Cancers

2 pages, 163 KB

Open AccessComment

Comment on Rao et al. The Oncological Outcome of Postoperative Radiotherapy in Patients with Node-Negative Early-Stage (T1/T2/N0) Oral Squamous Cell Carcinoma and Perineural Invasion: A Meta-Analysis. Cancers 2025, 17, 862

by Ganesh Datta Borewad, Bhavya Kanakarajulu, Zayba Noor, Arun Krishna, Shalini Thakur, Anand Subash and Vishal U. S. Rao

Cancers 2026, 18(10), 1520; https://doi.org/10.3390/cancers18101520 (registering DOI) - 9 May 2026

Abstract

We read with great interest the recent meta-analysis by Rao et al. [...] Full article

(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)

30 pages, 1866 KB

Open AccessArticle

TOP2 and NOS2 Orchestrate the Generation of DNA Breaks to Promote Colitis Cancer Initiation

by Ting-Kang Chang, Shiu-Ling Li, Anne-Cécile Brunac, Jia-Jun Huang, Yen-Hsiu Yeh, Pierre Brousset, Jean-Marc Egly and Tsai-Kun Li

Cancers 2026, 18(10), 1519; https://doi.org/10.3390/cancers18101519 (registering DOI) - 8 May 2026

Abstract

Background: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), increase colorectal cancer (CRC) risk. Methods: Mouse IBD and CRC models with a combination of pharmacological, knockout and knock-in approaches was employed to analyze the involvement of TOP2s and NOS2 [...] Read more.

Background: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), increase colorectal cancer (CRC) risk. Methods: Mouse IBD and CRC models with a combination of pharmacological, knockout and knock-in approaches was employed to analyze the involvement of TOP2s and NOS2 in CRC tumorigenesis. Key pathologies, such as inflammatory and neoplastic scores, were examined by immunohistochemical assays. Results: In colon tissues from acute, chronic colitis and CRC mouse models and from CD patients, the biomarkers γH2AX and 53BP1_pS25/S29 of DNA breaks (mainly representing DSBs) accumulated, alongside increases in topoisomerase II (TOP2) and nitric oxide synthase 2 (NOS2). Genetic ablation of NOS2 (Nos2^-/-) or TOP2β (Top2β^f/f) as well as pharmacological inhibition with ICRF-193 (a TOP2 inhibitor) or PTIO (a NO scavenger) reduced DSB formation and disease severity. Consistently, Nos2^-/-, or ICRF-treated, mice exhibited decreased tumor burden. DSBs and tumor accumulation were pronounced in the distal colon, mirroring human CRC distribution. While ICRF-193 suppressed tumor growth, Top2β^f/f deficiency (with a compensatory TOP2α upregulation) enhanced tumor development, indicating potential roles for TOP2 isozymes in tumor formation and progression. Conclusion: Collectively, these findings identify the cooperative action of TOP2 and NOS2 in driving DSBs, highlighting a potential therapeutic target in inflammation-associated CRC. Full article

(This article belongs to the Section Molecular Cancer Biology)

20 pages, 1947 KB

Open AccessReview

Squamous Cancers and Precancers of the Vulva: Emerging Diagnostic, Prognostic and Predictive Biomarkers in Pathology

by Somayah Alsolami, Jennifer Ji and Lynn Hoang

Cancers 2026, 18(10), 1518; https://doi.org/10.3390/cancers18101518 (registering DOI) - 8 May 2026

Abstract

Vulvar squamous cell carcinoma (VSCC) and its precursor lesions are relatively rare malignancies of the gynecologic tract. In recent years, international organizations and pathologic reporting guidelines endorse the subdivision of VSCC into human papillomavirus (HPV)-associated and HPV-independent types. There is also growing evidence [...] Read more.

Vulvar squamous cell carcinoma (VSCC) and its precursor lesions are relatively rare malignancies of the gynecologic tract. In recent years, international organizations and pathologic reporting guidelines endorse the subdivision of VSCC into human papillomavirus (HPV)-associated and HPV-independent types. There is also growing evidence for the further separation of HPV-independent into p53 abnormal and p53 wild-type cancers. Although the diagnosis and subclassification of VSCC is often straightforward, using immunohistochemical markers such as p16 and p53 as surrogate markers for high-risk HPV infection and TP53 mutation respectively, rare and unusual scenarios exist that can complicate VSCC classification. Herein we discuss these challenging scenarios in VSCC classification, as well as emerging VSCC prognostic biomarkers such as cyclin D1. In addition, the pathologic diagnosis of VSCC precursor lesions, particularly those of HPV-independent type, are frequently challenging to distinguish from benign conditions of the vulva. We discuss the recent literature describing the added diagnostic value of immunohistochemical biomarkers p53, CK17, CK13, SOX2, GATA3, GLUT1 and others, which may be particularly helpful when morphology is inconclusive. It is anticipated that with improved VSCC classification and precursor recognition, avenues for more tailored therapeutic strategies and earlier therapeutic intervention can be achieved. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Gynecological Cancers)

15 pages, 1905 KB

Open AccessArticle

Characterizing Pain in Peripheral Nerve Tumors: Interim Results from a Prospective Bicenter Cohort

by Nadja Grübel, Anne-Kathrin Uerschels, Karsten Wrede, Nora F. Dengler, Benjamin Mayer, Christian Rainer Wirtz and Maria Teresa Pedro

Cancers 2026, 18(10), 1517; https://doi.org/10.3390/cancers18101517 (registering DOI) - 8 May 2026

Abstract

Background/Objectives: This prospective study used a standardized preoperative assessment to characterize the full spectrum of pain in patients with peripheral nerve tumors, addressing the lack of structured pain phenotyping in this population. Methods: Between June 2024 and October 2025, preoperative pain [...] Read more.

Background/Objectives: This prospective study used a standardized preoperative assessment to characterize the full spectrum of pain in patients with peripheral nerve tumors, addressing the lack of structured pain phenotyping in this population. Methods: Between June 2024 and October 2025, preoperative pain symptoms were assessed in 91 patients, representing 16% of the Peripheral Nerve Tumor Registry (PNTR) cohort, using the PainDETECT questionnaire (0–38) at two centers: University Hospital Ulm, Günzburg (n = 72), and University Hospital Essen (n = 19). Results: Ninety-one patients (61.5% male; mean age, 49 years) were included. Most tumors were located in the lower extremity (54.9%). PainDETECT scores were ≤12 in 51.6%, 13–18 in 24.1%, and ≥19 in 21.9% of patients. Malignant tumors (6.5%) had the highest mean score (17), but benign tumors also showed a relevant pain burden (mean 11.9). Hybrid peripheral nerve sheath tumors and neurofibromas had numerically higher mean scores than schwannomas, although the difference was not statistically significant. Pain severity was not associated with tumor size, depth, or affected nerve. The most common sensory features were electric-shock-like and pressure-related pain, as reflected by a positive Tinel sign in 86.8% of patients. The most frequent pain pattern was intermittent attacks with pain-free intervals (46%). Conclusions: These interim results indicate that pain is common even in benign peripheral nerve tumors, challenging the assumption that these lesions are often asymptomatic. Malignant tumors showed the highest pain scores. The heterogeneous pain phenotypes highlight the need for individualized assessment and management. Expansion to a multicenter evaluation within the framework of the PNTR is planned. Full article

(This article belongs to the Special Issue Advances in Peripheral Nerve Tumors)

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21 pages, 737 KB

Open AccessArticle

Recruitment Strategies, Response Rates, and Non-Response Patterns in a Nationwide Registry-Based PRO Survey of Cancer Survivors and the General Population: The SURV-ICE Cohort

by Kristjana Sigurðardóttir, Nanna Friðriksdóttir, Nanna Margrét Kristinsdóttir, Lára Kristjánsdóttir, Hjalti Gunnlaugur Skúlason, Álfheiður Haraldsdóttir, Sigríður Ása Alfonsdóttir, Anna Kristín B. Jóhannesdóttir, Helgi Birgisson, Helga Tryggvadóttir, Freyja Birgisdóttir, Heiðdís Valdimarsdóttir, Thor Aspelund, Lonneke van de Poll-Franse and Sigríður Gunnarsdóttir

Cancers 2026, 18(10), 1516; https://doi.org/10.3390/cancers18101516 (registering DOI) - 8 May 2026

Abstract

Background: Population-based studies using patient-reported outcomes provide important insights into health-related quality of life (HRQoL) and the long-term impact of cancer and its treatment. Declining response rates and potential non-response bias have presented methodological challenges, particularly in registry-based surveys including both cancer [...] Read more.

Background: Population-based studies using patient-reported outcomes provide important insights into health-related quality of life (HRQoL) and the long-term impact of cancer and its treatment. Declining response rates and potential non-response bias have presented methodological challenges, particularly in registry-based surveys including both cancer survivors and population controls. The SURV-ICE study was established to assess HRQoL and health literacy among cancer survivors in Iceland while evaluating recruitment processes and participation patterns in a nationwide mixed-mode survey. Methods: SURV-ICE is a nationwide, population-based cross-sectional survey conducted in Iceland in 2025. Adults diagnosed with invasive cancer between 2014 and 2024 were identified through the Icelandic Cancer Registry and invited alongside an age- and gender-matched control group sampled from national registers. Participants completed validated EORTC instruments. Recruitment used a mixed-mode strategy including postal invitations, web-based and paper questionnaires, electronic reminders via the national health portal, and targeted telephone follow-up. Results: Among 10,005 cancer survivors 5489 (54.9%) responded to the questionnaires and among 5663 controls 2297 (40.6%) responded to the questionnaires. In both groups participation peaked among individuals aged 60–79 years and was lowest among the youngest and oldest groups. Cancer survivors had higher odds of participation than controls (OR 1.84; 95% CI 1.72–1.97). Most responses followed the initial postal invitation and first electronic reminder. Data completeness was high (≥80% item completion in 95.7% of instruments). Conclusions: Nationwide registry-based recruitment for large-scale PRO research is feasible in Iceland and can achieve competitive response rates without incentives. SURV-ICE provides an infrastructure for future research on cancer survivorship, HRQoL, and health literacy. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

30 pages, 962 KB

Open AccessSystematic Review

Risk Factors in Sporadic Early-Onset Colorectal Cancer, Current Evidence and Emerging Insights: A Systematic Review

by Meghana Maddula, Jordan E. Cohen, Dulitha Kumarasinghe, Mandy L. Ballinger, Jaqueline L. E. Tearle, Kylie R. James, Adnan Nagrial, Megan Barnet and Subotheni Thavaneswaran

Cancers 2026, 18(10), 1515; https://doi.org/10.3390/cancers18101515 (registering DOI) - 8 May 2026

Abstract

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising globally, yet its underlying risk factors remain incompletely understood, particularly in cases without recognised hereditary syndromes. Objectives: To update and synthesise the current body of evidence on modifiable and non-modifiable risk factors for [...] Read more.

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising globally, yet its underlying risk factors remain incompletely understood, particularly in cases without recognised hereditary syndromes. Objectives: To update and synthesise the current body of evidence on modifiable and non-modifiable risk factors for sporadic early-onset colorectal cancer. Methods: A systematic review of peer-reviewed articles published in English reporting original observational research examining risk factors for sporadic early-onset colorectal cancer (<50 years old) was conducted. PubMed and EMBASE databases were searched from inception to March 2025. Across studies, effect measures varied; therefore, the synthesis focused on the consistency of associations rather than the direct comparison of effect sizes. Results: The initial search identified 2575 papers; 34 studies were included after screening. Several consistent associations were identified, with dietary and lifestyle factors along with metabolic conditions emerging as key risk factors. EOCRC risk was higher in males (adjusted odds ratio (aOR) 1.36–2.21 across studies), individuals of Caucasian ethnicity (aORs 1.48–2.56), and in individuals whose age was approaching 50 years (per year, aORs 1.05–1.11). Putatively sporadic EOCRC was associated with a family history of CRC or other cancers (aORs up to 8.61). Other key factors linked to higher risk included obesity (aORs 1.92–2.88; adjusted Hazard Ratios (aHRs) 1.04–1.82), metabolic syndrome (aORs 1.25–2.48; aHRs 1.2–1.26), diabetes (aORs 1.24–3.42), Western dietary patterns (aORs 1.84–2.99), and sedentary behaviours (adjusted relative risks (aRR) 1.69–2.44). Moderate-to-vigorous exercise appeared protective (aORs 0.34–0.58), as did higher vitamin D levels (aHRs 0.41–0.61). Evidence for smoking, alcohol, medications and early/in utero environmental exposures was inconsistent. Conclusions: Lifestyle and metabolic factors, including Western dietary patterns, obesity and sedentary behaviours, were associated with sporadic EOCRC. Family history also emerged as a significant contributor to putatively sporadic disease, suggesting heritable influences beyond recognised syndromes and interplay between environmental factors and genetic predisposition. Future research should focus on integrated tumour and germline profiling, including broader genomic analyses in well-characterised cohorts, to better understand potential pathogenic mechanisms and support the development of risk stratification approaches. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

17 pages, 636 KB

Open AccessArticle

Placebo Response in Phase II-III Symptom Intervention Studies: A Focus on Chemotherapy-Induced Peripheral Neuropathy and Associated Neuropathic Pain

by David Zahrieh, Daniel Satele, Hiboombe Haamankuli, Xin Shelley Wang, Jennifer G. Le-Rademacher, Minji Lee, Heshan Liu, Julian Diaz-Cobo, Shu-En Shen, Selina Chow, Maryam Lustberg, Kathryn J. Ruddy and Ellen M. Lavoie Smith

Cancers 2026, 18(10), 1514; https://doi.org/10.3390/cancers18101514 (registering DOI) - 8 May 2026

Abstract

Background/Objectives. Decades of research have failed to uncover effective approaches to prevent chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of neurotoxic chemotherapy. Increased interest in placebo response as a potentially under-recognized confounder in CIPN trials was recently sparked by the results of [...] Read more.

Background/Objectives. Decades of research have failed to uncover effective approaches to prevent chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of neurotoxic chemotherapy. Increased interest in placebo response as a potentially under-recognized confounder in CIPN trials was recently sparked by the results of a multisite NCI-funded phase II-III CIPN prevention study of duloxetine, a promising serotonin–norepinephrine reuptake inhibitor that enhances pain-inhibitory mechanisms within the central nervous system. Study findings revealed high and nearly equivalent response rates in three randomized treatment groups—little to no CIPN was reported by 65.2%, 66.0%, and 68.0% of study participants who received duloxetine 30 mg, 60 mg, or placebo treatment, respectively. Methods. We performed a meta-analysis of placebo response rates from seven randomized, double-blinded, placebo-controlled trials conducted over the past 20 years and comprising 191 placebo participants that were specifically testing interventions for oxaliplatin- and paclitaxel-induced peripheral neuropathy and that serially collected patient responses on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Chemotherapy-Induced Neuropathy questionnaire. Additionally, we sought to identify trial- and patient-specific factors that predicted higher placebo response rates from a participant-level pooled analysis. Results. The placebo response rate was 10.0% [95% CI: 5.8%, 16.6%] when response was defined more conservatively as patients reporting no neuropathy at all. When the placebo response was defined more broadly based on patients reporting no or a little neuropathy, the placebo response rate was higher (39.6% [95% CI: 27.4%, 53.2%]). Male participants, receipt of oxaliplatin, and a 2:1 randomization ratio favoring the intervention arm were individually associated with a higher placebo response. Conclusions. High placebo response rates can threaten scientific progress toward identifying effective treatments for cancer treatment-associated side effects, like CIPN. Careful attention to study design factors, participant eligibility, and patient and research staff expectations may help to minimize placebo response rates in future CIPN intervention studies. Full article

(This article belongs to the Special Issue Advances in Clinical Trials: Outcome, Innovations, Challenges, and Ethical Practice in Cancer Research 2025–2026)

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15 pages, 2372 KB

Open AccessArticle

Clinical Impact of Staple-Line Oversewing in Totally Mechanical Collard Cervical Anastomosis for Esophageal Cancer

by Koshiro Ishiyama, Ryoko Nozaki, Ryota Kakuta, Shota Igaue, Eigo Akimoto, Daichi Utsunomiya, Daisuke Kurita, Yasuyuki Seto and Hiroyuki Daiko

Cancers 2026, 18(10), 1513; https://doi.org/10.3390/cancers18101513 (registering DOI) - 8 May 2026

Abstract

Background: Cervical esophagogastric anastomosis using a gastric conduit is commonly performed after esophagectomy for esophageal cancer, but anastomotic leakage remains a major postoperative complication. Totally mechanical Collard (TMC) anastomosis provides favorable stricture outcomes; however, leakage rates remain variable. The clinical benefit of staple-line [...] Read more.

Background: Cervical esophagogastric anastomosis using a gastric conduit is commonly performed after esophagectomy for esophageal cancer, but anastomotic leakage remains a major postoperative complication. Totally mechanical Collard (TMC) anastomosis provides favorable stricture outcomes; however, leakage rates remain variable. The clinical benefit of staple-line oversewing in TMC anastomosis has not been fully clarified. Methods: This retrospective cohort study included consecutive patients who underwent esophagectomy with TMC cervical anastomosis between January 2017 and December 2024. Patients were divided into oversewing and non-oversewing groups according to whether staple-line oversewing was performed. The primary endpoint was anastomotic leakage. Secondary endpoints included leakage severity, timing of leakage onset, healing duration, anastomotic stricture, and postoperative complications. Multivariable logistic regression analysis was used to identify independent risk factors for leakage. Results: A total of 803 patients were included (oversewing: n = 313; non-oversewing: n = 490). Baseline characteristics were well balanced between the two groups. The incidence of anastomotic leakage was significantly lower in the oversewing group than in the non-oversewing group (4.4% vs. 8.1%, p = 0.043). Leakage severity was also reduced, with Grade I leakage occurring more frequently in the oversewing group (78.5% vs. 30%, p = 0.004). Leakage occurred later in the oversewing group (12.7 ± 7.6 vs. 8.9 ± 4.2 days, p = 0.01), whereas healing duration was comparable between groups. The incidence of anastomotic stricture did not differ significantly between the two groups (3.5% vs. 5.3%, p = 0.3). Multivariable analysis identified body mass index ≥25 kg/m² (OR 2.37, 95% CI 1.08–4.93, p = 0.03) and the absence of staple-line oversewing (OR 2.15, 95% CI 1.03–4.82, p = 0.04) as independent risk factors for leakage. Conclusions: Staple-line oversewing of TMC cervical anastomosis was associated with a reduced incidence and milder severity of anastomotic leakage without increasing anastomotic stricture. This simple and reproducible technique may improve anastomotic stability after esophagectomy for esophageal cancer. Full article

(This article belongs to the Special Issue Current Status and Prospects of Multimodal Treatment for Upper Gastrointestinal Cancer)

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18 pages, 551 KB

Open AccessArticle

Persistently Elevated Gamma-Glutamyl Transferase and Hepatobiliary Malignancies: A Real-World Cohort Study

by Arkadeep Dhali, Dushyant Singh Dahiya, Abdul Rafae Faisal, Asad Zaman, Fayaz Khan, Jyotirmoy Biswas, Hareesha Rishab Bharadwaj and Saikat Mandal

Cancers 2026, 18(10), 1512; https://doi.org/10.3390/cancers18101512 (registering DOI) - 8 May 2026

Abstract

Background: Gamma-glutamyl transferase (GGT) has been associated with increased risks of multiple cancers and mortality. Because GGT is also a marker of hepatobiliary injury, metabolic dysfunction, and alcohol exposure, this study evaluated associations between persistently elevated GGT and hepatobiliary and pancreatic outcomes. Materials [...] Read more.

Background: Gamma-glutamyl transferase (GGT) has been associated with increased risks of multiple cancers and mortality. Because GGT is also a marker of hepatobiliary injury, metabolic dysfunction, and alcohol exposure, this study evaluated associations between persistently elevated GGT and hepatobiliary and pancreatic outcomes. Materials and Methods: This retrospective cohort study used TriNetX data from the US Collaborative Network to compare adults aged 40 years or older with persistently elevated GGT against those with normal GGT using a 65 U/L threshold on two occasions 6–12 months apart. Outcomes were assessed from 180 to 1095 days after the index event. Following 1:1 propensity score matching, 14,590 patients per cohort were analyzed. Cox proportional hazards analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Elevated GGT was associated with increased hazards of cholangiocarcinoma (HR 3.715, 95% CI 1.899–7.268), hepatocellular carcinoma (HR 2.260, 95% CI 1.677–3.045), acute pancreatitis (HR 3.359, 95% CI 2.284–4.941), chronic pancreatitis (HR 3.086, 95% CI 1.975–4.821), pancreatic cysts (HR 2.160, 95% CI 1.493–3.127), hospitalization (HR 1.363, 95% CI 1.236–1.503), and all-cause mortality (HR 2.250, 95% CI 2.051–2.467). No statistically significant association was observed with pancreatic cancer (HR 1.591, 95% CI 0.766–3.303; log-rank p = 0.209). Mean follow-up after matching was 799.722 ± 391.071 days in the elevated GGT cohort and 844.685 ± 374.676 days in controls. Conclusions: Persistent GGT elevation was associated with hepatobiliary malignancies, pancreatic inflammatory diseases, pancreatic cysts, hospitalization, and all-cause mortality, but not pancreatic cancer. These results suggest that persistent GGT elevation may be a non-specific clinical marker of underlying hepatobiliary and metabolic risk. Full article

(This article belongs to the Special Issue Screening, Early Detection and Therapeutic Advances in Gastrointestinal Cancers)

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14 pages, 638 KB

Open AccessArticle

Diagnostic Accuracy of Synovial Calprotectin in Megaprosthetic Reconstructions: A Prospective Cohort Study from a Tertiary Sarcoma Center

by Panayiotis Gavriil, Pavlos Altsitzioglou, Ioannis Trikoupis, Efthalia Maleka, Panagiotis Briassoulis, Jendrik Hardes, Panayiotis Papagelopoulos and Vasileios Kontogeorgakos

Cancers 2026, 18(10), 1511; https://doi.org/10.3390/cancers18101511 (registering DOI) - 8 May 2026

Abstract

Background/Objectives: Diagnosing periprosthetic joint infection (PJI) after megaprosthetic reconstruction may be difficult due to altered inflammatory responses, extensive prior surgery, and the limited performance of conventional criteria such as the 2018 ICM score. Synovial calprotectin is a rapid neutrophil-derived biomarker that may improve [...] Read more.

Background/Objectives: Diagnosing periprosthetic joint infection (PJI) after megaprosthetic reconstruction may be difficult due to altered inflammatory responses, extensive prior surgery, and the limited performance of conventional criteria such as the 2018 ICM score. Synovial calprotectin is a rapid neutrophil-derived biomarker that may improve diagnostic accuracy in this challenging setting. The primary aim of this study was to evaluate the diagnostic performance of synovial calprotectin in detecting periprosthetic infection in patients treated with tumor megaprostheses; secondary aims included comparison with ICM classification, assessment in infection classification-inconclusive cases, and exploratory performance in patients with low CRP. Methods: This prospective study included 20 consecutive megaprosthesis patients evaluated for suspected PJI at ATTIKON University Hospital, Athens, with a minimum follow-up of 1 year after biomarker testing. Synovial calprotectin was measured using a lateral-flow assay (positive ≥ 50 mg/L) and compared with a predefined infection reference standard. ICM final status (0 = aseptic, 1 = inconclusive, 2 = infected) was recorded for all cases. Other synovial biomarkers (α-defensin, leukocyte esterase, synovial D-dimer) were not routinely available. The cohort had a mean age of 52.9 ± 22.5 years, 70% were male, and reconstructions involved the knee (80%), hip (15%), and humerus (5%). Preoperative cultures were positive in 40%, the median systemic WBC was 7100/μL, and the median time from last surgery to testing was 1.0 years (IQR 0.46–2.0). Among infected cases, the most common microorganisms were coagulase-negative staphylococci (61.5%) and Staphylococcus aureus (23.1%), with 30.8% demonstrating polymicrobial infection. Results: Thirteen of 20 patients (65%) were classified as infected. Using the ≥50 mg/L threshold, synovial calprotectin demonstrated high apparent diagnostic accuracy in this exploratory cohort, and no false positives, yielding a sensitivity of 92.3%, specificity of 100%, PPV of 100%, NPV of 87.5%, LR+ = ∞, and LR− = 0.08. The AUC for continuous values was 1.00. Agreement with the ICM final classification was substantial (κ = 0.76), with no directional discordance (McNemar p = 1.00). Among the three ICM-inconclusive cases, calprotectin correctly reclassified two (66.7%). In patients with low CRP (<10 mg/L), a clinically difficult subgroup, calprotectin maintained strong performance (sensitivity 75%, specificity 100%, NPV 85.7%). Conclusion: Synovial calprotectin demonstrated promising diagnostic performance for PJI in megaprosthesis patients, with high sensitivity and specificity, and substantial agreement with the 2018 ICM criteria. It successfully clarified most ICM-inconclusive cases and remained reliable even in patients with low CRP. These findings support calprotectin as a valuable adjunctive biomarker in the complex diagnostic environment of megaprosthetic reconstruction and justify further validation in larger cohorts. Full article

(This article belongs to the Special Issue Sarcoma Management in Orthopaedic Oncology)

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19 pages, 676 KB

Open AccessArticle

Effect of Manual Lymph Drainage on Breast Edema After Breast-Conserving Surgery and Radiotherapy: A Preliminary Randomized Controlled Trial

by Faika Nur Erkol, Nuray Alaca, Nuran Beşe and Cihan Uras

Cancers 2026, 18(10), 1510; https://doi.org/10.3390/cancers18101510 (registering DOI) - 8 May 2026

Abstract

Background/Objectives: To evaluate the effectiveness of manual lymph drainage (MLD) in treating breast edema in patients who have undergone breast-conserving surgery and adjuvant radiotherapy. Methods: Twenty-five female participants who underwent breast-conserving surgery and received adjuvant radiotherapy were enrolled in the study. [...] Read more.

Background/Objectives: To evaluate the effectiveness of manual lymph drainage (MLD) in treating breast edema in patients who have undergone breast-conserving surgery and adjuvant radiotherapy. Methods: Twenty-five female participants who underwent breast-conserving surgery and received adjuvant radiotherapy were enrolled in the study. Twelve participants were assigned to the treatment group (education, compression, exercise therapy, and MLD), and 13 to the control group (education, compression, and exercise therapy). The participants were assessed after radiotherapy (baseline) and three months post-treatment. The following variables were evaluated: general body pain, fatigue, breast pain, breast edema (breast edema questionnaire and LENT-SOMA-breast criteria), anxiety, depression, and quality of life. Results: In both groups, within-group analyses showed improvements in general body pain, fatigue, breast pain, breast edema, anxiety, depression, and some quality of life subscales (p < 0.05). Between-group comparisons revealed additional improvements in breast pain, breast edema, and breast-related criteria in the treatment group compared with the control group (p < 0.05). Additionally, the treatment group showed greater improvements in some quality of life subscales (global health status, fatigue, pain, systemic treatment side effects, and breast and arm symptoms) compared with the control group (p < 0.05). Conclusions: The addition of MLD may provide additional benefits within complex decongestive therapy for breast edema following breast-conserving surgery and radiotherapy. However, these findings should be considered preliminary and interpreted with caution due to the small sample size, lack of objective outcome measures, absence of a no-treatment control group, and lack of blinding of participants and treating clinicians. As both groups received active treatment during a period of expected natural recovery, the independent effect of MLD cannot be fully isolated. Confirmation in future well-designed, blinded randomized controlled trials incorporating objective outcome measures is warranted. Full article

(This article belongs to the Section Methods and Technologies Development)

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18 pages, 3476 KB

Open AccessArticle

Differential Protumoral Mechanisms Induced by CAFs in Cervical Cancer Cells Occur Independently of 17β-Estradiol Stimulation

by Jonathan René García-Bernal, Luis Javier Reséndiz-Castillo, Marcela Guadalupe Martínez-Barajas, Carlos Daniel Díaz-Palomera, Adrián Ramírez-de-Arellano, Alejandra Natali Vega-Magaña, Lesly Jazmin Bueno-Urquiza, Luis Reneé González-Lucano, Marcela Peña-Rodríguez, Julio César Villegas-Pineda and Ana Laura Pereira-Suárez

Cancers 2026, 18(10), 1509; https://doi.org/10.3390/cancers18101509 (registering DOI) - 8 May 2026

Abstract

Background: E2 is fundamental to the onset and progression of CC. CAFs are the most abundant stromal population in the tumor microenvironment. CAFs have been shown to promote protumoral effects in CC cell lines; however, the effects of E2-stimulated CAFs remain to be [...] Read more.

Background: E2 is fundamental to the onset and progression of CC. CAFs are the most abundant stromal population in the tumor microenvironment. CAFs have been shown to promote protumoral effects in CC cell lines; however, the effects of E2-stimulated CAFs remain to be explored. Objectives: This study aimed to evaluate whether E2-stimulated CAFs modify the behavior of SiHa and HeLa tumor cells, including their metabolism, ROS production, migration, apoptosis, and gene expression. Methods: Characterization and estrogen receptor expression in primary CAF cultures were evaluated by immunofluorescence. Supernatants from non-stimulated and E2-stimulated CAFs were used to culture CC cells, and mitochondrial metabolism was measured by MTT, ROS production by H2DCFDA, migration using the wound-healing assay, apoptosis by Annexin V assay, and gene expression by next-generation RNA-seq. Results: Stimulation of CC cells with CAFs’ supernatants demonstrated that it influences tumor cells in different ways. In SiHa cells, the metabolic shift was supported by decreased mitochondrial metabolism, increased ROS production, and enhanced gene enrichment for glycolysis and hypoxia responses. On the other hand, in HeLa cells, CAFs enhanced migration and gene enrichment in KRAS signaling, epithelial-mesenchymal transition, and the proinflammatory response, via enrichment of the IL6/JAK/STAT3 signaling pathway, along with the overexpression of cytokines such as IFN-γ, IL-6, and IL-8. Conclusions: CAFs exert protumoral effects by promoting a metabolic shift in SiHa cells or enhancing migration and cytokine secretion in HeLa cells; these effects are independent of E2 stimulation in CAFs. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Gynecological Tumors)

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15 pages, 4966 KB

Open AccessArticle

Hypoxia Impairs CD8⁺ T Cell Fitness and Is Associated with a Dysfunctional CD8⁺ T Cell State in Pancreatic Cancer

by Ashley M. Mello, Marina Pasca di Magliano and Kyoung Eun Lee

Cancers 2026, 18(10), 1508; https://doi.org/10.3390/cancers18101508 (registering DOI) - 8 May 2026

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal microenvironment and profound hypoxia, which contribute to therapeutic resistance. Using an in vitro system incorporating pancreatic cancer cells and cancer-associated fibroblasts (CAFs), we show that hypoxia suppresses CD8⁺ T cell accumulation and, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal microenvironment and profound hypoxia, which contribute to therapeutic resistance. Using an in vitro system incorporating pancreatic cancer cells and cancer-associated fibroblasts (CAFs), we show that hypoxia suppresses CD8⁺ T cell accumulation and, in combination with cancer cell- and CAF-derived factors, further impairs T cell fitness by increasing cell death and reducing proliferation. Although the combination of hypoxia and cancer cell/CAF-derived factors enhances IFNγ and granzyme B expression in CD8⁺ T cells on a per-cell basis, the overall number of functional effector T cells is markedly reduced. Analysis of human PDAC single-cell RNA sequencing data corroborates these findings, revealing that CD8⁺ T cells enriched for hypoxia signatures exhibit elevated apoptosis and stress-response pathways. Furthermore, hypoxia is associated with downregulation of stemness-related genes and upregulation of terminal differentiation markers. Together, these data suggest that the integration of intrinsic hypoxic responses and extrinsic cues from tumor cells and CAFs impairs CD8⁺ T cell fitness and correlates with a terminally differentiated, dysfunctional T cell state. Full article

(This article belongs to the Section Tumor Microenvironment)

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1 pages, 136 KB

Open AccessRetraction

RETRACTED: Li et al. TRIM10 Is Downregulated in Acute Myeloid Leukemia and Plays a Tumor Suppressive Role via Regulating NF-κB Pathway. Cancers 2023, 15, 417

by Lin Li, Qi Li, Zhengrong Zou, Zoufang Huang and Yijian Chen

Cancers 2026, 18(10), 1507; https://doi.org/10.3390/cancers18101507 (registering DOI) - 8 May 2026

Abstract

The journal retracts the article “TRIM10 is downregulated in acute myeloid leukemia and plays a tumor suppressive role via regulating NF-κB pathway” [...] Full article

(This article belongs to the Section Tumor Microenvironment)

2 pages, 157 KB

Open AccessComment

JC Virus Reactivation Should Be Considered in Late Neurotoxicity Associated with Bispecific Antibody Therapy: A Comment. Comment on Bangolo et al. Comprehensive Review of Early and Late Toxicities in CAR T-Cell Therapy and Bispecific Antibody Treatments for Hematologic Malignancies. Cancers 2025, 17, 282

by Utku Iltar, Unal Atas, Orhan Kemal Yucel, Ozan Salim and Levent Ündar

Cancers 2026, 18(10), 1506; https://doi.org/10.3390/cancers18101506 (registering DOI) - 8 May 2026

Abstract

We read with great interest the comprehensive review by Bangolo et al [...] Full article

(This article belongs to the Special Issue Hematologic Malignancies and Related Disorders: Challenges from Diagnosis to Treatment)

15 pages, 493 KB

Open AccessReview

Smoldering Multiple Myeloma: Early Intervention or Structured Surveillance? A Comprehensive Review of Evidence for and Against Early Therapy

by Kirti Arora, Lara Soueid, Louis Williams, Jahanvi Grover, Diana Basali, Jack Khouri, Yuvraj Kaushal, Sandra Mazzoni, Rockey Dahiya, Beth Faiman, Jason Valent, Faiz Anwer and Shahzad Raza

Cancers 2026, 18(10), 1505; https://doi.org/10.3390/cancers18101505 - 7 May 2026

Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by a heterogeneous risk of progression to overt multiple myeloma (MM). Historically managed with active surveillance, advances in risk stratification and the development of novel therapeutics have renewed debate regarding early intervention, [...] Read more.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by a heterogeneous risk of progression to overt multiple myeloma (MM). Historically managed with active surveillance, advances in risk stratification and the development of novel therapeutics have renewed debate regarding early intervention, particularly in patients with high-risk disease. We conducted a narrative review of clinical trials and observational studies evaluating early treatment versus observation in SMM. Outcomes assessed included progression-free survival (PFS), time to progression (TTP), overall survival (OS), treatment-related toxicity, and quality-of-life measures, alongside evolving diagnostic criteria and risk-stratification models that influence therapeutic decision-making. Early randomized trials using conventional cytotoxic therapy did not demonstrate a survival advantage and supported observation as the standard management approach. However, contemporary studies using novel agents have demonstrated improved disease control in selected high-risk populations. The QuiRedex and ECOG-E3A06 trials showed significant reductions in progression risk with lenalidomide-based therapy, and long-term follow-up suggests a potential overall survival benefit in Qui-Redex. The phase III AQUILA trial further demonstrated delayed progression with daratumumab in high-risk SMM using updated diagnostic criteria. Phase II studies evaluating combination regimens, including KRd-based and daratumumab-containing approaches, have reported high response rates and MRD negativity, although survival data remain immature. Importantly, many benefits reflect delayed biochemical or imaging-defined progression rather than prevention of symptomatic end-organ damage. Current evidence supports selective early intervention in carefully defined high-risk SMM populations; however, uncertainties remain regarding long-term survival benefit, optimal treatment duration, quality-of-life impact, and clonal evolution. Active surveillance with modern monitoring remains appropriate for many patients. Full article

(This article belongs to the Special Issue State-of-the-Art Research on Multiple Myeloma Progression: 2nd Edition)

37 pages, 1949 KB

Open AccessReview

Multi Omics Integration in Colorectal Cancer: From Molecular Insights to Precision Oncology

by Zuoliang Liu, Mia Yang Ang and Chin Siang Kue

Cancers 2026, 18(10), 1504; https://doi.org/10.3390/cancers18101504 - 7 May 2026

Abstract

Colorectal cancer (CRC) is a biologically heterogeneous disease in which single-omics analyses incompletely capture the cross-layer mechanisms underlying tumor progression, immune evasion, and therapeutic resistance. This review critically examines how the integration of genomics, transcriptomics, proteomics, metabolomics, and microbiome profiling is redefining CRC [...] Read more.

Colorectal cancer (CRC) is a biologically heterogeneous disease in which single-omics analyses incompletely capture the cross-layer mechanisms underlying tumor progression, immune evasion, and therapeutic resistance. This review critically examines how the integration of genomics, transcriptomics, proteomics, metabolomics, and microbiome profiling is redefining CRC biology and precision oncology. Landmark integrative efforts, including TCGA analyses of 276 colorectal cancer samples, CPTAC proteogenomic profiling of 95 tumors, and recent whole-genome sequencing studies of 2023 CRC cases, have refined molecular subtyping, expanded the driver landscape, and revealed clinically relevant discordance between mRNA abundance and protein activity. Integrative studies further show that oncogenic signaling may be driven by post-transcriptional and post-translational regulation, while spatially resolved profiling and microbiome–metabolite analyses are uncovering previously obscured tumor–microenvironment interactions. We also discuss how artificial intelligence-based approaches, including factor analysis, deep learning, graph-based models, and explainable AI, are improving subtype classification, biomarker discovery, and treatment-response prediction, with particular relevance to microsatellite instability-high and early-onset CRC. Finally, we critically evaluate the principal barriers to clinical translation, including batch effects, cross-platform variability, limited external validation, regulatory constraints, and cost, and outline priorities for building reproducible, clinically deployable multi-omics pipelines for CRC management. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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43 pages, 3911 KB

Open AccessArticle

Leveraging Multi-Model Machine Learning Algorithms for Tumor–Normal Classification and Discovery of Biomarkers in Colorectal Cancer Using Multi-Omics Data

by Duaa Mohammad Alawad, Mark Fertel and Chindo Hicks

Cancers 2026, 18(10), 1503; https://doi.org/10.3390/cancers18101503 - 7 May 2026

Abstract

Background: Despite remarkable progress in clinical management and screening, colorectal cancer (CRC) remains a major cause of cancer-related deaths worldwide. Sadly, both the number of CRC incidences and the mortality rate are trending upwards, particularly in younger individuals. There is an urgent [...] Read more.

Background: Despite remarkable progress in clinical management and screening, colorectal cancer (CRC) remains a major cause of cancer-related deaths worldwide. Sadly, both the number of CRC incidences and the mortality rate are trending upwards, particularly in younger individuals. There is an urgent need for the identification of reliable diagnostic biomarkers and therapeutic targets, and the development of accurate algorithms to guide therapeutic decision-making at the point of care. Here, we leverage multi-model integrative Machine Learning (ML) algorithms using RNA-Seq and somatic mutation data for the classification of tumor–normal samples and the discovery of potential biomarkers and therapeutic targets. Methods: We used RNA sequencing (RNA-Seq) and somatic mutation data from The Cancer Genome Atlas (TCGA) for the development of classification models and the discovery of biomarkers and therapeutic targets. The models were validated using two independent datasets. Results: ML algorithms accurately classified tumor samples and identified a signature for 58 genes, which could serve as potential diagnostic biomarkers. Functional analysis revealed the Wnt and GPCR signaling pathways enriched for somatic mutations. Conclusions: Multi-model integrative ML algorithms integrating gene expression with somatic mutation data represent a powerful approach to the classification of tumor samples and the discovery of biomarkers. Full article

(This article belongs to the Section Cancer Biomarkers)

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7 pages, 210 KB

Open AccessEditorial

The Shifting Landscape of Debulking Surgery in Newly Diagnosed Advanced Ovarian Cancer

by Dimitrios Tsolakidis and Dimitrios Zouzoulas

Cancers 2026, 18(10), 1502; https://doi.org/10.3390/cancers18101502 - 7 May 2026

Abstract

Ovarian carcinoma is the third most common gynecological malignancy and the leading cause of death among breast and genital track cancers in women [...] Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Treatment: Past, Present and Future)

15 pages, 278 KB

Open AccessArticle

Development and Evaluation of the Personal Patient Profile–Bladder Cancer (P3-BC): A Web-Based Decision Support System for Patients Considering Cystectomy and Urinary Diversion

by Nihal E. Mohamed, Donna L. Berry, Justin McReynolds, Talia Korn, Holden Kata, Emma Benn, Danielle Scharp, John Sfakianos, Reza Mehrazin, Peter Wiklund and Bill Lober

Cancers 2026, 18(10), 1501; https://doi.org/10.3390/cancers18101501 - 7 May 2026

Abstract

Background/Objectives: Radical cystectomy with urinary diversion is the standard treatment for patients with muscle-invasive bladder cancer, which represents a complex, preference-sensitive decision about the diversion options. To facilitate patient-clinician shared decision-making, we developed and evaluated the feasibility and acceptability of the Personal Patient [...] Read more.

Background/Objectives: Radical cystectomy with urinary diversion is the standard treatment for patients with muscle-invasive bladder cancer, which represents a complex, preference-sensitive decision about the diversion options. To facilitate patient-clinician shared decision-making, we developed and evaluated the feasibility and acceptability of the Personal Patient Profile–Bladder Cancer (P3-BC), a web-based decision support system for patients considering urinary diversion options. Materials and Methods: We employed an iterative development approach following an established framework, including qualitative assessments of radical cystectomy patients’ (n = 30) needs to inform content development, followed by usability testing with 10 key stakeholders. We then conducted a feasibility study with patients newly diagnosed with bladder cancer undergoing cystectomy. Feasibility was assessed through P3-BC completion rates among patients randomized to the intervention and study retention rates. Acceptability was measured using a program-based 12-item questionnaire integrating the six-item Acceptability E-Scale. Secondary outcomes included decisional conflict, shared decision-making, psychological distress, and decisional regret. Results: Of 114 eligible patients, 24 provided consent (21% consent rate), and 15 were randomized to receive the P3-BC intervention (n = 10) or usual care (n = 5). Retention was 93% at 1 month and 73% at 3 months. Among intervention participants, P3-BC achieved high feasibility (100% accessed the program) and acceptability, with 86% reporting overall satisfaction and 86% reporting ease of use. No statistically significant between-group differences were observed in secondary outcomes. Although the study was not powered to examine group differences, numerical trends suggest improvements in decisional conflict and symptom burden over time, particularly in the intervention group. Conclusions: P3-BC demonstrated feasibility and acceptability as a web-based decision support intervention for patients with bladder cancer considering cystectomy and urinary diversion. Primary barriers to enrollment included treatment burden, limited diagnosis-treatment time, and technology concerns. Findings support progression to an adequately powered randomized controlled trial to evaluate clinical effectiveness. Full article

(This article belongs to the Special Issue Multidisciplinary Approach to Bladder Cancer Treatment and Care)

19 pages, 2315 KB

Open AccessArticle

A High-Fidelity Patient-Derived Organoid Platform Recapitulates the Dynamic Metabolic Landscape of Cisplatin Tolerance in Mesothelioma

by Zivile Useckaite, Ashleigh J. Hocking, Lauren A. Mortimer, John Salamon, Simon Lee, Yazad Irani, Lucy Franzon, Arya L. Arul, Sarita Prabhakaran and Sonja Klebe

Cancers 2026, 18(10), 1500; https://doi.org/10.3390/cancers18101500 - 7 May 2026

Abstract

Background: Pleural mesothelioma (PM) is characterised by often rapid therapeutic failure and chemotherapy resistance. While terminal resistance is well studied, the initial transition into a drug-tolerant phenotype remains poorly understood. Methods: We established patient-derived organoids (PDOs) from malignant pleural effusions to [...] Read more.

Background: Pleural mesothelioma (PM) is characterised by often rapid therapeutic failure and chemotherapy resistance. While terminal resistance is well studied, the initial transition into a drug-tolerant phenotype remains poorly understood. Methods: We established patient-derived organoids (PDOs) from malignant pleural effusions to model this transition. Cisplatin-tolerant lines were generated via repeated incremental exposure to cisplatin and compared to time-matched treatment-naive controls using RNA sequencing and Seahorse XFe96 metabolic flux analysis. Results: Integrated profiling suggested that the route to tolerance may be influenced by the underlying mutational profile. In this cohort, all BAP1-retained models (including those with KRAS mutations or MTAP loss) adopted an elevated basal metabolic hybrid phenotype, significantly upregulating baseline oxidative phosphorylation and glycolysis to fuel survival mechanisms. Conversely, BAP1-deficient models entered a hypometabolic state of dormancy, characterised by baseline bioenergetic suppression and reduced Ki-67 proliferation. Transcriptomic analysis identified a vesicular transport signature (SYNGR3, VPS52, PROM2) in plastic models, suggesting altered membrane trafficking as a potential survival strategy. Conclusions: Our findings demonstrate that mesothelioma therapeutic escape is not a uniform process. Identifying these patient-specific metabolic and transcriptomic trajectories via 3D PDOs provides a hypothesis-generating framework to explore potential avenues for future personalised therapy. Full article

(This article belongs to the Special Issue Mesothelioma Environmental Risk Factors and Epidemiological and Biological Insights)

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19 pages, 270 KB

Open AccessArticle

Risk Tier, Variant Certainty, and Real-World Care Patterns in Breast Cancer Patients with Germline Alterations in Breast Cancer Susceptibility Genes

by Tuba Baydaş, İlker Nihat Ökten, Filiz Özen, Süheyla Emre, İbrahim Çil, Metin Eser, Adnan Gündoğdu, Osman Cem Yılmaz and Mahmut Gümüş

Cancers 2026, 18(10), 1499; https://doi.org/10.3390/cancers18101499 - 7 May 2026

Abstract

Background: The increasing use of multigene germline testing in breast cancer has expanded the detection of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) across a broad range of breast cancer susceptibility genes. However, the extent to which pathogenic certainty and [...] Read more.

Background: The increasing use of multigene germline testing in breast cancer has expanded the detection of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) across a broad range of breast cancer susceptibility genes. However, the extent to which pathogenic certainty and penetrance level are associated with distinct clinicopathological phenotypes and management patterns remains incompletely defined. Methods: In this multicenter retrospective study, we included 405 breast cancer patients with germline alterations in breast cancer susceptibility genes. Patients were classified into three groups: high-penetrance P/LP (n = 116), moderate/low-penetrance P/LP (n = 69), and VUS (n = 220). The primary endpoint was non-luminal invasive breast cancer phenotype, defined as HER2-positive or triple-negative disease versus luminal A/B disease. Multivariable logistic regression was performed to assess the association between genetic group and non-luminal phenotype, adjusted for age at diagnosis and family history. Secondary analyses evaluated management patterns across groups and examined a prespecified non-BRCA cohort. Results: Patients with high-penetrance P/LP variants were younger at diagnosis and had higher Ki-67 values than those in the other groups. Molecular subtype distribution differed significantly across groups, with triple-negative disease most frequent in the high-penetrance P/LP group (33.9%) compared with the moderate/low-penetrance P/LP (9.8%) and VUS (12.9%) groups. In multivariable analysis, high-penetrance P/LP status was independently associated with increased odds of non-luminal phenotype compared with VUS (OR 1.79, 95% CI 1.06–3.04; p = 0.029), whereas moderate/low-penetrance P/LP status was not (OR 0.96, 95% CI 0.48–1.91; p = 0.911). Management patterns also differed significantly. Initial mastectomy was performed in 65.4% of evaluable patients in the high-penetrance P/LP group, compared with 46.4% in the moderate/low-penetrance P/LP group and 45.5% in the VUS group. Final bilateral mastectomy was observed in 62.6%, 17.5%, and 9.9%, respectively (p < 0.001). In the prespecified non-BRCA analysis, non-BRCA P/LP status was not associated with non-luminal phenotype compared with non-BRCA VUS (OR 0.83, 95% CI 0.40–1.72; p = 0.609). Conclusions: Among breast cancer patients with germline alterations in breast cancer susceptibility genes, high-penetrance P/LP variants are associated with a distinct clinicopathological profile characterized by younger age at diagnosis, higher proliferative activity, and increased likelihood of non-luminal disease. In contrast, moderate/low-penetrance P/LP variants, especially VUSs, do not show the same degree of phenotype specificity. These findings support a framework in which pathogenic certainty and penetrance level remain central to the interpretation of multigene germline testing in breast cancer. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

16 pages, 1661 KB

Open AccessArticle

Progress and Disparities in Lung Cancer Screening in Japan: A Bayesian Analysis Toward Achieving Health Japan 21 Targets

by Takao Suzuki, Hasan Jamil, Aminu Kende Abubakar, Tshewang Gyeltshen, Hellen Wairimu Babu and Phuong The Nguyen

Cancers 2026, 18(10), 1498; https://doi.org/10.3390/cancers18101498 - 7 May 2026

Abstract

Background: Japan’s national health promotion plan, Health Japan 21, aims to achieve 60% lung cancer screening coverage by 2028. This study projected screening uptake through 2028 and estimated the probability of achieving this target at the national and prefectural levels, stratified [...] Read more.

Background: Japan’s national health promotion plan, Health Japan 21, aims to achieve 60% lung cancer screening coverage by 2028. This study projected screening uptake through 2028 and estimated the probability of achieving this target at the national and prefectural levels, stratified by gender. Methods: We analyzed lung cancer screening in Japan using the Comprehensive Survey of Living Conditions data (2013, 2016, 2019, 2022) for adults aged 40–69. Bayesian linear regressions estimated trends in logit-transformed screening coverage, with projections through 2028. We estimated annual changes, the probability of reaching 60% by 2028, and the first year in which the probability of target attainment exceeded 80%. Results: National screening coverage increased from 42.3% in 2013 to 49.7% in 2022, with an annual percentage-point change of 0.83 (95% CrI: −0.20 to 1.80). At this rate, the probability of reaching 60% by 2028 is 12.2%. Only 11 of 47 prefectures are projected to meet the target, while 4 (Kyoto, Kumamoto, Kagoshima, and Okinawa) are unlikely to reach it. Sex disparities were observed, with the probability of achievement at 25.4% for men versus 7.1% for women. The female annual change (0.99) exceeded the male annual change (0.65). Conclusions: Lung cancer screening participation varies significantly across regions and between genders, reflecting uneven progress toward the national goal. If current trends continue, achieving 60% coverage by 2028 will be challenging for most prefectures. Policy and system reforms could speed up uptake by focusing on prefectures and populations with the lowest participation rates. Full article

(This article belongs to the Special Issue Epidemiology of Cancer and Risk Factors: Pushing Boundaries in Public Health Research and Policy)

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23 pages, 3588 KB

Open AccessArticle

Integrative Survival Prediction in Breast Cancer Using Extracellular Matrix Protease Transcript Signatures and Clinical Variables: A Machine Learning Approach

by Rami Babas, Demitrios H. Vynios, Aristotelis Kompothrekas, Basilis Boutsinas and Nikos Karamanos

Cancers 2026, 18(10), 1497; https://doi.org/10.3390/cancers18101497 - 7 May 2026

Abstract

Background/Objectives: Traditional breast cancer prognostic tools relying on clinical staging often miss molecular heterogeneity, leading to divergent patient outcomes. Extracellular matrix (ECM) remodeling, driven by the Matrix Metalloproteinase (MMP), ADAM, and ADAMTS enzyme families, is critical to tumor progression. This study evaluates [...] Read more.

Background/Objectives: Traditional breast cancer prognostic tools relying on clinical staging often miss molecular heterogeneity, leading to divergent patient outcomes. Extracellular matrix (ECM) remodeling, driven by the Matrix Metalloproteinase (MMP), ADAM, and ADAMTS enzyme families, is critical to tumor progression. This study evaluates whether integrating ECM protease transcript abundance with standard clinical variables improves survival prediction accuracy and personalized risk stratification. Methods: Clinical and transcriptomic data from The Cancer Genome Atlas (TCGA) breast cancer cohort were analyzed. We integrated the protein-coding transcripts per million (pTPM) of top-ranked protease genes with standard clinical covariates (age, ordinal stage). Cox Proportional Hazards (CoxPH), penalized Cox (CoxNet), Random Survival Forest (RSF), and Gradient Boosting Survival (GBS) models were evaluated under a stratified 70/30 train–test split, followed by five-fold cross-validation. The locked final RSF model was then externally tested in METABRIC without retraining or risk-cutoff optimization. Results: Univariate screening identified ADAM15, MMP15, and ADAMTSL1 as global risk factors, whereas ADAMTS8 and MMP7 were protective. Prognostic signals were subtype-dependent. Integrated multivariable models outperformed transcript-only approaches in internal testing. The integrative RSF achieved the highest held-out discrimination (C-index = 0.797), outperforming a clinical-only Cox baseline trained on age and stage alone (C-index = 0.742, 95% CI 0.636–0.826). In METABRIC, the external C-index was 0.581 (95% CI 0.562–0.598), with significant survival separation across training-defined risk groups (log-rank p < 0.0001). Conclusions: ECM protease transcript profiles provide complementary prognostic information in TCGA-BRCA and show partial transportability to METABRIC. However, the modest external C-index indicates limited individual-level discrimination across platforms, so these candidate markers should be interpreted as hypothesis-generating and require further validation before clinical implementation. Full article

(This article belongs to the Section Tumor Microenvironment)

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13 pages, 552 KB

Open AccessArticle

Racial and Socioeconomic Disparities in Survival Among Patients with Metastatic Prostate Cancer: A SEER Population-Based Study

by Onyekachi Anya, Ogbonna Chikere, Progress Asoluka and Helen Oletu

Cancers 2026, 18(10), 1496; https://doi.org/10.3390/cancers18101496 - 7 May 2026

Abstract

Background: Prostate cancer remains a major cause of cancer morbidity and mortality among men in the United States. Differences in diagnosis and survival across racial and socioeconomic groups continue to raise concern in clinical and public health research. Population-based datasets provide an [...] Read more.

Background: Prostate cancer remains a major cause of cancer morbidity and mortality among men in the United States. Differences in diagnosis and survival across racial and socioeconomic groups continue to raise concern in clinical and public health research. Population-based datasets provide an opportunity to examine patterns of advanced disease and survival outcomes across diverse demographic groups. Objective: This study evaluated racial and socioeconomic disparities in cancer-specific survival among patients with metastatic prostate cancer using a national population-based dataset. Methods: A retrospective population-based study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) program. Patients diagnosed with malignant prostate cancer between 2004 and 2020 with distant stage disease were included. The final analytic sample consisted of 54,062 patients. Variables included race and ethnicity, age group, metastatic sites at diagnosis, treatment variables, and median household income. Descriptive analyses compared characteristics by cancer-specific death using chi-square tests for categorical variables and t tests for continuous variables. Survival patterns were examined using Kaplan–Meier methods and log-rank tests. Multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios for factors associated with cancer-specific mortality. Results: Cancer-specific mortality differed across racial and socioeconomic groups. Higher mortality was observed among non-Hispanic Black patients (aHR = 1.15, 95% CI: 1.00 to 1.31, p = 0.046) and non-Hispanic American Indian or Alaska Native patients (aHR = 1.15, 95% CI: 1.10 to 1.20, p < 0.001) compared with non-Hispanic White patients, while Hispanic and non-Hispanic Asian or Pacific Islander patients showed lower mortality risk. Older age groups demonstrated higher mortality. Liver, lung, and brain metastases were associated with increased risk of prostate cancer death. Patients in higher income groups showed lower mortality compared with patients in lower income groups (aHR = 0.83, 95% CI: 0.80 to 0.87, p < 0.001). Conclusions: This study highlights persistent racial and socioeconomic differences in cancer-specific survival among patients with advanced prostate cancer in the United States. These findings support continued efforts to address disparities in early detection, access to care, and treatment pathways. Future research should further explore clinical and structural factors that influence survival differences across population groups. Full article

(This article belongs to the Special Issue Cancer Disparities: Biological, Social, and Environmental Determinants)

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