Showing papers in "International Journal of Cancer in 2021"

Cancer statistics for the year 2020: An overview

Abstract: Our study briefly reviews the data sources and methods used in compiling the International Agency for Research on Cancer (IARC) GLOBOCAN cancer statistics for the year 2020 and summarises the main results. National estimates were calculated based on the best available data on cancer incidence from population-based cancer registries (PBCR) and mortality from the World Health Organization mortality database. Cancer incidence and mortality rates for 2020 by sex and age groups were estimated for 38 cancer sites and 185 countries or territories worldwide. There were an estimated 19.3 million (95% uncertainty interval [UI]: 19.0-19.6 million) new cases of cancer (18.1 million excluding non-melanoma skin cancer) and almost 10.0 million (95% UI: 9.7-10.2 million) deaths from cancer (9.9 million excluding non-melanoma skin cancer) worldwide in 2020. The most commonly diagnosed cancers worldwide were female breast cancer (2.26 million cases), lung (2.21) and prostate cancers (1.41); the most common causes of cancer death were lung (1.79 million deaths), liver (830000) and stomach cancers (769000).

A meta-analysis of anal cancer incidence by risk group: Toward a unified anal cancer risk scale.

Abstract: Certain population groups are known to have higher than average anal cancer risk, namely persons living with HIV (PLHIV), men who have sex with men (MSM), women diagnosed with human papillomavirus (HPV)-related gynecological precancerous lesions or cancer, solid organ transplant recipients (SOTRs) and patients with autoimmune diseases. Our aim was to provide robust and comparable estimates of anal cancer burden across these groups. Summary incidence rates (IRs), as cases per 100 000 person-years (py), were calculated by fixed-effects meta-analysis. IRs were 85 (95% confidence interval [CI] = 82-89) for HIV-positive MSM (n = 7 studies; 2 229 234 py), 32 (95% CI = 30-35) for non-MSM male PLHIV (n = 5; 1626 448 py) and 22 (95% CI = 19-24) for female PLHIV (n = 6; 1 472 123 py), with strong variation by age (eg, from 16.8 10 years after transplant. Anal cancer IRs were 10 (95% CI = 5-19), 6 (95% CI = 3-11) and 3 (95% CI = 2-4) for systemic lupus erythematosus, ulcerative colitis and Crohn's disease, respectively. In conclusion, a unifying anal cancer risk scale, based upon comprehensive meta-analysis, can improve prioritization and standardization in anal cancer prevention/research initiatives, which are in their public health infancy.

Estimated global cancer incidence in the oldest adults in 2018 and projections to 2050

Abstract: Using GLOBOCAN estimates, we describe the estimated cancer incidence among adults aged 80 years or older at the regional and global level in 2018, reporting the number of new cancer cases, and the truncated age-standardised incidence rates (per 100 000) for all cancer sites combined for this age group. We also presented the five most frequent cancers diagnosed by region and globally among females and males aged 65 to 79 years old and 80 years or older. We, finally, estimated the number of new cancer cases in 2050, the proportion of cases aged 80 years or older, and the proportional increase between 2018 and 2050 by region, by applying population projections to the 2018 incidence rates. In 2018, an estimated 2.3 million new cancer cases (excluding nonmelanoma skin cancers) were aged 80 years or older worldwide (13% of all cancer cases), with large variation in the profiles at regional levels. Globally, breast, lung and colon were the most common cancer sites diagnosed in the oldest females, while prostate, lung and colon were most frequent in the oldest males. In 2050, an estimated 6.9 million new cancers will be diagnosed in adults aged 80 years or older worldwide (20.5% of all cancer cases). Due to the complexity of cancer management in the oldest patients, the expected increase will challenge healthcare systems worldwide, posing a tangible economic and social impact on families and society. It is time to consider the oldest population in cancer control policies.

Liquid biopsies: Potential and challenges.

Abstract: The analysis of tumor cells or tumor cell products obtained from blood or other body fluids ("liquid biopsy" [LB]) provides a broad range of opportunities in the field of oncology. Clinical application areas include early detection of cancer or tumor recurrence, individual risk assessment and therapy monitoring. LB allows to portray the entire disease as tumor cells or tumor cell products are released from all metastatic or primary tumor sites, providing comprehensive and real-time information on tumor cell evolution, therapeutic targets and mechanisms of resistance to therapy. Here, we focus on the most prominent LB markers, circulating tumor cells (CTCs) and circulating tumor-derived DNA (ctDNA), in the blood of patients with breast, prostate, lung and colorectal cancer, as the four most frequent tumor types in Europe. After a brief introduction of key technologies used to detect CTCs and ctDNA, we discuss recent clinical studies on these biomarkers for early detection and prognostication of cancer as well as prediction and monitoring of cancer therapies. We also point out current methodological and biological limitations that still hamper the implementation of LB into clinical practice.

Cancer associates with risk and severe events of COVID-19: A systematic review and meta-analysis.

Abstract: Evidence is mounting to indicate that cancer patients may have more likelihood of having coronavirus disease 2019 (COVID-19) but lack consistency. A robust estimate is urgently needed to convey appropriate information to the society and the public, in the time of ongoing COVID-19 pandemic. We performed a systematic review and meta-analysis through a comprehensive literature search in major databases in English and Chinese, and two investigators conducted publication selection and data extraction independently. A meta-analysis was used to obtain estimates of pooled prevalence of cancer in patients with COVID-19 and determine the association of cancer with severe events, after assessment of potential heterogeneity, publication bias, and correction for the estimates when necessary. Total 38 studies comprising 7094 patients with COVID-9 were included; the pooled prevalence of cancer was estimated at 2.3% (95% confidence limit [CL] [0.018, 0.029]; P < .001) overall and 3.2% (95% CL [0.023, 0.041]; P < .001) in Hubei province; the corresponding estimates were 1.4% and 1.9% after correction for publication bias; cancer was significantly associated with the events of severe cases (odds ratio [OR] = 2.20, 95% CL [1.53, 3.17]; P < .001) and death (OR = 2.97, 95% CL [1.48, 5.96]; P = .002) in patients with COVID-19, there was no significant heterogeneity and a minimal publication bias. We conclude that cancer comorbidity is associated with the risk and severe events of COVID-19; special measures should be taken for individuals with cancer.

Novel insights into the function of CD24: A driving force in cancer.

Abstract: CD24 is a highly glycosylated protein with a small protein core that is linked to the plasma membrane via a glycosyl-phosphatidylinositol anchor. CD24 is primarily expressed by immune cells but is often overexpressed in human tumors. In cancer, CD24 is a regulator of cell migration, invasion and proliferation. Its expression is associated with poor prognosis and it is used as cancer stemness marker. Recently, CD24 on tumor cells was identified as a phagocytic inhibitor ("do not eat me" signal) having a suppressive role in tumor immunity via binding to Siglec-10 on macrophages. This finding is reminiscent of the demonstration that soluble CD24-Fc can dampen the immune system in autoimmune disease. In the present review, we summarize recent progress on the role of the CD24-Siglec-10 binding axis at the interface between tumor cells and the immune system, and the role of CD24 genetic polymorphisms in cancer. We describe the specific function of cytoplasmic CD24 and discuss the presence of CD24 on tumor-released extracellular vesicles. Finally, we evaluate the potential of CD24-based immunotherapy.

The role of exosomes in liquid biopsy for cancer diagnosis and prognosis prediction.

Abstract: Liquid biopsy is a revolutionary strategy in cancer diagnosis and prognosis prediction, which is used to analyze cancer cells or cancer-derived products through biofluids such as blood, urine and so on. Exosomes play a crucial role in mediating cell communication. A growing number of studies have reported that exosomes are involved in tumorigenesis, tumor growth, metastasis and drug resistance by delivering cargos including nucleic acids and protein. Thus, exosomes, as a new type of liquid biopsy, have the potential to be diagnostic or prognostic biomarkers. Herein, we elaborate on the current methods and introduce novel techniques for exosome isolation and characterization. Moreover, we elucidate the advantages of exosomes compared to other biological components in liquid biopsy and summarize the different exosomal biomarkers in cancer diagnosis and prognosis prediction.

Epithelial-to-mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities

Abstract: Oral squamous cell carcinoma (OSCC) is the most common malignancy representing 90% of all forms of oral cancer worldwide. Although great efforts have been made in the past decades, the 5-year survival rate of OSCC patients is no more than 60% due to tumor metastasis and subsequent recurrence. The metastasis from the primary site is due to a complex process known as epithelial-to-mesenchymal transition (EMT). During the EMT, epithelial cells gradually acquire the structural and functional characteristics of mesenchymal cells, leading to the upregulation of cell migration and the promotion of tumor cell dissemination. Therefore, EMT attracted broad attention due to its close relationship with cancer invasion and metastasis. Therefore, in the present review, an extensive description of the current research on OSCC and the role of EMT in this cancer type is provided, including diverse EMT markers, regulatory networks and crucial EMT-inducing transcription factors in OSCC. Moreover, a brief summary was made regarding the current application of EMT-correlated indexes in the prognostic analysis of OSCC patients, and the potential therapeutic approaches against OSCC and difficulties in the development of an effective anti-EMT treatment are discussed. Our aim is to provide novel insights to develop new strategies to combat OSCC by targeting EMT.

Is it possible to halve the incidence of liver cancer in China by 2050

Abstract: A substantial proportion of liver cancers is attributable to chronic infection with hepatitis B and C (HBV/HCV). Liver cancer could become the second cancer, after cervical, to be effectively controlled globally, if proven interventions such as vaccination can be implemented on a large scale. In 2018, the global mortality rate for liver cancer was estimated to be 8.5 per 100 000 individuals. Given patterns of HBV infection and immigration across countries, liver cancer control requires combined, global action. Liver cancer trends vary between countries, in some Western countries, the incidence rates were relatively low but have increased in recent decades; conversely, in several Asian countries, the incidence rates have decreased over time. China has in the past contributed more than half of the global burden of liver cancer but more recently a national decline in liver cancer incidence has been observed. Here, we review the liver cancer burden and exposure to risk factors in China, compared to other countries. We also review the implementation status for primary and secondary prevention interventions and major outcomes achieved over the past three decades. Using Bayesian age-period-cohort analysis, we examine recent trends and based on these, predict that by 2050, the incidence of liver cancer in China could fall by half. We additionally survey the literature to identify current research needs, and review relevant national policies on liver cancer control in China. A comprehensive set of interventions is proposed to progress toward the long-term goal of liver cancer elimination based on the natural history and evidence-based interventions.

Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies.

Abstract: Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4-6, 6-8 and 8-10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.

Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer.

Abstract: Lipocalin 2 is a siderophore binding protein that regulates iron homeostasis. Lipocalin 2 expression is elevated in multiple tumor types; however, the mechanisms that drive tumor progression upon Lipocalin 2 expression remain unclear. When Lipocalin 2 is over-expressed it leads to resistance to 5-fluorouracil in colon cancer cell lines in vitro and in vivo by inhibiting ferroptosis. Lipocalin 2 inhibits ferroptosis by decreasing intracellular iron levels and stimulating the expression of glutathione peroxidase4 and a component of the cysteine glutamate antiporter, xCT. The increase in xCT levels is dependent on increased levels of ETS1 in Lipocalin 2 over-expressing cells. Inhibiting Lipocalin 2 function with a monoclonal antibody leads to a decrease in chemo-resistance and transformation in vitro, and a decrease in tumor progression and chemo-resistance in xenograft mouse models. Lipocalin 2 and xCT levels exhibit a positive correlation in human tumor samples suggesting that the pathway we have identified in cell lines is operative in human tumor samples. These results indicate that Lipocalin 2 is a potential therapeutic target and that the monoclonal antibody described in this study can serve as the basis for a potential therapeutic in patients that do not respond to chemotherapy.

muTarget: A platform linking gene expression changes and mutation status in solid tumors.

Abstract: Large oncology repositories have paired genomic and transcriptomic data for all patients. We used these data to perform two independent analyses: to identify gene expression changes related to a gene mutation and to identify mutations altering the expression of a selected gene. All data processing steps were performed in the R statistical environment. RNA-sequencing and mutation data were acquired from The Cancer Genome Atlas (TCGA). The DESeq2 algorithm was applied for RNA-seq normalization, and transcript variants were annotated with AnnotationDbi. MuTect2-identified somatic mutation data were utilized, and the MAFtools Bioconductor program was used to summarize the data. The Mann-Whitney U test was used for differential expression analysis. The established database contains 7876 solid tumors from 18 different tumor types with both somatic mutation and RNA-seq data. The utility of the approach is presented via three analyses in breast cancer: gene expression changes related to TP53 mutations, gene expression changes related to CDH1 mutations and mutations resulting in altered progesterone receptor (PGR) expression. The breast cancer database was split into equally sized training and test sets, and these data sets were analyzed independently. The highly significant overlap of the results (chi-square statistic = 16 719.7 and P < .00001) validates the presented pipeline. Finally, we set up a portal at http://www.mutarget.com enabling the rapid identification of novel mutational targets. By linking somatic mutations and gene expression, it is possible to identify biomarkers and potential therapeutic targets in different types of solid tumors. The registration-free online platform can increase the speed and reduce the development cost of novel personalized therapies.

Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD‐L1‐positive locally advanced or metastatic non–small‐cell lung cancer: KEYNOTE‐042 China Study

Abstract: In the global KEYNOTE‐042 study (Clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02220894","term_id":"NCT02220894"}}NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD‐L1)‐positive locally advanced/metastatic non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE‐042 enrolled from China in the global or extension study ({"type":"clinical-trial","attrs":{"text":"NCT03850444","term_id":"NCT03850444"}}NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD‐L1 tumor proportion score [TPS] ≥50% vs 1%‐49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD‐L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty‐two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow‐up, 33.0 [range, 25.6‐41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD‐L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43‐0.94]), TPS ≥20% (0.66 [0.47‐0.92]) and TPS ≥1% (0.67 [0.50‐0.89]). Grade 3 to 5 treatment‐related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE‐042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD‐L1 TPS ≥1%, supporting first‐line pembrolizumab monotherapy for PD‐L1‐positive advanced/metastatic NSCLC in China.

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization

Abstract: At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10−4). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR =.011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR =.008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR =.036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR =.746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer. (Less)

Drugging “undruggable” genes for cancer treatment: Are we making progress?

Abstract: RAS, TP53 (p53) and MYC are among the most frequently altered driver genes in cancer. Thus, RAS is the most frequently mutated oncogene, MYC the most frequently amplified gene and TP53 the most frequently mutated tumor suppressor gene and overall the most frequently mutated gene in cancer. Theoretically, therefore, these genes are highly attractive targets for cancer treatment. However, as the protein products of each of these genes lack an accessible hydrophobic pocket into which low molecular weight compounds might bind with high affinity, they have proved difficult to target and have traditionally been referred to as "undruggable." Despite this branding, several low molecular weight compounds targeting each of these proteins have recently been reported to have anticancer activity in preclinical models. Indeed, several drugs inhibiting mutant KRAS, MYC overexpression or reactivating mutant p53 have undergone or are currently undergoing clinical trials. For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a Phase III stage, that is, the mutant-p53 reactivating drug, APR-246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti-MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being "undruggable" would appear to be coming to an end.

Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study.

Abstract: In HPV cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID-SCREEN is a EU-multicentre, retrospective study conducted to evaluate the clinical performance of the FAM19A4/miR124-2 methylation-based molecular triage test as a substitute or addition to cytology as reflex testing of HPV screen positive women. FAM19A4/miR124-2 methylation test (QIAsure™ Methylation Test) was evaluated in 2384 HPV-positive cervical screening samples, from women 29-76 years of age, derived from four EU countries. Specimens were collected in ThinPrep or SurePath media, HPV-status, concurrent cytology, and histology diagnosis were provided by the parent institutes. The control population consisted of women with no evidence of disease within two years of follow-up. A total of 899 histologies were retrieved; 527 showed no disease, 124 CIN2 (5.2%), 228 CIN3 (9.6%) and 20 cervical cancers (0.8%); 19 of 20 screen-detected cervical cancers were found methylation-positive (sensitivity 95%). Overall specificity of FAM19A4/miR124-2 methylation test was 78.3% (n=2013; 95%CI: 76-80). The negative predictive value of hrHPV positive, methylation-negative outcomes were 99.9% for cervical cancer (N=1694; 95%CI: 99.6-99.99), 96.9% for ≥CIN3 (95%CI: 96-98), and 93.0% for ≥CIN2 (95%CI: 92-94). Overall sensitivity for CIN3 using FAM19A4/miR124-2 methylation test was 77% (n=228; 95%CI: 71-82). CIN3 sensitivity was uniform between centers independent of sample collection medias, DNA extraction methods and HPV screening tests. Being objectively reported compared to the subjectivity of cytology, equally performing across settings and screening methods, the FAM19A4/miR124-2 methylation constitute an alternative/supplement to cytology as triage method to be investigated in real-life pilot implementation. This article is protected by copyright. All rights reserved.

The European response to the WHO call to eliminate cervical cancer as a public health problem.

Abstract: The age-standardised incidence of cervical cancer in Europe varies widely by country (between 3 and 25/100000 women-years) in 2018. Human papillomavirus (HPV) vaccine coverage is low in countries with the highest incidence and screening performance is heterogeneous among European countries. A broad group of delegates of scientific professional societies and cancer organisations endorse the principles of the WHO call to eliminate cervical cancer as a public health problem, also in Europe. All European nations should, by 2030, reach at least 90% HPV vaccine coverage among girls by the age of 15 years and also boys, if cost-effective; they should introduce organised population-based HPV-based screening and achieve 70% of screening coverage in the target age group, providing also HPV testing on self-samples for nonscreened or underscreened women; and to manage 90% of screen-positive women. To guide member states, a group of scientific professional societies and cancer organisations engage to assist in the rollout of a series of concerted evidence-based actions. European health authorities are requested to mandate a group of experts to develop the third edition of European Guidelines for Quality Assurance of Cervical Cancer prevention based on integrated HPV vaccination and screening and to monitor the progress towards the elimination goal. The occurrence of the COVID-19 pandemic, having interrupted prevention activities temporarily, should not deviate stakeholders from this ambition. In the immediate postepidemic phase, health professionals should focus on high-risk women and adhere to cost-effective policies including self-sampling.

Dysbiosis of the endometrial microbiota and its association with inflammatory cytokines in endometrial cancer.

Abstract: The underlying molecular mechanisms involved in the pathogenesis of endometrial cancer (EC) are still not well understood. Our goal was to investigate the composition of the endometrial microbiota and the association with inflammatory cytokines in EC. Endometrial microbiota profiles of women with EC (n = 25) and benign uterine lesions (BUL, n = 25) were assessed by 16S ribosomal RNA gene amplicon sequencing. The expression levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-17 (IL-17) mRNA and protein in the endometrial tissues of the two groups were determined by real-time quantitative polymerase chain reaction and Western blot, respectively. There were significant differences in alpha diversity based on the observed operational taxonomic units (P = .002), Pielou evenness (P = .001), and Shannon index (P < .001) between EC and BUL groups. Significant differences were also found in Bray-Curtis (P = .001) and unweighted UniFrac (P = .001) beta diversity measures between the two groups. At the genus level, Micrococcus was more abundant in the EC group. Pseudoramibacter_Eubacterium, Rhodobacter, Vogesella, Bilophila, Rheinheimera, and Megamonas were enriched in the BUL group. There were no differences in IL-8 and IL-17 protein levels between the two groups, except IL-6 protein levels. However, the mRNA expression levels of IL-6, IL-8, and IL-17 were significantly different. Moreover, the relative abundances of Micrococcus was positively correlated with IL-6, and IL-17 mRNA levels. In conclusion, our results suggested that dysbiosis of endometrial microbiota and the inflammatory cytokines were associated with Micrococcus in EC patients, which might be useful for exploration of the mechanism between the endometrial microbiota and inflammatory responses in future studies.

GSDME and its role in cancer: From behind the scenes to the front of the stage

Abstract: Gasdermin E (GSDME), a gene originally involved in hereditary hearing loss, has been associated with several types of cancer in the last two decades. Recently, GSDME was identified as a pore-forming molecule, which is activated following caspase-3-mediated cleavage resulting in so-called secondary necrosis following apoptotic cell death, or in primary necrotic cell death without an apoptotic phase, so-called pyroptosis-like. This implication in cell death execution suggests its potential role as a tumor suppressor. GSDME also exhibited a cancer type-specific differential methylation pattern between tumor tissues and normal cells, implying GSDME gene methylation as both a pan-cancer and cancer type-specific detection biomarker. A bit paradoxically, GSDME protein expression is considered to be less suited as biomarker, and although its ablation does not protect the cell against eventual cell death, its protein expression might still operate in tumor immunogenicity due to its capacity to induce (secondary) necrotic cell death, which has enhanced immunogenic properties. Additionally, GSDME gene expression has been shown to be associated with favorable prognosis following chemotherapy, and it could therefore be a potential predictive biomarker. We provide an overview of the different associations between GSDME gene methylation, gene expression and tumorigenesis, and explore their potential use in the clinic. Our review only focuses on GSDME and summarizes the current knowledge and most recent advances on GSDME's role in cancer formation, its potential as a biomarker in cancer and on its promising role in immunotherapies and antitumor immune response.

Burden of pancreatic cancer along with attributable risk factors in Europe between 1990 and 2019, and projections until 2039.

Abstract: Projecting the burden of pancreatic cancer over time provides essential information to effectively plan measures for its management and prevention. Here, we obtained data from the Global Burden of Disease (GBD) Study between 1990 and 2019, to model how pancreatic cancer will affect the 27 countries of the European Union (EU) plus the United Kingdom (the pre-Brexit EU-28) until 2039 by conducting the Bayesian age-period-cohort analysis. The number of new pancreatic cancer cases in the EU-28 was 59 000 in 1990, 109 000 in 2019 and projected to be 147 000 in 2039. This corresponded to 60 000, 109 000 and 155 000 for deaths, and a loss of 1.3 million, 2.0 million and 2.7 million for disability-adjusted life years (DALYs), respectively. The most pronounced increase of the crude incidence rate was observed and projected to be in the population older than 80 years. The age-standardized rate (ASR) of incidence, however, increased from 8.6 to 10.1 per 100 000 person-years during 1990-2019 but was projected to remain stable during 2019-2039. At the same time, our models only predicted a mild increase in the ASR of mortality until 2039. The fraction of pancreatic cancer mortality attributable to tobacco consumption decreased during 1990-2019, but we found upward trends for the attributable fractions for high fasting plasma glucose and high body mass index. In conclusion, a substantial increase in counts of incidence, mortality and DALYs lost of pancreatic cancer in the EU-28 is projected over the next two decades, which indicates the need for future health policies and interventions.

The "unnatural" history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance

Abstract: Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.

Vulvar intraepithelial neoplasia: Incidence and long-term risk of vulvar squamous cell carcinoma.

Abstract: The risk of vulvar squamous cell carcinoma (VSCC) in patients with high-grade vulvar intraepithelial neoplasia (VIN) is considered lower in high-grade squamous intraepithelial lesion (HSIL) compared to differentiated VIN (dVIN), but studies are limited. Our study investigated both the incidence of high-grade VIN and the cumulative incidence of VSCC in patients with HSIL and dVIN separately. A database of women diagnosed with high-grade VIN between 1991 and 2011 was constructed with data from the Dutch Pathology Registry (PALGA). The European standardized incidence rate (ESR) and VSCC risk were calculated, stratified for HSIL and dVIN. The effects of type of VIN (HSIL vs dVIN), age and lichen sclerosis (LS) were estimated by Cox regression. In total, 1148 patients were diagnosed with high-grade VIN between 1991 and 2011. Between 1991-1995 and 2006-2011, the ESR of HSIL increased from 2.39 (per 100 000 woman-years) to 3.26 and the ESR of dVIN increased from 0.02 to 0.08. The 10-year cumulative VSCC risk was 10.3%; 9.7% for HSIL and 50.0% for dVIN (log rank P < .001). Type of VIN, age and presence of LS were independent risk factors for progression to VSCC, with hazard ratios of 3.0 (95% confidence interval [CI] 1.3-7.1), 2.3 (95% CI 1.5-3.4) and 3.1 (95% CI 1.8-5.3), respectively. The incidence of high-grade VIN is rising. Because of the high cancer risk in patients with dVIN, better identification and timely recognition are urgently needed.

Circulating insulin‐like growth factor‐I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank

Abstract: Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two-sample Mendelian randomisation (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis- and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment = 1.34, 1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.

Ibrutinib for improved chimeric antigen receptor T‐cell production for chronic lymphocytic leukemia patients

Abstract: Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naive-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naive-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.

Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers.

Abstract: Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue-DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA [median, 2 (range, 0-9)] and 100% (90/90) for tissue-DNA [median, 4 (range, 1-9)]. Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue-DNA. In 40 patients who had both ctDNA and tissue-DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue-DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA [But not statistical significance]). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression-free survival (hazard ratio [95%confidence interval], 0.60 [0.37-0.99]. P = .047 [multivariate]) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue-DNA is feasible in biliary tract cancers.

Trastuzumab in combination with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: A phase II trial of the AIO Gastric Cancer Study Group

Abstract: Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in patients with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24-hours 5-FU 2600 mg/m2 , leucovorin 200 mg/m2 , oxaliplatin 85 mg/mg2 , docetaxel 50 mg/m2 , trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER-2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease-free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty-six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3-4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3-year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising.

Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial.

Abstract: Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double-blind, placebo-controlled Phase II study in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count <0.5 × 109 cells per L) in Cycle 1 and occurrence of SN during the treatment period. Other endpoints were prespecified to assess the effects of trilaciclib on additional measures of myelopreservation, patient-reported outcomes, antitumour efficacy and safety. Fifty-two patients received trilaciclib prior to E/P/A and 53 patients received placebo. Compared to placebo, administration of trilaciclib resulted in statistically significant decreases in the mean duration of SN in Cycle 1 (0 vs 4 days; P < .0001) and occurrence of SN (1.9% vs 49.1%; P < .0001), with additional improvements in red blood cell and platelet measures and health-related quality of life (HRQoL). Trilaciclib was well tolerated, with fewer grade ≥3 adverse events compared with placebo, primarily due to less high-grade haematological toxicity. Antitumour efficacy outcomes were comparable. Administration of trilaciclib vs placebo generated more newly expanded peripheral T-cell clones (P = .019), with significantly greater expansion among patients with an antitumour response to E/P/A (P = .002). Compared with placebo, trilaciclib administered prior to E/P/A improved patients' experience of receiving treatment for ES-SCLC, as shown by reduced myelosuppression, and improved HRQoL and safety profiles.

S100 calcium-binding protein A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma.

Abstract: Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.

Histone lysine demethylases and their functions in cancer.

Abstract: Histone lysine demethylases (KDMs) are enzymes that remove the methylation marks on lysines in nucleosomes' histone tails. These changes in methylation marks regulate gene transcription during both development and malignant transformation. Depending on which lysine residue is targeted, the effect of a given KDM on gene transcription can be either activating or repressing, and KDMs can regulate the expression of both oncogenes and tumour suppressors. Thus, the functions of KDMs can be regarded as both oncogenic and tumour suppressive, contingent on cell context and the enzyme isoform. Finally, KDMs also demethylate nonhistone proteins and have a variety of demethylase-independent functions. These epigenetic and other mechanisms that KDMs control make them important regulators of malignant tumours. Here, we present an overview of eight KDM subfamilies, their most-studied lysine targets and selected recent data on their roles in cancer stem cells, tumour aggressiveness and drug tolerance.

Caspase-8: A key protein of cross-talk signal way in "PANoptosis" in cancer.

Abstract: Cysteinyl aspartate specific proteinase (Caspase)-8 has long been considered a promoter of apoptosis and part of the mechanism by which cytotoxic drugs kill cancer cells. With the continuous exploration of the types of programmed cell death, an increasing number of studies have confirmed that caspase-8 plays an important role in cancer. Recently, scholars have proposed the term "PANoptosis," which mainly includes three programmed cell death modes, namely pyroptosis, apoptosis and necroptosis. In addition to mediating endogenous apoptotic pathways, caspase-8 can also participate in the cleavage of gasdermin (GSDM) family proteins to induce pyroptosis. Furthermore, the expression of enzymatically inactive caspase-8 (C362S) can cause embryonic lethality and inflammatory tissue destruction in mice by inducing necroptosis and pyroptosis. Therefore, the activation and deletion of caspase-8 enzyme activity, as well as the knockout of the coding gene, are closely related to "PANoptosis." In addition, caspase-8 can also improve the tumor microenvironment and enhance tumor antiimmunity. Studies have shown that caspase-8 is also associated with tumor growth and invasion, angiogenesis and metastasis, therapeutic resistance and poor clinical outcomes. Therefore, it is very important to measure the cancer-promoting and anticancer effects of caspase-8 and find a balance, and to study its role in the effect of "PANoptosis" in depth. This article reviews the role of caspase-8 in "PANoptosis" in cancer to provide new strategies and targets for cancer.