Cancer, COVID-19, and Antiviral Immunity: The CAPTURE Study.

The SARS-CoV-2 pandemic has posed a significant challenge for risk evaluation and mitigation among cancer patients. Susceptibility to and severity of COVID-19 in cancer patients has not been studied in a prospective and broadly applicable manner. CAPTURE is a pan-cancer, longitudinal immune profiling study designed to address this knowledge gap.

Translation of Nutrient Level Recommendations to Control Serum Phosphate Into Food-Based Advice.

The control of hyperphosphatemia is key to the management of chronic kidney disease mineral and bone disorder. Dietary restriction of phosphorus is essential to control hyperphosphatemia. Guidelines for chronic kidney disease and end-stage kidney disease generally provide high-level guidance on whether a nutrient should be restricted e.g, restrict dietary phosphorus. Dietitians translate such guidance into nutrient-based strategies and finally into food-based practical dietary advice for patients to follow. The practical aspects of dietary advice are not well described in the literature, neither are the challenges of concurrently altering 1 nutrient e.g., phosphorus while continuing to restrict others e.g., potassium, while maintaining overall nutritional adequacy and quality of life. In this article, we describe how we translated updated nutrient level recommendations into practical dietary advice to be delivered at the bedside.

Revising Dietary Phosphorus Advice in Chronic Kidney Disease G3-5D.

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.

The Effect of Short-Term Vitamin D Supplementation on Calcium Status in Vitamin D Insufficient Renal Transplant Recipients at Risk of Hypercalcemia.

OBJECTIVE: Vitamin D insufficiency is highly prevalent among renal transplant recipients and in observational studies is associated with adverse outcomes. Hypercalcemia, usually due to persistent hyperparathyroidism, also commonly occurs in this population and often coexists with vitamin D insufficiency. However, concern that vitamin D supplementation might exacerbate the pre-existing hypercalcemia often leads clinicians to avoid vitamin D supplementation in such patients. This feasibility study aimed to quantify the effect on serum calcium of short-term low-dose cholecalciferol supplementation in a group of renal transplant recipients with a recent history of serum calcium levels >10 mg/dL. DESIGN: A 2-week, single arm, open-label trial. SETTING: Renal transplant follow-up clinic in an Irish University Hospital. SUBJECTS: Eighteen vitamin D-insufficient adult patients with a functioning renal allograft (estimated glomerular filtration rate > 30 mL/minute/1.73 m2) and a recent history of serum calcium >10 mg/dL. INTERVENTION: Two weeks of treatment with 1,000 IU cholecalciferol/day. MAIN OUTCOME MEASURE: Change in ionized calcium and urine calcium:creatinine ratio at follow-up compared with baseline. RESULTS: Mean (standard deviation [SD]) baseline 25 (OH) vitamin D (25 (OH) D) concentration was 15.9 (5.97) ng/mL and mean (SD) baseline serum calcium was 10.50 (0.6) mg/dL. Following the 2-week intervention, median (interquartile range [IQR]) change in serum calcium from baseline was -0.08 (-3.6 to 0.08) mg/dL, P = .3. Mean (SD) ionized calcium decreased from 5.24 (0.32) mg/dL at baseline to 5.16 (0.28) mg/dL, P = .05. Median (IQR) change in the urinary calcium:creatinine ratio was 0.001 (-0.026 to 0.299) mg/mg, P = .88. Median (IQR) change in 25 (OH) D was 3.6 (2.9-6.2) ng/mL, P < .05. CONCLUSIONS: In vitamin D-insufficient renal transplant recipients at risk of hypercalcemia, low-dose short-term oral cholecalciferol supplementation improves 25 (OH) D concentrations without exacerbating hypercalcemia or increasing the urinary calcium:creatinine ratio.

Structured social relationships: a review of volunteer home visiting programs for parents of young children.

Objective The aims of the present paper were to: (1) review the research literature that contributes to an understanding of the role of volunteer home visiting programs in supporting the health and well being of families with young children; and (2) propose a conceptual model outlining service pathways for families in need of additional support. Methods An integrative literature review method was used, with a mix of electronic and manual search methods for the period January 1980-January 2014. Forty-five studies were identified that met the inclusion criteria for review and were coded according to themes developed a priori. Results There is little formal research that has examined the effectiveness of volunteer home visiting programs for supporting family health and well being. The available research suggests that volunteer home visiting programs provide socioemotional support through structured social relationships; however, there is limited empirical evidence to explicate the factors that contribute to these outcomes. Conclusion In recognition of the importance of peer support for new parents, the not-for-profit sector has been involved in providing volunteer home visiting services to families for decades. However, the body of research to support this work is characterised by methodological limitations, and rigorous evidence is limited. What is clear anecdotally and qualitatively from the existing research is that parents who are in need of additional support value engagement with a community volunteer. These structured social relationships appear to fulfil a service need within the community, helping build bridges to support social networks, and thus complementing professional services and relationships. Overall, structured social relationships in the form of volunteer home visiting programs appear to provide an important pathway to support family health and well being. Findings from the existing research are mixed and often characterised by methodological limitations, pointing to a need for further rigorous research. What is known about the topic? Volunteer family support programs have been an important part of the service landscape for vulnerable families, both nationally and internationally, for many years. Anecdotal reports suggest that this is a valued form of support that increases a sense of community connectedness and breaks down barriers for families in accessing other community support services. What does this paper add? This paper proposes a model identifying broad service pathways impacting on family health and well being that takes into account the importance of structured social relationships and social connectedness. What are the implications for practitioners? The proposed model may encourage discussion by practitioners and organisations interested in models of support for families who are socially isolated and/or in need of assistance to access and engage with services within the community.

Sotrovimab restores neutralization against current Omicron subvariants in patients with blood cancer.

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.

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.

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.

Length-dependent retention of carbon nanotubes in the pleural space of mice initiates sustained inflammation and progressive fibrosis on the parietal pleura.

The fibrous shape of carbon nanotubes (CNTs) raises concern that they may pose an asbestos-like inhalation hazard, leading to the development of diseases, especially mesothelioma. Direct instillation of long and short CNTs into the pleural cavity, the site of mesothelioma development, produced asbestos-like length-dependent responses. The response to long CNTs and long asbestos was characterized by acute inflammation, leading to progressive fibrosis on the parietal pleura, where stomata of strictly defined size limit the egress of long, but not short, fibers. This was confirmed by demonstrating clearance of short, but not long, CNT and nickel nanowires and by visualizing the migration of short CNTs from the pleural space by single-photon emission computed tomographic imaging. Our data confirm the hypothesis that, although a proportion of all deposited particles passes through the pleura, the pathogenicity of long CNTs and other fibers arises as a result of length-dependent retention at the stomata on the parietal pleura.

Magnetic stabilization and vorticity in submillimeter paramagnetic liquid tubes.

It is possible to suppress convection and dispersion of a paramagnetic liquid by means of a magnetic field. A tube of paramagnetic liquid can be stabilized in water along a ferromagnetic track in a vertical magnetic field, but not in a horizontal field. Conversely, an "antitube" of water can be stabilized in a paramagnetic liquid along the same track in a transverse horizontal field, but not in a vertical field. The stability arises from the interaction of the induced moment in the solution with the magnetic field gradient in the vicinity of the track. The magnetic force causes the tube of paramagnetic liquid to behave as if it were encased by an elastic membrane whose cross-section is modified by gravitational forces and Maxwell stress. Convection from the tube to its surroundings is inhibited, but not diffusion. Liquid motion within the paramagnetic tube, however, exhibits vorticity in tubes of diameter 1 mm or less--conditions where classical pipe flow would be perfectly streamline, and mixing extremely slow. The liquid tube is found to slide along the track almost without friction. Paramagnetic liquid tubes and antitubes offer appealing new prospects for mass transport, microfluidics, and electrodeposition.

Identification of families in need of support: Correlates of adverse childhood experiences in the right@home sustained nurse home visiting program.

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.

Current Communication Practices Between Obstetrics and Gynecology Residency Applicants and Program Directors.

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.

The Women's Health Initiative cancer survivorship clinic incorporating electronic patient-reported outcomes: a study protocol for the Linking You to Support and Advice (LYSA) randomized controlled trial.

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.

Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study.

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.

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer.

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.

The effect of dietary phosphorus load and food matrix on postprandial serum phosphate in hemodialysis patients: a pilot study.

Background: Potential dietary strategies for controlling hyperphosphataemia include the use of protein sources with lower phosphorus bioavailability such as pulses and nuts, focus on phosphorus to protein ratios and the avoidance of all phosphate additives. Methods: We conducted a controlled crossover feeding study in 8 haemodialysis (HD) patients to investigate the acute postprandial effect of a modified versus standard low phosphorus diet for one day on serum phosphate, potassium and intact parathyroid levels in prevalent HD patients. Each participant consumed the modified diet on one day and the standard diet on a second day one week apart. The modified diet included beef and less dairy, with a lower phosphorus to protein ratio, as well as plant-based protein, whole grains, pulses and nuts containing phytates which reduces phosphorus bioavailability. Both diets were tailored for each participant to provide 1.1g protein/kg ideal body weight. Participants provided fasting bloods before breakfast, a pre-prandial sample before the lunch time main meal and samples at one-hour intervals for the four hours after the lunch time main meal, for analysis of phosphate, potassium and intact parathyroid hormone (iPTH). Results: At four hours post the lunch time main meal on each study day, individuals on the modified diet had serum phosphate readings 0.30 mmol/l lower than when on the standard diet (p-value = 0.015, 95% confidence interval [CI] -0.57, -0.04). The corresponding change in serum potassium at four hours was a decrease of 0.675 mmol/l (p-value = 0.011, CI -1.25, -0.10). Conclusions: Decreases in both serum phosphate and serum potassium readings on a modified low phosphorus diet encourage further larger studies to explore the possibility of greater food choice and healthier plant-based diets in HD patients.  ClinicalTrials.gov registration: NCT04845724 (15/04/2021).

Selection of metastasis competent subclones in the tumour interior.

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.

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2.

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.

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

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.

Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: The CAPTURE study.

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.