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Cancer stem cells, characterized by high tumorigenicity and drug-resistance, are often responsible for tumor progression and metastasis. Aldehyde dehydrogenases, often overexpressed in cancer stem cells enriched tumors, present a potential target for specific anti-cancer stem cells treatment. In this study, we report a self-assembled nano-prodrug composed of aldehyde dehydrogenases activatable photosensitizer and disulfide-linked all-trans retinoic acid for diagnosis and targeted treatment of cancer stem cells enriched tumors. The disulfide-linked all-trans retinoic acid can load with photosensitizer and self-assemble into a stable nano-prodrug, which can be disassembled into all-trans retinoic acid and photosensitizer in cancer stem cells by high level of glutathione. As for the released photosensitizer, overexpressed aldehyde dehydrogenase catalyzes the oxidation of aldehydes to carboxyl under cancer stem cells enriched microenvironment, activating the generation of reactive oxygen species and fluorescence emission. This generation of reactive oxygen species leads to direct killing of cancer stem cells and is accompanied by a noticeable fluorescence enhancement for real-time monitoring of the cancer stem cells enriched microenvironment. Moreover, the released all-trans retinoic acid, as a differentiation agent, reduce the cancer stem cells stemness and improve the cancer stem cells enriched microenvironment, offering a synergistic effect for enhanced anti-cancer stem cells treatment of photosensitizer in inhibition of in vivo tumor growth and metastasis.

Computer-assisted diagnosis (CAD) plays a key role in cancer diagnosis or screening. Whereas, current CAD performs poorly on whole slide image (WSI) analysis, and thus fails to generalize well. This research aims to develop an automatic classification system to distinguish between different types of carcinomas. Obtaining rich deep features in multi-class classification while achieving high accuracy is still a challenging problem. The detection and classification of cancerous cells in WSI are quite challenging due to the misclassification of normal lumps and cancerous cells. This is due to cluttering, occlusion, and irregular cell distribution. Researchers in the past mostly obtained the hand-crafted features while neglecting the above-mentioned challenges which led to a reduction of the classification accuracy. To mitigate this problem we proposed an efficient dual attention-based network (CytoNet). The proposed network is composed of two main modules (i) Efficient-Net and (ii) Dual Attention Module (DAM). Efficient-Net is capable of obtaining higher accuracy and enhancing efficiency as compared to existing Convolutional Neural Networks (CNNs). It is also useful to obtain the most generic features as it has been trained on ImageNet. Whereas DAM is very robust in obtaining attention and targeted features while negating the background. In this way, the combination of an efficient and attention module is useful to obtain the robust, and intrinsic features to obtain comparable performance. Further, we evaluated the proposed network on two well-known datasets (i) Our generated thyroid dataset (ii) Mendeley Cervical dataset (Hussain in Data Brief, 2019) with enhanced performance compared to their counterparts. CytoNet demonstrated a 99% accuracy rate on the thyroid dataset in comparison to its counterpart. The precision, recall, and F1-score values achieved on the Mendeley Cervical dataset are 0.992, 0.985, and 0.977, respectively. The code implementation is available on GitHub. https://github.com/naveedilyas/CytoNet-An-Efficient-Dual-Attention-based-Automatic-Prediction-of-Cancer-Sub-types-in-Cytol.

Cancer genomes are rife with genetic variants; one key outcome of this variation is widespread gain-of-cysteine mutations. These acquired cysteines can be both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain unidentified via chemoproteomics; identification is a critical step to enable functional analysis, including assessment of potential druggability and susceptibility to oxidation. Here, we pair cysteine chemoproteomics-a technique that enables proteome-wide pinpointing of functional, redox sensitive, and potentially druggable residues-with genomics to reveal the hidden landscape of cysteine genetic variation. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, and RNA-seq data, with a customized two-stage false discovery rate (FDR) error controlled proteomic search, which is further enhanced with a user-friendly FragPipe interface. Chemoproteogenomics analysis reveals that cysteine acquisition is a ubiquitous feature of both healthy and cancer genomes that is further elevated in the context of decreased DNA repair. Reference cysteines proximal to missense variants are also found to be pervasive, supporting heretofore untapped opportunities for variant-specific chemical probe development campaigns. As chemoproteogenomics is further distinguished by sample-matched combinatorial variant databases and is compatible with redox proteomics and small molecule screening, we expect widespread utility in guiding proteoform-specific biology and therapeutic discovery.

In cancer research, RAS biology has been focused on only a handful of tumor types. While RAS genes have long been suspected as common contributors to a wide spectrum of cancer types, robust evidence is required to firmly establish their critical oncogenic significance. We present a data mining study using DepMap genome-wide CRISPR screening data, which provide substantial evidence to support the prominent pervasive oncogenic role and tissue-specific permissiveness of RAS gene mutations. Differential analysis of CRISPR effect scores identifies K- or N-RAS genes as the most differential gene in contrasts of (K-, N-, combined) RAS mutant versus wild-type cell lines across multiple tissue types. The distinguished tissue-specific pattern of KRAS vs. NRAS as top differential genes in subsets of tissue types and evidence from genome data supported the idea of KRAS- and NRAS-engaged tissue types. To our knowledge, this is the first report of prominent pervasive oncogenic role of RAS mutations revealed by gene dependency data that is beyond the current understanding of the oncogenic role of RAS genes and their well-known involved tissue types. Our findings strongly support RAS mutations as primary oncogenic drivers beyond traditionally recognized cancer types and offer insights into their tissue-specific permissiveness.

Profound functional switch of key regulatory factors may play a major role in homeostasis and disease. Dysregulation of circadian rhythm (CR) is strongly implicated in cancer with mechanisms poorly understood. We report here that the function of REV-ERBα, a major CR regulator of the orphan nuclear receptor subfamily, is dramatically altered in tumors in both its genome binding and functional mode. Loss of CR is linked to a functional inversion of REV-ERBα from a repressor in control of CR and metabolic gene programs in normal tissues to a strong activator in different cancers. Through changing its association from NCoR/HDAC3 corepressor complex to BRD4/p300 coactivators, REV-ERBα directly activates thousands of genes including tumorigenic programs such as MAPK and PI3K-Akt signaling. Functioning as a master transcriptional activator, REV-ERBα partners with pioneer factor FOXA1 and directly stimulates a large number of signaling genes, including multiple growth factors, receptor tyrosine kinases, RASs, AKTs, and MAPKs. Moreover, elevated REV-ERBα reprograms FOXA1 to bind new targets through a BRD4-mediated increase in local chromatin accessibility. Pharmacological targeting with SR8278 diminishes the function of both REV-ERBα and FOXA1 and synergizes with BRD4 inhibitor in effective suppression of tumorigenic programs and tumor growth. Thus, our study revealed a functional inversion by a CR regulator in driving gene reprogramming as an unexpected paradigm of tumorigenesis mechanism and demonstrated a high effectiveness of therapeutic targeting such switch.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe Gain Route Identification and Timing In Cancer (GRITIC), a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors. Significance: Complex genomic gains are associated with whole-genome duplications, which are frequent across tumors, span a large fraction of their genomes, and are linked to poorer outcomes. GRITIC infers when these gains occur during tumor development, which will help to identify the genetic events that drive tumor evolution. See related commentary by Taylor, p. 1766.

Immune checkpoint blockade has emerged as a potent new tool in the war on cancer. However, only a subset of cancer patients benefit from this therapeutic modality, sparking a search for combination therapies to increase the fraction of responding patients. We argue here that inhibition of protein phosphatase 2A (PP2A) is a promising approach to increase responses to immune checkpoint blockade and other therapies that rely on the presence of tumor-reactive T cells. Inhibition of PP2A increases neoantigen expression on tumor cells, activates the cGAS/STING pathway, suppresses regulatory T cells, and increases cytotoxic T cell activation. In preclinical models, inhibition of PP2A synergizes with immune checkpoint blockade and emerging evidence indicates that patients who have tumors with mutations in PP2A respond better to immune checkpoint blockade. Therefore, inhibition of PP2A activity may be an effective way to sensitize cancer cells to immune checkpoint blockade and cell-based therapies using tumor-reactive T cells.

BackgroundMethodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies-ESMO-MCBS and ASCO Value Framework-do not integrate these important shortcomings.MethodsWe propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)-that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework.ResultsNot applicable.ConclusionsOur proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

BACKGROUND: Interindividual variability in oncology patients symptom experiences poses significant challenges in prioritizing symptoms for targeted intervention(s). In this study, computational approaches were used to unbiasedly characterize the heterogeneity of the symptom experience of oncology patients to elucidate symptom patterns and drivers of symptom burden. METHODS: Severity ratings for 32 symptoms on the Memorial Symptom Assessment Scale from 3088 oncology patients were analyzed. Gaussian Graphical Model symptom networks were constructed for the entire cohort and patient subgroups identified through unsupervised clustering of symptom co-severity patterns. Network characteristics were analyzed and compared using permutation-based statistical tests. Differences in demographic and clinical characteristics between subgroups were assessed using multinomial logistic regression. RESULTS: Network analysis of the entire cohort revealed three symptom clusters: constitutional, gastrointestinal-epithelial, and psychological. Lack of energy was identified as central to the network which suggests that it plays a pivotal role in patients overall symptom experience. Unsupervised clustering of patients based on shared symptom co-severity patterns identified six patient subgroups with distinct symptom patterns and demographic and clinical characteristics. The centrality of individual symptoms across the subgroup networks differed which suggests that different symptoms need to be prioritized for treatment within each subgroup. Age, treatment status, and performance status were the strongest determinants of subgroup membership. CONCLUSIONS: Computational approaches that combine unbiased stratification of patients and in-depth modeling of symptom relationships can capture the heterogeneity in patients symptom experiences. When validated, the core symptoms for each of the subgroups and the associated clinical determinants may inform precision-based symptom management.

This systematic review examines the landscape of extracellular vesicle (EV)-related clinical trials to elucidate the field's trends in clinical applications and EV-related methodologies, with an additional focus on the acknowledgement of EV subpopulations. By analysing data from public reporting repositories, we catalogued 471 EV-related clinical trials to date, with indications for over 200 diseases. Diagnostics and companion diagnostics represented the bulk of EV-related clinical trials with cancer being the most frequent application. EV-related therapeutics trials mainly utilized mesenchymal stromal cell (MSC) EVs and were most frequently used for treatment of respiratory illnesses. Ultracentrifugation and RNA-sequencing were the most common isolation and characterization techniques; however, methodology for each was not frequently reported in study records. Most of the reported characterization relied on bulk characterization of EV isolates, with only 11% utilizing EV subpopulations in their experimental design. While this may be connected to a lack of available techniques suitable for clinical implementation, it also highlights the opportunity for use of EV subpopulations to improve translational efforts. As academic research identifies more chemically distinct subpopulations and technologies for their enrichment, we forecast to more refined EV trials in the near future. This review emphasizes the need for meticulous methodological reporting and consideration of EV subpopulations to enhance the translational success of EV-based interventions, pointing towards a paradigm shift in personalized medicine.

The frequency of virus-associated cancers is growing worldwide, especially in resource-limited settings. One of the biggest challenges in cancer research among people living with HIV (PLWH) has been understanding how infection with both HIV and Kaposi sarcoma-associated herpesvirus (KSHV) promotes the pathogenesis of Kaposi sarcoma (KS), the most common cancer among PLWH worldwide and a significant public health problem in regions with high prevalence of HIV such as Sub-Saharan Africa (SSA). The AIDS and Cancer Specimen Resource (ACSR) provides samples for research, including dried blood spots (DBS) that were collected from large clinical epidemiology studies of KSHV and KS in PLWH conducted more than a decade ago in SSA. Here, we validated the quality of DNA derived from DBS samples from SSA studies and provided evidence of quantitative recovery of inflammatory cytokines using these DBS samples through comparison with paired frozen plasma. Significant differences in DNA, protein yields, and inflammatory biomarker levels were also observed between PLWH with/without KS. Establishing the fitness of DBS samples for studies of KS pathogenesis extends the number of projects that can be supported by these ACSR special collections and provides evidence that DBS collection for future KS research is a practical option in resource-limited settings.

Cardamom (cardamum) is a spice produced from the seeds of several Elettaria and Amomum plants of the Zingiberaceae family. Cardamom has been demonstrated to offer numerous benefits, including its antioxidant, antimicrobial, anti-inflammatory, and other metabolic (anti-diabetic) properties, and its potential to reduce cancer risk. Recently, researchers have extracted and tested multiple phytochemicals from cardamom to assess their potential effectiveness against various types of human malignancy. These studies have indicated that cardamom can help overcome drug resistance to standard chemotherapy and protect against chemotherapy-induced toxicity due to its scavenging properties. Furthermore, chemical compounds in cardamom, including limonene, cymene, pinene, linalool, borneol, cardamonin, indole-3-carbinol, and diindolylmethane, primarily target the programmed cell death lignin-1 gene, which is more prevalent in cancer cells than in healthy cells. This review provides the medicinal properties and pharmacological uses of cardamom, its cellular effects, and potential therapeutic uses in cancer prevention and treatment, as well as its use in reducing drug resistance and improving the overall health of cancer patients. Based on previous preclinical studies, cardamom shows significant potential as an anti-cancer agent, but further exploration for clinical use is warranted due to its diverse mechanisms of action.

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label phase I/II study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase II dose, and characterize the pharmacokinetics; exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were of grade 1/2 severity. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The recommended phase II dose was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7-46.9), and the objective response rate as assessed by independent radiological review using RECIST version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT not amenable to surgery.

OBJECTIVES: Cancer is a leading cause of death in unhoused adults. We sought to examine the association between housing status, stage at diagnosis and all-cause survival following cancer diagnosis at a public hospital. DESIGN: Retrospective cohort study examining new cancer diagnoses between 1 July 2011 and 30 June 2021. SETTING: A public hospital in San Francisco. EXPOSURE: Housing status (housed, formerly unhoused, unhoused) was ascertained via a county-wide integrated dataset that tracks both observed and reported homelessness. METHODS: We reported univariate analyses to investigate differences in demographic and clinical characteristics by housing group. We then constructed Kaplan-Meier curves stratified by housing group to examine unadjusted all-cause mortality. Finally, we used multivariable Cox proportional hazards models to compare the hazard rate of mortality for each housing status group, adjusting for demographic and clinical factors. RESULTS: Our cohort included 5123 patients with new cancer diagnoses, with 4062 (79%) in housed patients, 623 (12%) in formerly unhoused patients and 438 (9%) in unhoused patients. Unhoused and formerly unhoused patients were more commonly diagnosed with stage 4 disease (28% and 27% of the time, respectively, vs 22% of housed patients). After adjusting for demographic and clinical characteristics, unhoused patients with stage 0-3 disease had a 50% increased hazard of death (adjusted HR (aHR) 1.5, 95% CI 1.1 to 1.9; p

BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

BackgroundImmune checkpoint inhibitor (ICI) therapies have become increasingly popular treatment options for patients with cancer, even for patients in non-metastatic settings. Survival and responses have been reported for individual tumor types, but little is known about these outcomes, collectively. We sought to provide an overview of overall survival (OS) and progression-free survival (PFS) in ICI drugs tested in registration trials.MethodsIn a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we searched for supporting ICI registration trials. We characterized these trials, regarding differences in median OS and PFS between patients in intervention and control arm participants in ICI registration trials; percentage of patients who receive ICI crossover; and whether there is correlation between the percentage of crossover and differences in OS or PFS.ResultsFifty-six (54.4 %) approvals had trials that reported median OS for both intervention and control arms (median difference was 2.8 months; IQR: 2.2 to 5.0 months). Sixty-five (63.1 %) approvals had trials that reported PFS data for both arms (median of 0.9 months; IQR: -0.2 to 3.0 months). Subsequent therapy was common (median=18.9 %) and was significantly correlated with a higher difference in median OS in all studies with reported differences (R2 =0.15; p = 0.001).ConclusionICIs are increasingly used in the treatment of cancer, yet the median OS improvement is modest, and many ICIs have not been tested for OS benefit. OS is the outcome most meaningful for patients, and drug regulation should require better testing and reporting of these data.

ImportanceThere is an increasing number of cancer 'survivors' and increasing research into supportive care. However, it is unknown how patterns of attention and citation differ between supportive and non-supportive cancer care research. We sought to estimate the engagement of high-impact studies of supportive compared to non-supportive cancer care papers.MethodsIn a cross-sectional review of top oncology journals (2016-2023), we reviewed studies examining supportive care strategies and a frequency-matched random sampling of studies on non-supportive interventions. We compared data on social engagement metrics, as represented by Altmetric scores and citations and funding status, by supportive care or non-supportive care articles.ResultsWe found overall Altmetric scores were no different between articles that did not test supportive care and those that did, with a numerically higher score for supportive care articles (86.0 vs 102; p=0.416). Other bibliometric statistics (such as the number of blogs, number of X users, and the number of X posts) obtained from Altmetric did not differ significantly between the two groups. Non-supportive cancer care papers had a significantly higher number of citations than supportive cancer care papers (45.6 in supportive care vs 141 in non-supportive care papers; p

BACKGROUND: The global cancer burden is rising, particularly in low- and middle-income countries (LMIC), highlighting a critical research gap in understanding disparities in supportive care access. To address this, the Multinational Association of Supportive Care in Cancer (MASCC) Health Disparities Committee initiated a global survey to investigate and delineate these disparities. This study aims to explore and compare supportive care access disparities between LMIC and High-Income Countries (HIC). METHODS: An online cross-sectional survey was conducted among active members of MASCC. Members, representing diverse healthcare professions received email invitations. The survey, available for 3 weeks, comprised sections covering (1) sociodemographic information; (2) clinical service/practice-related disparities in their region/nation; (3) population groups facing disparities within their region or country. Chi-squared or Fishers exact test for cross-sectional analyses, and a multivariable logistic regression model was employed for statistical analysis. RESULTS: A total of 218 active members participated, with one-quarter (26.6%) from LMIC and 18.4% ethnic minorities, timely cancer care (43.7%) and timely supportive care (45.0%) emerged as the most pressing disparities globally. Notably, participants from LMIC underscored cancer drug affordability (56.4%) and supportive care guideline implementation (56.4%) as critical issues. Economically disadvantaged populations were noted as more likely to face disparities by both LMIC and HIC (non-US-based) respondents, while US-based respondents identified racial/ethnic minorities as facing more disparities. CONCLUSION: This global survey reveals significant disparities in cancer supportive care between LMIC and HIC, with a particular emphasis on medication affordability and guideline implementation in LMIC. Addressing these disparities requires targeted intervention, considering specific regional priorities.

BACKGROUND: Cancer is the fourth leading cause of death in adolescents and young adults (AYA) worldwide. Although successful treatment of cancer in AYA has increased in recent years in most of the world, this is not true for many low- and middle-income countries (LMIC) where over 80% of all AYA live. This study investigated the needs of AYA with cancer in parts of Latin America (LATAM) through the perspectives of non-physician health care providers and partners. METHODS: Semi-structured interviews (in Spanish) were conducted with non-physician partners from Mexico, Peru, Central America, and the Caribbean over Zoom. Participants were recruited through previously identified local physicians and international non-physician professionals working in these countries. Transcripts were coded and key themes identified until thematic saturation was reached (Atlas.ti). FINDINGS: Thirty participants representing eight countries were interviewed, providing 1202 min of transcript data. Data were organized into barriers, facilitators, and strategies to improve the delivery of health care for AYA with cancer in LATAM at the patient- (e.g., financial barriers, continued schooling), parent- (e.g., limited medical literacy, advocacy), and hospital-level (e.g., structural barriers, increasing funding). INTERPRETATION: There are many similarities in the barriers and facilitators to AYA care between LATAM and high-income countries (HIC); however, some characteristics are more unique to LATAM, for example, strict age restrictions for pediatric care and abandonment of therapy. As LATAM countries continue to build cancer control programs, there is an opportunity to consider our identified barriers, facilitators, and strategies to address the unique needs of AYA with cancer.

BACKGROUND: PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591). PATIENTS AND METHODS: In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed. RESULTS: PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease. CONCLUSIONS: Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.

Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.

The review article titled CD39 Transforming Cancer Therapy by Modulating Tumor Microenvironment published in June 2024 in Cancer Letters provides a comprehensive overview of CD39's multifaceted roles in cancer, particularly its influence on immunoregulation, angiogenesis, and metabolic reprogramming within the tumor microenvironment (TME). This commentary builds on that foundation by incorporating recent advancements in CD39 research, highlighting unresolved issues, and proposing future research directions. We delve into the therapeutic potential of targeting CD39, addressing clinical translation challenges, and exploring the integration of CD39-based strategies into precision oncology.

Lifelong, guideline-based monitoring for late effects is recommended for childhood cancer survivors (CCS). We examined rates of receiving surveillance tests among at-risk young adult CCS in a population-based study (n = 253; 50% Hispanic/Latino; mean post-treatment interval 14.5 years, range: 5-22). Adherence rates were 36.1%, 31.9%, and 36.4% among those indicated for cardiac (n = 119), thyroid (n = 68), and breast (n = 66) surveillance, respectively, indicating that poor surveillance among long-term CCS is widespread. Receipt of any of these surveillance tests was positively associated with being in follow-up care, having any health insurance (vs. none), and receiving education about need for follow-up with surveillance (all p-values less than .05).