Abstract

Axillary surgery for patients with breast cancer (BC) in 2024 is becoming increasingly specific, moving away from the previous ‘one size fits all’ radical approach. The goal is to spare morbidity whilst maintaining oncologic safety. In the upfront surgery setting, a first landmark randomized controlled trial (RCT) on the omission of any surgical axillary staging in patients with unremarkable clinical examination and axillary ultrasound showed non-inferiority to sentinel lymph node (SLN) biopsy (SLNB). The study population consisted of 87.8% postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative BC. Patients with clinically node-negative breast cancer and up to two positive SLNs can safely be spared axillary dissection (ALND) even in the context of mastectomy or extranodal extension. In patients enrolled in the TAXIS trial, adjuvant systemic treatment was shown to be similar with or without ALND despite the loss of staging information. After neoadjuvant chemotherapy (NACT), targeted lymph node removal with or without SLNB showed a lower false-negative rate to determine nodal pathological complete response (pCR) compared to SLNB alone. However, oncologic outcomes do not appear to differ in patients with nodal pCR determined by either one of the two concepts, according to a recently published global, retrospective, real-world study. Real-world studies generally have a lower level of evidence than RCTs, but they are feasible quickly and with a large sample size. Another global real-world study provides evidence that even patients with residual isolated tumor cells can be safely spared from ALND. In general, few indications for ALND remain. Three randomized controlled trials are ongoing for patients with clinically node-positive BC in the upfront surgery setting and residual disease after NACT. Pending the results of these trials, ALND remains indicated in these patients.

Introduction

Axillary surgery for breast cancer (BC) has evolved significantly from a previous “one size fits all” approach that involved radical surgery, including lymph node dissection extending from the axilla to the neck, to an increasingly granular and individualized surgical treatment. Axillary lymph node dissection (ALND) was the standard of care for all patients with BC until the nineties, which was considered to be a therapeutic procedure. The rationale behind it was that a complete surgical removal of locoregional tumor residues would result in improved survival, a hypothesis that has never been proven and was already questioned by the NSABP-04 trial [1,2,3]. In this landmark study, patients with clinically node-negative and node-positive BC were shown to have similar 10-year overall survival outcomes, no matter whether ALND or axillary radiotherapy (ART) were performed [3]. These results could be confirmed in clinically node-negative patients, who underwent breast-conserving surgery (BCS) and adjuvant radiotherapy of the breast [4]. Therefore, radical surgery and its associated morbidity was increasingly questioned. Axillary staging information was still deemed necessary, leading to the development of the sentinel lymph node (SLN) biopsy (SLNB). Whilst showing a false-negative rate of around 10%, excellent oncologic outcomes were achieved [5,6,7,8]. Notably, SLNB dramatically reduced surgical morbidity and improved quality of life [5,9,10,11,12,13,14,15,16,17]. Nevertheless, approximately 5% of patients still experience surgery-related morbidity [9]. Therefore, studies to identify patients in whom surgical axillary staging can be altogether abandoned have been initiated.

Conclusions

Efforts to de-escalate axillary surgery in BC have led to major changes in treatment paradigms, sparing thousands of women the associated morbidity of ALND whilst remaining oncologically safe, as shown in randomized controlled trials with a high level of evidence. Few indications for ALND remain, with real-world studies being indicative of safe omission possibilities even if ITCs are found after NACT. Such studies generally have a lower level of evidence. However, they can address clinically relevant questions in a global manner, quickly, with the largest number of participants, and therefore the strongest statistical power available. For patients with clinically node-positive BC, the results of three randomized controlled trials—namely, the Alliance A011202 trial, the ADARNAT trial, and the OPBC-03/TAXIS trial—are eagerly awaited.

Abstract

One in eight women will develop breast cancer in the US. For women with moderate (15–20%) to average (12.5%) risk of breast cancer, there are few options available for risk reduction. For high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies are limited to evidence-based surgical removal of breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness in risk reduction, not many high-risk individuals opt for surgical or hormonal interventions due to severe side effects and potentially life-changing outcomes as key deterrents. Thus, better communication about the benefits of existing strategies and the development of new strategies with minimal side effects are needed to offer women adequate risk-reducing interventions. We extensively review and discuss innovative investigational strategies for primary prevention. Most of these investigational strategies are at the pre-clinical stage, but some are already being evaluated in clinical trials and others are expected to lead to first-in-human clinical trials within 5 years. Likely, these strategies would be initially tested in high-risk individuals but may be applicable to lower-risk women, if shown to decrease risk at a similar rate to existing strategies, but with minimal side effects.

Introduction

For women in the US, breast cancer (BC) is the most prevalent cancer and the second-leading cause of cancer-related deaths. Projections for 2023 estimate that 55,720 women will be diagnosed with carcinoma in situ, 297,790 with invasive carcinoma, and 43,170 women will die from BC [1]. With the number of new diagnoses still on the rise, one in eight women will develop BC within their lifetime, but all women are at risk. Therefore, there is a need to develop new strategies for primary prevention with a focus on high-risk (>20%) individuals, but that can also be applied to moderate- (15–20%) and average (12.5%)-risk individuals.

There are well-established risk factors that contribute to the absolute risk of developing BC [2,3]. There are modifiable risk factors such as having a healthy diet, regular exercise, and limiting alcohol consumption [2,4]. Cumulative exposure of breast tissue to estrogen is an important risk factor for BC. This risk can be minimized by various actions such as having their first-born before age 30, limiting the use of hormonal birth control medications, and avoiding hormone replacement therapy. Non-modifiable risk factors that increase cumulative exposure to estrogen include younger age at menarche and older age at natural menopause [2]. There are non-modifiable genetic risk factors that include known mutations in a high-penetrant BC gene such as BRCA1 and BRCA2, cumulative interaction of risk-associated alleles of BC susceptible SNPs, and/or family history with multiple incidences of BC [5]. There are also non-modifiable risk factors related to the personal history of radiation therapy to the chest, and the number of breast biopsies [4].

Conclusions and Future Directions

BC is the leading cause of new cancer cases and is the second leading cause of cancer-related deaths in women. The limited, approved prevention interventions available for high-risk individuals can have severe and long-term side effects that deter many women from making proactive choices. Regrettably, BC prevention is an area of translational research that is currently underfunded by federal agencies [182]. Therefore, emerging and novel approaches for the primary prevention of BC that provide the same or superior protection while minimizing the side effects of current interventions should be pursued and prioritized. These approaches seek to eradicate BC and align well with NIH’s All of US Research Program—a nationwide initiative for precision health interventions that proactively prevent rather than treat disease in high-risk individuals. We provide a comprehensive review of emerging approaches for BC prevention based on non-modifiable risk factors that put women at a higher risk of developing BC. Virtually all of these studies were performed in rodent models of BC, which have some limitations and challenges for direct translation to at-risk individuals. Additional scalability and validation studies in larger animal models will be an important step in bridging the gap between discovery and clinical evaluation. Although currently underutilized, rabbit studies should be considered as an appropriate intermediate model. Evolutionarily, anatomically, and physiologically, rabbit mammary glands are more similar to humans than those of rodent models or other large animals such as cows and sheep [183,184]. Female rabbits have four pairs of mammary glands each containing four ductal trees [177], which can be cannulated for ID injection [177,185,186,187,188,189] using a procedure very similar to ID administration of contrast agents in clinical ductography [190,191] and chemotherapeutic agents in first-in-human clinical research [92,145]. Alternatively, or complementary to validation studies in larger animals, judicious determination based on the scientific rigor and clinical feasibility of these emerging approaches should be applied to prioritize those interventions more likely to have an impact on primary prevention of BC.

Abstract

Breast cancer affected more than 2.3 million women in 2022 and is the most diagnosed cancer among women worldwide. The incidence rates are greater in developed regions and are significantly higher among women with higher education and socioeconomic status. Therefore, it is reasonable to assume that the way women live their lives may impact their risk of being diagnosed with breast cancer. This systematic review aimed to identify what is known about the causes and risk factors of breast cancer, excluding genetic causes. A comprehensive systematic search identified 2387 systematic reviews, 122 were included and six overall themes identified. In our “top list” with the 36 most important findings, a study of breast density had the highest effect size for increasing the risk of breast cancer, and a high sex-hormone-binding globulin level was the most protective factor. Many of the included studies investigating the same topics had conflicting results. The conclusion from this evidence synthesis reveals a lack of consensus of factors associated with the causes and risk of breast cancer. These findings suggest that recommendations about lifestyle and breast cancer should be made with caution.

Introduction

Breast cancer affected more than 2.3 million women in 2022 and is the most diagnosed cancer among women worldwide [1,2]. Breast cancer is also the number one cause of death from cancer in women; 670,000 women died from this disease in 2022 [2]. That is approximately 7% of all cancer deaths worldwide. The incidence rates are greater than 80 per 100,000 in developed regions of the world, such as Europe and North America, Australia, and New Zealand, and less than 40 per 100,000 in developing countries [3,4]. However, statistics from some developing countries may be attributed to underreporting [5]. The differences in incidence between countries could be due to changes in exposure to environmental risk factors, behavior, and lifestyle factors of different population groups [6]. These facts provide good reasons to study the causes and risk factors of breast cancer.

The causes of breast cancer in women are still unclear, and nonhereditary causes and risk factors predominate [7]. These include early menarche, hormone intake, nutrition, alcohol consumption, smoking, and obesity, all of which are commonly reported as risk factors [6]. Heredity accounts for only 5–10% of breast cancer cases, with germline mutations in BRCA1 or BRCA2 accounting for 30% of inheritable breast cancer cases [7]. Several researchers are working on the identification of specific genes as a cause of breast cancer, while others are conducting studies on the combinations of genes and other factors [8]. A study published in the Lancet in 2005 concluded that 21% of all breast cancer deaths worldwide were attributable to physical inactivity, overweight and obesity, and alcohol use [9]. An update from 2017 examined the connection between breast cancer incidence and environmental factors such as chemicals and radiation and found that exposure to these substances may lead to an increased risk of developing breast cancer [10]. However, numerous studies have identified late age of first full-term (if any) pregnancy, short periods of breast-feeding, dietary habits, quality and composition of meals, physiologic factors, lower age at menarche, and later menopause as causes and risk factors of breast cancer in women [11].

Conclusions

Six overall themes and more than 27 topics were identified. In our “top list” of the 36 most important findings, high breast density had the highest effect size for increasing the risk of breast cancer, and a high sex-hormone-binding globulin level was identified as the most protective factor in decreasing breast cancer risk. Notwithstanding the comprehensive work in performing these studies, there is still a large degree of uncertainty with respect to what exactly triggers or may influence or cause breast cancer. Unfortunately, this extensive work has not provided a clear and convincing answer as to why women develop breast cancer. Based on our review, however, it is important to point out this lack of consensus because the recommendations from some health authorities use several uncertain consensus statements to guide us to a healthy lifestyle. We therefore argue that this review of systematic reviews provides a valuable contribution to the research portfolio regarding breast cancer in women. We also argue that it highlights that health professionals should be careful because there still remains a great deal of uncertainty regarding the risk factors and causes of breast cancer in women.

Abstract

Hypertension is the key leading risk factor for death globally, affecting ∼1.3 billion adults, particularly in low- and middle-income countries. Most people living with hypertension have uncontrolled high blood pressure, increasing their likelihood of cardiovascular events. Significant issues preventing blood pressure control include lack of diagnosis, treatment, and response to existing therapy. For example, monotherapy and combination therapy are often unable to lower blood pressure to target levels. New therapies are urgently required to tackle this issue, particularly those that target the mechanisms behind hypertension instead of treating its symptoms. Acting via an increase in systemic and tissue-specific inflammation, the immune system is a critical contributor to blood pressure regulation and is considered an early mechanism leading to hypertension development. Here, we review the immune system’s role in hypertension, evaluate clinical trials that target inflammation, and discuss knowledge gaps in pre-clinical and clinical data. We examine the effects of anti-inflammatory drugs colchicine and methotrexate on hypertension and evaluate the blockade of pro-inflammatory cytokines IL-1β and TNF-α on blood pressure in clinical trials. Lastly, we highlight how we can move forward to target specific components of the immune system to lower blood pressure. This includes targeting isolevuglandins, which accumulate in dendritic cells to promote T cell activation and cytokine production in salt-induced hypertension. We discuss the potential of the dietary fibre-derived metabolites short-chain fatty acids, which have anti-inflammatory and blood pressure-lowering effects via the gut microbiome. This would limit adverse events, leading to improved medication adherence and better blood pressure control.

Targeting the immune system in hypertension through diet and gut microbiome

The gut microbiome (all microbes including bacteria, viruses, fungal, and their genes) (Berg et al., 2020) has emerged as a contributing factor to many health states and diseases (Vos et al., 2022), including hypertension (O’Donnell et al., 2023). The gastrointestinal tract not only harbours the largest collection of microbes compared to other sites in the human body, but also houses the largest compartment of immune cells (Mowat and Agace, 2014). It is, therefore, reasonable that the gut microbiome influences the immune system, and vice-versa (Zheng et al., 2020). These two compartments are separated only by a single layer of cells, primarily epithelial but also Goblet cells and other cell types, which actively produce substances such as mucus to maintain the barrier between the microbes and the host (Snelson et al., 2024). In addition to a physical and chemical barrier, both compartments affect the barrier by affecting tight junctions between the cells (Schreiber et al., 2024). Epithelial cells also express many different receptors to metabolites produced by the gut microbiota, some pro- and others anti-inflammatory (Didriksen et al., 2024; Ghosh et al., 2021; Kim, 2023). These gut microbiota-derived metabolites have been extensively studied in the past decade, but importantly, they influence many facets of physiology, including the immune system (Yang and Cong, 2021; Zheng et al., 2020). The absence of the gut microbiome results in impaired immune function, supporting the fact that the gut microbiome is required for the maturation and maintenance of the immune system (Fiebiger et al., 2016; Round and Mazmanian, 2009).

Conclusion

To effectively lower hypertension rates globally, new treatments are urgently required. Dampening immune system activation and inflammation in targeted patient groups may be an effective way to control BP. A greater understanding of how the immune system is triggered in different patient subgroups is required to facilitate a personalised medicine approach, which may be needed to determine which treatment would likely yield the best results.

Summary

     To eliminate tuberculosis globally, a new, effective, and affordable vaccine is urgently needed, particularly for use in adults and adolescents in low-income and middle-income countries. We have created a roadmap that lists the actions needed to accelerate tuberculosis vaccine research and development using a participatory process. The vaccine pipeline needs more diverse immunological approaches, antigens, and platforms. Clinical development can be accelerated by validated preclinical models, agreed laboratory correlates of protection, efficient trial designs, and validated endpoints. Determining the public health impact of new tuberculosis vaccines requires understanding of a country’s demand for a new tuberculosis vaccine, how to integrate vaccine implementation with ongoing tuberculosis prevention efforts, cost, and national and global demand to stimulate vaccine production. Investments in tuberculosis vaccine research and development need to be increased, with more diversity of funding sources and coordination between these funders. Open science is important to enhance the efficiency of tuberculosis vaccine research and development including early and freely available publication of study findings and effective mechanisms for sharing datasets and specimens. There is a need for increased engagement of industry vaccine developers, for increased political commitment for new tuberculosis vaccines, and to address stigma and vaccine hesitancy. The unprecedented speed by which COVID-19 vaccines have been developed and introduced provides important insight for tuberculosis vaccine research and development.

Introduction

     With an estimated 10 million new cases and 1·5 million deaths per year, tuberculosis is one of the most devastating infectious diseases worldwide.1 The global elimination of tuberculosis requires innovative interventions, including safe and more effective vaccines.2 The current vaccine, Bacille Calmette-Guérin (BCG), has low and inconsistent protective efficacy against pulmonary tuberculosis in adolescents and adults, who are the main source of transmission.3 WHO has set three goals for the development of new tuberculosis vaccines: a safe, effective, and affordable tuberculosis vaccine for adolescents and adults; an affordable tuberculosis vaccine for neonates and infants with improved safety and efficacy compared with BCG; and a therapeutic vaccine to improve tuberculosis treatment outcomes.4,  5,  6 A vaccine for adolescents and adults has the greatest potential to produce a rapid global health impact.7,  8

     The research and development of new tuberculosis vaccines has been slow, faced with scientific setbacks and poor funding.9,  10 Two phase 2b trials have shown protection signals against Mycobacterium tuberculosis infection for BCG revaccination and protection against tuberculosis disease for candidate M72/AS01E.11,  12,  13 With several tuberculosis vaccine candidates in the pipeline,14 there is an urgent need to prioritise resources to research and development efforts and for a common vision of the knowledge and evidence required to guarantee the impact of new tuberculosis vaccines at the population and patient levels.

Conclusion

     This research and development roadmap sets research priorities for the discovery, preclinical development, clinical development, preparation for introduction, and implementation of new tuberculosis vaccines. It brings together the views and visions of a broad range of stakeholders in the field that included researchers, end users, funders, regulators, and industry professionals. The overall call is for acceleration towards achieving health impact through new approaches in vaccine discovery, better validated animal models, more efficient clinical development, proactive mapping of postlicensure use and demand, and removing barriers to effective scale up. Tuberculosis vaccine research and development requires more funding and a more effective use of existing resources, open exchange of data, specimens, and results, and strong engagement with stakeholders at the political, commercial, public health, and community levels. The rapid development and deployment of COVID-19 vaccines provides several examples to build on. The next step is for the various actors to follow the roadmap.

Abstract

Background

     More than 130 million individuals in the United States have now received at least one dose of a COVID-19 vaccine. Currently, all adults in the Unites States now have access to one of three COVID-19 vaccines. As part of the vaccination procedure, Emergency Use Authorization (EUA) fact sheets, which contain information regarding the vaccine, are provided. The purpose of this study was to analyze the ease of reading (i.e., readability) of the EUA-approved fact sheets for the vaccines currently available in the United States, the V-Safe adverse event survey script, and the Centers for Disease Control and Prevention (CDC) website information on COVID-19 vaccines designed for the general public in the United States.

Methods

     We acquired the Pfizer, Moderna, and Janssen EUA fact sheets, as well as the V-Safe survey script and the CDC website information regarding COVID-19 vaccines. These documents were analyzed for their complexity regarding the following readability factors: average length of paragraphs, sentences, and words; font size and style; use of passive voice; the Gunning-Fog index; the Flesch Reading Ease index; and the Flesch-Kincaid Grade Level index.

Results

     Only the V-Safe adverse-event survey script met readability standards for adequate comprehension. The mean readability scores of the EUA fact sheets and the CDC website were as follows: Flesch Reading Ease score (44.35 avg); Flesch-Kincaid Grade Level (10.48 avg); and Gunning-Fog index (11.8 avg). These scores indicate that at least a 10th-grade level education would be required to understand these reading materials.

Conclusion

     The average person in the United States would have difficulty understanding the information provided in the EUA fact sheets and CDC COVID-19 vaccine website documents; however, the V-Safe survey was written at an adequate reading level. To ensure that the general public fully understands information regarding COVID-19 vaccines, greater care and effort should be given to the development of simplified information material.

Introduction

     The 2019 coronavirus disease (COVID-19) has resulted in a global pandemic and the subsequent development of vaccines. Vaccine recipients are encouraged to read several vaccine information documents before they receive a vaccine, including reviewing the Centers for Disease Control and Prevention (CDC) website on COVID-19 vaccines and the vaccine-specific emergency-use authorization (EUA) fact sheet for the Pfizer, Moderna, or Janssen vaccine they are receiving. Subjects are also encouraged to sign up for an adverse-event tracking survey called V-Safe after they receive their vaccination. In addition, the CDC website on COVID-19 and the EUA fact sheets contain basic vaccine information for the general public, including potential benefits, risks, side effects, and necessary precautions. The purpose of this study was to analyze the readability of the EUA fact sheets, the CDC website on COVID-19 vaccine questions, and the V-Safe adverse-event survey script for vaccines in the United States to determine if they meet the guidelines for adequate public readability.

Results

     We reviewed the COVID-19 vaccine fact sheets for the Pfizer, Moderna, and Janssen vaccines available under EUA in the US, the complete V-Safe adverse event survey script, and the CDC general public website on information about COVID-19 vaccines. No significant differences were detected in the Microsoft scoring metrics between the two independent study authors who analyzed readability.

     Document length ranged from 5 to 18 pages (8.25 avg). The number of words (including headers) ranged from 1,662 to 5,564 (3,086.8 avg). Average words per page ranged from 175.9 to 334.2 (294.8 avg), and average words per paragraph ranged from 7.0 to 25.1 (17.76 avg). Font size ranged from 11 to 16 points. All documents used sans serif fonts. The average word length ranged from 4.9 to 5.4 characters (5.18 avg). Average sentence length ranged from 9.8 to 18.7 words (14.4 avg). See Table 2.

Abstract

Background

     Strengthening leadership and management competencies among national Expanded Programme on Immunization (EPI) teams will be critical to achieving global immunization targets and other sustainable developmental goals. However, there is little empirical evidence of the effectiveness of investments in leadership and management capacity in the context of national EPI programs. Therefore, we sought to evaluate the EPI Leadership and Management Programme (EPI LAMP), a nine-month certificate program for EPI teams in national Ministries of Health from Gavi priority countries in Anglophone and Francophone Africa and Asia.

Methods

     We used a mixed-methods longitudinal evaluation to describe EPI LAMP at four levels: (1) participant response to the training experience based on program administration records and satisfaction surveys; (2) change in management and leadership skill based on competency surveys and exit interviews; (3) change in behavior in the workplace based on exit interviews; and (4) impact of the training on EPI program performance based on the results of each delegate’s leadership project.

Results

     In the first three cohorts, the programme engaged 16 countries (63 participants) and achieved an 86% graduation rate (54 alumni). Participants demonstrated significant improvement in management and leadership competencies across eight domains with the largest improvement observed in the domain of governance and leadership. Women showed greater increases than men, especially in the domains of Operations Management and Political Advocacy and Dialogue. We observed no difference in the gains made by French-speaking delegates compared to English-speaking participants. Breakthrough projects developed by each team improved EPI program performance, as measured by metrics specific to each project.

Discussion

     Our results show that team-based leadership programs can foster improvements in management practice, collaboration, and problem-solving, and that engagement the broader policy and organizational context is needed to foster the systems thinking capacity required to address complex challenges and improve system performance.

Introduction

     Immunization is one of the most cost-effective investments in global health [1], and reaching every child with immunization is the major strategic goal of Gavi, the Vaccine Alliance. Despite significant increase in vaccination coverage in low- and middle-income countries (LMICs), 14 million children were not reached by routine immunization in 2019 [2]. EPI programs must adapt and evolve to address complexities such as reaching zero- dose children, reaching children in conflict settings and other humanitarian crises, managing an increasingly complex portfolio of routine immunizations, overcoming weaknesses in primary health care systems, and, more recently, ensuring continuity of services in light of COVID-19. Strengthening leadership and management competencies [3], [4] among national EPI teams will be critical to achieving global immunization targets and other sustainable development goals [5], [6], [7].

     In response, Gavi has developed a small but strategic portfolio of investments in leadership and management to support EPI program performance. Drawing on literature from primary health systems strengthening more broadly, leadership and management is associated with better health systems performance in LMIC settings [8], and can be improved through practical approaches to education and mentorship for healthcare professionals at all levels of the health system [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. Leadership and management trainings conducted at the facility level have been linked with the reduction of wait times and patient crowdedness in hospitals in Egypt [13] and the increase in the number of women receiving counseling during antenatal care in Cameroon [14]. At the district level, a number of studies [8], [15], [16], [17], [18], [19] reported the impact of management and leadership training on primary care system performance. However, there is little empirical evidence of the effectiveness of investments in leadership and management capacity in the context of national EPI programs.

Conclusion

     Strengthening leadership and management competencies among national EPI teams will be critical to achieving global immunization targets and other sustainable developmental goals, and can be significantly improved through participation in a team-based program customized to meet the needs of immunization professionals across Gavi-eligible countries. Programs that foster development of a cross-country learning community, engage multiple levels of hierarchy, and equip teams to address complex adaptive challenges are likely to be superior to brief training programs focused on individual participants. The results of this study may be useful to educators, practitioners, and government officials seeking to strengthen EPI programme performance, as well as policymakers and global partners seeking to invest in evidence-based management and leadership development models.

Highlights

Abstract

Keywords

1. Introduction

2. Methods

3. Results

4. Discussion

5. Conclusion

Funding

Declaration of competing interest

References

Abstract

Background
Liver transplant (LT) is the second most common transplant intervention. The rate of acute cellular rejection (ACR) is 15–25% after LT, while being higher in chronic rejection (CR). Clinical trials had a major role in getting more potent and selective immunosuppressive medications. Our study plays an important role by evaluating and tracking clinical trials related to liver transplant rejection, focusing on interventional therapeutic trials.

Methods
On October 28, we searched Clinicaltrials.gov for interventional clinical trials related to liver transplant rejection. A total of 27 clinical trials included in this study. Characteristics on each trial were collected, and availability of linked publications was searched using Medline/PubMed and Embase/Scopus. Content of publications was reviewed and main findings were summarized.

Results
Majority of trials were completed (15 out of 27). Eleven trials had between 11 and 50 participants, and 10 had above 100. The study duration was between 1 and 4 years for the majority of trials (16 trials), with an average of 3.77 years. Most of the trials were done in Europe/UK/Russia (n = 12). The results were provided in 9 trials but published in 4, showing the possible tolerogenic efficacy of MSC in liver transplantation, increased success of immunosuppression (IS) withdrawal after sirolimus addition, efficacy of Alemtuzumab, normal graft function and stability within 1 year of immunosuppression withdrawal.

Conclusion
This study revealed a low number of trials, lack of variety in location and low publishing rates. The focus of trials was mainly towards side effects and safety of immunosuppressants, and their withdrawal. These trials reached results that must be built on to reach definitive guidelines and treatment strategies. This highlights the need for better management of human and financial resources, in order to reach new and more effective therapeutic strategies, leading to the decrease in rate of LTR.

Summary

Introduction

Results

Discussion

STAR Methods

Acknowledgments

REFERENCES

Summary

     The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. In this study, we show that T cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (∼21%) with a >50% reduction in T cell reactivity to the Omicron spike. Evaluation of functional CD4+ and CD8+ memory T cell responses confirmed these findings and revealed that reduced recognition to Omicron spike is primarily observed within the CD8+ T cell compartment potentially due to escape from HLA binding. Booster vaccination enhanced T cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T cell responses to the Omicron variant, although with reduced reactivity in some individuals.

Introduction

     The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529), first identified in November 2021, has been the cause of a new surge of infections globally (Viana et al., 2021). With as many as 36 substitutions in the viral spike protein and 59 mutations in total throughout its genome, Omicron has been found to evade neutralization by infection- and vaccine-induced antibodies with unprecedented frequency (Garcia-Beltran et al., 2021a; Hoffmann et al., 2021) and escape neutralization by most therapeutic monoclonal antibodies (Ikemura et al., 2021; VanBlargan et al., 2021). Additional booster vaccine doses partially compensate for this effect (Garcia-Beltran et al., 2022; Hoffmann et al., 2021), but the durability of such protective antibody response remains to be determined. Thus, whether additional arms of the adaptive immune response, namely T cell responses, can augment protection against Omicron infection and disease are of considerable interest and have implications for predicting the course of future SARS-CoV-2 variants.

     In individuals with previous SARS-CoV-2 infection and vaccinees, robust T cell responses are quantitatively and qualitatively associated with milder outcomes (Moderbacher et al., 2020). Early induction of antigen-specific CD4+ T cells following vaccination is associated with coordinated generation of antibody and CD8+ T cell responses (Painter et al., 2021). Previous studies have also shown a key role for CD8+ T cells in mitigating COVID-19 disease severity and inducing long-term immune protection. Mild COVID-19 disease is associated with increased clonal expansion of CD8+ T cells in bronchoalveloar lavage fluid (Liao et al., 2020), robust CD8+ T cell reactivity to SARS-CoV-2 epitopes (Peng et al., 2020; Sekine et al., 2020), and rapid CD8+ T cell-mediated viral clearance (Tan et al., 2021). In addition, depletion of CD8+ T cells from convalescent macaques reduced protective immunity (McMahan et al., 2021). Given that T cells can target regions across the SARS-CoV-2 proteome and are not limited solely to the spike protein, it is perhaps not unexpected that prior SARS-CoV-2 variants were able to escape neutralizing antibody responses (Garcia-Beltran et al., 2021a), but not T cells (Geers et al., 2021). Thus, in light of the emergence of the Omicron variant, we sought to determine the extent to which mutations in the variant spike and nonspike proteins affect CD4+ and CD8+ T cell reactivities.

Results

     To assess the cross-reactivity of T cell responses to the Omicron variant, we studied anti-SARS-CoV-2 T cell responses in 76 ambulatory adult volunteers in Chelsea, Massachusetts sampled prior to vaccination, after primary series vaccination, and/or after receipt of additional “booster” doses. Study groups were stratified by prior infection (confirmed by anti-nucleocapsid antibody testing) and vaccination status (Table S1). In total, we studied 101 samples from 76 donors (Figure 1A). The median age was 45 years (range 37–60 years), and 64% were female. Of the previously infected individuals, we included 11 unvaccinated, 12 vaccinated sampled after initial vaccination series, and 13 vaccinated and sampled after booster doses individuals. Among individuals without previous infection, we included 10 unvaccinated, 24 sampled after initial vaccination series, and 31 vaccinated and sampled after booster doses individuals. Samples were obtained at a median 220 (range 130–286) days after primary series vaccination or 10 days (range 8–54) after additional booster doses. The primary analysis of host, vaccine, and variant variables that affect T cell responses was by multivariate regression.