Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours.

Although more than a decade has passed since the approval of immune checkpoint inhibitors (ICIs) for the treatment of melanoma and non-small-cell lung, breast and gastrointestinal cancers, many patients still show limited response. US Food and Drug Administration (FDA)-approved biomarkers include programmed cell death 1 ligand 1 (PDL1) expression, microsatellite status (that is, microsatellite instability-high (MSI-H)) and tumour mutational burden (TMB), but these have limited utility and/or lack standardized testing approaches for pan-cancer applications. Tissue-based analytes (such as tumour gene signatures, tumour antigen presentation or tumour microenvironment profiles) show a correlation with immune response, but equally, these demonstrate limited efficacy, as they represent a single time point and a single spatial assessment. Patient heterogeneity as well as inter- and intra-tumoural differences across different tissue sites and time points represent substantial challenges for static biomarkers. However, dynamic biomarkers such as longitudinal biopsies or novel, less-invasive markers such as blood-based biomarkers, radiomics and the gut microbiome show increasing potential for the dynamic identification of ICI response, and patient-tailored predictors identified through neoadjuvant trials or novel ex vivo tumour models can help to personalize treatment. In this Perspective, we critically assess the multiple new static, dynamic and patient-specific biomarkers, highlight the newest consortia and trial efforts, and provide recommendations for future clinical trials to make meaningful steps forwards in the field.

Specific oncogene activation of the cell of origin in mucosal melanoma.

Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we developed a zebrafish model in which all melanocytes experienced CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only developed from melanocytes lining internal organs, analogous to the location of patient MM. We found that zebrafish MMs had a unique chromatin landscape from cutaneous melanoma. Internal melanocytes could be labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes shared a gene expression signature with MMs. Patient and zebrafish MMs have increased migratory neural crest gene and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests the cell state of the originating melanocyte influences the behavior of derived melanomas. Our animal model phenotypically and transcriptionally mimics patient tumors, allowing this model to be used for MM therapeutic discovery.

Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator.

PURPOSE: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients. METHODS: Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models). RESULTS: The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated. CONCLUSION: The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

The Impact of T-cell Aging on Alloimmunity and Inflammaging.

Aging affects immunity broadly through changes caused by immunosenescence, clinically resulting in augmented susceptibility to infections, autoimmunity, and cancer. The most striking alterations associated with immunosenescence have been observed in the T-cell compartment with a significant shift toward a terminally differentiated memory phenotype taking on features of innate immune cells. At the same time, cellular senescence impairs T-cell activation, proliferation, and effector functions, compromising the effectiveness of immunity. In clinical transplantation, T-cell immunosenescence has been the main driver of less frequent acute rejections in older transplant recipients. This patient population, at the same time, suffers more frequently from the side effects of immunosuppressive therapy including higher rates of infections, malignancies, and chronic allograft failure. T-cell senescence has also been identified as an instigator of age-specific organ dysfunction through a process that has been coined "inflammaging," accelerating organ injury and potentially contributing to the limited lifetime of organ transplants. Here, we provide a summary of the latest evidence on molecular characteristics of T-cell senescence affecting alloimmunity and organ quality while dissecting the consequences of unspecific organ injury and immunosuppression on T-cell senescence. Rather than conceptualizing immunosenescence as a broad and general "weaker" alloimmune response, it appears critical to understand both mechanisms and clinical effects in detail as a basis to refine treatment.

Factors Affecting Recurrence and Survival for Patients with High-Risk Stage II Melanoma.

BACKGROUND: In the current era of effective adjuvant therapies and de-escalation of surgery, distinguishing which patients with high-risk stage II melanoma are at increased risk of recurrence after excision of the primary lesion is essential to determining appropriate treatment and surveillance plans. METHODS: A single-center retrospective study analyzed patients with stage IIB or IIC melanoma. Demographic and tumor data were collected, and genomic analysis of formalin-fixed, paraffin-embedded tissue samples was performed via an internal next-generation sequencing (NGS) platform (SNaPshot). The end points examined were relapse-free survival (RFS), distant metastasis-free survival (DMFS), overall survival (OS), and melanoma-specific survival (MSS). Uni- and multivariable Cox regressions were performed to calculate the hazard ratios. RESULTS: The study included 92 patients with a median age of 69 years and a male/female ratio of 2:1. A Breslow depth greater than 4 mm, a higher mitotic rate, an advanced T stage, and a KIT mutation had a negative impact on RFS. A primary lesion in the head and neck, a mitotic rate exceeding 10 mitoses per mm2, a CDH1 mutation, or a KIT mutation was significantly associated with a shorter DMFS. Overall survival was significantly lower with older age at diagnosis and a higher mitotic rate. An older age at diagnosis also had a negative impact on MSS. CONCLUSION: Traditional histopathologic factors and specific tumor mutations displayed a significant correlation with disease recurrence and survival for patients with high-risk stage II melanoma. This study supported the use of genomic testing of high-risk stage II melanomas for prognostic prediction and risk stratification.

Prognostic biomarkers for survival in mucosal melanoma.

Mucosal melanoma (MM) is a rare subtype of melanoma with an aggressive clinical course. In cutaneous melanoma (CM), the absence of pigmentation and presence of NRAS/KRAS mutations are biomarkers indicating an aggressive clinical course with shorter overall survival. Similar data for MM are missing. We present the real-world outcome data in a cohort of genotyped MM patients and assessed the prognostic relevance of pigmentation- and NRAS/KRAS mutation status. We correlated pathological reports and clinical data with overall survival of patients with MM. Furthermore, we performed clinically integrated molecular genotyping and analyzed real world treatment regimens for covariates associated with clinical outcome. We identified 39 patients with available clinical and molecular data. Patients with amelanotic MM had a significantly shorter overall survival (p = .003). In addition, the presence of a NRAS or KRAS mutation was significantly associated with poor overall survival (NRAS or KRAS p = .024). Currently, it is unknown if the same prognostic relevance for the lack of pigmentation and RAS mutations in CM, exists in MM. Here we analyzed a cohort of MM for outcome measures and determined that two known prognostic biomarkers for CM are in fact novel prognosticators for MM.

Health worker education during the COVID-19 pandemic: global disruption, responses and lessons for the future-a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis identified early evidence quantifying the disruption to the education of health workers by the COVID-19 pandemic, ensuing policy responses and their outcomes. METHODS: Following a pre-registered protocol and PRISMA/AMSTAR-2 guidelines, we systematically screened MEDLINE, EMBASE, Web of Science, CENTRAL, clinicaltrials.gov and Google Scholar from January 2020 to July 2022. We pooled proportion estimates via random-effects meta-analyses and explored subgroup differences by gender, occupational group, training stage, WHO regions/continents, and study end-year. We assessed risk of bias (Newcastle-Ottawa scale for observational studies, RοB2 for randomized controlled trials [RCT]) and rated evidence certainty using GRADE. RESULTS: Of the 171 489 publications screened, 2 249 were eligible, incorporating 2 212 observational studies and 37 RCTs, representing feedback from 1 109 818 learners and 22 204 faculty. The sample mostly consisted of undergraduates, medical doctors, and studies from institutions in Asia. Perceived training disruption was estimated at 71.1% (95% confidence interval 67.9-74.2) and learner redeployment at 29.2% (25.3-33.2). About one in three learners screened positive for anxiety (32.3%, 28.5-36.2), depression (32.0%, 27.9-36.2), burnout (38.8%, 33.4-44.3) or insomnia (30.9%, 20.8-41.9). Policy responses included shifting to online learning, innovations in assessment, COVID-19-specific courses, volunteerism, and measures for learner safety. For outcomes of policy responses, most of the literature related to perceptions and preferences. More than two-thirds of learners (75.9%, 74.2-77.7) were satisfied with online learning (postgraduates more than undergraduates), while faculty satisfaction rate was slightly lower (71.8%, 66.7-76.7). Learners preferred an in-person component: blended learning 56.0% (51.2-60.7), face-to-face 48.8% (45.4-52.1), and online-only 32.0% (29.3-34.8). They supported continuation of the virtual format as part of a blended system (68.1%, 64.6-71.5). Subgroup differences provided valuable insights despite not resolving the considerable heterogeneity. All outcomes were assessed as very-low-certainty evidence. CONCLUSION: The COVID-19 pandemic has severely disrupted health worker education, inflicting a substantial mental health burden on learners. Its impacts on career choices, volunteerism, pedagogical approaches and mental health of learners have implications for educational design, measures to protect and support learners, faculty and health workers, and workforce planning. Online learning may achieve learner satisfaction as part of a short-term solution or integrated into a blended model in the post-pandemic future.

Teaching and Assessment of Medical Students During Complex Multifactorial Team-Based Tasks: The "Virtual on Call" Case Study.

Abstract: Although considerable efforts have been made to incorporate simulation-based learning (SBL) in undergraduate medical education, to date, most of the medical school curricula still focus on pure knowledge or individual assessment of objective structured clinical examination skills (OSCE). To this end, we designed a case study named "iG4 (integrated generation 4) virtual on-call (iVOC)". We aimed to simulate an on-call shift in a high-fidelity virtual hospital setting in order to assess delegates' team-based performance on tasks related to patient handovers (prioritisation, team allocation). Methods: A total of 41 clinical year medical students were split into 3 cohorts, each of which included 3 groups of 4 or 5 people. The groups consisted of a structured mix of educational and cultural backgrounds of students to achieve homogeneity. Each performing group received the handover for 5 patients in the virtual hospital and had to identify and deal with the acutely unwell ones within 15 minutes. We used TEAMTM tool to assess team-based performances. Results: The mean handover performance was 5.44/10 ± 2.24 which was the lowest across any performance marker. The overall global performance across any team was 6.64/10 ± 2.11. The first rotating team's global performance for each cycle was 6.44/10 ± 2.01, for the second 7.89/10 ± 2.09 and for the third 6.78/10 ± 1.64 (p = 0.099 between groups). Conclusion: This is one of the first reported, high-fidelity, globally reproducible SBL settings to assess the capacity of students to work as part of a multinational team, highlighting several aspects that need to be addressed during undergraduate studies. Medical schools should consider similar efforts with the aim to incorporate assessment frameworks for individual performances of students as part of a team, which can be a stepping-stone for enhancing safety in clinical practice.

Treatment of aortic arch rupture grade III with hybrid arch replacement: the key role of perfusion preservation.

Hybrid arch replacement is a well-accepted method for the treatment of lesions involving the aortic arch, though its benefits compared to classic surgical techniques remain controversial. Multiple surgical approaches have been analyzed in the literature for the treatment of such a challenging pathology. In this case report, we describe the surgical management of a 72-year-old man presenting with a complicated aortic arch rupture. The patient was treated urgently with a type I hybrid arch replacement in two stages, with total preservation of cerebral and systemic perfusion. Our case shows that hybrid arch methods are applicable even in emergency cases.

Postgraduate Assessment Approaches Across Surgical Specialties: A Systematic Review of the Published Evidence.

PURPOSE: Ensuring competence for surgical trainees requires holistic assessment of the qualities and competencies necessary to practice safely and effectively. To determine the next steps toward achieving this aim, the authors conducted a systematic review to summarize and appraise the available evidence related to any assessment approach to postgraduate surgical training and to identify the dominant themes for assessment approaches across different specialties or countries. METHOD: Medline and Embase were searched on January 10, 2019, without language or time restrictions. Any peer-reviewed study that described an assessment framework (in practice or novel) throughout postgraduate surgical training globally was included. An iterative review and thematic analysis were performed on full-text articles to determine assessment themes. Studies were then grouped by assessment themes. A tailored quality assessment of the studies included in the final analysis was conducted. Assessment themes and validity were compared across surgical specialties and countries. RESULTS: From an initial 7,059 articles, 91 studies (evaluating 6,563 surgical trainees) were included in the final analysis. Ten defined assessment themes were extracted. Ten studies (11.0%) were deemed low risk of bias based on the quality assessment tool used and thus were determined to be high quality. Minor differences in assessment themes were observed between specialties and countries. Assessment themes neglected by individual surgical specialties and assessment themes that need validated assessment tools were identified. CONCLUSIONS: This review highlights the low quality of evidence and fragmented efforts to develop and optimize surgical assessments. The minor differences observed demonstrate a common approach, globally and across specialties, related to surgical assessments. A paradigm shift in assessment approaches, which will require national and international collaboration, is required to optimize design and validation so that a comprehensive assessment of surgical competence can be implemented.

Pediatric surgery during the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has had a major impact on pediatric surgery. The infection is often asymptomatic and atypical in children, while overlapping presentations with other infectious diseases generate additional diagnostic challenges. The high probability of missed pediatric cases and the invasive nature of surgery generate great concern for widespread transmission in this setting. Current guidelines suggest that triage of cases should be made on a case-by-case basis by a multidisciplinary team of experts. Decision-making can be assisted by classifying cases as elective, urgent, or an emergency according to the risks of delaying their surgical management. A workflow diagram should ideally guide the management of all cases from admission to discharge. When surgery is necessary, all staff should use appropriate personal protective equipment, and high-risk practices, such as aerosol-generating tools or procedures, should be avoided if possible. Furthermore, carefully designed organizational protocols should be established to minimize transmission while ensuring the uninterrupted operation of pediatric surgery units. For example, surgical teams can be divided into small weekly rotating groups, and healthcare workers should be continuously monitored for COVID-19 symptoms. Additionally, team protocols in the operating room can optimize communication and improve adherence to personal protective equipment use. Isolated operating rooms, pediatric intensive care units, and surgical wards should be specifically designed for suspected or confirmed COVID-19 cases. Finally, transportation of patients should be minimal and follow designated short routes. All these measures can help mitigate the effects of the COVID-19 pandemic on pediatric surgery units.

Medical and Surgical Education Challenges and Innovations in the COVID-19 Era: A Systematic Review.

The aim of this systematic review was to identify the challenges imposed on medical and surgical education by the COVID-19 pandemic, and the proposed innovations enabling the continuation of medical student and resident training. A systematic review on the MEDLINE and EMBASE databases was performed on April 18th, 2020, and yielded 1288 articles. Sixty-one of the included manuscripts were synthesized in a qualitative description focused on two major axes, "challenges" and "innovative solutions", and two minor axes, "mental health" and "medical students in the frontlines". Shortage of personal protective equipment, suspension of clinical clerkships and observerships and reduction in elective surgical cases unavoidably affect medical and surgical education. Interesting solutions involving the use of virtual learning, videoconferencing, social media and telemedicine could effectively tackle the sudden cease in medical education. Furthermore, trainee's mental health should be safeguarded, and medical students can be involved in the COVID-19 clinical treatment if needed.

Student Views on a Novel Holistic Surgical Education Curriculum (iG4): A Multi-national Survey in a Changing Landscape.

AIM: Essential Skills in the Management of Surgical Cases (ESMSC Marathon Course™) Integrated Generation 4 (iG4) is the first reported multifaceted undergraduate surgical course aiming to provide holistic surgical teaching. In this prospective observational study, we explored students' views on the iG4 curriculum, and identified how it can potentially address modern challenges in surgical training. MATERIAL AND METHODS: Medical students were invited to apply to the course online and were screened against pre-defined criteria. A multi-national structured questionnaire incorporating five domains related to the course curriculum and our dedicated research network, was designed and distributed to participants after successful completion of the course. RESULTS: Forty-one students from European and Asian medical schools completed the course and filled in the survey. The median overall evaluation score of the course was 4.73 out of 5 (interquartile range=4.21-4.72) and all students found that iG4 served the vision of holistic surgical education. ESMSC had a positive motivational effect towards following a career in surgery (p=0.012) and 92.7% of students declared that it should be an essential part of a future medical school curriculum. There was no statistically significant difference (p>0.05) in results between participants of different countries of study, year of studies or age group. CONCLUSION: The ESMSC Marathon Course™ is perceived as a unique course model, with an established educational value and a positive motivational effect towards surgery. It might potentially be implemented in future medical school curricula as an essential element of undergraduate surgical education. The iG4 curriculum has opened a new exciting horizon of opportunities for advancing undergraduate holistic surgical education.

Retrospective qualitative study evaluating the application of IG4 curriculum: an adaptable concept for holistic surgical education.

OBJECTIVES: Faced with a costly and demanding learning curve of surgical skills acquisition, the growing necessity for improved surgical curricula has now become irrefutable. We took this opportunity to formulate a teaching framework with the capacity to provide holistic surgical education at the undergraduate level. SETTING: Data collection was conducted in all the relevant healthcare centres the participants worked in. Where this was not possible, interviews were held in quiet public places. PARTICIPANTS: We performed an in-depth retrospective evaluation of a proposed curriculum, through semi-structured interviews with 10 participants. A targeted sampling technique was employed in order to identify senior academics with specialist knowledge in surgical education. Recruitment was ceased on reaching data saturation after which thematic data analysis was performed using NVivo 11. RESULTS: Thematic analysis yielded a total of 4 main themes and 29 daughter nodes. Majority of study participants agreed that the current landscape of basic surgical education is deficient at multiple levels. While simulation cannot replace surgical skills acquisition taking place in operating rooms, it can be catalytic in the transition of students to postgraduate training. Our study concluded that a standardised format of surgical teaching is essential, and that the Integrated Generation 4 (IG4) framework provides an excellent starting point. CONCLUSIONS: Through expert opinion, IG4 has been validated for its capacity to effectively accommodate learning in a safer and more efficacious environment. Moreover, we support that through dissemination of IG4, we can instil a sense of motivation to students as well as develop robust data sets, which will be amenable to data analysis through the application of more sophisticated methodologies.