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Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants.
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COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , SARS-CoV-2 , Neoplasias Hematológicas/tratamiento farmacológicoRESUMEN
Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.
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Neoplasias Encefálicas , Melanoma , Humanos , Melanoma/patología , Mutación , Evolución Molecular , ADNRESUMEN
BACKGROUND: The improved survival rate for many cancers in high-income countries demands a coordinated multidisciplinary approach to survivorship care and service provision to ensure optimal patient outcomes and quality of life. This study assesses the feasibility of introducing a Women's Health Initiative cancer survivorship clinic in Ireland. METHODS: The trial https://spcare.bmj.com/content/9/2/209.short comprises an intervention and control arm. Two hundred participants will be recruited. Key eligibility (1) women with early-stage hormone receptor-positive breast or gynecologic cancer (cervix or endometrial), within 12 months of completion of primary curative therapy, and (2) access to the Internet. The complex intervention comprises a nurse-led clinic targeting symptom management through a trigger alert system, utilizing electronic patient-reported outcome (ePRO) assessments at baseline, and 2, 4, 6, 8, 10, and 12 months. It also includes input from a dietitian monitoring diet and nutritional status. The control group will receive their usual care pathway standard of care and attend the cancer survivorship clinic and complete ePRO assessments at the start and end of the study. The primary endpoint (feasibility) includes the proportion of enrolled participants who complete baseline and follow-up ePRO surveys and partake in health professional consultations after ePRO data triggers. Secondary endpoints include changes in cancer-related symptom scores assessed by ePROs, health-related Quality of Life Questionnaire (QLQ) scores, Appraisal Self-Care Agency-R scores, and adjuvant endocrine therapy medication adherence. A process evaluation will capture the experiences of participation in the study, and the healthcare costs will be examined as part of the economic analysis. Ethical approval was granted in December 2020, with accrual commencing in March 2021. DISCUSSION: This protocol describes the implementation of a parallel arm randomized controlled trial (RCT) which examines the feasibility of delivering a Cancer Survivorship Clinic. The ePRO is an innovative symptom monitoring system which detects the treatment-related effects and provides individualized support for cancer survivors. The findings will provide direction for the implementation of future survivorship care. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05035173 . Retrospectively registered on September 5, 2021.
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Importance: In order to equitably improve the residency application process, it is essential to understand the problems we need to address. Objective: To determine how obstetrics and gynecology (OBGYN) applicants and faculty communicate applicants' interest to residency programs, and how program directors report being influenced by these communications. Design, Setting, and Participants: This survey study was conducted with email surveys of OBGYN application stakeholders in 2022. Included participants were OBGYN applicants, clerkship directors, and residency program directors in medical education associations' email listservs. Exposures: Surveys sent by the American Association of Medical Colleges, Association of Professors of Gynecology and Obstetrics, and Council on Resident Education in Obstetrics and Gynecology. Main Outcomes and Measures: Whether applicants themselves, or faculty on their behalf, communicated to residency programs, and the influence program directors reported placing on these communications for their decision-making. Descriptive statistics and χ2 tests were used to analyze differences. Results: A total 726 of 2781 applicants (26.1%) responded to the survey and were included in analysis (79 of 249 [31.7%] clerkship directors; 200 of 280 [71.4%] program directors). The self-reported racial and ethnic demographics of the 726 applicant respondents were 86 Asian (11.8%), 54 Black (7.4%), 41 Latinx (5.6%), 1 Native Hawaiian or Pacific Islander (0.1%), 369 White (52.2%), 45 with multiple racial identities (6.2%), and 91 (21.5%) preferring not to answer. The majority of applicants (590 [82.9%]) sent communications at some point in the application process. Applicants who identified as White (336 [88.7%]) or Asian (75 [87.2%]) were more likely than those who identified as Black (40 [74.1%]) or Latinx (33 [80.5%]) to reach out to programs (P = .02). There were also differences in type of medical school, with 377 of 427 MD applicants (88.3%), 109 of 125 DO applicants (87.2%), and 67 of 87 International Medical Graduate applicants (77.7%) reporting sending communications (P = .02). Approximately one-third (254 applicants [35.7%]) had faculty reach out to programs on their behalf. White (152 [40.1%]) and Asian (37 [43.0%]) applicants were more likely to have faculty reach out compared with Black (6 [11.1%]) and Latinx (12 [29.3%]) applicants (P = .01). Program directors reported that preinterview communications from faculty they knew (64 [32.2%]) and other program directors (25 [12.6%]) strongly influenced their decisions, and otherwise rarely reported that communications strongly influenced their decisions. Conclusions and Relevance: The current state of communications may increase inequities in residency application processes; differences between faculty communications for applicants from different racial and ethnic backgrounds are particularly concerning given that program directors are more likely to weigh communications from faculty in their decision-making. A centralized, equitable means for applicants to signal their interest to programs is urgently needed.
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Ginecología , Internado y Residencia , Obstetricia , Humanos , Obstetricia/educación , Comunicación , Encuestas y CuestionariosRESUMEN
Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.
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Vacunas contra la COVID-19 , COVID-19 , Neoplasias , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , Estudios Clínicos como Asunto , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Inmunidad , SARS-CoV-2RESUMEN
BACKGROUND: Little is known about the efficacy of pregnancy screening tools using non-sensitive sociodemographic questions to identify the possible presence of as yet undiagnosed disease in individuals and later adverse childhood events disclosure. OBJECTIVES: The study aims were to: 1) record the prevalence of risk disclosed by families during receipt of a sustained nurse home visiting program; and 2) explore patterns of relationships between the disclosed risks for their child having adverse experiences and the antenatal screening tool, which used non-sensitive demographic questions. DESIGN: Retrospective, observational study. PARTICIPANTS AND METHODS: Data about the participants in the intervention arm of the Australian right@home trial, which is scaffolded on the Maternal Early Childhood Sustained Home-visiting model, collected between 2013 and 2017 were used. Screening data from the 10-item antenatal survey of non-sensitive demographic risk factors and disclosed risks recorded by the nurse in audited case files during the subsequent 2 year intervention were examined (n = 348). Prevalence of disclosed risks for their child having adverse experiences were analysed in 2019 using multiple response frequencies. Phi correlations were conducted to test associations between screening factors and disclosed risks. RESULTS: Among the 348 intervention participants whose files were audited, 300 were noted by nurses to have disclosed risks during the intervention, with an average of four disclosures. The most prevalent maternal disclosures were depression or anxiety (57.8%). Mental health issues were the most prevalent partner and family disclosures. Screening tool questions on maternal smoking in pregnancy, not living with another adult, poverty and self-reporting anxious mood were significantly associated with a number of disclosed risks for their child having adverse experiences. CONCLUSIONS: These findings suggest that a non-sensitive sociodemographic screening tool may help to identify families at higher risk for adverse childhood experiences for whom support from a sustained nurse home visiting program may be beneficial.
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Experiencias Adversas de la Infancia , Adulto , Australia/epidemiología , Niño , Preescolar , Femenino , Visita Domiciliaria , Humanos , Atención Posnatal , Embarazo , Estudios RetrospectivosAsunto(s)
Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/biosíntesis , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Neoplasias Hematológicas/inmunología , Inmunización Secundaria , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/complicaciones , COVID-19/epidemiología , Neoplasias Hematológicas/complicaciones , Humanos , Inmunogenicidad Vacunal , Neoplasias/complicaciones , Neoplasias/inmunología , Evaluación de SíntomasRESUMEN
Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.
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Neoplasias , Evolución Clonal , HumanosRESUMEN
CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wildtype (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic.
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Inmunidad Adaptativa/inmunología , Anticuerpos Neutralizantes/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Carcinoma de Células Renales/complicaciones , Neoplasias Renales/complicaciones , SARS-CoV-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Vacuna BNT162/administración & dosificación , Vacuna BNT162/inmunología , COVID-19/complicaciones , COVID-19/epidemiología , Vacunas contra la COVID-19/administración & dosificación , ChAdOx1 nCoV-19/administración & dosificación , ChAdOx1 nCoV-19/inmunología , Femenino , Humanos , Inmunogenicidad Vacunal/inmunología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pandemias/prevención & control , Estudios Prospectivos , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Linfocitos T/inmunología , Linfocitos T/virología , Vacunación/métodosRESUMEN
ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.
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Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Nivolumab/administración & dosificación , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T CD8-positivos , Carcinoma de Células Renales/genética , Ensayos Clínicos Fase II como Asunto , Retrovirus Endógenos/genética , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Renales/genética , Nivolumab/farmacología , Estudios Prospectivos , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Escape del Tumor , Microambiente Tumoral , Secuenciación del ExomaRESUMEN
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer.
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Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.
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Vacunas contra la COVID-19/efectos adversos , Neoplasias Colorrectales/metabolismo , Síndrome de Liberación de Citoquinas , COVID-19/metabolismo , COVID-19/prevención & control , Humanos , Masculino , SARS-CoV-2/aislamiento & purificaciónRESUMEN
The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
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Variaciones en el Número de Copia de ADN , Neoplasias , Evolución Molecular , Genómica , Humanos , MutaciónRESUMEN
We summarize how practicing dietitians combined available evidence with clinical experience, to define revised dietary recommendations for phosphorus in chronic kidney disease G3-5D. As well as a review of the evidence base, 4 priority topics were reviewed. These were translated into 3 nutrient level recommendations: the introduction of some plant protein where phosphorus is largely bound by phytate; consideration of protein intake in terms of phosphorus load and the phosphorus to protein ratio; and an increased focus on avoiding phosphate additives. This review summarizes and interprets the available evidence in order to support the development of practical food-based advice for patients with chronic kidney disease.
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Fallo Renal Crónico , Fósforo Dietético , Insuficiencia Renal Crónica , Humanos , Fosfatos , FósforoRESUMEN
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.
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Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/inmunología , Neoplasias/complicaciones , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/inmunología , Estudios Prospectivos , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto JovenRESUMEN
Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.