Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes ( CFHR1 and LRP6 ) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.

Acute pulmonary injury in hematology patients supported with pathogen-reduced and conventional platelet components.

ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Fate and behaviour of Microplastics (> 25µm) within the water distribution network, from water treatment works to service reservoirs and customer taps.

Water treatment works have previously shown high efficiency in removing microplastics > 25 µm from raw source water. However, what is less well known is the extent to which microplastics of this size class are generated or lost within the water distribution network, particularly whether there is a greater presence in the customer tap than in the water treatment works outlet. This study focused on the presence of 21 different types of synthetic polymer particles with sizes larger than 25 µm examined through multiple rounds of sampling at outlets of water treatment works (WTW), service reservoirs (SR), and customer taps (CT) managed by seven different water companies in Britain. Nineteen different types of polymers were detected; their signature and concentration varied based on the round of sampling, the location within the water supply network, and the water company responsible for managing the supply. Among the polymers examined, polyamide (PA), polyethene terephthalate (PET), polypropylene (PP), and polystyrene (PS) were the most commonly found. Apart from PET having its highest concentration of 0.0189 microplastic per litre (MP/L) in the SR, the concentrations of the other three most frequent polymers (PS = 0.017 MP/L, PA = 0.0752 MP/L, PP= 0.1513 MP/L) were highest in the CT. The overall prevalence of this size of microplastics in the network is low, but there was a high variability of polymer types and occurrences. These spatial and temporal variations suggested that the MP in the distribution network may exist as a series of pulses. Given the presence and polymer types, the potential for some of the microplastics to originate from materials used in the water network and domestic plumbing systems cannot be ruled out. As found before, the absolute number of microplastics in the water distribution network remained extremely low.

Assessment of the impacts of GABA and AChE targeting pesticides on freshwater invertebrate family richness in English Rivers.

Globally, riverine system biodiversity is threatened by a range of stressors, spanning pollution, sedimentation, alterations to water flow, and climate change. Pesticides have been associated with population level impacts on freshwater invertebrates for acute high-level exposures, but far less is known about the chronic impact of episodic exposure to specific classes of pesticides or their mixtures. Here we employed the use of the UK Environment Agency's monitoring datasets over 40 years (covering years 1980 to 2019) to assess the impacts of AChE (acetylcholinesterase) and GABA (gamma-aminobutyric acid) receptor targeting pesticides on invertebrate family richness at English river sites. Concentrations of AChE and GABA pesticides toxic to freshwater invertebrates occurred (measured) across 18 of the 66 river sites assessed. For one of the three river sites (all found in the Midlands region of England) where data recorded over the past 40 years were sufficient for robust modelling studies, both AChE and GABA pesticides associated with invertebrate family richness. Here, where AChE total pesticide concentrations were classified as high, 46 of 64 invertebrate families were absent, and where GABA total pesticide concentration were classified as high, 16 of 64 invertebrate families were absent. Using a combination of field evidence and laboratory toxicity thresholds for population relevant endpoints we identify families of invertebrates most at risk in the selected English rivers to AChE and GABA pesticides. We, furthermore, provide strong evidence that the absence of the invertebrate family Polycentropodidae (caddisfly) from one field site is due to exposure effects to AChE pesticides.

Genetic and nongenetic drivers of platelet reactivity in healthy Tanzanian individuals.

BACKGROUND: Platelets play a key role in hemostasis, inflammation, and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown. OBJECTIVES: We aimed to investigate the nongenetic and genetic determinants of platelet reactivity in healthy adults living in a rapidly urbanizing area in Northern Tanzania. METHODS: Platelet activation and reactivity were measured by platelet P-selectin expression and the binding of fibrinogen in unstimulated blood and after ex vivo stimulation with adenosine diphosphate and PAR-1 and PAR-4 ligands. We then analyzed the associations of platelet parameters with host genetic and nongenetic factors, environmental factors, plasma inflammatory markers, and plasma metabolites. RESULTS: Only a few associations were found between platelet reactivity parameters and plasma inflammatory markers and nongenetic host and environmental factors. In contrast, untargeted plasma metabolomics revealed a large number of associations with food-derived metabolites, including phytochemicals that were previously reported to inhibit platelet reactivity. Genome-wide single-nucleotide polymorphism genotyping identified 2 novel single-nucleotide polymorphisms (rs903650 and rs4789332) that were associated with platelet reactivity at the genome-wide level (P < 5 × 10-8) as well as a number of variants in the PAR4 gene (F2RL3) that were associated with PAR4-induced reactivity. CONCLUSION: Our study uncovered factors that determine variation in platelet reactivity in a population in East Africa that is rapidly transitioning to an urban lifestyle, including the importance of genetic ancestry and the gradual abandoning of the traditional East African diet.

Angiotensin-II for vasoplegia following cardiac surgery.

INTRODUCTION: The objective of this study was to describe the implementation and outcomes of a protocol outlining angiotensin-II utilization for vasoplegia following cardiac surgery. METHODS: This was a retrospective chart review at a single-center university hospital. Included patients received angiotensin-II for vasoplegia refractory to standard interventions, including norepinephrine 20 mcg/min and vasopressin 0.04 units/min, following cardiac surgery between April 2021 and April 2022. RESULTS: 30 patients received angiotensin-II for refractory vasoplegia. Adjunctive agents at angiotensin-II initiation included corticosteroids (26 patients; 87%), epinephrine (26 patients; 87%), dobutamine (17 patients; 57%), dopamine (9 patients; 30%), milrinone (2 patients; 7%), and hydroxocobalamin (4 patients; 13%). At 3 hours, the median mean arterial pressure increased from baseline (70 vs 61.5 mmHg, p = .0006). Median norepinephrine doses at angiotensin-II initiation, 1 hour, 3 hours, and angiotensin-II discontinuation were 0.22, 0.16 (p = .0023), 0.10 (p < .0001), and 0.07 (p < .0001) mcg/kg/min. Median dobutamine doses decreased throughout angiotensin-II infusion from eight to six mcg/kg/min (p = .0313). Other vasoactive medication doses were unchanged. Three patients (10%) subsequently received hydroxocobalamin. Thirteen (43.3%) and five (16.7%) patients experienced mortality by day 28 and venous or arterial thrombosis events, respectively. CONCLUSIONS: The administration of angiotensin-II to vasoplegic patients following cardiac surgery was associated with increased mean arterial pressure, reduced norepinephrine dosages, and reduced dobutamine dosages.

The Regulation of Nucleic Acid Vaccine Responses by the Microbiome.

Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine responses and which may determine their effectiveness. The microbiome is recognized as a significant regulator of immune development and response, whose role in regulating some traditional vaccine platforms has recently been discovered. Using germ-free and specific pathogen-free mouse models in combination with different protein, DNA, and mRNA vaccine regimens, we demonstrate that the microbiome is a significant regulator of nucleic acid vaccine immunogenicity. Although the presence of the microbiome enhances CD8+ T cell responses to mRNA lipid nanoparticle immunization, the microbiome suppresses Ig and CD4+ T cell responses to DNA-prime, DNA-protein-boost immunization, indicating contrasting roles for the microbiome in the regulation of these different nucleic acid vaccine platforms. In the case of mRNA lipid nanoparticle vaccination, germ-free mice display reduced dendritic cell/macrophage activation that may underlie the deficient vaccine response. Our study identifies the microbiome as a relevant determinant of nucleic acid vaccine response with implications for continued therapeutic development and deployment of these vaccines.

Office-based facial plastics procedures: Neuromodulators.

Botulinum toxin is a potent neuromodulator commonly used for cosmetic applications in the clinic. In this article, we reviewed the various formulations of botulinum toxin type A commercially available in the United States, as well as clinical pearls for preprocedural planning, common in-office injections, and management of complications.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R 2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified TCL1A , NRIP1 , and TERT locus variants as modulators of mCA clonal expansion rate.

Robot-assisted Surgery in the Field of Urology: The Most Pioneering Approaches 2015-2023.

Robot-assisted surgery has emerged as a transformative technology, revolutionizing surgical approaches and techniques that decades ago could barely be imagined. The field of urology has taken charge in pioneering a new era of minimally invasive surgery with the ascent of robotic systems which offer enhanced visualization, precision, dexterity, and enabling surgeons to perform intricate maneuvers with improved accuracy. This has led to improved surgical outcomes, including reduced blood loss, lower complication rates, and faster patient recovery. The aim of our review is to present an evidence-based critical analysis on the most pioneering robotic urologic approaches described over the last eight years (2015-2023).

Artificial Urinary Sphincters for Moderate Post-Prostatectomy Incontinence: Current Research and Proposed Approach.

Male urinary incontinence is a common complication after radical prostatectomy. The severity of incontinence can be assessed in various ways and helps determine the best surgical intervention to restore continence. While most patients with mild incontinence receive a sling and those with severe incontinence receive an artificial urinary sphincter (AUS), there are no clear guidelines on how to manage patients with moderate post-prostatectomy incontinence (PPI). Our discussion will focus on the current literature, which demonstrates that an AUS should be considered first-line in men with moderate PPI despite perceived concerns over complications and reintervention rates.

Annual incidence and assessment of risk factors for early-onset deep surgical site infection following primary total knee arthroplasty in osteoarthritis.

Aims: This study aims to determine difference in annual rate of early-onset (≤ 90 days) deep surgical site infection (SSI) following primary total knee arthroplasty (TKA) for osteoarthritis, and to identify risk factors that may be associated with infection. Methods: This is a retrospective population-based cohort study using prospectively collected patient-level data between 1 January 2013 and 1 March 2020. The diagnosis of deep SSI was defined as per the Centers for Disease Control/National Healthcare Safety Network criteria. The Mann-Kendall Trend test was used to detect monotonic trends in annual rates of early-onset deep SSI over time. Multiple logistic regression was used to analyze the effect of different patient, surgical, and healthcare setting factors on the risk of developing a deep SSI within 90 days from surgery for patients with complete data. We also report 90-day mortality. Results: A total of 39,038 patients underwent primary TKA for osteoarthritis during the study period. Of these, 275 patients developed a deep SSI within 90 days of surgery, representing a cumulative incidence of 0.7%. The annual infection rate did not significantly decrease over the seven-year study period (p = 0.162). Overall, 13,885 (35.5%) cases were excluded from the risk analysis due to missing data. Risk factors associated with early-onset deep SSI included male sex, American Society of Anesthesiologists grade ≥ 3, blood transfusion, acute length of stay, and surgeon volume < 30 TKAs/year. Early-onset deep SSI was not associated with increased 90-day mortality. Conclusion: This study establishes a reliable baseline infection rate for early-onset deep SSI after TKA for osteoarthritis using robust Infection Prevention and Control surveillance data, and identifies several potentially modifiable risk factors.

South African Consumers' Knowledge, Opinions and Awareness of Whole Grains and Their Health Benefits: A Cross-Sectional Online Survey.

Evidence indicates that whole-grain food consumption reduces the risk of cardiovascular disease, type-2 diabetes, and some cancers. Increasing whole-grain consumption in developing countries is likely to significantly benefit the health of the population. However, there is very limited information on consumer whole-grain knowledge, attitudes, and behaviors in developing countries. An online cross-sectional survey was conducted among 1000 South African consumers with sufficient income to make food purchase choices and who were generally representative in terms of gender, age, and ethnicity. Most respondents (64%) were confident of their whole-grain knowledge. However, 60% of all participants selected incorrect definitions of whole grains. Whilst most correctly identified common cereals as whole grains, at most 50% of participants correctly identified common whole-grain foods. Also, whilst most (67%) thought that they were consuming enough whole grains, the majority (62%) underestimated the recommended level of consumption. Furthermore, respondent knowledge regarding whole-grain food attributes and the health benefits of whole-grain consumption was generally poor. Clearly, consumer-focused strategies are needed in developing countries to increase whole-grain food consumption to help the broader population achieve a healthy and sustainable diet. Actions proposed include: simple-to-understand information on whole-grain content relative to recommendations on food product labels, the provision of whole-grain foods in school nutrition schemes, and coordinated social and behavior change communication initiatives.

Alcohol intake including wine drinking is associated with decreased platelet reactivity in a large population sample.

BACKGROUND: Alcohol consumption is linked to decreased platelet function. Whether this link is dependent on sex or type of beverage remains unclear. METHODS: Cross-sectional data were obtained from the Framingham Heart Study (N = 3427). Alcohol consumption was assessed by using standardized medical history and Harvard semi-quantitative food frequency questionnaires. Five bioassays measured 120 platelet reactivity traits across agonists in whole-blood and platelet-rich plasma samples. Linear mixed-effects models adjusted for age, sex and aspirin use, hypertension, body mass index, cholesterol, high-density lipoprotein, triglycerides, smoking and diabetes evaluated associations between platelet reactivity and alcohol consumption. Beta effects, the regression coefficients that estimate the amount of change in each unit of the predictor variable whereas all other predictor variables remain fixed, for heavy alcohol consumption were compared with effects of aspirin use. RESULTS: Alcohol consumption was associated with decreased platelet reactivity, with more associations among wine and liquor compared with beer. Many platelet-alcohol associations in the full sample (86%, P < 0.01) had larger effect sizes in females. Lower light transmission aggregometry adenosine diphosphate (1.82 µM) maximum aggregation (P = 2.6E-3, 95% CI = -0.07, -0.02, ß = -0.042) and area under the curve (P = 7.7E-3, 95% CI = -0.07, -0.01, ß = -0.039) were associated with white wine consumption; however, red wine had no associations with platelet reactivity. The effect of aspirin use was on average 11.3 (±4.0) times greater than that of heavy drinking in our full sample. CONCLUSIONS: We confirm associations between alcohol consumption and decreased platelet reactivity. Effects appeared larger for liquor and wine intake and in our female cohort. Red wine consumption is not associated with lower platelet function, contrasting with prior population studies. Although we report an inhibitory relationship between alcohol intake and platelet function, these effects appear much smaller than that of aspirin use.

Sources of variability in the human platelet transcriptome.

Platelets are anucleated cells produced by megakaryocytes, from which they inherit all the components necessary to carry their functions. They circulate in blood vessels where they play essential roles in coagulation, wound repair or inflammation, and have been implicated in various pathological conditions such as thrombosis, viral infection or cancer progression. The importance of these cells has been established over a century ago, and effective anti-platelet medications with different mechanisms of action have since been developed. However, these therapies are not always effective and can incur adverse events, thus a better understanding of platelets molecular processes is needed to address these issues and improve our understanding of platelet functions. In recent years, an increasing number of studies have leveraged OMICs technologies to analyze their content and identify molecular signatures and mechanisms associated with platelet functions and platelet related disorders. In particular, the increased accessibility of microarrays and RNA sequencing opened the way for studies of the platelet transcriptome under a wide array of conditions. These studies revealed distinct expression profiles in diverse pathologies, which could lead to the discovery of novel biomarkers and therapeutic targets, and suggests a dynamic transcriptome that could influence platelet mechanisms. In this review, we highlight the different sources of transcript level variability in platelets while summarizing recent advances and discoveries from this emerging field.

Hepatosplenic mucormycosis due to Rhizomucor pusillus identified by panfungal PCR/sequencing of ribosomal ITS2 and LSU regions in a patient with acute myelogenous leukemia: A case report.

Background: Angioinvasive Rhizomucor pusillus infection with dissemination to the liver and spleen is exceedingly uncommon, representing less than 1% of reported cases of mucormycosis. Methods: Diagnosis of mucormycosis is often difficult using conventional methods that rely on broad-based non-septate hyphae present on histologic examination and morphological identification of the cultured organism. Our laboratory also uses an in-house panfungal molecular assay to rapidly diagnose invasive fungal infection when conventional methods do not provide definitive results. Results: Herein we present a case of disseminated mucormycosis with hepatosplenic involvement in a 49-year-old female with acute myelogenous leukemia following induction chemotherapy. But in this case repeated tissue biopsy cultures were negative. R. pusillus infection was diagnosed using an in-house panfungal PCR/sequencing assay based on dual priming oligonucleotide primers. Conclusions: New molecular assays facilitate prompt diagnosis of invasive fungal infections.

Historique: L'infection à Rhizomucor pusillus angio-invasive avec dissémination au foie et à la rate est très peu courante, puisqu'elle représente 1% des cas de mucormycose déclarés. Méthodologie: Le diagnostic de mucormycose est souvent difficile à poser au moyen des méthodes habituelles, qui reposent sur la présence d'hyphes non cloisonnées généralisées à l'examen histologique et sur l'identification morphologique de l'organisme mis en culture. Le laboratoire recourt également à un dosage moléculaire panfongique maison pour diagnostiquer rapidement l'infection fongique invasive lorsque les méthodes habituelles ne fournissent pas de résultats définitifs. Résultats: Les chercheurs présentent un cas de mucormycose disséminée avec atteinte hépatosplénique chez une femme de 49 ans atteinte de leucémie myélogène aiguë après une chimiothérapie d'induction. Dans ce cas, les résultats des biopsies tissulaires répétées étaient négatifs. L'infection à R. pusillus a été diagnostiquée au moyen d'un dosage maison par séquençage ou PRC panfongique d'après des amorces oligonucléotidiques à double usage. Conclusions: Les nouveaux dosages moléculaires facilitent un diagnostic rapide d'infection fongique invasive.

The Regulation of Nucleic Acid Vaccine Responses by the Microbiome.

Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine responses and which may determine their effectiveness. The microbiome is recognized as a significant regulator of immune development and response, whose role in regulating some traditional vaccine platforms has recently been discovered. Using germ-free and specific-pathogen-free mouse models in combination with different protein, DNA, and mRNA vaccine regimens, we demonstrate that the microbiome is a significant regulator of nucleic acid vaccine immunogenicity. While the presence of the microbiome enhances CD8+ T cell responses to mRNA lipid nanoparticle (LNP) immunization, the microbiome suppresses immunoglobulin and CD4+ T cell responses to DNA-prime, DNA-protein-boost immunization, indicating contrasting roles for the microbiome in the regulation of these different nucleic acid vaccine platforms. In the case of mRNA-LNP vaccination, germ-free mice display reduced dendritic cell/macrophage activation that may underlie the deficient vaccine response. Our study identifies the microbiome as a relevant determinant of nucleic acid vaccine response with implications for their continued therapeutic development and deployment.

Identifying Early-Phase Clinical Trial Participants at Risk for Experiencing Worse Clinical Outcomes.

PURPOSE: To identify early-phase clinical trial (EP-CT) participants at risk for experiencing worse clinical outcomes and describe receipt of supportive care services. METHODS: A retrospective review of the electronic health records of consecutive patients enrolled in EP-CTs from 2017 to 2019 examined baseline characteristics, clinical outcomes, and receipt of supportive care services. The validated Royal Marsden Hospital (RMH) prognosis score was calculated using data at the time of EP-CT enrollment (scores range from 0 to 3; scores ≥ 2 indicate poor prognosis). Differences in patient characteristics, clinical outcomes, and receipt of supportive care services were compared on the basis of RMH scores. RESULTS: Among 350 patients (median age = 63.2 years [range, 23.0-84.3 years], 57.1% female, 98.0% metastatic cancer), 31.7% had an RMH score indicating a poor prognosis. Those with poor prognosis RMH scores had worse overall survival (hazard ratio [HR], 2.00; P < .001), shorter time on trial (HR, 1.53; P < .001), and lower likelihood of completing the dose-limiting toxicity period (odds ratio, 0.42; P = .006) versus those with good prognosis scores. Patients with poor prognosis scores had greater risk of emergency room visits (HR, 1.66; P = .037) and hospitalizations (HR, 1.69; P = .016) while on trial, and earlier hospice enrollment (HR, 2.22; P = .006). Patients with poor prognosis scores were significantly more likely to receive palliative care consultation (46.8% v 27.6%; P < .001), but not other supportive care services. CONCLUSION: This study found that RMH prognosis score could identify patients at risk for decreased survival, shorter time on trial, and greater use of health care services. The findings underscore the need to develop supportive care interventions targeting EP-CT participants' distinct needs.

Second-line treatment options for patients with metastatic pancreatic ductal adenocarcinoma: A systematic literature review.

INTRODUCTION: The aim of this review was to characterize the second- and later-line (≥2L) treatment landscape for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). METHODS: This systematic literature review (PROSPERO: CRD42021279753) involved searches of MEDLINE® and Embase to identify results from prospective studies of ≥2L treatment options for metastatic pancreatic cancer published from 2016 to 2021. Publications were screened according to predetermined eligibility criteria; population-level data were extracted using standardized data fields. Publication quality was assessed according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The data were analyzed descriptively, grouped by drug class. RESULTS: Sixty publications were identified, including 23 relating to comparative trials. GRADE assessment found that, of these 23 trials, 83% reported high or moderate-quality evidence. Of the publications relating to comparative trials, nine (three trials) reported favorable results: the pivotal phase 3 NAPOLI-1 trial for liposomal irinotecan; a phase 3 trial of non-liposomal irinotecan within the FOLFIRINOX regimen; and a phase 2 trial of eryaspase plus chemotherapy. CONCLUSIONS: The level of unmet need for ≥2L treatment options for mPDAC remains high. Irinotecan-based regimens currently offer the greatest promise. Investigations into paradigm-changing agents and combination approaches continue.