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The first descriptions of "non-specific" killing of tumor cells by lymphocytes were reported in 1973, and subsequently, the mediators of the activity were named "natural killer" (NK) cells by Rolf Kiessling and colleagues at the Karolinska Institute in 1975. The activity was detected in mice, rats, and humans that had no prior exposure to the tumors, major histocompatibility complex (MHC) antigen matching of the effectors and tumor cells was not required, and the cells responsible were distinct from MHC-restricted, antigen-specific T cells. In the ensuing five decades, research by many labs has extended knowledge of NK cells beyond an in vitro curiosity to demonstrate their in vivo relevance in host defense against tumors and microbial pathogens and their role in regulation of the immune system. This brief Perspective highlights a timeline of a few selected advancements in NK cell biology from a personal perspective of being involved in this quest.

Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.

BackgroundCancer patients are at risk of pulmonary embolism (PE). Catheter-based therapies (CBT) are novel reperfusion options for PE though data in patients with cancer is lacking.Study design and methodsPatients with intermediate- or high-risk PE were identified using the National Readmission Database (NRD) from 2017 to 2020. Primary outcome were in-hospital death and 90-day readmission. Secondary outcomes were in-hospital bleeding, 90-day readmission for venous thromboembolism (VTE)-related or right heart failure-related reasons and bleeding. Propensity scores were estimated using logistic regression and inverse-probability treatment weighting (IPTW) was utilized to compare outcomes between CBT and no CBT as well as CBT versus systemic thrombolysis.ResultsA total of 7785 patients were included (2511 with high-risk PE) of whom 1045 (13.4%) were managed with CBT. After IPTW, CBT was associated with lower rates of index hospitalization death (OR 0.89, 95% CI 0.83-0.96) and 90-day readmission (HR 0.75, 95% CI 0.69-0.81) but higher rates of in-hospital bleeding (OR 1.11, 95% CI 1.03-1.20) which was predominantly post-procedural bleeding. CBT was associated with lower risk of major bleeding (20.8% vs 24.8%; OR 0.80, 95% CI 0.68-0.94) compared with systemic thrombolysis.InterpretationAmong patients with cancer with intermediate or high-risk PE, CBT was associated with lower in-hospital death and 90-day readmission. CBT was also associated with decreased risk of index hospitalization major bleeding compared with systemic thrombolysis. Prospective, randomized trials with inclusion of patients with cancer are needed to confirm these findings.

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy.

UNLABELLED: We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

BackgroundThe Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.MethodsMedicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences (DID) approach was used to compare changes in TTI (within 60 days) and 3-year OS between patients in ME states versus nonexpansion (NE) states before (2010-2013) and after (2015-2018) ME. Adjusted DID estimates for TTI and 3-year OS were calculated using multivariable linear regression and Cox proportional hazards regression models, respectively.ResultsME was associated with a relative increase in TTI within 60 days for breast (DID = 4.6; p

OBJECTIVE: To evaluate social drivers of health and how they impact pediatric oncology patients clinical outcomes during pediatric intensive care unit (PICU) admission via correlation with patient ZIP codes. METHODS: Demographic, clinical, and outcome variables from Virtual Pediatric Systems®, LLC for oncology patients (2009-2021) in California PICUs (excluding postoperative) using 3-digit ZIP Codes with social drivers of health variables linguistic isolation, poverty, race/ethnicity, and education abstracted from American Community Survey data for 3-digit ZIP Codes using the Environmental Protection Agencys EJScreen tool. Outcomes of length of stay (LOS), mortality, acuity scores, were compared with social variables. RESULTS: Positive correlation between mortality and minority racial groups (Hispanic/Latino) across ZIP Codes (correlation coefficients of 0.45 (95% CI: 0.22-0.64, p

BACKGROUND: Persons who speak languages other than English are underrepresented in clinical trials, likely in part because of inadequate multilevel resources. We conducted a survey of institutions affiliated with the Childrens Oncology Group (COG) to characterize current research recruitment practices and resources regarding translation and interpretation services. METHODS: In October 2022, a 20-item survey was distributed electronically to institutions affiliated with COG to assess consent practices and resources for recruiting participants who speak languages other than English to COG trials. Descriptive statistics were used to summarize responses; responses were compared by institution size and type as well as respondent role. RESULTS: The survey was sent to 230 institutions, and the response rate was 60% (n = 139). In total, 60% (n = 83) of those respondents had access to short-form consent forms. Full consent form translation was required at 50% of institutions, and 12% of institutional review boards restricted use of centrally translated consent forms. Forty-six percent (n = 64) of institutions reported insufficient funding to support translation costs; 19% (n = 26) had access to no-cost translation services. Forty-four percent (n = 61) were required to use in-person interpreters for consent discussions; the most frequently cited barrier (56%) to obtaining consent was lack of available in-person interpreters. Forty-seven percent (n = 65) reported that recruiting persons who speak languages other than English to clinical trials was somewhat or very difficult. CONCLUSIONS: Institutions affiliated with COG face resource-specific challenges that impede recruitment of participants who speak languages other than English for clinical trials. These findings indicate an urgent need to identify strategies aimed at reducing recruitment barriers to ensure equitable access to clinical trials.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%), thyroid cancer (1.6%), and soft-tissue sarcoma (1.5%). Currently, there are 2 US Food and Drug Administration-approved targeted therapies for NTRK gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. To date, the real-world uptake of tyrosine receptor kinase inhibitor (TRKi) use for NTRK-positive solid tumors in academic cancer centers remains largely unknown. OBJECTIVE: To describe the demographics, clinical and genomic characteristics, and testing and treatment patterns of patients with NTRK-positive solid tumors treated at US academic cancer centers. METHODS: This was a retrospective chart review study conducted in academic cancer centers in the United States. All patients diagnosed with an NTRK fusion-positive (NTRK1, NTRK2, NTRK3) solid tumor (any stage) and who received cancer treatment at participating sites between January 1, 2012, and July 1, 2023, were included in this study. Patient demographics, clinical characteristics, genomic characteristics, NTRK testing data, and treatment patterns were collected from electronic medical records and analyzed using descriptive statistics as appropriate. RESULTS: In total, 6 centers contributed data for 55 patients with NTRK-positive tumors. The mean age was 49.3 (SD = 20.5) years, 51% patients were female, and the majority were White (78%). The median duration of time from cancer diagnosis to NTRK testing was 85 days (IQR = 44-978). At the time of NTRK testing, 64% of patients had stage IV disease, compared with 33% at cancer diagnosis. Prevalent cancer types in the overall cohort included head and neck (15%), thyroid (15%), brain (13%), lung (13%), and colorectal (11%). NTRK1 fusions were most common (45%), followed by NTRK3 (40%) and NTRK2 (15%). Across all lines of therapy, 51% of patients (n = 28) received a TRKi. Among TRKi-treated patients, 71% had stage IV disease at TRKi initiation. The median time from positive NTRK test to initiation of TRKi was 48 days (IQR = 9-207). TRKis were commonly given as first-line (30%) or second-line (48%) therapies. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies. CONCLUSIONS: This study reports on contemporary real-world NTRK testing patterns and use of TRKis in solid tumors, including time between NTRK testing and initiation of TRKi therapy and duration of TRKi therapy.

INTRODUCTION: Identifying reliable biomarkers that reflect cancer survivorship symptoms remains a challenge for researchers. DNA methylation (DNAm) measurements reflecting epigenetic changes caused by anti-cancer therapy may provide needed insights. Given lack of consensus describing utilization of DNAm data to predict survivorship issues, a review evaluating the current landscape is warranted. OBJECTIVE: Provide an overview of current studies examining associations of DNAm with survivorship burdens in cancer survivors. METHODS: A literature review was conducted including studies if they focused on cohorts of cancer survivors, utilized peripheral blood cell DNAm data, and evaluated the associations of DNAm and survivorship issues. RESULTS: A total of 22 studies were identified, with majority focused on breast (n = 7) or childhood cancer (n = 9) survivors, and half studies included less than 100 patients (n = 11). Survivorship issues evaluated included those related to neurocognition (n = 5), psychiatric health (n = 3), general wellness (n = 9), chronic conditions (n = 5), and treatment specific toxicities (n = 4). Studies evaluated epigenetic age metrics (n = 10) and DNAm levels at individual CpG sites or regions (n = 12) for their associations with survivorship issues in cancer survivors along with relevant confounding factors. Significant associations of measured DNAm in the peripheral blood samples of cancer survivors and survivorship issues were identified. DISCUSSION/CONCLUSION: Studies utilizing epigenetic age metrics and differential methylation analysis demonstrated significant associations of DNAm measurements with survivorship burdens. Associations were observed encompassing diverse survivorship outcomes and timeframes relative to anti-cancer therapy initiation. These findings underscore the potential of these measurements as useful biomarkers in survivorship care and research.

BackgroundChildhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks.ObjectiveThis population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring.MethodsData on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers.ResultsOffspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth.ConclusionsIn this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression.

The cellular components of tumors and their microenvironment play pivotal roles in tumor progression, patient survival, and the response to cancer treatments. Unveiling a comprehensive cellular profile within bulk tumors via single-cell RNA sequencing (scRNA-seq) data is crucial, as it unveils intrinsic tumor cellular traits that elude identification through conventional cancer subtyping methods. Our contribution, scBeacon, is a tool that derives cell-type signatures by integrating and clustering multiple scRNA-seq datasets to extract signatures for deconvolving unrelated tumor datasets on bulk samples. Through the employment of scBeacon on the The Cancer Genome Atlas (TCGA) cohort, we find cellular and molecular attributes within specific tumor categories, many with patient outcome relevance. We developed a tumor cell-type map to visually depict the relationships among TCGA samples based on the cell-type inferences.

SHP2, a pivotal component downstream of both receptor and non-receptor tyrosine kinases, has been underscored in the progression of various human cancers and neurodevelopmental disorders. Allosteric inhibitors have been proposed to regulate its autoinhibition. However, oncogenic mutations, such as E76K, convert SHP2 into its open state, wherein the catalytic cleft becomes fully exposed to its ligands. This study elucidates the dynamic properties of SHP2 structures across different states, with a focus on the effects of oncogenic mutation on two known binding sites of allosteric inhibitors. Through extensive modeling and simulations, we further identified an alternative allosteric binding pocket in solution structures. Additional analysis provides insights into the dynamics and stability of the potential site. In addition, multi-tier screening was deployed to identify potential binders targeting the potential site. Our efforts to identify a new allosteric site contribute to community-wide initiatives developing therapies using multiple allosteric inhibitors to target distinct pockets on SHP2, in the hope of potentially inhibiting or slowing tumor growth associated with SHP2.

PurposeReal world evidence is crucial to understanding the diffusion of new oncologic therapies, monitoring cancer outcomes, and detecting unexpected toxicities. In practice, real world evidence is challenging to collect rapidly and comprehensively, often requiring expensive and time-consuming manual case-finding and annotation of clinical text. In this Review, we summarise recent developments in the use of artificial intelligence to collect and analyze real world evidence in oncology.MethodsWe performed a narrative review of the major current trends and recent literature in artificial intelligence applications in oncology.ResultsArtificial intelligence (AI) approaches are increasingly used to efficiently phenotype patients and tumors at large scale. These tools also may provide novel biological insights and improve risk prediction through multimodal integration of radiographic, pathological, and genomic datasets. Custom language processing pipelines and large language models hold great promise for clinical prediction and phenotyping.ConclusionsDespite rapid advances, continued progress in computation, generalizability, interpretability, and reliability as well as prospective validation are needed to integrate AI approaches into routine clinical care and real-time monitoring of novel therapies.

PurposeHigh blood glucose (hBG) in patients undergoing [18F]FDG PET/CT scans often results in rescheduling the examination, which may lead to clinical delay for the patient and decrease productivity for the department. The aim of this study was to evaluate whether long-axial field-of-view (LAFOV) PET/CT can minimize the effect of altered bio-distribution in hBG patients and is able to provide diagnostic image quality in hBG situations.Materials and methodsOncologic patients with elevated blood glucose (≥ 8.0 mmol/l) and normal blood glucose ( 11 mmol/l). Tracer uptake in the liver, muscle, and tumor was evaluated. Furthermore, image quality was compared between long acquisitions (ultra-high sensitivity mode, 360 s) on a LAFOV PET/CT and routine acquisitions equivalent to a short-axial field-of-view scanner (simulated (sSAFOV), obtained with high sensitivity mode, 120 s). Tumor-to-background ratio (TBR) and contrast-to-noise ratio (CNR) were used as the main image quality criteria.ResultsThirty-one hBG patients met the inclusion criteria and were matched with 31 nBG patients. Overall, liver uptake was significantly higher in hBG patients (SUVmean, 3.07 ± 0.41 vs. 2.37 ± 0.33; p = 0.03), and brain uptake was significantly lower (SUVmax, 7.58 ± 0.74 vs. 13.38 ± 3.94; p  11 mmol/l) patients examined with LAFOV PET/CT showed no statistical significant difference in CNR (19.84 ± 8.40 vs. 17.79 ± 9.3, p = 0.08).ConclusionWhile elevated blood glucose (> 11 mmol) negatively affected TBR and CNR in our cohort, the images from a LAFOV PET-scanner had comparable CNR to PET-images acquired from nBG patients using sSAFOV PET/CT. Therefore, we argue that oncologic patients with increased blood sugar levels might be imaged safely with LAFOV PET/CT when rescheduling is not feasible.

BACKGROUND: Nutritional impairment is associated with treatment toxicity and worse overall survival in patients with cancer. We aimed to (1) evaluate the association of nutritional impairment with psychological health and quality of life (QOL) and (2) examine which measures of nutrition had the strongest association with psychological health and QOL among older adults receiving cancer treatment with palliative intent. METHODS: This secondary analysis was performed on baseline data from a nationwide cluster randomized clinical trial (ClinicalTrials.gov identifier: NCT02107443; PI: Mohile). Adults age ≥70 with advanced cancer and ≥1 geriatric assessment (GA) impairment were enrolled from 2014 to 2017. In line with geriatric oncology standards, we defined nutritional impairment as Mini Nutritional Assessment Short Form (MNA-SF) ≤11, body mass index (BMI) 10% involuntary weight loss in the past 6 months. We conducted multivariable linear regressions to evaluate the association of nutritional impairment with each measure of psychological health and QOL: Geriatric Depression Scale (GDS-15, range 0-15), Generalized Anxiety Disorder-7 (GAD-7, range 0-21), NCCN Distress Thermometer (NCCN DT, range 0-10), and Functional Assessment of Cancer Therapy-General (FACT-G, range 0-108). Analyses were adjusted for patient demographics, clinical characteristics, and GA. RESULTS: Among 541 patients, the mean age was 77 (range 70-96) and 60% had nutritional impairment. Mean baseline scores: GDS-15 3.1 (SD 2.7), GAD-7 2.9 (SD 4.0), NCCN DT 2.9 (SD 2.7), and FACT-G 80 (SD 15). In the adjusted model, compared to those with no nutritional impairment, older adults with nutritional impairment had greater depression (β = 0.79, 95% CI 0.36-1.23) and anxiety severity (β = 0.86, 95% CI 0.19-1.53), and worse QOL (β = -6.31, 95% CI -8.62 to -4.00). Of the measures of nutrition, MNA-SF ≤11 demonstrated the strongest associations with depression, anxiety, distress, and QOL. CONCLUSION: Nutritional impairment is associated with impaired psychological health and worse QOL. Clinicians should use the MNA-SF to screen older adults for nutritional impairment and offer tailored supportive interventions.

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Womens Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend

BackgroundMaternal solvent exposure has been suspected to increase offspring cancer risk. The study aimed to evaluate the associations between maternal residential exposure to solvents from industrial pollution during pregnancy and childhood cancer.MethodsThe present study included 15,744 cancer cases (aged 0-19 years at diagnosis) identified from California Cancer Registry and 283,141 controls randomly selected from California Birth Registry (20:1 frequency-matched by birth year: 1998-2016). We examined industrial releases of tetrachloroethylene and 1,1,1-trichloroethane within 3 km of the birth address, while we used a 5 km buffer for carbon disulfide. We calculated the total exposure from all linked Toxic Release Inventory sites during each index pregnancy and assigned "ever/never" and "high/low exposed/unexposed" exposure, using median values. We performed quadratic decay models to estimate cancer risks associated with maternal solvent exposure in pregnancy.Results1,1,1-Trichloroethane was associated with rhabdomyosarcoma (adjusted Odds Ratio (aOR): 1.96; 95% Confidence Interval (CI): 1.16, 3.32) in the "ever exposed" group. Ever exposure to carbon disulfide was associated with increased risks of medulloblastoma (OR = 1.85, 95% CI 1.01, 3.40) and ependymoma (OR = 1.63, 95% CI 0.97, 2.74).ConclusionsOverall, our findings suggested maternal residential exposure to solvents from industrial sources might be associated with elevated childhood cancer risks.

Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer's disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5'UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes and are associated to specific transcriptional programs and to patient survival patterns. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many involving receptor-biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including, e.g., muscarinic, adenosine, 5-hydroxytryptamine, and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens, which we further validated. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it).

BACKGROUND: In recent decades, the survival of children with congenital anomalies and paediatric cancer has improved dramatically such that there has been a steady shift towards understanding their lifelong health outcomes. Paediatric surgeons will actively manage such conditions in childhood and adolescence, however, adult surgeons must later care for these grown-ups in adulthood. This article aims to highlight some of those rare disorders encountered by paediatric surgeons requiring long-term follow-up, their management in childhood and their survivorship impact, in order that the adult specialist may be better equipped with skills and knowledge to manage these patients into adulthood. METHODS: A comprehensive literature review was performed to identify relevant publications. Research studies, review articles and guidelines were sought, focusing on the paediatric management and long-term outcomes of surgical conditions of childhood. The article has been written for adult surgeon readership. RESULTS: This article describes the aforementioned conditions, their management in childhood and their lifelong implications, including: oesophageal atresia, tracheo-oesophageal fistula, malrotation, short bowel syndrome, duodenal atresia, gastroschisis, exomphalos, choledochal malformations, biliary atresia, Hirschsprung disease, anorectal malformations, congenital diaphragmatic hernia, congenital lung lesions and paediatric cancer. CONCLUSION: The increasing survivorship of children affected by surgical conditions will translate into a growing population of adults with lifelong conditions and specialist healthcare needs. The importance of transition from childhood to adulthood is becoming realized. It is hoped that this timely review will enthuse the readership to offer care for such vulnerable patients, and to collaborate with paediatric surgeons in providing successful and seamless transitional care.

UNLABELLED: Continuous tobacco use in patients with cancer is linked to substantial healthcare costs due to increased risks and complications, whereas quitting smoking leads to improved treatment outcomes and cost reductions. Addressing the need for empirical evidence on the economic impact of smoking cessation, this study examined the association between smoking cessation and healthcare cost utilization among a sample of 930 patients with cancer treated at The University of Texas MD Anderson Cancer Centers Tobacco Research and Treatment Program (TRTP). Applying conditional quantile regression and propensity scores to address confounding, our findings revealed that abstinence achieved through the TRTP significantly reduced the median cost during a 3-month period post-quitting by $1,095 [β = -$1,095, P = 0.007, 95% confidence interval (CI), = (-$1,886 to -$304)]. Sensitivity analysis corroborated these conclusions, showing a pronounced cost reduction when outlier data were excluded. The long-term accrued cost savings from smoking cessation could potentially offset the cost of participation in the TRTP program, underscoring its cost effectiveness. An important implication of this study is that by reducing smoking rates, healthcare systems can more efficiently allocate resources, enhance patient health outcomes, and lessen the overall cancer burden. PREVENTION RELEVANCE: This study emphasizes the dual impact of smoking cessation programs in patients with cancer: quitting smoking and reducing healthcare costs. It highlights the importance of integrating cessation programs into cancer prevention strategies, ensuring both individual health benefits and broader, system-wide economic efficiencies. See related Spotlight, p. 197.

UNLABELLED: AXIN1 is a major component of the β-catenin destruction complex and is frequently mutated in various cancer types, particularly liver cancers. Truncating AXIN1 mutations are recognized to encode a defective protein that leads to β-catenin stabilization, but the functional consequences of missense mutations are not well characterized. Here, we first identified the GSK3β, β-catenin, and RGS/APC interaction domains of AXIN1 that are the most critical for proper β-catenin regulation. Analysis of 80 tumor-associated variants in these domains identified 18 that significantly affected β-catenin signaling. Coimmunoprecipitation experiments revealed that most of them lost binding to the binding partner corresponding to the mutated domain. A comprehensive protein structure analysis predicted the consequences of these mutations, which largely overlapped with the observed effects on β-catenin signaling in functional experiments. The structure analysis also predicted that loss-of-function mutations within the RGS/APC interaction domain either directly affected the interface for APC binding or were located within the hydrophobic core and destabilized the entire structure. In addition, truncated AXIN1 length inversely correlated with the β-catenin regulatory function, with longer proteins retaining more functionality. These analyses suggest that all AXIN1-truncating mutations at least partially affect β-catenin regulation, whereas this is only the case for a subset of missense mutations. Consistently, most colorectal and liver cancers carrying missense variants acquire mutations in other β-catenin regulatory genes such as APC and CTNNB1. These results will aid the functional annotation of AXIN1 mutations identified in large-scale sequencing efforts or in individual patients. SIGNIFICANCE: Characterization of 80 tumor-associated missense variants of AXIN1 reveals a subset of 18 mutations that disrupt its β-catenin regulatory function, whereas the majority are passenger mutations.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

OBJECTIVE: This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. BACKGROUND: The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. METHODS: On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. RESULTS: Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. CONCLUSION: We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

BackgroundLong-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships.MethodsWe performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status.ResultsAnalysis was restricted to 3475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 years (interquartile range [IQR] = 33-46 years and 47 years (IQR = 39-59 years), respectively. Survivors resided in areas with greater deprivation (ADI ≥ 50: 38.7% survivors vs 31.8% siblings; P < .001). One quintile increases in deprivation were associated with small increases in behavioral (second quintile, P = .017) and psychological financial hardship (second quintile, P = .009; third quintile, P = .014). Lower psychological financial hardship was associated with individual factors including greater household income (≥$60 000 income, P < .001) and being single (P = .048).ConclusionsChildhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Neighborhood-level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships.

PURPOSE: Little is known about the shared decision-making (SDM) needs, barriers, and facilitators of patients with newly diagnosed advanced cancer in the hospital. Understanding this may improve SDM and cancer care quality in this vulnerable population. METHODS: A single-site, mixed-methods study of hospitalized patients with newly diagnosed advanced cancer, caregivers, and oncologists was conducted. After discharge, patient ± caregiver semi-structured interviews exploring SDM needs, barriers, and facilitators regarding their most important upcoming cancer-related decision were conducted. Oncologists were surveyed about patient knowledge and SDM needs using closed- and open-ended questions, respectively. Thematic analysis was performed for qualitative data with a focus on themes unique to or amplified by hospitalization. Descriptive statistics and the Chi-squared test were performed for quantitative data. RESULTS: Patients and caregivers reported high SDM needs surrounding treatment and prognostic information, leading to decisional conflict. Eight themes emerged: anticipated cancer treatment decisions, variable control preferences in decision-making, high cancer-related information needs and uncertainty, barriers and facilitators to information gathering during and post hospitalization, and decision-making facilitators. Among 32 oncologists, most (56%) reported patients were poorly informed about treatment and prognosis. Oncologists reported variable expectations about patient knowledge after hospitalization, facilitators to patient decision-making, and patient uncertainty while awaiting an outpatient oncologist appointment. CONCLUSION: Patients newly diagnosed with advanced cancer in the hospital have high SDM needs and experience decisional conflict. This may be due to barriers unique to or exacerbated by hospitalization. Further research is needed to develop strategies to address these barriers and enhance the facilitators identified in this study.

The blood-brain barrier (BBB) poses a significant obstacle in developing therapeutics for neurodegenerative diseases and central nervous system (CNS) disorders. P-glycoprotein (P-gp), a multidrug resistance protein, is a critical gatekeeper in the BBB and plays a role in cancer chemoresistance. This paper uses cryo-EM P-gp structures as starting points with an induced fit docking (IFD) model to evaluate 19 pairs of compounds with known P-gp efflux data. The study reveals significant differences in binding energy and sheds light on structural modifications impact on efflux properties. In the cases examined, fluorine incorporation influences the efflux by altering the molecular conformation rather than proximal heteroatom basicity. Although there are limitations in addressing covalent interactions or when binding extends into the more flexible vestibule region of the protein, the results provide valuable insights and potential strategies to overcome P-gp efflux, contributing to the advancement of drug development for both CNS disorders and cancer therapies.

BACKGROUND: The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. METHODS: We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross-sectional analysis of US FDA oncology drug approvals (2006-2023). We searched for OS data in registration trials and the peer-reviewed literature. RESULTS: We found 392 oncology drug approvals. Eighty-seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. CONCLUSION: About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival.

In 2020, we identified cancer-specific microbial signals in The Cancer Genome Atlas (TCGA) [1]. Multiple peer-reviewed papers independently verified or extended our findings [2-12]. Given this impact, we carefully considered concerns by Gihawi et al. [13] that batch correction and database contamination with host sequences artificially created the appearance of cancer type-specific microbiomes. (1) We tested batch correction by comparing raw and Voom-SNM-corrected data per-batch, finding predictive equivalence and significantly similar features. We found consistent results with a modern microbiome-specific method (ConQuR [14]), and when restricting to taxa found in an independent, highly-decontaminated cohort. (2) Using Conterminator [15], we found low levels of human contamination in our original databases (~1% of genomes). We demonstrated that the increased detection of human reads in Gihawi et al. [13] was due to using a newer human genome reference. (3) We developed Exhaustive, a method twice as sensitive as Conterminator, to clean RefSeq. We comprehensively host-deplete TCGA with many human (pan)genome references. We repeated all analyses with this and the Gihawi et al. [13] pipeline, and found cancer type-specific microbiomes. These extensive re-analyses and updated methods validate our original conclusion that cancer type-specific microbial signatures exist in TCGA, and show they are robust to methodology.

Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.

PURPOSE: To elucidate existing decision aids (DAs) in supporting cancer survivors decisions to engage in cancer survivorship care services after primary treatment. Secondary objectives are to assess the DA acceptability, impact of DAs, and implementation barriers. METHODS: Databases (PubMed, Embase, PsycINFO, CINAHL) were searched to collect publications from inception through September 2021. Studies describing the development or evaluation of DAs used for survivorship care services after primary cancer treatment were included. Article selection and critical appraisal were conducted independently by two authors. RESULTS: We included 16 studies that described 13 DAs and addressed multiple survivorship care domains: prevention of recurrence/new cancers in Hodgkin lymphoma survivors and breast cancer gene mutation carriers, family building options, health insurance plans, health promotion (substance use behavior, cardiovascular disease risk reduction), advanced care planning, and post-treatment follow-up intensity. The electronic format was used to design most DAs for self-administration. The content presentation covered decisional context, options, and value clarification exercises. DAs were acceptable and associated with higher knowledge but presented inconclusive decisional outcomes. Implementation barriers included lack of design features for connectivity to care, low self-efficacy, and low perceived DA usefulness among healthcare professionals. Other survivor characteristics included age, literacy, preferred timing, and setting. CONCLUSIONS: A diverse range of DAs exists in survivorship care services engagement with favorable knowledge outcomes. Future work should clarify the impact of DAs on decisional outcomes. IMPLICATIONS FOR CANCER SURVIVORS: DA characterization and suggestions for prospective developers could enhance support for cancer survivors encountering complex decisions throughout the survivorship continuum.

BACKGROUND: While much progress has been made in reducing tobacco use in many countries, both active and passive smoking remain challenges. The benefits of smoking cessation are universally recognized, and the hospital setting is an ideal setting where smokers can access smoking cessation services as hospital admission can be a cue to action. Consistent delivery of good quality smoking cessation care across health services is an important focus for reducing the harm of tobacco use, especially among continued smokers. AIMS: Our objective was to document the smoking cessation medication and support services provided by specialist adult cancer hospitals across Ireland, a country with a stated tobacco endgame goal. METHODS: A cross-sectional survey based on recent national clinical guidelines was used to determine smoking cessation care delivery across eight specialist adult cancer tertiary referral university hospitals and one specialist radiotherapy center. Survey responses were collected using Qualtrics, a secure online survey software tool. The data was grouped, anonymized, and analyzed in Microsoft Excel. RESULTS: All responding hospitals demonstrated either some level of smoking cessation information or a service available to patients. However, there is substantial variation in the type and level of smoking cessation information offered, making access to smoking cessation services inconsistent and inequitable. CONCLUSION: The recently launched National Clinical Guideline for smoking cessation provides the template for all hospitals to ensure health services are in a position to contribute to Irelands tobacco endgame goal.

Cancer early detection and treatment response prediction continue to pose significant challenges. Cancer liquid biopsies focusing on detecting circulating tumor cells (CTCs) and DNA (ctDNA) have shown enormous potential due to their non-invasive nature and the implications in precision cancer management. Recently, liquid biopsy has been further expanded to profile glycoproteins, which are the products of post-translational modifications of proteins and play key roles in both normal and pathological processes, including cancers. The advancements in chemical and mass spectrometry-based technologies and artificial intelligence-based platforms have enabled extensive studies of cancer and organ-specific changes in glycans and glycoproteins through glycomics and glycoproteomics. Glycoproteomic analysis has emerged as a promising tool for biomarker discovery and development in early detection of cancers and prediction of treatment efficacy including response to immunotherapies. These biomarkers could play a crucial role in aiding in early intervention and personalized therapy decisions. In this review, we summarize the significant advance in cancer glycoproteomic biomarker studies and the promise and challenges in integration into clinical practice to improve cancer patient care.

Many machine learning techniques are used as drug discovery tools with the intent to speed characterization by determining relationships between compound structure and biological function. However, particularly in anticancer drug discovery, these models often make only binary decisions about the biological activity for a narrow scope of drug targets. We present a feed-forward neural network, PECAN (Prediction Engine for the Cytostatic Activity of Natural product-like compounds), that simultaneously classifies the potential antiproliferative activity of compounds against 59 cancer cell lines. It predicts the activity to be one of six categories, indicating not only if activity is present but the degree of activity. Using an independent subset of NCI data as a test set, we show that PECAN can reach 60.1% accuracy in a six-way classification and present further evidence that it classifies based on useful structural features of compounds using a within-one measure that reaches 93.0% accuracy.

Photodynamic therapy (PDT) is a promising cancer treatment but has limitations due to its dependence on oxygen and high-power-density photoexcitation. Here, we report polymer-based organic photosensitizers (PSs) through rational PS skeleton design and precise side-chain engineering to generate •O2- and •OH under oxygen-free conditions using ultralow-power 808 nm photoexcitation for tumor-specific photodynamic ablation. The designed organic PS skeletons can generate electron-hole pairs to sensitize H2O into •O2- and •OH under oxygen-free conditions with 808 nm photoexcitation, achieving NIR-photoexcited and oxygen-independent •O2- and •OH production. Further, compared with commonly used alkyl side chains, glycol oligomer as the PS side chain mitigates electron-hole recombination and offers more H2O molecules around the electron-hole pairs generated from the hydrophobic PS skeletons, which can yield 4-fold stronger •O2- and •OH production, thus allowing an ultralow-power photoexcitation to yield high PDT effect. Finally, the feasibility of developing activatable PSs for tumor-specific photodynamic therapy in female mice is further demonstrated under 808 nm irradiation with an ultralow-power of 15 mW cm-2. The study not only provides further insights into the PDT mechanism but also offers a general design guideline to develop an oxygen-independent organic PS using ultralow-power NIR photoexcitation for tumor-specific PDT.

Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.

BACKGROUND: Symptom assessment is key to effective symptom management and palliative care for patients with advanced cancer. Symptom prevalence and severity estimates vary widely, possibly dependent on the assessment tool used. Are symptoms specifically asked about or must the patients add them as additional symptoms? This study compared the prevalence and severity of patient-reported symptoms in two different versions of a multi-symptom assessment tool. In one version, three symptoms dry mouth, constipation, sleep problems were among those systematically assessed, while in the other, these symptoms had to be added as an Other problem. METHODS: This retrospective cross-sectional study included adult patients with advanced cancer at an inpatient palliative care unit. Data were collected from two versions of the Edmonton Symptom Assessment System (ESAS): modified (ESAS-m) listed 11 symptoms and revised (ESAS-r) listed 9 and allowed patients to add one Other problem. Seven similar symptoms were listed in both versions. RESULTS: In 2013, 184 patients completed ESAS-m, and in 2017, 156 completed ESAS-r. Prevalence and severity of symptoms listed in both versions did not differ. In ESAS-m, 83% reported dry mouth, 73% constipation, and 71% sleep problems, but on ESAS-r, these symptoms were reported by only 3%, 15% and

PURPOSE: The capability of ultrahigh dose rate FLASH radiation therapy to generate the FLASH effect has opened the possibility to enhance the therapeutic index of radiation therapy. The contribution of the immune response has frequently been hypothesized to account for a certain fraction of the antitumor efficacy and tumor kill of FLASH but has yet to be rigorously evaluated. METHODS AND MATERIALS: To investigate the immune response as a potentially important mechanism of the antitumor effect of FLASH, various murine tumor models were grafted either subcutaneously or orthotopically into immunocompetent mice or in moderately and severely immunocompromised mice. Mice were locally irradiated with single dose (20 Gy) or hypofractionated regimens (3 × 8 or 2 × 6 Gy) using FLASH (≥2000 Gy/s) and conventional (CONV) dose rates (0.1 Gy/s), with/without anti-CTLA-4. Tumor growth was monitored over time and immune profiling performed. RESULTS: FLASH and CONV 20 Gy were isoeffective in delaying tumor growth in immunocompetent and moderately immunodeficient hosts and increased tumor doubling time to >14 days versus >7 days in control animals. Similar observations were obtained with a hypofractionated scheme, regardless of the microenvironment (subcutaneous flank vs ortho lungs). Interestingly, in profoundly immunocompromised mice, 20 Gy FLASH retained antitumor activity and significantly increased tumor doubling time to >14 days versus >8 days in control animals, suggesting a possible antitumor mechanism independent of the immune response. Analysis of the tumor microenvironment showed similar immune profiles after both irradiation modalities with significant decrease of lymphoid cells by ∼40% and a corresponding increase of myeloid cells. In addition, FLASH and CONV did not increase transforming growth factor-β1 levels in tumors compared with unirradiated control animals. Furthermore, when a complete and long-lasting antitumor response was obtained (>140 days), both modalities of irradiation were able to generate a long-term immunologic memory response. CONCLUSIONS: The present results clearly document that the tumor responses across multiple immunocompetent and immunodeficient mouse models are largely dose rate independent and simultaneously contradict a major role of the immune response in the antitumor efficacy of FLASH. Therefore, our study indicates that FLASH is as potent as CONV in modulating antitumor immune response and can be used as an immunomodulatory agent.

BACKGROUND: At University of California, Irvine (UCI), a seminar course focused on cancer survivorship was developed and offered to non-healthcare professional undergraduate students. Utilizing the knowledge, attitude, and perception (KAP) framework, this study was designed to examine the impact on students who have taken this course, and to clarify the value of this course for undergraduate students. METHODS: This was a cross-sectional survey. Undergraduate students enrolled in the Life After Cancer Freshmen Seminar course (Uni Stu 3) at UCI between 2021 and 2023 were invited to participate. The survey consisted of 4 main sections: (1) demographics, (2) knowledge of cancer survivorship, (3) attitude towards cancer survivorship, and (4) perception and awareness of cancer survivorship. The survey was administered prior to the implementation of the course, and the same survey was administered at the end of the course. RESULTS: A total of 33 students completed the pre-implementation survey and 30 students completed the post-implementation survey. Comparing pre- and post-course implementation, there was an increase of perception and awareness of (i) resources and guidelines for cancer survivors (pre, 9.1% vs. post, 36.7%), (ii) mental health complications among cancer survivors (pre, 36.4% vs. post, 56.7%), (iii) benefits of cancer survivorship care (pre, 15.2% vs. post, 40%), latest research in cancer survivorship (pre, 0% vs. post, 23.3%), and (iv) tailoring survivors needs according to their age groups (pre, 24.2% vs. post, 66.7%). Knowledge and attitude towards caring of cancer survivors were similar comparing pre- and post-course implementation. CONCLUSION: In an undergraduate seminar course focused on cancer survivorship, we observed an improvement of non-healthcare students perception and awareness of cancer survivorship-related issues, advocating the value on introducing highly prevalent cancer survivorship topics early to both undergraduate STEM and non-STEM students.

Recent advancements in AI-driven technologies, particularly in protein structure prediction, are significantly reshaping the landscape of drug discovery and development. This review focuses on the question of how these technological breakthroughs, exemplified by AlphaFold2, are revolutionizing our understanding of protein structure and function changes underlying cancer and improve our approaches to counter them. By enhancing the precision and speed at which drug targets are identified and drug candidates can be designed and optimized, these technologies are streamlining the entire drug development process. We explore the use of AlphaFold2 in cancer drug development, scrutinizing its efficacy, limitations, and potential challenges. We also compare AlphaFold2 with other algorithms like ESMFold, explaining the diverse methodologies employed in this field and the practical effects of these differences for the application of specific algorithms. Additionally, we discuss the broader applications of these technologies, including the prediction of protein complex structures and the generative AI-driven design of novel proteins.

PurposeChronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN.Experimental designWe randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome.ResultsThe Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention.ConclusionsWith dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions.SignificanceDiet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

INTRODUCTION: The primary objective of this study was to determine whether workplace culture in academic oncology differed by gender, during the COVID-19 pandemic. MATERIALS AND METHODS: We used the Culture Conducive to Womens Academic Success (CCWAS), a validated survey tool, to investigate the academic climate at an NCI-designated Cancer Center. We adapted the CCWAS to be applicable to people of all genders. The full membership of the Cancer Center was surveyed (total faculty = 429). The questions in each of 4 CCWAS domains (equal access to opportunities, work-life balance, freedom from gender bias, and leadership support) were scored using a 5-point Likert scale. Median score and interquartile ranges for each domain were calculated. RESULTS: A total of 168 respondents (men = 58, women = 106, n = 4 not disclosed) submitted survey responses. The response rate was 39% overall and 70% among women faculty. We found significant differences in perceptions of workplace culture by gender, both in responses to individual questions and in the overall score in the following domains: equal access to opportunities, work-life balance, and leader support, and in the total score for the CCWAS. CONCLUSIONS: Our survey is the first of its kind completed during the COVID-19 pandemic at an NCI-designated Cancer Center, in which myriad factors contributed to burnout and workplace challenges. These results point to specific issues that detract from the success of women pursuing careers in academic oncology. Identifying these issues can be used to design and implement solutions to improve workforce culture, mitigate gender bias, and retain faculty.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Infection, autoimmunity, and cancer are principal human health challenges of the 21st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A+ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.

Abstract: