Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity.

Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10-19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR-expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window.

Pediatric Dermatology for People of Color.

When evaluating pediatric patients of color, it is essential to consider the unique diagnostic and treatment factors that apply to this population. Certain dermatologic conditions are more common in these patients, including postinflammatory hyperpigmentation, pityriasis alba, progressive macular hypomelanosis, tinea capitis, traction alopecia, keloids, hypertrophic scars, pseudofolliculitis barbae, acne keloidalis nuchae, and hidradenitis suppurativa. Furthermore, conditions such as vitiligo are more noticeable in people of color. This can lead to a significantly diminished quality of life, so these conditions should be quickly recognized and treated. Notably, inflammation can be difficult to recognize on the skin of people of color, which can lead to the underestimation of severity as well as inappropriate treatment. Treatment recommendations can also differ based on lifestyle or cultural norms, such as the use of tinted sunscreens and the consideration of hair care practices. Pediatricians should be aware of these conditions and treatment considerations to best treat pediatric patients of color. [Pediatr Ann. 2024;53(4):e146-e151.].

Digital filtering of ghost signal in phase measuring deflectometry.

We introduce a method of geometric screen modification to remove ghost reflections commonly observed in deflectometry optical testing. The proposed method modifies the optical layout and illumination source area to bypass the generation of reflected rays from the undesired surface. The layout flexibility of deflectometry allows us to design specific system layouts that avoid the generation of interrupting secondary rays. The proposed method is supported by optical raytrace simulations, and experimental results are demonstrated with convex and concave lens case studies. Finally, the limitations of the digital masking method are discussed.

Apolipoprotein A1 Protects Against Necrotic Core Development in Atherosclerotic Plaques: PDZK1-Dependent High-Density Lipoprotein Suppression of Necroptosis in Macrophages.

BACKGROUND: Atherosclerosis is a chronic disease affecting artery wall and a major contributor to cardiovascular diseases. Large necrotic cores increase risk of plaque rupture leading to thrombus formation. Necrotic cores are rich in debris from dead macrophages. Programmed necrosis (necroptosis) contributes to necrotic core formation. HDL (high-density lipoprotein) exerts direct atheroprotective effects on different cells within atherosclerotic plaques. Some of these depend on the SR-B1 (scavenger receptor class B type I) and the adapter protein PDZK1 (postsynaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1). However, a role for HDL in protecting against necroptosis and necrotic core formation in atherosclerosis is not completely understood. METHODS: Low-density lipoprotein receptor-deficient mice engineered to express different amounts of ApoA1 (apolipoprotein A1), or to lack PDZK1 were fed a high fat diet for 10 weeks. Atherosclerotic plaque areas, necrotic cores, and key necroptosis mediators, RIPK3 (receptor interacting protein kinase 3), and MLKL (mixed lineage kinase domain-like protein) were characterized. Cultured macrophages were treated with HDL to determine its effects, as well as the roles of SR-B1, PDZK1, and the PI3K (phosphoinositide 3-kinase) signaling pathway on necroptotic cell death. RESULTS: Genetic overexpression reduced, and ApoA1 knockout increased necrotic core formation and RIPK3 and MLKL within atherosclerotic plaques. Macrophages were protected against necroptosis by HDL and this protection required SR-B1, PDZK1, and PI3K/Akt pathway. PDZK1 knockout increased atherosclerosis in LDLRKO mice, increasing necrotic cores and phospho-MLKL; both of which were reversed by restoring PDZK1 in BM-derived cells. CONCLUSIONS: Our findings demonstrate that HDL in vitro and ApoA1, in vivo, protect against necroptosis in macrophages and necrotic core formation in atherosclerosis, suggesting a pathway that could be a target for the treatment of atherosclerosis.

Modeling and characterization of OASIS inflatable primary antenna by dual modality metrology.

OASIS (Orbiting Astronomical Satellite for Investigating Stellar Systems) is a space-based observatory with a 14 m diameter inflatable primary antenna that will perform high spectral resolution observations at terahertz frequencies. The large inflatable aperture, non-traditional surface configuration, and the double layered membrane structure afford unique challenges to the modeling and testing of the primary antenna. A 1-meter prototype of the primary antenna (A1) was built to validate our technical approach. A laser radar coordinate measuring system was adopted to measure the shape of A1. In addition, deflectometry was performed to monitor the stability of A1 during the radar measurement. Test cases pertaining to specific operational conditions expected for the 14 m OASIS primary were explored. The measured data were then compared to the Fichter model and Finite-element Analyzer for Inflatable Membranes (FAIM).

Neurological adverse effects associated with anti-PD1 antibodies alone or in combination with ipilimumab: a multicenter case series.

Anti-programmed cell death protein 1 (PD1) antibodies, pembrolizumab and nivolumab, alone or in combination with ipilimumab, have become standard treatment for melanoma and multiple other malignancies. Neurological adverse effects are rare and have not been well characterized to date. Patients who developed neurological adverse effects while being treated with PD1, alone or in combination with ipilimumab, were retrospectively identified from 10 cancer centers. Fifty-eight patients were included, and the median time from treatment initiation to development of neurological adverse effects was 7 weeks (range, 1-86.5 weeks). Thirty-seven (64%) toxicities affected the peripheral nervous system. Fifty (86%) patients were treated with corticosteroids, with 22 (37%) patients requiring further immunomodulation including intravenous immunoglobulin (16), plasmapheresis (7), mycophenolate mofetil (4), cyclophosphamide (1), and rituximab (1). Twenty-seven (46%) had a complete resolution of their neurological symptoms, and two (4%) patients died secondary to complications from their neurological adverse effects. The response rate of the cancer to immunotherapy was 78%, and the median progression free survival was not reached. Neurological adverse effects can occur with PD1 treatment, do not appear to impact treatment response, but may be irreversible or worsen in some patients. Management may require immunomodulation beyond corticosteroids.

Non-planar illumination deflectometry for axicon metrology.

We introduce an on-axis deflectometry test configuration for axicon metrology. Axicons are challenging to measure due to their characteristically steep, convex geometry. However, if an axicon is coaxially aligned with a camera and a surrounding cylindrical illumination source, high-resolution surface measurements can be obtained via the principle of deflectometry. Emitted from the temporally modulated source, light deflects at the conical surface and into the entrance pupil of a camera, illuminating the full axicon aperture except the ø 0.5-mm rounded tip. Deflectometry measurements of a 100° and 140° axicon show holistic cone angle agreement within 0.035° against touch probe data and up to 7.93 root µm mean square difference from a best-fit cone. We discuss the non-planar illumination architecture, sensitivity, and experimental results of arbitrary apex angle axicons.

Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.

BACKGROUND: Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. OBJECTIVES: To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. METHODS: Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. RESULTS: In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. CONCLUSIONS: Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.

Stage-Specific Generation of Human Pluripotent Stem Cell Derived Lung Models to Measure CFTR Function.

Human embryonic stem cells (ES) and induced pluripotent stem cells (iPSC) are powerful tools that have the potential to generate in vitro human lung epithelial cells. However, challenges in efficiency and reproducibility remain in utilizing the cells for therapy discovery platforms. Here, we optimize our previously published protocols to efficiently generate three developmental stages of the lung model (fetal lung epithelial progenitors, fLEP; immature airway epithelial spheroid, AES; air-liquid interface culture, ALI), and demonstrate its potential for cystic fibrosis (CF) drug discovery platforms. The stepwise approach directs differentiation from hPSC to definitive endoderm, anterior ventral foregut endoderm, and fetal lung progenitor cells. The article also describes the generation of immature airway epithelial spheroids in Matrigel with epithelial cells sorted by a magnetic-activated cell sorting system, and the generation of adult-like airway epithelia through air-liquid interface conditions. We demonstrate that this optimized procedure generates remarkably higher cystic fibrosis transmembrane conductance regulator (CFTR) expression and function than our previous method, and thus is uniquely suitable for CF research applications. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: hESC/hiPSC differentiation to fetal lung progenitors Basic Protocol 2: Formation of airway epithelial spheroids Alternate Protocol 1: Cryopreservation of airway epithelial spheroids Basic Protocol 3: Differentiation and maturation in air-liquid interface culture Alternate Protocol 2: Differentiation and maturation of epithelial progenitors from airway epithelial spheroids in ALI culture.

Occupational performance issues in older adults with subjective cognitive decline.

PURPOSE: To describe and categorize difficulties in daily activities of older adults with subjective cognitive decline (SCD) compared to individuals with mild cognitive impairment (MCI). METHODS: Deductive quantitative content analysis was used to classify reported issues in the performance of meaningful daily activities, in older adults with SCD (n = 67; age= 70 ± 6.3) or MCI (n = 42; age= 72 ± 6.6). The occupational performance issues were identified using the Canadian Occupational Performance Measure, a semi-structured interview, and categorised using the International Classification of Functioning, Disability and Health (ICF). RESULTS: Both groups identified issues in all nine ICF "Activities and Participation" domains, with no significant group effects on seven of them. The most frequently affected "Activities and Participation" domains in both groups were "Self-care" (e.g. exercise and diet); "Community, social and civic life" (e.g. social-leisure activities); and "General tasks and demands" (e.g. time management). Over 90% of the issues in both groups were described in the context of difficulties in "Mental functions" (e.g. memory and higher-level cognitive functions). CONCLUSIONS: Older adults with SCD, although independent, identified a variety of daily activities that they are not performing satisfactorily, remarkably similar in nature to the occupational performance issues described by older adults with MCI.Implications for RehabilitationOlder adults with SCD identified difficulties in performing social and leisure activities, maintaining healthy lifestyle behaviours, and managing multiple daily tasks.The daily challenges described by older adults with SCD are similar in nature to those identified by those with MCI.Older adults with SCD and MCI describe their daily challenges are related not only to memory problems, but also to executive dysfunction.Interventions for older adults with SCD should aim to improve self-identified problems in everyday functioning.

Computational vector fiducial for deflectometry system alignment.

One of deflectometry's cardinal strengths is its ability to measure highly dynamically sloped optics without needing physical null references. Accurate surface measurements using deflectometry, however, require precise calibration processes. In this Letter, we introduce an alignment technique using a computational fiducial to align a deflectometry system without additional hardware equipment (i.e., algorithmic innovation). Using the ray tracing program, we build relationships between the plane of the screen and detector and algorithmically generate a fiducial pattern for the deflectometry configuration. Since the fiducial pattern is based on ideal system geometry, misalignment of the unit under test with its target position causes a discrepancy between the actual image on the camera detector and the ideal fiducial image. We leverage G and C vector polynomials to quantify misalignment and estimate the alignment status through a reverse optimization method. Simulation and experimental results demonstrate that the proposed algorithm can align the 195mm×80mm of a rectangular aperture freeform optic within 10 µm of peak-to-valley accuracy. The computational fiducial-based alignment algorithm is simple to apply and can be an essential procedure for conventional methods of deflectometry system alignment.

A Developmental Role of the Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Lung Disease Pathogenesis.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein is a cAMP-activated anion channel that is critical for regulating fluid and ion transport across the epithelium. This process is disrupted in CF epithelia, and patients harbouring CF-causing mutations experience reduced lung function as a result, associated with the increased rate of mortality. Much progress has been made in CF research leading to treatments that improve CFTR function, including small molecule modulators. However, clinical outcomes are not necessarily mutation-specific as individuals harboring the same genetic mutation may present with varying disease manifestations and responses to therapy. This suggests that the CFTR protein may have alternative functions that remain under-appreciated and yet can impact disease. In this mini review, we highlight some notable research implicating an important role of CFTR protein during early lung development and how mutant CFTR proteins may impact CF airway disease pathogenesis. We also discuss recent novel cell and animal models that can now be used to identify a developmental cause of CF lung disease.

Gene therapy for cystic fibrosis: new tools for precision medicine.

The discovery of the Cystic fibrosis (CF) gene in 1989 has paved the way for incredible progress in treating the disease such that the mean survival age of individuals living with CF is now ~58 years in Canada. Recent developments in gene targeting tools and new cell and animal models have re-ignited the search for a permanent genetic cure for all CF. In this review, we highlight some of the more recent gene therapy approaches as well as new models that will provide insight into personalized therapies for CF.

How are economic evaluations carried out for primary caries prevention strategies?

Aims To summarise evidence on economic evaluations (EEs) of primary caries prevention in preschool children aged 2-5 years and to evaluate the reporting quality of full EE studies using a quality assessment tool.Methods Systematic literature search from several databases. The reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist.Results In total, 808 studies were identified and 39 were included in review. Complex multi-component interventions were the most common followed by water fluoridation. Cost analysis and cost-effectiveness were the most common EEs. Parameters that were not reported well were: characterising uncertainty, study perspective, sensitivity analysis and discount rate.Conclusions The number of EEs has increased but there is inconsistency in how EEs are conducted and reported.

Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy.

PURPOSE: Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear. EXPERIMENTAL DESIGN: In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed. RESULTS: Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10-13.70; P < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20-16.09; P < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04-2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15-3.39; P = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results. CONCLUSIONS: Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.

Cutaneous adverse events caused by immune checkpoint inhibitors.

IMPORTANCE: Immune checkpoint inhibitors (ICIs) have emerged as active therapies for a variety of cancers. Cutaneous toxicities are common immune-related adverse events and patients will often be referred to dermatologists for evaluation. OBSERVATIONS: Cutaneous adverse events to ICIs can have a variety of clinical presentations. Among the more common are eczematous, morbilliform, and lichenoid dermatoses, as well as vitiligo and pruritus. Less common adverse events include psoriasiform dermatoses, bullous disorders, and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Because of the immunologic mechanism of ICIs, there are also a variety of rheumatologic adverse reactions with cutaneous manifestations, such as scleroderma, dermatomyositis, cutaneous lupus erythematosus, and various vasculitides. These cutaneous reactions often respond to topical or systemic steroids, although specific toxicities may have alternative treatments available. CONCLUSIONS AND RELEVANCE: As they become more widely prescribed, dermatologists will see an increasing number of patients with cutaneous adverse events caused by ICI therapies. Accurately diagnosing and treating these toxicities is paramount to achieving the most favorable outcomes for patients.

How can children be involved in developing oral health education interventions?

This review examined the oral health interventions that have been developed for elementary school age children and the involvement of children in these intervention studies. Eight randomised controlled trials involving 3,232 children were analysed using deductive content analysis by two authors. Child involvement was categorised using the Typology of Youth Participation and Empowerment TYPE model. In all eight studies, the interventions were designed by the researchers and adult-led without involvement of children. Further studies with participatory research methodology are recommended to better understand the role of involvement of children in oral health education.Data sources The data search was carried out in April 2018 using PubMed, CINAHL, Embase and Scopus databases. The search focused on elementary age school children (6-12 years) who were involved in oral health education intervention studies. Exclusion criteria were studies involving children with mental or physical impairment, undergoing hospital or orthodontic treatment, preventative treatments or solely targeted towards parents/caregivers or teachers.Study selection A systematic review method of randomised controlled trials (RCTs) was selected. Titles and abstracts were included or excluded before full text analysis for eligibility was carried out. Studies were assessed by two authors with a third author to be consulted in cases of disagreement.Data extraction and synthesis Study sample, intervention duration and content, selection, use of educational methods including use of a theoretical framework and outcomes were extracted from the data. Child involvement was categorised using the Typology of Youth Participation and Empowerment (TYPE) pyramid (Wong et al., 2010).1 The quality of studies was assessed using the CONSORT checklist and the Cochrane risk of bias tool. The methodological quality of the studies was relatively low with a score of 14-22 out of 36. Three studies were rated as being fair quality in terms of risk of bias. The remaining five were rated as either unclear or high risk of bias.Results Eight RCTs were selected for review. Sixty-five articles were assessed for eligibility and 57 articles were excluded due to non-RCT design, excluded/unreported ages and full text unavailability. Nine different methods of oral health education were identified: lecture; printed material; demonstration; toothbrushing diary; game; video; workshop; discussion; and oral hygiene training. None of the reported studies demonstrated a rationale for selecting their educational method. Four reports described a theoretical framework for development their intervention: social learning theory (Parcel and Baranowski, 1981) was used by Haleem et al. (2012); Health Belief Model (Becker, 1974) by Yekaninejad et al. (2012), Wolf's health learning capacity (2009) by Freeman et al. (2016) and Ajzen's theory of planned behaviour (1991) by Simpriano and Mialhe (2017). However, the use of these theories was limited and no attempts to introduce children's perspectives into the theoretical framework was identified.Five outcomes to measure effectiveness were found: clinical oral health status; oral health-related behaviour; oral health knowledge; attitudes towards oral health; and oral health related quality of life. Clinical oral health status was the most commonly used outcome (seven of the eight studies). Positive outcomes were found in all eight studies. None of the reports considered the potential for enhancing intervention effects by involving children more actively. The children's role in the interventions was mostly the Vessel type of participation from the TYPE pyramid model. Partially symbolic participation was detected in two studies - Haleem et al. (2012) trained children to conduct oral health education in the role of peer educators and Simpriano and Mialhe (2017) trained children to create their own plans for daily toothbrushing and how to overcome situations preventing that task. There were no reports of consultation or collaboration with children for their perspectives before or after the interventions. Interventions appear to have been created by the researchers alone.Conclusions In all of the included studies, children were only involved during the intervention implementation phase. The interventions were all adult designed and adult led. Lack of detail in the reports meant that reported positive outcomes could not be clearly attributed to the activities carried out by the children. Further studies with participatory research methodology are recommended to better understand the potential role of children in oral health education and research.

Calcium channel blocker induced gingival enlargement following implant placement in a fibula free flap reconstruction of the mandible: a case report.

BACKGROUND: Gingival tissue enlargement is a common side effect of antiepileptic medications (e.g. phenytoin and sodium valproate), immunosuppressing drugs (e.g. cyclosporine) and calcium channel blockers (e.g. nifedipine, verapamil, amlodipine) (Murakami et al. 2018, Clin Periodontol 45:S17-S27, 2018). The clinical and histological appearances of lesions caused by these drugs are indistinguishable from one another (Murakami et al. 2018, Clin Periodontol 45:S17-S27, 2018). Drug-induced gingival enlargement is rarely seen in edentulous patients. CASE PRESENTATION: This case presents a 72-year-old female with a history of squamous cell carcinoma of the floor of the mouth treated with surgical excision and fibula-free flap reconstruction. Following the uncovering of osseointegrated implants placed in the fibular-free flap, the patient developed gingival enlargement of the floor of the mouth. Cessation of amlodipine and switching to an alternative medication lead to a resolution of the enlarged tissue. CONCLUSIONS: This case illustrates that gingival enlargement can occur around dental implants, most notably in rehabilitation cases in patients who have had head and neck cancer. Clinicians should be aware of the risk of gingival enlargement in hypertensive patients taking calcium channel blockers prior to implant placement.

Impact of body composition on outcomes from anti-PD1 +/- anti-CTLA-4 treatment in melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed treatment for melanoma, but identifying reliable biomarkers of response and effective modifiable lifestyle factors has been challenging. Obesity has been correlated with improved responses to ICI, although the association of body composition measures (muscle, fat, etc) with outcomes remains unknown. METHODS: We performed body composition analysis using Slice-o-matic software on pretreatment CT scans to quantify skeletal muscle index (SMI=skeletal muscle area/height2), skeletal muscle density (SMD), skeletal muscle gauge (SMG=SMI × SMD), and total adipose tissue index (TATI=subcutaneous adipose tissue area + visceral adipose tissue area/height2) of each patient at the third lumbar vertebrae. We then correlated these measures to response, progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Among 287 patients treated with ICI, body mass index was not associated with clinical benefit or toxicity. In univariable analyses, patients with sarcopenic obesity had inferior PFS (HR 1.4, p=0.04). On multivariable analyses, high TATI was associated with inferior PFS (HR 1.7, p=0.04), which was particularly strong in women (HR 2.1, p=0.03). Patients with intermediate TATI and high SMG had the best outcomes, whereas those with low SMG/high TATI had inferior PFS and OS (p=0.02 for both PFS and OS). CONCLUSIONS: Body composition analysis identified several features that correlated with improved clinical outcomes, although the associations were modest. As with other studies, we identified sex-specific associations that warrant further study.

Survivorship in immune therapy: Assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand.

AIM: Antibodies to programmed death-1 receptor and its ligand (anti-PD-1/PD-L1) produce durable responses in many cancers. However, the long-term effects of anti-PD-1/PD-L1 blockade are not well defined. We identified the toxicities, health outcomes and health-related quality of life (HRQoL) amongst long-term survivors treated with anti-PD-1/PD-L1. METHODS: We assessed 217 patients who received anti-PD-1/PD-L1 for melanoma, renal cell carcinoma or non-small-cell lung carcinoma between 2009 and 2017, with survival greater than two years after treatment. Patient and tumour characteristics, immune-related adverse events (irAEs), cardiometabolic parameters (glucose, blood pressure, body mass index [BMI]), body composition (using automated body composition analyser, computed tomography and Slice-o-matic software) and HRQoL outcomes were tracked. RESULTS: Among the included patients, most were men (70.3%) and at anti-PD-1/PD-L1 initiation had an average age of 61.0 years and median BMI of 28.5. Median overall survival was not reached; 33 (15.2%) died during the follow-up primarily from progressive cancer (n = 28). At the last follow-up, most patients' Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose or BMI from baseline to two years after treatment initiation. Body composition showed increased adiposity (p = 0.05), skeletal muscle mass (p = 0.03) and skeletal muscle gauge (p = 0.04). We observed chronic irAEs at the last follow-up including hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%) and neuropathy (2.8%). New diagnoses of type 2 diabetes (6.5%) and hypertension (6.0%) were observed, with uncertain relationship to anti-PD-1/PD-L1. Patient-reported outcomes compared favourably with cancer and general populations, although younger age (p = 0.003) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL outcomes. CONCLUSION: Durable responses to anti-PD-1/PD-L1 therapy and favourable HRQoL outcomes are encouraging. Chronic events may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.