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This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1- and 2-year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p = .0208), or N (83.8%, 75.2%; p = .0539). BRAF-mutated(mut) CM demonstrated significantly lower PFS (p = .0022) and decreased DMFS (p = .0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS-mut CM tended to perform worse than wt CM upon ICI (PFS: p = .1349; DMFS: p = .0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p < .001), without significant differences between the subgroups. Organ-specific DMFS was significantly altered for primary cases with bone (p = .0367) or brain metastases (p = .0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS-mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF-mut CM., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Experimental research has uncovered lipocalin 2 (LCN2) as a novel biomarker implicated in the modulation of intestinal inflammation, metabolic homeostasis, and colon carcinogenesis. However, evidence from human research has been scant. We, therefore, explored the association of pre-diagnostic circulating LCN2 concentrations with incident colorectal cancer (CRC) in a nested case-control study within the in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. LCN2 was measured in 1267 incident CRC cases matched to 1267 controls using incidence density sampling. Conditional logistic regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) according to tumor subsite and sex. Weighted Cox proportional hazard regression was used to explore associations by adiposity status. In multivariable-adjusted analyses, the IRR [95% CI] per doubling in LCN2 concentration was 1.16 [0.98-1.37] for CRC overall, 1.26 [1.00-1.59] for colon cancer, and 1.08 [0.85-1.38] for rectal cancer. The association for colon cancer was more pronounced in women (IRR [95% CI], 1.66 [1.20-2.30]) and for proximal colon cancer (IRR [95% CI], 1.96 [1.15-3.34]), whereas no association was seen in men and distal colon cancer. The association for colon cancer was positive in individuals with high waist circumference (hazard ratio [95% CI], 1.69 [1.52-1.88]) and inverse in individuals with low waist circumference (hazard ratio [95% CI], 0.86 [0.76-0.98], P interaction<0.01). Overall, these data suggest that pre-diagnostic LCN2 concentrations were positively associated with colon cancer, particularly occurring in the proximal colon, in women and among individuals with abdominal adiposity., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer cells in single-cell data. We find that our method and others based on gene expression or allelic imbalances identify overlapping sets of colorectal cancer versus normal colon epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10 -5 ). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association., (© 2024 UICC.)

Nasopharyngeal carcinoma (NPC) risk prediction models based on Epstein-Barr virus (EBV)-antibody testing have shown potential for screening of NPC; however, the long-term stability is unclear. Here, we investigated the kinetics of two EBV-antibody NPC risk scores within the Taiwan NPC Multiplex Family Study. Among 545 participants with multiple blood samples, we evaluated the stability of a 2-marker enzyme-linked immunosorbent assay score and 13-marker multiplex serology score using the intra-class correlation coefficient (ICC) by fitting a linear mixed model that accounted for the clustering effect of multiple measurements per subject and age. We also estimated the clustering of positive tests using Fleiss's kappa statistic. Over an average 20-year follow-up, the 2-marker score showed high stability over time, whereas the 13-marker score was more variable (p < .05). Case-control status is associated with the kinetics of the antibody response, with higher ICCs among cases. Positive tests were more likely to cluster within the same individual for the 2-marker score than the 13-marker score (p < .05). The 2-marker score had an increase in specificity from ~90% for single measurement to ~96% with repeat testing. The 13-marker score had a specificity of ~73% for a single measurement that increased to ~92% with repeat testing. Among individuals who developed NPC, none experienced score reversion. Our findings suggest that repeated testing could improve the specificity of NPC screening in high-risk NPC multiplex families. Further studies are required to determine the impact on sensitivity, establish optimal screening intervals, and generalize these findings to general population settings in high-risk regions., (© 2024 UICC.)

Measuring pre-diagnostic blood metabolites may help identify novel risk factors for prostate cancer. Using data from 4387 matched case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we investigated the associations of 148 individual metabolites and three previously defined metabolite patterns with prostate cancer risk. Metabolites were measured by liquid chromatography-mass spectrometry. Multivariable-adjusted conditional logistic regression was used to estimate the odds ratio per standard deviation increase in log metabolite concentration and metabolite patterns (OR1SD) for prostate cancer overall, and for advanced, high-grade, aggressive. We corrected for multiple testing using the Benjamini-Hochberg method. Overall, there were no associations between specific metabolites or metabolite patterns and overall, aggressive, or high-grade prostate cancer that passed the multiple testing threshold (padj <0.05). Six phosphatidylcholines (PCs) were inversely associated with advanced prostate cancer diagnosed at or within 10 years of blood collection. metabolite patterns 1 (64 PCs and three hydroxysphingomyelins) and 2 (two acylcarnitines, glutamate, ornithine, and taurine) were also inversely associated with advanced prostate cancer; when stratified by follow-up time, these associations were observed for diagnoses at or within 10 years of recruitment (OR 1SD 0.80, 95% CI 0.66-0.96 and 0.76, 0.59-0.97, respectively) but were weaker after longer follow-up (0.95, 0.82-1.10 and 0.85, 0.67-1.06). Pattern 3 (8 lyso PCs) was associated with prostate cancer death (0.82, 0.68-0.98). Our results suggest that the plasma metabolite profile changes in response to the presence of prostate cancer up to a decade before detection of advanced-stage disease., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Treatment modifications and contact restrictions were common during the COVID-19 pandemic and can be stressors for mental health. There is a lack of studies assessing pandemic-related risk factors for anxiety and depression of cancer patients and survivors systematically in multifactorial models. A total of 2391 participants, mean age 65.5 years, ≤5 years post-diagnosis of either lung, prostate, breast, colorectal cancer, or leukemia/lymphoma, were recruited in 2021 via the Baden-Württemberg Cancer Registry, Germany. Sociodemographic information, pandemic-related treatment modifications, contact restrictions, and anxiety/depression (Hospital Anxiety and Depression Scale, HADS) were assessed via self-administered questionnaire. Clinical information (diagnosis, stage, and treatment information) was obtained from the cancer registry. Overall, 22% of participants reported oncological care modifications due to COVID-19, mostly in follow-up care and rehabilitation. Modifications of active cancer treatment were reported by 5.8%. Among those, 50.5% had subclinical anxiety and 55.4% subclinical depression (vs. 37.4% and 45.4%, respectively, for unchanged active treatment). Age <60 years, female sex, lung cancer, low income, and contact restrictions to peer support groups or physicians were identified as independent risk factors for anxiety. Risk factors for depression were lung cancer (both sexes), leukemia/lymphoma (females), recurrence or palliative treatment, living alone, low income, and contact restrictions to relatives, physicians, or caregivers. The study demonstrates that changes in active cancer treatment and contact restrictions are associated with impaired mental well-being. The psychological consequences of treatment changes and the importance for cancer patients to maintain regular contact with their physicians should be considered in future responses to threats to public health., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

We aimed to evaluate the role of adjuvant chemotherapy and loco-regional therapy for stage IA (pT1, pN0) triple-negative breast cancer (TNBC) in a real-world setting. We identified patients with pT1, pN0 TNBC diagnosed between 2009 and 2021 within the Baden-Württemberg cancer registry (BWCR), Germany. Overall survival (OS) was assessed using Kaplan-Meier statistics and multivariate Cox regression models (adjusted for age, use of chemotherapy, local therapy (breast conserving therapy [breast conserving surgery + radiotherapy] vs. mastectomy), and tumor histologic subtype). A total of 1231 patients with a median follow-up of 45.9 months were identified: 1.0% (12 of 1231) with pT1mi stage, 9.5% (117 of 1231) with pT1a, 23.7% (292 of 1231) with pT1b, and 65.8% (810 of 1231) with pT1c. Multivariate Cox regression analysis revealed no significant influence for the use of chemotherapy on OS in pT1b patients (HR 0.90, 95% CI 0.43-1.90). For pT1c patients with Grade 1-2 tumors, the use of chemotherapy was not significantly associated OS (HR 1.01, 95% CI 0.48-2.11) but breast conserving therapy was associated with improved OS (HR 0.41, 95% CI 0.18-0.93). For pT1c patients with Grade 3 tumors, the use of chemotherapy (HR 0.51, 95% CI 0.33-0.78) as well as breast conserving therapy (HR 0.42, 95% CI 0.23-0.76) was associated with OS. This data suggests that OS in stage IA TNBC is strongly influenced by local therapy rather than the use of chemotherapy, except for pT1c patients with Grade 3 tumors. Larger studies with longer-term follow-up are welcomed to fully inform this discussion., (© 2024 UICC.)

Endometrial cancer (EC) is one of the most common female cancers and there is currently no routine screening strategy for early detection. An altered abundance of circulating microRNAs (miRNAs) and other RNA classes have the potential as early cancer biomarkers. We analyzed circulating RNA levels using small RNA sequencing, targeting RNAs in the size range of 17-47 nucleotides, in EC patients with samples collected prior to diagnosis compared to cancer-free controls. The analysis included 316 cases with samples collected 1-11 years prior to EC diagnosis, and 316 matched controls, both from the Janus Serum Bank cohort in Norway. We identified differentially abundant (DA) miRNAs, isomiRs, and small nuclear RNAs between EC cases and controls. The top EC DA miRNAs were miR-155-5p, miR-200b-3p, miR-589-5p, miR-151a-5p, miR-543, miR-485-5p, miR-625-p, and miR-671-3p. miR-200b-3p was previously reported to be among one of the top miRNAs with higher abundance in EC cases. We observed 47, 41, and 32 DA miRNAs for EC interacting with BMI, smoking status, and physical activity, respectively, including two miRNAs (miR-223-3p and miR-29b-3p) interacting with all three factors. The circulating RNAs are altered and show temporal dynamics prior to EC diagnosis. Notably, DA miRNAs for EC had the lowest q-value 4.39-6.66 years before diagnosis. Enrichment analysis of miRNAs showed that signaling pathways Fc epsilon RI, prolactin, toll-like receptor, and VEGF had the strongest associations., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID rs9604789 variant with an increased risk of developing the disease (OR Meta  = 1.31, p = 9.67 × 10 -6 ). We also confirmed the association of TP63 rs1515496 and TP63 rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10 -8 and OR = 1.16, p = 2.74 × 10 -5 ). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63 rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10 -4 and p = 1.56 × 10 -3 ), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10 -4 ). These results were in agreement with research suggesting that the TP63 rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Low-dose antiangiogenic therapies have demonstrated the ability to enhance normalization of tumor vessels, consequently improving hypoxia levels, drug delivery, and promoting anticancer immune responses. Mast cells have been identified as contributors to resistance against antiangiogenic therapy and facilitators of abnormal neoangiogenesis. In this study, we demonstrate that by simultaneously targeting intratumoral mast cells with Imatinib and administering low-dose anti-VEGFR2 therapy, antitumor efficacy can be enhanced in preclinical models. Thus, combinatory treatment overcomes therapy resistance, while concurrently promoting tumor vessel normalization. Notably, histomorphometric analysis of tumor sections revealed that vessel perfusion could be improved through mast cell inhibition and, despite a significantly reduced microvessel density, the combination treatment did not result in elevated tumor hypoxia levels compared to anti-VEGFR2 therapy alone. Short-term Imatinib application effectively increased antitumor efficacy, and by prolonging the application of Imatinib tumor vessel normalization was additionally improved. The combination of mast cell depletion and antiangiogenic treatments has not been investigated in detail and promises to help overcoming therapy resistance. Further studies will be required to explore their impact on other treatment approaches, and subsequently to validate these findings in a clinical setting., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, N ε -[carboxy-methyl]lysine (CML), N ε -[carboxy-ethyl]lysine (CEL) and N δ -[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (P interaction  = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HR Q5vs.Q1  = 1.67, 95% CI: 1.21-2.30, P trend  = .02) or any cause (HR Q5vs.Q1  = 1.38, 95% CI: 1.05-1.83, P trend  = .09). These associations tended to be stronger among cases with diabetes (P interaction  = .03) and pre-diabetes (P interaction  <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes., (© 2024 UICC.)

Local recurrence after radiotherapy is common in locally advanced head and neck cancer (HNC) patients. Re-irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re-radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow-up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV-based ctDNA burden was detected in 8/16 patients and 25/94 plasma samples. Ten additional ctDNA-positive samples were identified by tracking patient-specific CNVs found in earlier sequential plasma samples. ctDNA-positivity after 5 and 10 radiation fractions (both: log-rank, p = .050) as well as at the end of irradiation correlated with short progression-free survival (log-rank, p = .006). Moreover, a pronounced decrease of ctDNA toward re-radiotherapy termination was associated with worse treatment outcome (log-rank, p = .005). Dynamic ctDNA tracking in serial plasma beyond re-radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re-radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow-up intervals, and dose prescription., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Immunocompromised patients are at high risk to fail clearance of SARS-CoV-2. Prolonged COVID-19 constitutes a health risk and a management problem as cancer treatments often have to be disrupted. As SARS-CoV-2 evolves, new variants of concern have emerged that evade available monoclonal antibodies. Moreover, antiviral therapy promotes SARS-CoV-2 escape mutations, particularly in immunocompromised patients. These patients frequently suffer from prolonged infection. No successful treatment has been established for persistent COVID-19 infection. Here, we report on a series of 21 immunocompromised patients with COVID-19-most of them hematologic malignancies-treated with plasma obtained from recently convalescent or vaccinated donors or a combination thereof. Repeated dosing of SARS-CoV-2-antibody-containing plasma could clear SARS-CoV-2 infection in 16 out of 21 immunocompromised patients even if COVID-19-specific treatments failed to induce sustained viral clearance or to improve clinical course of SARS-CoV-2 infection. Ten patients were major responders defined as an increase delta(d)Ct of > = 5 after the first administration of convalescent and/or vaccinated plasma (C/VP). On average, SARS-CoV-2 PCR Ct values increased from a median value of 22.55 (IQR = 19.10-24.25) to a median value of 29.57 (IQR = 27.55-34.63; p = <.0001) in the major response subgroup. Furthermore, when treated a second time with C/VP, even 4 out of 5 of the initial nonresponders showed an increase in Ct-values from a median value of 23.13 (IQR = 17.75-28.05) to a median value of 32.79 (IQR = 31.75-33.75; p = .013). Our results suggest that C/VP could be a feasible treatment of COVID-19 infection in patients with hematologic malignancies who did not respond to antiviral treatment., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The role of diet in colorectal cancer prognosis is not well understood and specific lifestyle recommendations are lacking. We searched for randomised controlled trials (RCTs) and longitudinal observational studies on post-diagnosis dietary factors, supplement use and colorectal cancer survival outcomes in PubMed and Embase from inception until 28th February 2022. Random-effects dose-response meta-analyses were conducted when at least three studies had sufficient information. The evidence was interpreted and graded by the CUP Global independent Expert Committee on Cancer Survivorship and Expert Panel. Five RCTs and 35 observational studies were included (30,242 cases, over 8700 all-cause and 2100 colorectal cancer deaths, 3700 progression, recurrence, or disease-free events). Meta-analyses, including 3-10 observational studies each, were conducted for: whole grains, nuts/peanuts, red and processed meat, dairy products, sugary drinks, artificially sweetened beverages, coffee, alcohol, dietary glycaemic load/index, insulin load/index, marine omega-3 polyunsaturated fatty acids, supplemental calcium, circulating 25-hydroxyvitamin D (25[OH]D) and all-cause mortality; for alcohol, supplemental calcium, circulating 25(OH)D and colorectal cancer-specific mortality; and for circulating 25(OH)D and recurrence/disease-free survival. The overall evidence was graded as 'limited'. The inverse associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), whole grains, total, caffeinated, or decaffeinated coffee and all-cause mortality and the positive associations between unhealthy dietary patterns, sugary drinks and all-cause mortality provided 'limited-suggestive' evidence. All other exposure-outcome associations provided 'limited-no conclusion' evidence. Additional, well-conducted cohort studies and carefully designed RCTs are needed to develop specific lifestyle recommendations for colorectal cancer survivors., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Based on the World Cancer Research Fund Global Cancer Update Programme, we performed systematic reviews and meta-analyses to investigate the association of post-diagnosis adiposity, physical activity, sedentary behaviour, and dietary factors with colorectal cancer prognosis. We searched PubMed and Embase until 28th February, 2022. An independent expert committee and expert panel graded the quality of evidence. A total of 167 unique publications were reviewed, and all but five were observational studies. The quality of the evidence was graded conservatively due to the high risk of several biases. There was evidence of non-linearity in the associations between body mass index and colorectal cancer prognosis. The associations appeared reverse J-shaped, and the quality of this evidence was graded as limited (likelihood of causality: limited-no conclusion). The evidence on recreational physical activity and lower risk of all-cause mortality (relative risk [RR] highest vs. lowest: 0.69, 95% confidence interval [CI]: 0.62-0.77) and recurrence/disease-free survival (RR: 0.80, 95% CI: 0.70-0.92) was graded as limited-suggestive. There was limited-suggestive evidence for the associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), intake of whole grains and coffee with lower risk of all-cause mortality, and between unhealthy dietary patterns and intake of sugary drinks with higher risk of all-cause mortality. The evidence for other exposures on colorectal cancer outcomes was sparse and graded as limited-no conclusion. Analyses were conducted excluding cancer patients with metastases without substantial changes in the findings. Well-designed intervention and cohort studies are needed to support the development of lifestyle recommendations for colorectal cancer patients., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The adiposity influence on colorectal cancer prognosis remains poorly characterised. We performed a systematic review and meta-analysis on post-diagnosis adiposity measures (body mass index [BMI], waist circumference, waist-to-hip ratio, weight) or their changes and colorectal cancer outcomes. PubMed and Embase were searched through 28 February 2022. Random-effects meta-analyses were conducted when at least three studies had sufficient information. The quality of evidence was interpreted and graded by the Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel. We reviewed 124 observational studies (85 publications). Meta-analyses were possible for BMI and all-cause mortality, colorectal cancer-specific mortality, and cancer recurrence/disease-free survival. Non-linear meta-analysis indicated a reverse J-shaped association between BMI and colorectal cancer outcomes (nadir at BMI 28 kg/m 2 ). The highest risk, relative to the nadir, was observed at both ends of the BMI distribution (18 and 38 kg/m 2 ), namely 60% and 23% higher risk for all-cause mortality; 95% and 26% for colorectal cancer-specific mortality; and 37% and 24% for cancer recurrence/disease-free survival, respectively. The higher risk with low BMI was attenuated in secondary analyses of RCTs (compared to cohort studies), among studies with longer follow-up, and in women suggesting potential methodological limitations and/or altered physiological state. Descriptively synthesised studies on other adiposity-outcome associations of interest were limited in number and methodological quality. All the associations were graded as limited (likelihood of causality: no conclusion) due to potential methodological limitations (reverse causation, confounding, selection bias). Additional well-designed observational studies and interventional trials are needed to provide further clarification., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Low physical activity and high sedentary behaviour have been clearly linked with colorectal cancer development, yet data on their potential role in colorectal cancer survival is limited. Better characterisation of these relationships is needed for the development of post-diagnosis physical activity and sedentary behaviour guidance for colorectal cancer survivors. We searched PubMed and Embase through 28 February 2022 for studies assessing post-diagnosis physical activity, and/or sedentary behaviour in relation to all-cause and cause-specific mortality and recurrence after colorectal cancer diagnosis. Total and recreational physical activity were assessed overall and by frequency, duration, intensity, and volume using categorical, linear, and non-linear dose-response random-effects meta-analyses. The Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel interpreted and graded the likelihood of causality. We identified 16 observational studies on 82,220 non-overlapping patients from six countries. Physical activity was consistently inversely associated with colorectal cancer morbidity and mortality outcomes, with 13%-60% estimated reductions in risk. Sedentary behaviour was positively associated with all-cause mortality. The evidence had methodological limitations including potential confounding, selection bias and reverse causation, coupled with a limited number of studies for most associations. The CUP Global Expert panel concluded limited-suggestive evidence for recreational physical activity with all-cause mortality and cancer recurrence. Total physical activity and its specific domains and dimensions, and sedentary behaviour were all graded as limited-no conclusion for all outcomes. Future research should focus on randomised trials, while observational studies should obtain objective and repeated physical activity measures and better adjustment for confounders., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Human papillomavirus (HPV) proteins may elicit antibody responses in the process toward HPV-related malignancy. However, HPV seroepidemiology in noncervical HPV-related cancers remains poorly understood, particularly in populations with a high prevalence of human immunodeficiency virus (HIV). Using a glutathione S-transferase-based multiplex serology assay, antibodies against E6, E7 and L1 proteins of HPV16 and HPV18 were measured in sera of 535 cases of noncervical HPV-related cancers (anal (n = 104), vulval (n = 211), vaginal (n = 49), penile (n = 37) and oropharyngeal (n = 134)) and 6651 non-infection-related cancer controls, from the Johannesburg Cancer Study that recruited Black South African with newly diagnosed cancer between 1995 and 2016. Logistic and Poisson regression models were used to calculate adjusted odds ratios (aOR) and prevalence ratios (aPR) and 95% confidence intervals (CI) in cases versus controls. HPV16 E6 was more strongly associated with noncervical HPV-related cancers than HPV16 L1 or E7, or HPV18 proteins: anal (females (HPV16 E6 aOR = 11.50;95%CI:6.0-22.2), males (aOR = 10.12;95%CI:4.9-20.8), vulval (aOR = 11.69;95%CI:7.9-17.2), vaginal (aOR = 10.26;95%CI:5.0-21), penile (aOR = 18.95;95%CI:8.9-40), and oropharyngeal (females (aOR = 8.95;95%CI:2.9-27.5), males (aOR = 3.49;95%CI:1.8-7.0)) cancers. HPV16-E6 seropositivity ranged from 24.0% to 35.1% in anal, vulval, vaginal and penile cancer but was significantly lower (11.2%) in oropharyngeal cancer. After adjustment for HIV, prevalence of which increased from 22.2% in 1995-2005 to 54.1% in 2010-2016, HPV16 E6 seropositivity increased by period of diagnosis (aPR for 2010-2016 vs. 1995-2006 = 1.84;95%CI:1.1-3.0). Assuming HPV16 E6 seroprevalence reflects HPV attributable fraction, the proportion of certain noncervical-HPV-related cancers caused by HPV is increasing over time in South Africa. This is expected to be driven by the increasing influence of HIV., (© 2024 International Agency for Research on Cancer. International Agency for Research on Cancer retains copyright and all other rights in the manuscript of this article as submitted for publication.)

BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients., (© 2024 UICC.)

Mutations in histone H3.3-encoding genes causing mutant histone tails are associated with specific cancers such as pediatric glioblastomas (H3.3-G34R/V) and giant cell tumor of the bone (H3.3-G34W). The mechanisms by which these mutations promote malignancy are not completely understood. Here we show that cells expressing H3.3-G34W exhibit DNA double-strand breaks (DSBs) repair defects and increased cellular sensitivity to ionizing radiation (IR). Mechanistically, H3.3-G34W can be deposited to damaged chromatin, but in contrast to wild-type H3.3, does not interact with non-homologous end-joining (NHEJ) key effectors KU70/80 and XRCC4 leading to NHEJ deficiency. Together with defective cell cycle checkpoints reported previously, this DNA repair deficiency in H3.3-G34W cells led to accumulation of micronuclei and cytosolic DNA following IR, which subsequently led to activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immune-stimulatory cytokines. These findings suggest a potential for radiotherapy for tumors expressing H3.3-G34W, which can be further improved by combination with STING agonists to induce immune-mediated therapeutic efficacy., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, often diagnosed at stages that dis-qualify for surgical resection. Neoadjuvant therapies offer potential tumor regression and improved resectability. Although features of the tumor biology (e.g., molecular markers) may guide adjuvant therapy, biological alterations after neoadjuvant therapy remain largely unexplored. We performed mass spectrometry to characterize the proteomes of 67 PDAC resection specimens of patients who received either neoadjuvant chemo (NCT) or chemo-radiation (NCRT) therapy. We employed data-independent acquisition (DIA), yielding a proteome coverage in excess of 3500 proteins. Moreover, we successfully integrated two publicly available proteome datasets of treatment-naïve PDAC to unravel proteome alterations in response to neoadjuvant therapy, highlighting the feasibility of this approach. We found highly distinguishable proteome profiles. Treatment-naïve PDAC was characterized by enrichment of immunoglobulins, complement and extracellular matrix (ECM) proteins. Post-NCT and post-NCRT PDAC presented high abundance of ribosomal and metabolic proteins as compared to treatment-naïve PDAC. Further analyses on patient survival and protein expression identified treatment-specific prognostic candidates. We present the first proteomic characterization of the residual PDAC mass after NCT and NCRT, and potential protein candidate markers associated with overall survival. We conclude that residual PDAC exhibits fundamentally different proteome profiles as compared to treatment-naïve PDAC, influenced by the type of neoadjuvant treatment. These findings may impact adjuvant or targeted therapy options., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, p trend  = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, p trend  = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, p trend  = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women., (© 2024 The World Health Organization. The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HR Q4vsQ1  = 0.95, 95% CI: 0.73-1.23; P trend  = .97; and HR per doubling of resistin concentration  = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

At the 2023 EUROGIN workshop scientific basis for strategies to accelerate the elimination of cervical cancer and its causative agent, human papillomavirus (HPV) were reviewed. Although some countries have reached key performance indicators toward elimination (>90% of girls HPV vaccinated and >70% of women HPV screened), most are yet to reach these targets, implying a need for improved strategies. Gender-neutral vaccination, even with moderate vaccination coverage was highlighted as a strategy to achieve elimination more rapidly. It is more resilient against major disturbances in vaccination delivery, such as what happened during the coronavirus pandemic. Further, an analysis of ethical/legal issues indicated that female-restricted vaccination is problematic. Extended catch-up of vaccination with concomitant screening, and outreach to vulnerable groups were highlighted. Although birth cohorts with high coverage of HPV vaccination at school are protected against HPV, and HPVs have a very low reproductive rate in women above age 35, adult women below age 30 have inadequate direct protection. In addition to herd protection from gender-neutral vaccination, this group can be protected by offering concomitant catch-up HPV vaccination and HPV screening. Furthermore, hepatitis B vaccination experiences indicate that elimination cannot be achieved without prioritizing vulnerable/migrant populations. The long-lasting durability of vaccination-induced antibody responses suggests prolonged protection with HPV vaccines when adequately administrated. Finally, cost-effectiveness modelling suggests that high-coverage HPV vaccination in multiple population segments will be resource-saving due to reduced need for screening. In summary, the workshop found that strategically optimal deployment of vaccination will accelerate elimination of HPV and cervical cancer., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS-spectrum (LSS) cancers, including high-grade gliomas and colorectal cancer, causality has been supported by typical MMR-related tumor characteristics, but for non-LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non-LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non-LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR-deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non-LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Infection by certain pathogens is associated with cancer development. We conducted a case-cohort study of ~2500 incident cases of esophageal, gastric and duodenal cancer, and gastric and duodenal ulcer and a randomly selected subcohort of ~2000 individuals within the China Kadoorie Biobank study of >0.5 million adults. We used a bead-based multiplex serology assay to measure antibodies against 19 pathogens (total 43 antigens) in baseline plasma samples. Associations between pathogens and antigen-specific antibodies with risks of site-specific cancers and ulcers were assessed using Cox regression fitted using the Prentice pseudo-partial likelihood. Seroprevalence varied for different pathogens, from 0.7% for Hepatitis C virus (HCV) to 99.8% for Epstein-Barr virus (EBV) in the subcohort. Compared to participants seronegative for the corresponding pathogen, Helicobacter pylori seropositivity was associated with a higher risk of non-cardia (adjusted hazard ratio [HR] 2.73 [95% CI: 2.09-3.58]) and cardia (1.67 [1.18-2.38]) gastric cancer and duodenal ulcer (2.71 [1.79-4.08]). HCV was associated with a higher risk of duodenal cancer (6.23 [1.52-25.62]) and Hepatitis B virus was associated with higher risk of duodenal ulcer (1.46 [1.04-2.05]). There were some associations of antibodies again some herpesviruses and human papillomaviruses with risks of gastrointestinal cancers and ulcers but these should be interpreted with caution. This first study of multiple pathogens with risk of gastrointestinal cancers and ulcers demonstrated that several pathogens are associated with risks of gastrointestinal cancers and ulcers. This will inform future investigations into the role of infection in the etiology of these diseases., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid antitumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS-mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate antitumor activity and also immunological effects in NRAS-mutant melanoma, providing an ideal backbone for combination treatments. In our study, the MEKi binimetinib, cobimetinib and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS-mutant melanoma cells using two- and three-dimensional cell culture models as well as RNA sequencing analyses. Furthermore, NRAS-mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS-mutant melanoma cells thereby significantly enhancing the antiproliferative and proapoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS-L, components of antigen-presenting machinery and the "don't eat me signal" molecule CD47 in the melanoma cells. The BRAFi/MEKi-resistant, NRAS-mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen-activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, our study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS-mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS-mutant melanoma., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Cancer-related fatigue is a frequent, burdensome and often insufficiently treated symptom. A more targeted treatment of fatigue is urgently needed. Therefore, we examined biomarkers and clinical factors to identify fatigue subtypes with potentially different pathophysiologies. The study population comprised disease-free breast cancer survivors of a German population-based case-control study who were re-assessed on average 6 (FU1, n = 1871) and 11 years (FU2, n = 1295) after diagnosis. At FU1 and FU2, we assessed fatigue with the 20-item multidimensional Fatigue Assessment Questionnaire and further factors by structured telephone-interviews. Serum samples collected at FU1 were analyzed for IL-1ß, IL-2, IL-4, IL-6, IL-10, TNF-a, GM-CSF, IL-5, VEGF-A, SAA, CRP, VCAM-1, ICAM-1, leptin, adiponectin and resistin. Exploratory cluster analyses among survivors with fatigue at FU1 and no history of depression yielded three clusters (CL1, CL2 and CL3). CL1 (n = 195) on average had high levels of TNF-α, IL1-β, IL-6, resistin, VEGF-A and GM-CSF, and showed high BMI and pain levels. Fatigue in CL1 manifested rather in physical dimensions. Contrarily, CL2 (n = 78) was characterized by high leptin level and had highest cognitive fatigue. CL3 (n = 318) did not show any prominent characteristics. Fatigued survivors with a history of depression (n = 214) had significantly higher physical, emotional and cognitive fatigue and showed significantly less amelioration of fatigue from FU1 to FU2 than survivors without depression. In conclusion, from the broad phenotype "cancer-related fatigue" we were able to delineate subgroups characterized by biomarkers or history of depression. Future investigations may take these subtypes into account, ultimately enabling a better targeted therapy of fatigue., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16 INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The expansion of acute myeloid leukemia (AML) blasts not only suppresses normal hematopoiesis, but also alters the microenvironment. The interplay of different components of the bone marrow gives rise to altered metabolic states and activates signaling pathways which lead to resistance and impede effective therapy. Therefore, the underlying processes and mechanisms represent attractive therapeutic leverage points for overcoming therapy resistance in AML. Here, we briefly discuss resistance mechanisms based on cell interactions and secreted soluble factors in the hematopoietic niche and provide an overview of niche-related therapeutic targets currently undergoing preclinical and clinical investigation which may help improve the outcome in AML therapy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Age-standardized cancer incidence has decreased over the last years for many cancer sites in developed countries. Whether these trends led to narrowing or widening socioeconomic inequalities in cancer incidence is unknown. Using cancer registry data covering 48 million inhabitants in Germany, the ecological association between age-standardized total and site specific (colorectal, lung, prostate and breast) cancer incidence in 2007 to 2018 and a deprivation index on district level (aggregated to quintiles) was investigated. Incidence in the most and least deprived districts were compared using Poisson models. Average annual percentage changes (AAPCs) and differences in AAPCs between deprivation quintiles were assessed using Joinpoint regression analyses. Age-standardized incidence decreased strongly between 2007 and 2018 for total cancer and all cancer sites (except female lung cancer), irrespective of the level of deprivation. However, differences in the magnitude of trends across deprivation quintiles resulted in increasing inequalities over time for total cancer, colorectal and lung cancer. For total cancer, the incidence rate ratio between the most and least deprived quintile increased from 1.07 (95% confidence interval: 1.01-1.12) to 1.23 (1.12-1.32) in men and from 1.07 (1.01-1.13) to 1.20 (1.14-1.26) in women. Largest inequalities were observed for lung cancer with 82% (men) and 88% (women) higher incidence in the most vs the least deprived regions in 2018. The observed increase in inequalities in cancer incidence is in alignment with trends in inequalities in risk factor prevalence and partly utilization of screening. Intervention programs targeted at socioeconomically deprived and urban regions are highly needed., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Fatigue is common in breast-cancer survivors. Our study assessed fatigue longitudinally in breast cancer patients receiving adjuvant radiotherapy (RT) and aimed to identify risk factors associated with long-term fatigue and underlying fatigue trajectories. Fatigue was measured in a prospective multicenter cohort (REQUITE) using the Multidimensional Fatigue Inventory (MFI-20) and analyzed using mixed models. Multivariable logistic models identified factors associated with fatigue dimensions at 2 years post-RT and latent class growth analysis identified individual fatigue trajectories. A total of 1443, 1302, 1203 and 1098 patients completed the MFI-20 at baseline, end of RT, after 1 and 2 years. Overall, levels of fatigue significantly increased from baseline to end of RT for all fatigue dimensions (P < .05) and returned to baseline levels after 2 years. A quarter of patients were assigned to latent trajectory high (23.7%) and moderate (24.8%) fatigue classes, while 46.3% and 5.2% to the low and decreasing fatigue classes, respectively. Factors associated with multiple fatigue dimensions at 2 years include age, BMI, global health status, insomnia, pain, dyspnea and depression. Fatigue present at baseline was consistently associated with all five MFI-20 fatigue dimensions (OR GeneralFatigue  = 3.81, P < .001). From latent trajectory analysis, patients with a combination of factors such as pain, insomnia, depression, younger age and endocrine therapy had a particularly high risk of developing early and persistent high fatigue years after treatment. Our results confirmed the multidimensional nature of fatigue and will help clinicians identify breast cancer patients at higher risk of having persistent/late fatigue so that tailored interventions can be delivered., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (P interaction  < 5 × 10 -8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10 -7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (P interaction  = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10 -6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Surgical resection is a mainstay of treatment for pediatric low-grade glioma (LGG) within all current therapy algorithms, yet associated morbidity is scarcely reported. As supratentorial midline (SML) interventions are particularly challenging, we investigated the frequency of neurosurgical complications/new impairments aiming to identify their risk factors. Records were retrospectively analyzed from 318 patients with SML-LGG from successive German multicenter LGG studies, undergoing surgery between May 1998 and June 2020. Exactly 537 operations (230 resections, 167 biopsies, 140 nontumor procedures) were performed in 318 patients (54% male, median age: 7.6 years at diagnosis, 9.5 years at operation, 11% NF1, 42.5% optic pathway glioma). Surgical mortality rate was 0.93%. Applying the Drake classification, postoperative surgical morbidity was observed following 254/537 (47.3%) and medical morbidity following 97/537 (18.1%) patients with a 40.1% 30-day persistence rate for newly developed neurological deficits (65/162). Neuroendocrine impairment affected 53/318 patients (16.7%), visual deterioration 34/318 (10.7%). Postsurgical morbidity was associated with patient age <3 years at operation, tumor volume ≥80 cm 3 , presence of hydrocephalus, complete resection, surgery in centers with less than median reported tumor-related procedures and during the earlier study period between 1998 and 2006, while the neurosurgical approach, tumor location, NF1 status or previous nonsurgical treatment were not. Neurosurgery-associated morbidity was frequent in pediatric patients with SML-LGG undergoing surgery in the German LGG-studies. We identified patient- and institution-associated factors that may increase the risk for complications. We advocate that local multidisciplinary teams consider the planned extent of resection and surgical skills., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Cancer-related fatigue is commonly treated in an undifferentiated manner, because its pathophysiology is still not well understood. Therefore, we investigated if bioelectrical phase angle (PhA), a non-invasive marker of cell integrity, could help to single out specific fatigue subtypes. In a randomized controlled strength training intervention trial, PhA was measured by bioelectrical impedance analysis in 158 breast cancer patients. Fatigue was assessed with the multidimensional 20-item Fatigue Assessment Questionnaire. Multiple regression analyses considering changes in PhA and fatigue from baseline to post-intervention and ANCOVA models investigating the strength training effect on PhA were conducted. Further, explorative mediation and moderation analyses were performed. Decrease (=worsening) in PhA was significantly associated with increase in physical (P = .010) and emotional (P = .019) fatigue. These associations were markedly stronger in patients with normal BMI (interaction P = .059 and .097) and with low pre-diagnosis exercise level (interaction P = .058 and .19). Among patients with normal BMI strength training was associated with an increase in PhA (ANCOVA P = .059), but not among overweight/obese patients (interaction P = .035). Chemotherapy was a major determinant for low PhA, but PhA did not mediate the effect of chemotherapy on fatigue. In conclusion, PhA has a significant inverse association with physical and emotional fatigue. This association is moderated by BMI and previous exercise. Significant relationships of PhA were also observed with chemotherapy and strength training. Thus, PhA might be a marker that could help in the classification of subtypes of fatigue with different pathophysiology, which may require specifically tailored treatment. Further research on this is warranted., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Contemporary population-based data on ovarian cancer survival using current subtype classifications and by surgical status are sparse. We evaluated 1-, 3-, 5- and 7-year relative (and overall) survival, and excess hazards in patients with borderline tumors or invasive epithelial ovarian cancer diagnosed 2012 to 2021 in a nationwide registry-based cohort in Norway. Outcomes were evaluated by histotype, FIGO stage, cytoreduction surgery and residual disease. Overall survival was evaluated for non-epithelial ovarian cancer. Survival of women with borderline ovarian tumors was excellent (≥98.0% 7-year relative survival). Across all evaluated invasive epithelial ovarian cancer histotypes, 7-year relative survival for cases diagnosed with stages I or II disease was ≥78.3% (stage II high-grade serous). Survival for ovarian cancers diagnosed at stage ≥III differed substantially by histotype and time since diagnosis (eg, stage III, 5-year relative survival from 27.7% [carcinosarcomas] to 76.2% [endometrioid]). Overall survival for non-epithelial cases was good (91.8% 5-year overall survival). Women diagnosed with stage III or IV invasive epithelial ovarian cancer and with residual disease following cytoreduction surgery had substantially better survival than women not operated. These findings were robust to restriction to women with high reported functional status scores. Patterns for overall survival were similar to those for relative survival. We observed relatively good survival with early stage at diagnosis even for the high grade serous histotype. Survival for patients diagnosed at stage ≥III invasive epithelial ovarian cancer was poor for all but endometrioid disease. There remains an urgent need for strategies for risk reduction and earlier detection, together with effective targeted treatments., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Colorectal cancer (CRC) incidence and mortality are higher among men than among women. We aimed to estimate overall and age-specific risk advancement periods (RAPs) for men compared to women, which quantify how many years earlier comparable levels of risk are reached by men. RAPs were derived by Cox regression models among 331 224 participants aged 40 to 69 at baseline of the UK Biobank with no previous diagnosis of CRC and no previous CRC screening examination who were followed with respect to CRC incidence for up to 13 years. Men were at substantially higher risk of CRC than women in age groups 50 to 59 and 60 to 69, with RAPs (95% confidence intervals) as high as 8.7 (4.5-13.0) and 6.2 (4.5-7.9), respectively. These RAPs were higher than those for family history of CRC in these age groups. By contrast, no significant sex difference but a major impact of family history was seen in age group 40 to 49 (P-value for interaction between sex and age = .00079). The observed patterns suggest that consideration of gender-specific starting ages of screening might be warranted in countries in which screening offers start at ages above 50 years., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10 -9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases., (© 2022 UICC.)

Mammography screening has been shown to be able to reduce breast cancer mortality, leading most European countries to implement mammography-based screening programmes. In our study, we analysed key characteristics of breast cancer screening programmes and mammography use in European countries. Information on screening programmes were obtained from the 2017 European Union (EU) screening report, websites from governments and cancer registries, and through literature search in PubMed (studies published up to 20 June 2022). Data on self-reported mammography use in the past 2 years were obtained from Eurostat and had been derived from the European health interview survey (cross-sectional survey), conducted in the 27 EU countries, Iceland, Norway, Serbia, Turkey and the UK in 2013 to 2015 and 2018 to 2020. Data were analysed for each country according to their human development index (HDI). By 2022, all included countries besides Bulgaria and Greece had introduced an organised mammography-based screening programme; Romania and Turkey had only pilot programmes. Screening programmes differ substantially across countries, particularly in timing of implementation (e.g., in Sweden, the Netherlands before 1990; Belgium, France between 2000 and 2004; Denmark, Germany between 2005 and 2009; Austria, Slovakia after 2010). Self-reported mammography use also differed considerably across countries, and went along with HDI-from <36% in all countries with HDI <0.85 to >70% in most countries with HDI >0.90. The data call for efforts to improve mammography screening use across Europe, particularly in countries with lower development levels where breast cancer mortality rates are also among the highest in the region., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Ablative radiotherapy is a highly efficient treatment modality for patients with metastatic prostate cancer (PCa). However, a subset of patients does not respond. Currently, this subgroup with bad prognosis cannot be identified before disease progression. We hypothesize that markers indicative of radioresistance, stemness and/or bone tropism may have a prognostic potential to identify patients profiting from metastases-directed radiotherapy. Therefore, circulating tumor cells (CTCs) were analyzed in patients with metastatic PCa (n = 24) during radiotherapy with CellSearch, multicolor flow cytometry and imaging cytometry. Analysis of copy-number alteration indicates a polyclonal CTC population that changes after radiotherapy. CTCs were found in 8 out of 24 patients (33.3%) and were associated with a shorter time to biochemical progression after radiotherapy. Whereas the total CTC count dropped after radiotherapy, a chemokine receptor CXCR4-expressing subpopulation representing 28.6% of the total CTC population remained stable up to 3 months. At once, we observed higher chemokine CCL2 plasma concentrations and proinflammatory monocytes. Additional functional analyses demonstrated key roles of CXCR4 and CCL2 for cellular radiosensitivity, tumorigenicity and stem-like potential in vitro and in vivo. Moreover, a high CXCR4 and CCL2 expression was found in bone metastasis biopsies of PCa patients. In summary, panCK + CXCR4 + CTCs may have a prognostic potential in patients with metastatic PCa treated with metastasis-directed radiotherapy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n = 3941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR = 0.98 [95% confidence interval (CI) 0.86-1.11, P = .7731]). By comparison, targeted therapy showed a benefit for PFS (HR = 0.83 [95% CI 0.74-0.94, P = .0037]), especially for patients with an unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, P = .0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR = 0.70 [95% CI 0.61-0.80, P = .0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared to standard care. However, no improvement in OS was observed with any of the targeted agents., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)