quality of data collection in HCC research will help inform the development of more successful programs and interventions that take into consideration the unique HCC-related experiences of each racial and ethnic group.HCC-related disparities by race and ethnicity exist both regionally and nationally in the United States. Observed differences along the HCC care continuum are related to many individual, interpersonal, community, and societal factors that span multiple spheres of influence including biological, behavioral, physical/built environment, sociocultural environment, and health care system domains. As we described in this narrative review, racial and ethnic disparities in HCC care are complex. As a result, we propose the use of an adapted NIMHD Research Framework to help organize and evaluate the intersection of factors that affect each step along the HCC care continuum to better address liver cancer disparities. We also present multiple strategies that may help improve the quality of future HCC studies as a way to enhance HCC care for racial and ethnic minority patients in the United States.


Clinical practice guidelines (CPGs) are evaluated for quality with the Appraisal of Guidelines for Research and Evaluation (AGREE) tool, and this is increasingly done for different countries and regional groupings. This scoping review aimed to describe, map, and compare these geographical synthesis studies, that assessed CPG quality using the AGREE tool. This allowed a global interpretation of the current landscape of these country-wide or regional synthesis studies, and a closer look at its methodology and results.A scoping review was conducted searching databases Medline, Embase, Epistemonikos, and grey literature on 5 October 2021 for synthesis studies using the later versions of AGREE  to evaluate country-wide or regional CPG quality. Country-wide or regional synthesis studies were the units of analysis, and simple descriptive statistics was used to conduct the analysis. AGREE scores were analysed across subgroups into one of the seven Sustainable Development Goal regions, to allow for meaningful interpretation.n = 10) reported development methods, and 19% (n = 11) reported use of Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Overall scores for domains Rigor of development and Editorial independence were low, notably in middle-income countries. Editorial Independence scores, especially, were low across all regions with a maximum domain score of 46%. There were no studies from low-income countries.Fifty-seven studies fulfilled our eligibility criteria, which had included a total of 2918 CPGs. Regions of the Global North, and Eastern and South-Eastern Asia were most represented. Studies were consistent in reporting and presenting their AGREE domain and overall results, but only 18% (Editorial Independence. Transparent reporting of funding and competing interests, as well as highlighting evidence-to-decision processes, should assist in further improving CPG quality as clinicians are in dire need of high-quality guidelines.There is an increasing tendency to appraise country-wide and regionally grouped CPGs, using quality appraisal tools. The AGREE tool, evaluated in this scoping review, was used well and consistently across studies. Findings of low report rates of development of CPGs and of use of GRADE is concerning, as is low domain scores globally for The online version contains supplementary material available at 10.1186/s12874-023-02101-5. Clinical practice guidelines (CPGs) play an integral part of medical practice, policy, and politics; and wherever possible should be informed by systematic reviews of the best available evidence, while considering benefits and harms. Clinical practice guideline development groups, researchers and clinicians enjoy considerable resources to support and inform guideline development , reportiFor example, in a study evaluating African hypertension guidelines, recommendations were reported as a mixture of standard treatment guidelines (adapting), WHO guidelines (adopting) and de novo CPG development . NotablyOver the last two decades, steady inroads have been made in terms of levelling CPG quality using quality appraisal tools . These tThe AGREE tools have been used for a variety of reasons, from appraising individual CPGs for guideline adaptation, to appraising specific grouped CPGs, including: a sample from the National Guideline Clearinghouse when the AGREE-REX tool was developed ; severalRigor of development and Editorial independence. These two important domains have been historically considered [This scoping review aimed to fill this knowledge gap by describing and mapping national and regional CPG synthesis studies that used the most recent versions of the AGREE tool  towards unpacking how AGREE is used and reported in guideline assessment studies. This allowed a comprehensive global view of the characteristics of these national and regional synthesis studies; quantity and quality of the included CPGs; and a global and regional evaluation of the six AGREE domain scores. Additionally, it allowed a focus on specific domains nsidered , and agansidered , as haviThis scoping review described the methodology and characteristics of CPG synthesis studies and its included CPGs; and subsequently mapped and compared studies that used later versions of the AGREE tool, to assess CPG quality country-wide and/or regionally. This includes describing the use of the AGREE tool, comparing domain scores, and ascertaining use of the overall assessment. A protocol was developed a priori , Medline (Pubmed), Epistemonikos, and grey literature . The search was conducted on 5 October 2021. Studies published in any language were included until full-text stage. The full Medline and Embase search strategies are listed in Additional file Secondary research on CPG quality including scoping reviews; methods studies ; reviews; systematic reviews of CPGs; and evaluation/analysis of quality of CPGs were considered. Synthesis studies on country-wide, regional, and topical CPGs were considered. Grey literature including thesis, dissertations and unpublished studies were considered. Exclusions based on study types, were international scoping reviews collating different countries into a topical review.Any guideline synthesis study that used AGREE II, AGREE GRS , and AGREE-REX  were considered. This tool uses six domains with 23 items, each scored 1–7 (strongly disagree to strongly agree) as well as two overall assessments. The overall assessment requires each assessor to firstly rate the overall quality of the guideline  and secondly to make a judgement as to whether this guideline is recommended for use . Exclusions included studies that used other tools or scores to appraise the quality of its CPGs.All countries or regions worldwide and their medical specialities and sub-specialities, including allied health and traditional medicine, were considered. Regions according to WHO, United Nation or Sustainable Development Goals (SDG) regional groupings were considered. Only CPGs answering human, health-related questions were considered. Exclusions included humanitarian, military combat, health-system related and non-human studies.We exported the retrieved records into a Mendeley Library and subsequently uploaded it to the Rayyan web platform  and remoA single reviewer (MMA) extracted data from most included records using a data extraction tool (created in Microsoft Excel), assisted by a reviewer extracting the four Spanish records (IF) and checked by another reviewer (SS). This tool was piloted on a small sample of possible included studies, identified in a previous review. Only English and Spanish records were included, as the study was limited in its access to translation services. Data extracted included study types and methodology; characteristics of included CPGs; and AGREE tool use including domain and overall score results. Included synthesis studies were the units of analysis, and simple descriptive statistics was used to conduct the analysis using STATA 14.Categorical variables were described as percentages; whereas continuous variables were described by means and standard deviations (sd) where data was normally distributed, otherwise reported as median and interquartile range. Data normality was determined graphically and using the skewness-kurtosis test. Studies that calculated median overall scores for AGREE domains were converted to a mean score, as recommended by Hozo et al.      . This alAGREE scores were analysed across subgroups into one of the seven SDG regions. A list of included studies is found in Additional file The results of the search and study inclusion are presented in Fig. n = 14) of studies evaluated all country-wide or regional CPGs. Most studies  only searched local/regional databases and grey literature for including CPGs, whilst 20 studies (35%) searched both locally and internationally . The number of included studies increased as the year of publication range increased, mostly published after 2019  and the median year-range of included CPGs was 8.5 years (IQR 6). The general aim of most studies was to describe and determine quality (or lack thereof) of CPGs, in either specific topical areas or country-wide; to enhance future CPG development and/or implementation of current CPGs. This included identifying areas of variability and vulnerability to speak to compliance and conformity. Most studies then used a cross-sectional design and topical purposeful sampling and were published by academic societies or researchers. However, a substantial number n = 4 of studn = 5, 50% of the 10 studies). Additionally, overall, only 11 studies (19%) reported the use of GRADE in the development of the included CPGs.Table n = 43, 74%) reported the overall guideline assessment; most studies reporting only one overall assessment and modifying it.AGREE use and completeness, was well reported and presented in all included studies. Most studies used two to four assessors to assess domain scores, and inter-observer agreement scores were used by 36 (63%). Almost three quarters of studies (Rigor of development domain score > 60% and iii) using a cut-off sliding scale of most domain scores > 60% being ‘recommended’, scores of 30–60% ‘recommended with modifications’, and if most scores were < 30% ‘not recommended’. It was noted that even among these three groupings, slight variation existed. Additionally, there was no regional pattern regarding this modification. Latin America and the Caribbean , and Europe and Northern America , used this overall assessment in most of their studies.The method of formulating the overall quality assessment score of CPGs varied in most of our included studies. The majority of 43 studies (74%) made use of this overall assessment. Twenty-nine studies used one assessment only and thirteen studies used both assessments. However, 24 studies (57%) modified this overall assessment and did not apply it as per the AGREE manual, where 12 variations of modification were found. The three most common modifications included: i) calculating an overall average across the six AGREE domains ii) using a cut-off of Rigor of development (ROD), Applicability, and Editorial independence (EI); moderate for Stakeholder involvement; and higher for Scope and purpose and Clarity and presentation . Despite this, many AGREE domains across geography had either moderate or high-quality scores, and the tendency to appraise country-wide or regional CPGs appear to be increasing.This scoping review provided a global view investigating the heterogeneity of CPG synthesis studies across different countries and regions, as noted in other studies , 37. DesRegions of Eastern and South-Eastern Asia, and Europe and Northern America were the best represented in terms of quantity of studies included. This was recently seen in a living systematic review of Covid-19 rapid guidelines, where 45% of guidelines originated from high income countries (HICs) and no guidelines from low-income countries . The incRegarding the use of GRADE methods, either in evidence synthesis or as part of the evidence to decision process, only 11 synthesis studies (19%) reported using any GRADE methods, two of these primarily assessing GRADE adherence. Lack of reporting of GRADE and other methods of judging the certainty of evidence, along with how evidence is used to develop recommendations, is concerning. Reviewers of CPGs are encouraged to highlight the importance of how these evidence-to-decision processes evolve, to strengthen guideline development and assessment in the future. Regional quality assessments have shown that there is a slow but increasing incorporation of these requirements , 44. OnlReciprocally, the low reporting rate of guideline development methods and absence of Covid-19 or rapid guidelines included in this scoping review, could signify areas of much needed growth. Through multiple online high-quality/tech savvy platforms created for the Covid pandemic, the guideline community can be inspired to make use of these types of resources to further advance guideline quality. This can assist in processes like guideline adaptation, that aim to reduce research waste and duplication of effort; by using living reviews and guideline repositories , recommeThe Inclusive Internet Index is an example of a starting point to plug LMICs into these resources. As the 2021 report  indicateRigor of development domain. Two recent studies attempted rating the importance of the different AGREE domains on the overall assessment, indicating that Rigor of development, Clarity of presentation, Applicability, and Editorial independence had a significant influence on the overall quality assessment [Rigor of development, particularly used in the overall CPG quality consideration, is often scored as low [Editorial independence is becoming increasingly scrutinized as important for guideline quality [AGREE tool use was well reported where most synthesis studies used a recommended two to four assessors per CPG, reported on interobserver agreement and assessed all 6 domains; similar to previous reviews , 39. Thesessment , 51. Almsessment . Those osessment . This cod as low , 10, 21, quality . In fact quality –56; and  quality , howeverThe scoping review design used in this study allowed us to attain a global overall view. This review focused on studies that used the AGREE tool for quality assessment and cannot comment on synthesis studies of guidelines using other appraisal tools. Additionally, there might be included studies that applied AGREE to other types of documents (such as end-user guidance documents or broad summary documents). There has been an indication that other types of ‘guidance documents’ have lower AGREE scores than true CPGs , and thiRigor of development varies between HICs and LMICs, necessitating building further guideline development capacity, including use of GRADE for guidelines. Improved reporting of funding and competing interests, as well as guideline development approaches and their underlying evidence sources, can further enhance regional quality of guidelines. Assessing country-wide or regional guidelines with quality appraisal tools, could advance overall guideline quality for all areas globally. This is an important step forward and toward global guideline uniformity, as clinicians are in dire need of high-quality guidelines to improve delivery and quality of care.When looking at the landscape of guideline quality, there has been various attempts to level the playfield and inroads have been made. There is a current tendency to critically evaluate guideline quality in country-wide and regional approaches and AGREE is overarchingly used well in this practice. However, guideline Additional file 1.


In recent years, the biomedical engineering field has seen remarkable advancements, focusing mainly on developing novel solutions for enhancing tissue regeneration or improving therapeutic outcomes. One of the key components of the latest developments is polymers , due to their indisputable wide range of properties and functionalities that transform them into ideal materials for designing drug delivery systems or scaffolds for tissue engineering.Bombyx mori silk fibroin (SF) and recombinant spider silk protein eADF4(C16) into a hydrogel that showed superior mechanical and biological performance when compared with the characteristics of individual materials.The Special Issue “Polymer Materials for Drug Delivery and Tissue Engineering” gathers a multidisciplinary collection of articles that merge the knowledge and expertise of worldwide researchers that present their latest research in the field of polymer-based materials. This Special Issue brings together articles that report original research on the design and synthesis of novel drug delivery systems and scaffolds or highlight insights into polymer interaction ,2,3,4,5.Furthermore, this Special Issue reveals other biomedical applications of polymers such as the development of organ-on-a-chip platforms. With a focus on the urology field, Galateanu et al.  presenteEscherichia coli) and Gram-positive (Staphylococcus aureus) bacteria.For tissue engineering purposes, polymers are widely used for the design and fabrication of biomimetic scaffolds that can substitute the defective tissue while maintaining a suitable environment to promote healing . Dependif-GO dressing material that exhibits both antimicrobial and anticancer activities.For wound healing applications, Al. Arjan and collaborators  proposedAs in tissue engineering applications, the biocompatibility and biodegradability of polymers are essential features that promote their use for drug delivery system development, such as nanoparticles, micelles, and hydrogels . Drug deBombyx mori silk sericin was successfully developed for doxorubicin delivery and induced cytotoxicity and genotoxicity in MCF-7 tumor cells selected as an in vitro model for breast cancer [Moreover, especially for drug delivery systems developed for cancer treatment, functionalization strategies can be employed to direct nanoshuttles to tumor cells, thus increasing the therapeutic efficacy of the drug cargo while reducing toxicity . For colt cancer .In conclusion, polymers are valuable tools for the development of drug delivery systems and biomimetic scaffolds due to their tailorable design, versatility, attractive physiochemical properties, and excellent biocompatibility. With ongoing advancements in polymer science and personalized medicine, polymers hold great promise in revolutionizing the current landscape of the biomedical field, providing a real opportunity for designing personalized biomedical products that can be easily adjusted to meet patients’ needs.


There are several sustainability issues that the linear economy of today’s society cannot adequately tackle . As a result, the scientific community and policymakers give high priority to the implementation of the circular economy concept. The sustainable development goals of the United Nations are in line with the European Union’s (EU) commitment to a smooth transition to a circular economy. Circular business models require a shift in technical elements involving R strategies to replace traditional business models . Monitoring circular economy to provide quantifiable, measurable data is necessary for a successful transition. Monitoring tools  enable decision-makers to measure circular economy performance and identify circularity’s advantages and disadvantages. To stimulate the adoption of a circularity model addressing critical issues of excessive waste production and resource use, this mini review aims to address the literature gap of waste metrics in the framework of circular economy and offer insights on circular economy indicators to aid for a seamless transition to a more sustainable society. For this purpose, Preferred Reporting Items for Systematic Reviews and Meta-Analysis method was chosen to assess literature. The authors collected and analysed data from 101 records, 70 articles and 31 reports related to the topic under consideration. Through the literature review, it is obvious that moving away from linear production model frequently leads to the development of new internal capabilities along the value chain and, eventually, high efficiency that reduces costs, increasing productivity, encourages brand names, minimizes threats, creates new products and fulfils regulations and green consumer expectations. Environmental pollution and resources scarcity are among the major challenges of sustainability in today’s world, as a result of urbanization and industrialization over the last decade . IncreasAccording to The circular economy concept strives to transform traditional practices of production and economic growth, which are considered as linear systems, into circular dynamics that connect resource use and waste generation to reduce pollution and waste production . In respThis mini review intends to provide insights on waste key performance indicators (KPIs) in the framework of circular economy for the adoption of a circularity model that encourages the approach to crucial concern of over-exploitation of natural resources and excessive waste production. The exploration of waste monitoring specific to circular economy in literature is deficient, whereas a collective evaluation of all existing tools for measuring circular economy will be deemed crucial for a smooth transition towards a more sustainable society.The European countries that have achieved significant results in implementing the principles of the circularity approach are mainly characterized by their continued attempts to transition to a circular economy, as well as their targets and goals. Given the several principles of circular economy, and how diversely one single nation could indeed score on each of these concepts, it still is challenging to precisely classify how countries achieve in terms of circular economy. Germany leads in certain aspects of circular economy, such as waste management and recycling . France The European Commission’s initiatives including European Green Deal (EGD), Fitfor55 strategy, Zero Pollution Act, European Industrial Strategy, etc. are also noteworthy, with concerning a state of play for a global and circular economy and the new Circular Economy Action Plan (CEAP) being one of the main blocs of the green deal , 2021b. In the context of current environmental, social and economic issues, many efforts have been taken in global and European level in order to identify and implement efficiency actions through the establishment of legislated and non-legislative initiatives, setting specific goals and targets . Up untiLater on in 2015, the United Nations published the 2030 Agenda for Sustainable Development, which includes 17 SDGs and 169 targets that can be measured using 230 specific qualitative and as well as quantitative indicators . RegardiFurther on, the EGD was approved by the European Commission, in 2019. It introduced a roadmap attempting to make the EU’s economic system sustainable by transforming climate and environmental issues into opportunities in all policy priorities. The EGD aims to increase resource efficiency by transitioning to circular economy, as well as to inhibit climate change, reverse biodiversity loss and reduce pollution . The objThe first circular economy action plan was finalized in 2019, and its 54 actions have been completed . Later o2 emissions are linked to the manufacturing of materials used every day. Transitioning towards a circular economy model may provide advantages such as reducing environmental pressures, improving raw material supply security, enhancing business competitiveness, enhance economic growth (an extra added 0.5% of GDP) and creating more jobs . Consumers will additionally have more long–lasting and innovative products that will improve their life quality  method was chosen to assess the state of the art . The proBoth inclusion and exclusion criteria were used as eligibility criteria. The inclusion criteria include the following: (i) research related with key performance indicators, circularity waste production and management; (ii) published articles and reports from 1990 to the present; (iii) review papers; (iv) methodical demonstration and synthesis of research results and (v) records identified using the authors’ keywords. The exclusion criteria include the following: (i) narrative reviews and (ii) available papers in languages other than English. For the literature review, the database of Scopus was preferred. As Scopus database option search were ‘title, abstract, keywords’ the following keywords were used: *circular economy* AND *model*, *waste* AND *circular economy* OR *waste management*, *Sustainable development goals*, OR *waste production*, OR *waste strategies* OR *environmental management systems*, OR, *KPI indicators* AND *Circular Economy*. All authors participated in the literature review in order to reduce random errors and bias during the research procedure.The screening of the titles and abstracts for potential inclusion began with consideration of the criteria. Inconsistencies regarding whether a particular study/report/manuscript should be included or excluded were resolved through extensive discussion among the authors. The 2100 Scopus references were cross-checked with Mendeley software  to identify any duplicated studies. When the review team was unsure whether a particular paper met or did not meet the inclusion criteria, full papers were downloaded for further evaluation. The authors collected and analysed data from 101 records, 70 articles and 31 reports related to the topic under consideration. The final records used in the manuscript were agreed upon by all of the authors.A circular economy model is critical for achieving waste management goals and targets through new and innovative business strategies . CirculaThe role of KPIs in evaluating circularity performance within waste management could provide valuable knowledge for decision-making methodologies . KPIs arAccording to Loizia et al. (2019) among the most applicable and suitable, well-known KPIs to assess the level of circularity in waste management are Municipal Solid Waste Production, Waste Composition, Municipal Solid Waste Recycling, Waste Recovery Index, Recycle Bins per Population, Clean Index, Accumulation Rate, Waste Accumulation Index and Waste Generation Rate .Developing circular economy indicator metrics does not come without obstacles. One of the main concerns seems to be that, while the transition to a circular economy is strongly related to Europe’s climate agenda and SGDs, a focus on materials would not imitate all environmental issues, rendering to the 2030 Agenda for Sustainable Development. Even though underappreciated, the use of KPIs and targets will be vital. Admittedly, ‘what you can’t measure, you can’t manage’. Until 2019, there have been numerous attempts to create waste metrics in the framework of circular economy to be used in the private or public sectors. Despite these remarkable initiatives, there has yet to be an aligned metrics research area . WheneveTaking into consideration the above obstacles, the stakeholders and policymakers, both at Global and European level, proceeded to develop specific frameworks with targeted indicators to measure the circular economy, including specific indicators for waste production management. Except those efforts, additionally initiatives from national and private sector have been implemented in an attempt to capture circular economy progress .Waste metrics in the framework of circular economy are commonly consolidated at EU and national levels by statistical offices, who use relevant information from economy-wide material flow accounts, economic and financial data and waste statistics . At the same time, when integrated into circular economy, such metrics can aid with the core principles of circularity such as resource monitoring and efficiency (extension of products lifespan), the reduction of environmental impacts, economic benefits and new economic opportunities (based on data and not assumptions), as well as innovation potential . These mOne of the most concerted efforts to develop a widely accepted framework for measuring circular economy was the Platform for Accelerating the Circular Economy (PACE) published in 2018 . PACE waOver the last couple of years, China has prioritized the concept of the circular economy as a national regulatory policy priority. This enhanced the circular economy principle at three different levels: the independent firm, the eco-industrial park and the eco-province level. Circular economy mainly includes eco-design and greener production strategies at the firm level . Eco-indWith the Law for Promotion of Effective Utilization of Resources adopted by Japanese Government, Japan established a basic legislative framework for empowering circular economy 25 years ago (1991). A Law for Establishing a Material-cycling Society (2000) applied to recycling of automobiles, packaging waste, domestic appliances, demolition waste and food wastes. Extensive and consumer-friendly refund systems, including prepayment for return and recycling at the point of sale as well as cooperation among producers in recycling .An Australian circular economy measurement framework included headline, impact, and transition indicators that record different aspects of the circular economy. The following measurement framework targets also defined communication, priority setting, tracking and correlative performance metrics throughout cities and counties, as well as an acceptable indicator hierarchy .The headline indicators provide a high-level index about how circular economy represented by percentage or resources consumed per unit, the impact indicators examine the effect of consumption of resources, including the economy, environment and society, and the transition indicators examine how the circular economy is tracking against makers of progress towards the future state .Another important step for circular economy measurement and evaluation were the models that used a set of steps or levels or strategies of circular economy, commonly beginning with the letter ‘R’ in English. The first one, widely recognized as the ‘Three R principle’, was ‘Reduce, Reuse, Recycle’, which dates back to the 1970s. Similarly, Even though, the initial emphasis of research community, business and governance was mainly on the creation of re-X strategies  it soon became apparent that advanced technologies progressively exceeded their implementation. Multiple stakeholders work collaboratively to utilize this technology for the transition to a circular economy. This turned its attention to business-model innovation as a crucial lever for circular technology adoption . Rheaply is an example of a new tech that puts an emphasis on investment management and disposition that enables organizations transitioning to circular economy business model .. CirculTo strengthen the circular model, the scientific and research community developed specific standards with specific requirements. In 2017, the British Standards Institution developed and published the first circular economy standard, ‘BS 8001:2017 Framework for implementing the principles of the circular economy in organizations’, to provide credible guidance to organizations implementing circular economy strategies . The staIn 2018, the International Organization for Standardization (ISO) developed a technical committee (TC 323) in the sector of circular economy to generate frameworks, guidelines and specifications for the execution of initiatives by all relevant stakeholders in order to increase their contribution to SDGs. Six new ISO standards are currently being developed under the direct supervision of this technical committee: (i) ISO/CD 59004 Circular Economy – Terminology, Principles and Guidance for Implementation; (ii) ISO/CD 59010 Circular Economy – Guidance on the transition of business models and value networks; (iii) ISO/CD 59020 Circular Economy – measuring and assessing circularity; (iv) ISO/CD TR 59031 Circular economy – Performance-based approach – Analysis of cases studies; (v) ISO/CD TR 59032.2 Circular economy – Review of business model implementation and (vi) ISO/WD 59040.2 Circular Economy – Product Circularity Data Sheet .In addition to the above initiative, digitalization and digital technologies  are considered to be core elements for scaling up the circular economy. The key role of digital technologies in speeding up the circular economy transition, also known as the data economy, is underlined with the EGD . The smaAs automation and real-time monitoring help to integrate circular economy into daily operations, the adoption of digitalization has the potential to minimize resource usage. The concepts of digitization, circular economy and sustainable development may be used as principles for managing uncertainty in product development processes. In order to facilitate informed decision-making, digitization is being utilized in many businesses and industries for accounting administration .In order though for circular economy models to be implemented and quantified, several incentives need to be in place for all major players, including but not limited to policymakers, producers, urban planners and the public. Offering financial incentives, such as tax breaks, subsidies or grants, and other regulatory relief measures, can encourage businesses and individuals to adopt circular practices. These incentives can be targeted towards activities such as resource recycling, product repair or the development of innovative circular business models . At the In addition to encouraging circular economy initiatives in the commercial and industrial sectors, policymakers may also embrace digital transformation to boost sustainability and the economy . AccordiThe circular economy does not seek to disrupt profit maximization paradigms in enterprises. Instead, it offers an alternative approach to maintaining a competitive advantage while addressing the environmental and socioeconomic challenges of the 21st century. Shifting away from linear production models often leads to the development of new internal capabilities across the value chain, resulting in increased efficiency, cost reduction, enhanced productivity, brand enhancement, risk mitigation, product innovation and compliance with regulations and green consumer expectations. The integration of digital technologies, such as artificial intelligence, blockchain and the IoT, can help overcome barriers and facilitate the transition to a circular economy, while also significantly influencing consumption and production patterns in today’s society. Harnessing the benefits of Industry 4.0 can have substantial positive effects on the pillars of sustainability . For the successful implementation and quantification of circular economy models, it is necessary to establish various incentives for all key stakeholders, including policymakers, producers, urban planners and the public. These incentives should encompass a range of measures, including but not limited to financial incentives such as tax breaks, subsidies and grants, as well as regulatory relief. By providing such incentives, businesses and individuals can be motivated to embrace circular practices. However, monitoring alone will not suffice for a seamless transition; it is crucial to involve all relevant stakeholders. To improve quality of life and minimize the human impact on the environment, future efforts must promote a hybrid approach that combines monitoring the circular economy with citizen participation and public awareness.


Schistosoma Mansoni, S. japonicum, and S. haematobium, each with different geographic distributions. Praziquantel is the drug predominantly used to treat this disease, which offers low effectiveness against immature and juvenile parasite forms. In addition, reports of drug resistance prompt the development of novel therapeutic approaches. Natural products represent an important source of new compounds, especially those obtained from plant sources. This review compiles data from several in vitro and in vivo studies evaluating various compounds and essential oils derived from plants with cercaricidal and molluscicidal activities against both juvenile and adult forms of the parasite. Finally, this review provides an important discussion on recent advances in molecular and computational tools deemed fundamental for more rapid and effective screening of new compounds, allowing for the optimization of time and resources.It is estimated that 250 million people worldwide are affected by schistosomiasis. Disease transmission is related to the poor sanitation and hygiene habits that affect residents of impoverished regions in tropical and subtropical countries. The main species responsible for causing disease in humans are  S. mansoni and S. japonicum  and S. haematobium (which affects the genitourinary system) pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing the new chemical scaffolds, were found to exert activity against schistosomula and adult worms at low micromolar concentrations, thus constituting promising antischistosomal agents [With regard to metabolic targets, QSAR-based virtual screening of l agents . A combil agents . The appS. mansoni drugs based on molecular docking is evidenced in a study by Moreira et al., in which a panel of 85,000 molecules from the Managed Chemical Compounds Collection (MCCC) of the University of Nottingham (UK) were investigated against five protein kinases . Computational analysis narrowed the initial number of molecules down to 169, which were predicted to bind to SmERK1, SmERK2, SmFES, SmJNK, and/or Smp38, and were thus selected for testing in in vitro screening assays using schistosomula and adult worms. This combination of in silico and in vitro assays helped optimize the search for the most promising compounds, leading to a total of 89 molecules that were considered active by experimental assays [Another example of combining CADD methods for the virtual screening of anti-l assays , with 17l assays . WormAssS. mansoni (SmVKR2). This strategy combined the use of an initial in vitro experimental screening approach that applied the surface plasmon resonance (SPR) technique to determine molecule binding constants, with just 12 demonstrating molecular interactions on a micromolar level. These twelve molecules were then tested against S. mansoni ex vivo, resulting in the identification of four compounds with antiparasitic activity under testing including the WormAssay for phenotypic determination. Furthermore, the crystal structure of the kinase domain of SmVKR2 obtained by the authors improved in silico docking, thus paving the way to identify more potent inhibitors against the VKR2 receptor in the future [In the search for inhibitors of venus kinase receptors (VKR), important to schistosome growth and egg deposition, 645 molecules from GlaxoSmithKline (GSK) set 2 were screened against one of the target proteins of e future .Targeting potential epigenomic effects on the parasite, a structure-based virtual screening approach was applied in the search for histone deacetylase 8 (SmHDAC8) inhibitors using molecular docking of a compound library containing 550,000 molecules (the Interbioscreen database) against the crystallized structure of SmHDAC8 deposited in the PDB. The Glide docking program identified eight novel N--n-alkylhydroxamate derivatives, which were found to be active in the low micromolar range against smHDAC8 by utilizing an established in vitro assay for protein–ligand interaction and apoptosis induction .S. mansoni, have shown the importance of achieving a deeper understanding of this parasite’s gene expression and the integration of data to advance the development of schistosomiasis control strategies. This is relevant not only with respect to the new drug discovery, but also in many diverse aspects, including populational variations that may reflect on the response to treatment, as well as mechanisms involved in the development of resistance to chemotherapy [Modern methods and technologies that combine functional genomic approaches, including genomics, transcriptomics, proteomics and epigenetics of otherapy ,97.S. mansoni, as well as related species S. japonicum and S. haematobium, was first published in 2009, followed by updated revisions [https://parasite.wormbase.org/; accessed on 14 June 2023). Genomic data from publicly available databases serve as resources for establishing relationships between drugs and targets, allowing for the identification of compounds from searches based on sequence homology and functional motifs. Neves and colleagues demonstrated the use of this type of approach in their search for drug repositioning for schistosomiasis [S. mansoni in areas where mass drug administration strategies had been conducted [The genome of evisions ,95 whichsomiasis . Whole-gonducted ,109.Data available from proteomics studies permit greater knowledge surrounding the profile of differentially expressed proteins under a variety of conditions to which the parasite is exposed. A comparative study of the excretory/secretory proteome of adult male and female worms identified approximately 1000 proteins, of which 370 and 140 were secreted solely or abundantly by males and females, respectively. The use of functional genomic analysis tools served to indicate which classes of proteins were more related to secretion by males than females, providing valuable information on host–parasite interplay and male–female interaction .S. mansoni isolates through exposure to PZQ enabled the evaluation of impact on protein expression profile in worms exhibiting reduced sensitivity to PZQ in comparison to a susceptible population. This resulted in the identification of two proteins, Ca2+-ATPase and HSP70, that revealed differentiated expression under diverse analyzed conditions [The response to treatment on the parasite’s proteome is also a relevant topic of investigation. For example, laboratory resistance selection of nditions . PZQ-resnditions . This tyIn a similar context, many studies have also evaluated the profile of differentially expressed genes through RNA-seq, which has proven to be a very robust tool in identifying altered mRNA levels under both natural and experimental conditions ,114. MorStudies employing a combination of strategies, including bioinformatics tools, cheminformatics, and functional genomics, have been shown to efficiently select molecular targets involved in epigenetic regulatory processes, as reported by Padalino et al. , who utiThus, the use and integration of “omics” technologies has provided data deemed fundamental to defining new perspectives on the identification and application of natural products with anti-schistosomal properties.In conclusion, natural compounds have demonstrated significant potential as antischistosomal agents. Both in vitro and in vivo studies have evidenced the effectiveness of natural compounds against schistosomes under various approaches, including prophylactic interventions and adult parasite, cercariae, and schistosomula killing, as well as suppressive strategies that inhibit worm egg-laying. However, specific mechanisms of action, toxicological testing, and in vivo activities require better characterization in further investigations to allow transposing the use of natural products in clinical studies involving subjects with schistosomiasis. Overall, natural products have provided a valuable source of potential antischistosomal agents that may aid in the development of new treatments for schistosomiasis, a disease that continues to cause significant morbidity and mortality in endemic areas.


Cancer is a disease characterized by the accumulation of somatic mutations. The types of somatic mutations vary, and include substitutions, indels, rearrangements and copy number variations, which are found at different frequencies across different cancer types and patient samples. Mutational signatures represent the mutational processes that are responsible for this accumulation of mutations, and these different types of processes include DNA replication infidelity, carcinogens, including tobacco products and UV light exposure, DNA repair deficiencies, such as mismatch repair and homologous recombination repair deficiencies, and enzymatic DNA editing, among others. The ever-increasing amount of data related to cancer genomes provide a wealth of information for the development of novel insights on mutagenic processes, biological mechanisms involved and opportunities for new therapies. The identification of tumor vulnerabilities also enables patient stratification and the development of targeted therapies, which implore treatment outcomes.The analysis of the activity of mutational processes in the cancer genome provides insights to the active biological mechanisms that drive it. Furthermore, the tumor mutational burden, which represents the somatic mutations found in a tumor sample, associates with the success of immunotherapies, such as those based on immunomodulators or those that target neoantigens.The relationship between the tumor microenvironment (TME) and immunological response is another topic of active research. It remains, however, unclear how the tumor’s immune microenvironment influences the accumulation, location and frequency of somatic mutations and how it affects the ability of the immune system to elicit a response against cancer cells.The collection of works for this Research Topic (RT), includes the characterization of somatic mutations and their association with DNA repair deficiencies and the examination of different biomarkers for cancer prognosis and response to immunotherapies. The RT also provides important insights into the TME and its association with mutations, cancer development and immune response.Liu et al. investigated fatty acid metabolism-related genes in soft tissue sarcoma and identified a new score based on fatty acid metabolism, which may be provided as a potential biomarker and treatment strategy in this disease. What’s more, Loizides et al. discuss the role of high immunogenicity, specific immune activation signatures, as well as that of high expression of immunosuppressive genes and high levels of stromal tumor infiltrating lymphocytes (TILs), as key elements of the immune-driven landscape associated with triple negative breast cancer. In another study, Wang et al., the authors developed an angiogenesis-related gene risk assessment model to predict the prognosis of lung adenocarcinoma patients. This model was suggested to help in patient classification and the selection of medications for them. In addition, Dai et al. shows that PBRM1 mutation is closely related to immune efficacy and immune microenvironment, including killer cell mediated immunity regulation, cell cytokine production, CD8+ T-cell activation and MHC protein binding process. This correlation between PBRM1 mutation and prognosis and immune response, suggests that it may be used as a promising immunotherapeutic signature that could guide clinical management and personalized immunotherapy. Furthermore, Borch et al. explored different tumor associated characteristics for their association with favorable clinical outcome in a diverse cohort of cancer patients treated with immune checkpoint inhibitors. Their study revealed that even across this diverse cohort, patients achieving clinical benefit had significantly higher neoepitope load, higher expression of T cell signatures, and higher PD-L2 expression, which also correlated with improved progression-free and overall survival. Finally, the study by Huang et al. evaluated copy number deletion events as candidate targets across 17 cancer types. The authors identified a broad range of significant genes hit by copy deletion, where RB1, PTEN and CDKN2A were the most significantly deleted genes among all cancer types.In a pertinent study published in this RT, Overall, the studies in this RT contribute to an improved understanding of different mutational patterns in the TME and how they could provide further therapeutic opportunities for cancer patients. We would like to thank all the authors who contributed their original work to our RT and the reviewers for their valuable comments. We also thank the Frontiers Editorial Office for providing us with the opportunity to host this RT.


Lymphoma that occurs in adolescents and young adults (AYA) between ages 15 and 39 years is associated with unique incidence, race, and gender distribution . FurtherRecognizing this unmet need, the Lymphoma Research Foundation (LRF) began an initiative to engage and support the AYA research community, patients, and their families. In 2015, LRF convened an AYA Symposium with clinicians and basic scientists from pediatric and adult disciplines to examine the state of the science for AYA lymphoma, precisely review the gaps in research for this population, and discuss the unique challenges and treatment/disease burdens for the AYA lymphoma population . Before A summary of the symposium proceedings was published in Blood Advances in October 2017 . This puWith the findings of the original Symposium in hand and preliminary results from a range of research funded by the LRF, the first AYA Consortium meeting was held in 2019. The meeting involved panel discussions describing the latest findings in AYA lymphoma, the development of blueprints for subsequent AYA lymphoma research, and drafting an action plan for the Consortium. Blueprints included strategies for understanding features of AYA biology, immunobiology, and epidemiology, guiding clinical trials and drug development, characterizing ideal care delivery and patient outcomes, and better understanding survivorship and late effects. The action plan outlined the need for research to define AYA lymphoma and to support a focus on AYA lymphoma as a distinct patient group.Subsequently, in June 2022, pediatric and adult oncology physicians and scientists from more than 40 North American academic and medical institutions, federal agencies, pharmaceutical companies, and patient advocates were brought together in Jersey City, New Jersey, for the second LRF AYA Lymphoma Workshop. The workshop focused on research and clinical developments in the areas highlighted by the 2019 AYA blueprint, focusing on the needs of AYA patients, including current treatment paradigms and new collaborative clinical trial efforts, epidemiology, care delivery, survivorship, and cutting‐edge scientific research to better understand and serve these patients. Each session of the meeting included both lectures by select expert faculty and interactive panel discussions where audience members could ask questions, learn from colleagues in different disciplines, and work to develop cooperative strategies to improve AYA care.eJHaem entitled “Lymphoma in adolescents and young adults: navigating a path forward together,” a multitude of experts from the 2022 AYA Lymphoma Workshop review the current status, discuss significant new developments in the field, and provide recommendations for scientific prioritization, including: (1) the pathobiology of select rare AYA lymphomas; (2) scientific techniques in AYA lymphomas; (3) current directions in the treatment of Hodgkin lymphoma; (4) treatment of mature B‐cell lymphomas in AYAs; (5) overcoming barriers to drug development and enrollment in clinical trials for AYAs with lymphoma; (6) outcomes of AYAs with lymphoma: treatment effects; and (7) disparities and vulnerable AYA lymphoma populations  as well as a similarly constructed large study in early‐stage Hodgkin lymphoma, AHOD 2131 .Current progress and unmet needs in mediastinal large‐cell lymphomas are reviewed, and the pediatric mature B‐cell lymphoma landscape and factors impacting outcomes for patients are examined; a more focused discussion regarding the optimal incorporation of novel agents in the management of diffuse large B‐cell lymphoma for AYAs is presented. A collaborative review amongst the Cancer Therapy Evaluation Program (CTEP), biotech, and academia includes an overview of the structure of the NCTN and the identification of methods to overcome barriers to drug approval and the time and resources needed for running clinical trials that include a substantial number of AYA patients.A review of the AYA outcomes includes the postacute and long‐term complications in AYA lymphomas, the use of multisource data to characterize outcomes after initial Hodgkin lymphoma treatment, the discussion of treatment toxicity and tolerability in AYA, and an examination of survivorship guidelines for AYA lymphomas. Finally, a synopsis of current data on access and disparities in AYA lymphomas, focusing on opportunities for engagement, including specialized AYA models of care, financial toxicity, and disparities in AYA lymphoma, is provided. This review provides an enhanced understanding of the interplay of social and structural determinants of health with features of healthcare, economic, educational, environmental, and community structures.eJHaem represent critical stepping stones to help navigate a path forward together. With the positive momentum and robust collaborative efforts via the initial AYA Lymphoma Workshops, the LRF recently founded an AYA Lymphoma Consortium [Altogether, the reviews and associated recommendations in this special issue of nsortium . This coAE collected and analyzed the data, interpreted the data, and co‐wrote the manuscript. KK collected and analyzed the data, interpreted the data, and co‐wrote the manuscript.AME: Advisory Board with honorarium (research related): Seattle Genetics, Hutchmed, Incyte, Daiichi Sankyo, Novartis, Abbvie, Pharmacyclics and Epizyme. KMK: Scientific Steering Committee: Merck, and Advisory Board without honorarium: Seattle Genetics. No financial support was necessary for the preparation of this manuscript or acquiring data.The authors have confirmed ethical approval statement is not needed for this submission.