Cancers

21 pages, 386 KB

Open AccessReview

Current and Emerging Therapies in Primary Vitreoretinal Lymphoma: A Narrative Review

by Mihai-Luca Cioboată, Suher Abduraman, Ioana Tofolean, Radu Burcea, Miruna Cioboată, Ali Rıza Cenk Çelebi and Florian Baltă

Cancers 2026, 18(17), 2865; https://doi.org/10.3390/cancers18172865 (registering DOI) - 4 Sep 2026

Abstract

This review aims to provide a comprehensive overview of the currently available therapies for primary vitreoretinal lymphoma (PVRL) and to evaluate emerging therapeutic strategies that may improve patient outcomes. A comprehensive literature search was conducted in databases including PubMed/MEDLINE, Embase, and Scopus for [...] Read more.

This review aims to provide a comprehensive overview of the currently available therapies for primary vitreoretinal lymphoma (PVRL) and to evaluate emerging therapeutic strategies that may improve patient outcomes. A comprehensive literature search was conducted in databases including PubMed/MEDLINE, Embase, and Scopus for studies published up to 2026. Search terms included “primary vitreoretinal lymphoma”, “intravitreal methotrexate”, “rituximab”, “radiotherapy”, “targeted therapy”, and “immunotherapy”. Eligible publications included randomized controlled trials, prospective and retrospective studies, observational studies, systematic reviews, relevant clinical guidelines, case series, and case reports. Studies were independently screened and assessed by two reviewers. Current therapeutic strategies include intravitreal chemotherapy, systemic high-dose methotrexate-based regimens, and radiotherapy, either as monotherapy or in combination. While intravitreal approaches provide effective local disease control, they fail to address occult or subsequent central nervous system (CNS) dissemination, necessitating the use of systemic treatments in selected patients. In recent years, significant progress in the understanding of PVRL pathophysiology, including the role of MYD88 mutations and interleukin-10 signaling, has paved the way for the development of targeted and immunomodulatory therapies. Agents such as Bruton’s tyrosine kinase inhibitors, immunomodulatory drugs, and immune checkpoint inhibitors have demonstrated promising results in early clinical studies, particularly in relapsed or refractory disease. Despite advances in diagnostic techniques, the management of PVRL remains challenging due to its heterogeneous presentation, high relapse rates, and frequent progression to CNS involvement. Full article

(This article belongs to the Section Cancer Therapy)

15 pages, 5893 KB

Open AccessArticle

Dynamic Prediction of Survival Outcomes in Multiple Myeloma

by Kelly Quek, Cindy H. Lee, Yang Zhang, Barbara J. McClure, Runzhe Chen, Hamish S. Scott, Kate Vandyke, Andrew C. W. Zannettino and Chung Hoow Kok

Cancers 2026, 18(17), 2864; https://doi.org/10.3390/cancers18172864 (registering DOI) - 4 Sep 2026

Abstract

Background: Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by marked clinical heterogeneity. Existing prognostic frameworks, including the International Staging System (ISS) and FISH-defined cytogenetic risk, are anchored at diagnosis and do not capture the evolutionary dynamics of disease or [...] Read more.

Background: Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by marked clinical heterogeneity. Existing prognostic frameworks, including the International Staging System (ISS) and FISH-defined cytogenetic risk, are anchored at diagnosis and do not capture the evolutionary dynamics of disease or treatment response, leaving an unmet need for risk models that retain prognostic validity longitudinally. Methods: Using transcriptomic data from 762 CD138-selected MM plasma cells from newly diagnosed patient samples in the MMRF CoMMpass study (NCT01454297), we computed single-sample pathway activity scores for 469 curated cancer-relevant pathways (MSigDB Hallmark; Reactome) and learned a Bayesian causal network linking pathway activity to survival. The model was validated in five independent diagnostic cohorts (n = 1255) and in two independent treatment and relapsed/refractory cohorts (n = 319). Longitudinal risk tracking was additionally assessed in a 46-patient subset of the discovery cohort with serial pre- and post-treatment sampling. Results: The network identified five pathways associated with survival: unfolded protein response (UPR), FLT3 signaling through SRC family kinases, G2M DNA replication checkpoint, metabolism of selenium compound (SeMet), and nicotinate metabolism. The composite survival score stratified patients into high-risk (n = 76; 10%) and standard-risk groups with markedly divergent survival (median 1170 days vs. not reached; p < 0.0001). The score remained an independent prognostic factor after adjustment for age, sex, ISS stage, and KRAS, TP53, and UBR5 mutational status (HR 4.93; 95% CI 2.96–8.19; p < 0.001), and replicated across all five external diagnostic cohorts. Critically, the model retained prognostic discrimination in previously treated (GSE57317; p < 0.0001) and relapsed/refractory (GSE9782; p < 0.0001) settings, and patients transitioning from standard- to high-risk between serial samples exhibited significantly inferior survival compared to standard-risk patients. Conclusions: This pathway-based Bayesian network provides a reproducible, dynamically applicable risk model for MM that captures information complementary to ISS and FISH-defined cytogenetics. The framework supports longitudinal patient monitoring and may inform trial enrichment strategies and closer surveillance for high-risk subpopulations. Full article

(This article belongs to the Special Issue Advances in Cancer Data and Statistics: 2nd Edition)

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19 pages, 1008 KB

Open AccessArticle

HistoNav: AI-Based H&E Histopathology Predicts Disease-Specific Survival and Guides Adjuvant Chemotherapy Decisions in Stage II/IIIA Colorectal Cancer

by Xianhong Xu, Susan Fotheringham, Surya Rajan, Jamil Aliyev and David J. Kerr

Cancers 2026, 18(17), 2863; https://doi.org/10.3390/cancers18172863 (registering DOI) - 4 Sep 2026

Abstract

Background: Stage II/IIIA colorectal cancer (CRC) patients have a relatively high 5-year overall survival rate after surgical resection alone, but more than 50% of patients receive adjuvant chemotherapy. This study investigates a technology that applies artificial intelligence (AI) to conventional histopathology images [...] Read more.

Background: Stage II/IIIA colorectal cancer (CRC) patients have a relatively high 5-year overall survival rate after surgical resection alone, but more than 50% of patients receive adjuvant chemotherapy. This study investigates a technology that applies artificial intelligence (AI) to conventional histopathology images to identify patients at risk of recurrence. Methods: HistoNav, a novel AI deep-learning algorithm based on Vision Transformer, Graph Neural Networks and Convolutional Neural Networks was designed to analyse H&E-stained formalin-fixed paraffin-embedded (FFPE) samples (n = 2095) to stratify Stage II/IIIA CRC patients into low-, intermediate-, and high-risk groups. Results: Data analysis revealed a 5-year disease-specific survival (DSS) of 93.2%, 84.3%, and 69.3% for low-, intermediate-, and high-risk groups, respectively. The hazard ratio for the high versus low-risk group (HR = 4.611, 95% CI: 2.776–7.662; p < 0.000001) was statistically significant, demonstrating HistoNav’s potential to stratify patients based on recurrence risk. Conclusions: HistoNav can effectively identify CRC patients with good prognosis using the digital images of H&E-stained resection samples and will support clinical decisions around the use of adjuvant chemotherapy. Full article

(This article belongs to the Special Issue AI-Driven Oncology: Advancing Cancer Detection, Diagnosis, and Personalized Treatment)

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16 pages, 1884 KB

Open AccessArticle

The Global Immune–Nutrition–Inflammation Index (GINI) as a Candidate Prognostic Marker in Patients with Cutaneous Squamous Cell Carcinoma Treated with Cemiplimab

by Tara Coreanu, Ido Amir, Nofar Edri, Itamar Averbuch, Aviram Mizrachi, Amit Ritter, Moran Amit, Noga Kurman, Eyal Yosefof and Dan Yaniv

Cancers 2026, 18(17), 2862; https://doi.org/10.3390/cancers18172862 (registering DOI) - 4 Sep 2026

Abstract

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent malignancy. While Cemiplimab has transformed the treatment landscape across various disease stages, reliable pretreatment biomarkers for risk stratification remain lacking.. The Global Immune–Nutrition–Inflammation Index (GINI) is a composite biomarker integrating systemic inflammation [...] Read more.

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent malignancy. While Cemiplimab has transformed the treatment landscape across various disease stages, reliable pretreatment biomarkers for risk stratification remain lacking.. The Global Immune–Nutrition–Inflammation Index (GINI) is a composite biomarker integrating systemic inflammation and nutritional status into a single score. This study aimed to evaluate the prognostic value of the pretreatment GINI in patients with cSCC receiving Cemiplimab across all treatment settings. Methods: This retrospective cohort study evaluated 73 patients with unresectable, locally advanced, or metastatic cSCC treated with Cemiplimab between 2020 and 2023. Pretreatment laboratory parameters were extracted to calculate the GINI score. Receiver operating characteristic (ROC) curve analysis determined the optimal GINI cutoff to stratify patients into low- and high-GINI groups. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were analyzed using Kaplan–Meier curves and multivariable Cox proportional hazards models. Results: An optimal GINI cutoff of 74.4 divided the cohort into low-GINI (38%) and high-GINI (62%) groups. In the multivariable Cox regression models, a high pretreatment GINI remained independently associated with both inferior OS (adjusted HR 2.51, 95% CI 1.05–6.01, p = 0.039) and inferior PFS (adjusted HR 3.22, 95% CI 1.45–7.14, p = 0.004). When compared against five established inflammatory biomarkers (NLR, PLR, LMR, PNI, and CAR), the GINI consistently demonstrated comparable prognostic performance across multiple statistical approaches. Conclusions: The pretreatment GINI is a candidate prognostic marker for patients with cSCC undergoing Cemiplimab therapy. Given its cost-effectiveness and ready availability from routine clinical laboratory workups, the GINI score may improve prognostic risk stratification and could potentially inform risk assessment and clinical monitoring in real-world oncological practice. Full article

(This article belongs to the Special Issue Mechanisms of Resistance and Response to Immune Checkpoint Inhibitors in Squamous Cell Carcinomas)

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14 pages, 269 KB

Open AccessReview

Neoadjuvant Systemic Therapy for Resectable Intrahepatic Cholangiocarcinoma: From Retrospective Studies to Randomized Evidence

by Hironobu Suto, Asahiro Morishita, Hiroyuki Matsukawa, Mina Nagao, Takuro Fuke, Yoshio Shimizu, Yasuhisa Ando, Minoru Oshima, Ryosuke Imado, Mai Nakahara, Kyoko Oura, Tomoko Tadokoro, Koji Fujita, Joji Tani, Hideki Kobara, Kensuke Kumamoto and Keiichi Okano

Cancers 2026, 18(17), 2861; https://doi.org/10.3390/cancers18172861 (registering DOI) - 4 Sep 2026

Abstract

Complete resection remains the only potentially curative treatment for localized intrahepatic cholangiocarcinoma (iCCA), yet postoperative recurrence is common, particularly in patients with high-risk disease. Neoadjuvant systemic therapy may permit earlier control of occult micrometastatic disease, optimize the delivery of systemic treatment, and provide [...] Read more.

Complete resection remains the only potentially curative treatment for localized intrahepatic cholangiocarcinoma (iCCA), yet postoperative recurrence is common, particularly in patients with high-risk disease. Neoadjuvant systemic therapy may permit earlier control of occult micrometastatic disease, optimize the delivery of systemic treatment, and provide an in vivo assessment of tumor biology prior to major hepatectomy. These potential benefits must be balanced against treatment-related toxicity, surgical delay, and the risk of disease progression precluding resection. Early evidence was primarily derived from retrospective studies, which yielded inconsistent survival outcomes and exhibited substantial vulnerability to confounding and treatment-selection bias. The single-arm NEO-GAP trial subsequently demonstrated the feasibility of administering neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel followed by surgical resection. More recently, the randomized phase II–III ZSAB-neoGOLP trial showed that neoadjuvant gemcitabine–oxaliplatin, lenvatinib, and toripalimab followed by surgery prolonged median event-free survival compared with upfront surgery (median: 18.0 vs. 8.7 months) without substantially compromising surgical feasibility. However, the interim overall survival analysis was inconclusive, and the generalizability of these findings beyond selected, medically fit patients treated at Chinese centers remains uncertain. This narrative review critically appraises the evolving evidence, discusses patient selection and perioperative treatment, and identifies priorities for future research. Current evidence supports the selective consideration of neoadjuvant therapy in medically fit patients with technically resectable but oncologically high-risk iCCA, rather than its routine use in all resectable cases. Full article

(This article belongs to the Special Issue Advances in Biliary Tract Cancer: Multidisciplinary Perspectives in Surgery, Endoscopic Management, and Epidemiology)

19 pages, 674 KB

Open AccessArticle

The Impact of Comorbidity on Severe Procedure-Coded Inpatient Events in Head and Neck Cancer and Thyroid Cancer Hospitalizations in Germany: A Nationwide DRG Analysis, 2005–2021

by Lisa-Marie Müller-Anderski, Mussab Kouka, Peter Schlattmann and Orlando Guntinas-Lichius

Cancers 2026, 18(17), 2860; https://doi.org/10.3390/cancers18172860 (registering DOI) - 4 Sep 2026

Abstract

Background: Comorbidity is an important determinant of treatment selection and in-hospital complications in patients with head and neck cancer (HNC) and thyroid cancer (TC), yet population-based evidence on this relationship remains limited. Methods: We analyzed nationwide Diagnosis-Related Groups (DRG) data from 1,552,028 inpatient [...] Read more.

Background: Comorbidity is an important determinant of treatment selection and in-hospital complications in patients with head and neck cancer (HNC) and thyroid cancer (TC), yet population-based evidence on this relationship remains limited. Methods: We analyzed nationwide Diagnosis-Related Groups (DRG) data from 1,552,028 inpatient HNC and TC treatments of patients aged ≥30 years in Germany between 2005 and 2021. The aim was to characterize the association of comorbidity and severe treatment-related procedure-coded inpatient events (IEs) with gender, age, tumor subsite, and treatment type. Results: The largest proportion of treatments occurred in patients aged 60–69 years (33.5%). The most frequent tumor subsites were the oropharynx, thyroid gland, oral cavity, larynx, and hypopharynx, with 35.52, 33.84, 33.60, 26.12, and 15.76 treatments per 100,000 population per year, respectively. Overall, 38% of cases had a Charlson Comorbidity Index (CCI) ≥ 1, with the highest mean CCI observed for C14 (other sites of the lip, oral cavity and pharynx) and C12 (piriform sinus). IEs requiring additional in-hospital treatment occurred in 19.3% of cases. After adjustment for age, tumor location, and treatment type, men had a lower risk of IEs than women (OR 0.929; CI 0.919–0.939; p < 0.001). Increasing comorbidity was associated with a higher IE risk, reaching a plateau at CCI ≥ 4 (OR 2.135; CI 2.029–2.246; p < 0.001). IE risk was high during chemotherapy/immunotherapy (OR 29.527; CI 28.897–30.170; p < 0.001), followed by surgery (OR 3.465; CI 3.433–3.498; p < 0.001), whereas radiotherapy showed the lowest risk (OR 1.339; CI 1.313–1.366; p < 0.001). Conclusions: These findings highlight substantial heterogeneity in comorbidity and IE risk among patients with HNC or TC. Full article

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

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12 pages, 529 KB

Open AccessArticle

Biopsy Provides Actionable Information Associated with Treatment Decisions for 2–7 cm Renal Masses

by Daniel F. Roadman, Daniel D. Shapiro, Paz Lotan, Tudor Borza, Isabelle SueJin Lee, J. Louis Hinshaw, Fred T. Lee, Jr., Edwarda Golden, Erica Knavel Koepsel, Paul Laeseke, David F. Jarrard, Kyle A. Richards, Elizabeth L. Koehne, Glenn O. Allen, Michael C. Risk and E. Jason Abel

Cancers 2026, 18(17), 2859; https://doi.org/10.3390/cancers18172859 (registering DOI) - 4 Sep 2026

Abstract

Background/Objectives: Renal mass biopsy (biopsy) is increasingly incorporated into the evaluation of localized renal masses, yet its role in guiding management remains variable among clinical practices. We evaluated the clinical association of biopsy using a simplified classification system categorizing biopsy results as [...] Read more.

Background/Objectives: Renal mass biopsy (biopsy) is increasingly incorporated into the evaluation of localized renal masses, yet its role in guiding management remains variable among clinical practices. We evaluated the clinical association of biopsy using a simplified classification system categorizing biopsy results as Biopsy Actionable for Immediate Treatment (BAIT) or Biopsy Actionable for Active Surveillance (BAAS)—assessing how biopsy-derived histology influences real-world management. Methods: We identified all patients undergoing biopsy for a renal mass measuring 2–7 cm at a single academic center between 2010 and 2025. After excluding nondiagnostic biopsies, repeat biopsies, and biopsies performed for metastatic diagnosis, 1395 patients formed the analytic cohort. Histologic subtypes and initial treatment were evaluated. Multivariable logistic regression assessed predictors of (1) radical versus partial nephrectomy, (2) surgery versus thermal ablation, and (3) active surveillance versus intervention, adjusting for tumor diameter, age, and BAIT/BAAS status. Results: Of 1395 patients, 1119 (80.2%) had BAIT pathology and 276 (19.8%) had BAAS pathology. Initial management included surgery (36.3%), thermal ablation (36.3%), active surveillance (24.2%), no treatment (1.7%), and radiation (1.5%). BAAS pathology was strongly associated with the selection of active surveillance (OR 21.80, p < 0.001). Larger tumor diameter was the principal driver of radical nephrectomy (OR 2.04/cm, p < 0.001) and of choosing surgery over ablation (OR 2.05/cm, p < 0.001). Younger age was associated with selection of surgery over ablation (OR 0.93/year, p < 0.001). Biopsy histology showed a stronger association with surveillance selection than either tumor diameter or age. Conclusions: Biopsy provides actionable diagnostic information for patients with 2–7 cm renal masses, identifying benign or indolent pathology in nearly one in five patients. BAIT/BAAS categorization was strongly associated with the selection of active surveillance for renal masses. Full article

(This article belongs to the Special Issue Clinical Trials and Evolving Treatment Paradigms in Urologic Cancers)

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14 pages, 3937 KB

Open AccessArticle

Reflectance Confocal Microscopy for Treatment Response Monitoring in Locally Advanced Basal Cell Carcinoma Treated with Sonidegib: A Prospective Observational Study

by Federico Venturi, Carlotta Baraldi, Barbara Corti, Barbara Melotti, Elisabetta Magnaterra, Biagio Scotti and Emi Dika

Cancers 2026, 18(17), 2858; https://doi.org/10.3390/cancers18172858 - 3 Sep 2026

Abstract

Background/Objectives: Conventional clinical and dermoscopic assessment may overestimate treatment response in locally advanced basal cell carcinoma (laBCC) treated with Hedgehog pathway inhibitors due to treatment-induced fibrosis, pigment retention, and stromal remodeling. Reflectance confocal microscopy (RCM) enables noninvasive, near-histologic resolution skin imaging and may [...] Read more.

Background/Objectives: Conventional clinical and dermoscopic assessment may overestimate treatment response in locally advanced basal cell carcinoma (laBCC) treated with Hedgehog pathway inhibitors due to treatment-induced fibrosis, pigment retention, and stromal remodeling. Reflectance confocal microscopy (RCM) enables noninvasive, near-histologic resolution skin imaging and may improve response evaluation accuracy. This study evaluated the role of RCM in monitoring treatment response and guiding presurgical planning in laBCC patients treated with sonidegib. Methods: In this prospective, single-center, observational pilot study, 15 consecutive patients with laBCC unsuitable for upfront surgery received sonidegib 200 mg daily. Treatment response was assessed using integrated clinical examination and RCM at baseline and follow-up. Study-specific response categories (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]) were adapted from RECIST principles. Presurgical RCM mapping was performed in partial responders. Interobserver agreement between two blinded RCM readers was assessed using Cohen’s kappa (κ). Results: The objective response rate was 93.3% (CR: 26.7%; PR: 66.7%; PD: 6.7%). Dose modifications were required in 73.3% of patients; adverse events occurred in 60.0%, most commonly dysgeusia (33.3%) and muscle cramps (20.0%). Clinical–RCM discordance was identified in 13.3% of patients: lesions classified as CR by conventional evaluation were reclassified as PR after RCM detected persistent basaloid tumor nests, prompting treatment continuation (Interobserver agreement: κ = 0.62–0.86). Conclusions: RCM identified residual disease missed by conventional assessment, directly influencing treatment decisions. These findings support integrating RCM into a multimodal, response-adapted management strategy for laBCC. However, the limited sample size warrants cautious interpretation, and larger multicenter studies are required before broad clinical implementation. Full article

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

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17 pages, 8385 KB

Open AccessArticle

CT-Derived Muscle and Adipose Tissue Characteristics and Survival in Advanced NSCLC Treated with First-Line Immunotherapy-Based Regimens

by Blerina Resuli, Amanda Tufman, Friederike Völter, Diego Kauffmann-Guerrero, Paula Mras, Paola Arnold, Clemens Bleistein, Jürgen Behr, Victoriya Vasileva, Lalith Kumar Shiyam Sundar, Jens Ricke, Clemens Cyran, Wolfgang G. Kunz, Matthias P. Fabritius and Nabeel Mansour

Cancers 2026, 18(17), 2857; https://doi.org/10.3390/cancers18172857 - 3 Sep 2026

Abstract

Background: Host-related factors such as skeletal muscle and adipose tissue characteristics are increasingly recognized as determinants of outcome in advanced non-small cell lung cancer (aNSCLC). However, the prognostic relevance of integrated body composition phenotypes in patients receiving first-line immunotherapy-based treatment remains unclear. Methods: [...] Read more.

Background: Host-related factors such as skeletal muscle and adipose tissue characteristics are increasingly recognized as determinants of outcome in advanced non-small cell lung cancer (aNSCLC). However, the prognostic relevance of integrated body composition phenotypes in patients receiving first-line immunotherapy-based treatment remains unclear. Methods: We retrospectively analyzed patients with aNSCLC treated with first-line immune checkpoint inhibitors (ICI) alone or combined with chemotherapy (ICI–CT) between October 2018 and December 2023 at LMU University Hospital. AI-derived CT biomarkers included skeletal muscle volume index (SMVI), skeletal muscle density (SMD), visceral adipose volume index (VAVI), and subcutaneous adipose volume index (SAVI), normalized for height. Individual body composition parameters were analyzed as standardized continuous variables. For exploratory phenotype analyses, SMVI and VAVI were categorized using cohort-specific sex-stratified median values. An integrated body composition phenotype was defined as “high-muscle/low-visceral-adiposity” (high SMVI/low VAVI) or “low-muscle/high-visceral-adiposity” (low SMVI/high VAVI), with patients not meeting either definition classified as having an intermediate phenotype. Multivariable Cox regression adjusted for age, sex, treatment modality, and metastatic burden evaluated associations with progression-free survival (PFS) and overall survival (OS). Results: Of 116 screened patients, 103 with evaluable baseline CT imaging were included. The cohort predominantly comprised ever-smokers (81.6%) and patients with adenocarcinoma (62.1%). Higher SMD (per one standard deviation increase) was associated with improved overall survival (HR 0.72, 95% CI 0.52–1.00; p = 0.047), and higher VAVI was associated with a higher risk of death (HR 1.29, 95% CI 1.00–1.65; p = 0.048). Neither SMD nor VAVI was significantly associated with PFS, and SMVI and SAVI were not significantly associated with OS or PFS. In the exploratory integrated phenotype analysis, median OS was 29.5 months in the high-muscle/low-visceral-adiposity group, 16.2 months in the intermediate group, and 19.3 months in the low-muscle/high-visceral-adiposity group; however, the overall Kaplan–Meier comparison was not statistically significant (log-rank p = 0.385). Conclusions: AI-derived CT body composition assessment may provide complementary prognostic information in patients with aNSCLC receiving first-line immunotherapy-based treatment. Higher skeletal muscle density was associated with a lower risk of death, whereas higher visceral adiposity was associated with a higher risk of death. The exploratory integrated phenotype analysis did not demonstrate a consistent risk gradient across phenotype categories. These findings require validation in larger prospective cohorts before clinical implementation. Full article

(This article belongs to the Special Issue First-Line Therapy in Thoracic Oncology)

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33 pages, 1656 KB

Open AccessReview

Lung Cancer Survivorship: Challenges and Care Needs

by Massimiliano Cani, Paolo Cotogni, Alessandra Greco, Giacomo Ronconi, Elisa Lombardi, Matteo Fracchiolla, Stefania Vallone, Maria Vittoria Pacchiana, Irene Capizzi, Valentina Bertaglia, Simona Carnio, Luisella Righi, Maurizio Balbi, Lorenzo Belluomini, Paolo Bironzo and Silvia Novello

Cancers 2026, 18(17), 2856; https://doi.org/10.3390/cancers18172856 - 3 Sep 2026

Abstract

Advances in lung cancer treatment have progressively improved survival across all disease stages. Some patients now achieve long-term survival, while others may remain on treatment for several years, particularly with immune checkpoint inhibitors and selected tyrosine kinase inhibitors. These advances have increased recognition [...] Read more.

Advances in lung cancer treatment have progressively improved survival across all disease stages. Some patients now achieve long-term survival, while others may remain on treatment for several years, particularly with immune checkpoint inhibitors and selected tyrosine kinase inhibitors. These advances have increased recognition of the survivorship needs of patients with lung cancer, including persistent symptoms, treatment-related toxicities, and social, psychological, and caregiver-related concerns. The integration of palliative care has also become increasingly relevant, reflecting a shift in the traditional care paradigm by extending supportive approaches beyond the end-of-life setting to patients living long-term with active disease. However, evidence and care models addressing lung cancer survivorship remain fragmented and focus predominantly on patients treated with curative intent. This narrative review provides a comprehensive overview of survivorship in lung cancer, from screening and early-stage to locally advanced and metastatic disease, while also examining more cross-cutting physical, psychological and social domains. Greater recognition and systematic assessment of these needs is essential to develop structured, coordinated, and personalized survivorship pathways for the growing and clinically heterogeneous population of individuals living with and beyond lung cancer. Full article

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

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18 pages, 506 KB

Open AccessArticle

The Impact of Chemotherapy on Gonadal Function in Female Patients with Hodgkin and Non-Hodgkin Lymphoma: A Comprehensive Analysis of Hormonal Kinetics and Implications for Fertility and Contraceptive Planning

by Angeliki N. Georgopoulou, Theodoros P. Vassilakopoulos, Andreas Giannakou, Neoklis A. Georgopoulos, Sophia Kalantaridou, Konstantinos Keramaris, Eleni Lalou, Eleni Loukari, Konstantinos Konstantopoulos, Marina P. Siakantaris, Anastasia Kopsaftopoulou, Chrysovalanto Chatzidimitriou, Maria Arapaki, Marina Belia, Iliana Konstantinou, Ioannis Asimakopoulos, Irene Mammali and Maria K. Angelopoulou

Cancers 2026, 18(17), 2855; https://doi.org/10.3390/cancers18172855 - 3 Sep 2026

Abstract

Background/Objectives: Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL) affect young women, with cure rates exceeding 80%. Treatment-related gonadal insufficiency is recognized for its impact on fertility, yet fertility preservation remains underutilized, and prospective data are limited. The aim of this [...] Read more.

Background/Objectives: Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL) affect young women, with cure rates exceeding 80%. Treatment-related gonadal insufficiency is recognized for its impact on fertility, yet fertility preservation remains underutilized, and prospective data are limited. The aim of this study is to prospectively evaluate gonadal function in women ≤40 years old with lymphoma undergoing chemotherapy. Methods: Ovarian reserve and endocrine ovarian function were evaluated by sequential measurements of follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), progesterone, and estradiol at diagnosis, during, and after chemotherapy. Results: 81 female patients ≤40 years old were enrolled, including 53 with HL and 28 with NHL (16 with PMBCL). HL patients had significantly lower AMH values for their respective age group compared to all other diagnoses (p = 0.05), which was more striking for patients ≤30 years old (p = 0.039), indicating pre-existing reduced ovarian reserve in HL. In HL, both FSH and AMH levels indicate gonadal dysfunction for at least six months post-chemotherapy, with AMH serving as a more sensitive biomarker than FSH. For PMBCL patients treated with R-DA-EPOCH, AMH suppression was noticed, with no evidence of recovery up to 18 months post-treatment. At all time points, the PMBCL patients had significantly lower AMH values compared to the HL patients (AMH6: p = 0.03, AMH12 and AMH18: p = 0.05). AMH emerged as the most sensitive marker of ovarian damage, with pretreatment levels <7 pmol/L predicting impaired ovarian reserve in HL patients. Conclusions: For HL, the pretreatment cut-off of 7 pmol/L could discriminate patients with ovarian insufficiency post-treatment, whereas no statistically significant predictive association was identified in PMBCL. These findings require validation in larger cohorts. Full article

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

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27 pages, 4933 KB

Open AccessArticle

Tumor Topography Remodels TME Signalling via Compartment-Specific Host–Microbiome–Tumor Crosstalk in Hepatoblastoma

by Beate Obermüller, Sabine Obermüller, Karin Wagner, Maximilian Nepel, Holger Till, Georg Singer and Bettina Leber

Cancers 2026, 18(17), 2854; https://doi.org/10.3390/cancers18172854 - 3 Sep 2026

Abstract

Background & Aims: Signaling within the tumor microenvironment (TME) emerges from dynamic crosstalk among cancer cells, host tissues, and the microbiome. Orthotopic and ectopic xenograft models are widely used in preclinical liver cancer research, yet it remains unclear to what extent tumor [...] Read more.

Background & Aims: Signaling within the tumor microenvironment (TME) emerges from dynamic crosstalk among cancer cells, host tissues, and the microbiome. Orthotopic and ectopic xenograft models are widely used in preclinical liver cancer research, yet it remains unclear to what extent tumor location shapes systemic host responses and gut–liver communication. We therefore investigated how anatomical context influences host transcriptomes and spatially resolved intestinal microbial ecosystems in hepatoblastoma (HB). Methods: We integrated bacterial/archaeal ecology with host and xenograft transcriptomes in orthotopic versus ectopic hepatoblastoma xenografts in male athymic CAnN.Cg-Foxn1nu/Crl mice. Single-sample GSEA, sparsity-aware networks, and DIABLO multi-block integration mapped pathway-level coordination across intestinal segments, stool, secondary lymphoid organs, livers, and tumors. Results: Tumor localization was associated with compartment-specific differences in host signaling, with the mesenteric lymph node and liver showing prominent shifts in TNFA/NF-κB, hypoxia, unfolded protein response, xenobiotic metabolism, mTORC1, KRAS, epithelial–mesenchymal transition, and MYC/E2F cell-cycle axes. Archaea exhibited pronounced, niche-specific signatures that showed positive correlations with proliferative and inflammatory Hallmarks and negative correlations with interferon pathways. Multi-omics integration (r ≥ 0.85) indicated coordinated variation linking specific microbial families to host and tumor programs and positioned the xenograft block as a hub connecting EMT, mTORC1, and angiogenesis to defined archaeal and bacterial taxa. Conclusions: Tumor topography remodels TME signaling through compartment-dependent host–microbiome–tumor crosstalk, with archaeal domains emerging as salient correlates of proliferative and stress-response networks. These findings provide a systems framework and testable hypotheses for therapeutic modulation of TME signaling via interkingdom interactions. Full article

(This article belongs to the Special Issue Signaling Pathways and Molecular Crosstalk in the Tumor Microenvironment)

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14 pages, 1202 KB

Open AccessArticle

Identification of Factors That Determine Adherence for Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer

by Cynthia Araradian, Emmett Hunnicutt, Siting Chen, Shawna Rivedal, Shelby Willis, Maura Walsh, Vassiliki Liana Tsikitis and Sandy Hwang Fang

Cancers 2026, 18(17), 2853; https://doi.org/10.3390/cancers18172853 - 3 Sep 2026

Abstract

Background: Locally advanced rectal cancer (LARC) treatment has shifted from the utilization of neoadjuvant chemoradiation (NACRT), followed by total mesorectal excision (TME) and adjuvant chemotherapy (AC) to the implementation of total neoadjuvant therapy (TNT). This transition was influenced by data from multiple [...] Read more.

Background: Locally advanced rectal cancer (LARC) treatment has shifted from the utilization of neoadjuvant chemoradiation (NACRT), followed by total mesorectal excision (TME) and adjuvant chemotherapy (AC) to the implementation of total neoadjuvant therapy (TNT). This transition was influenced by data from multiple studies reporting suboptimal compliance rates to adjuvant chemotherapy. As a result, a paradigm shift to TNT occurred, consisting of chemoradiation with chemotherapy, based on the RAPIDO and PRODIGE-23 studies. Methods: Following IRB approval, a single-institution retrospective chart review was conducted at a tertiary care academic institution for patients with LARC. Demographic, clinical, and treatment data were collected using REDCap. Patients were excluded if under 18 years of age, pregnant, or had stage 1 or metastatic rectal cancer. The primary objective was to evaluate TNT adherence; secondary objectives assessed adherence associations with demographic and clinical variables. Results: Two hundred twenty-nine patients with rectal cancer were initially included in the database, including 153 patients with LARC from 2019 to 2024. One hundred twenty-seven patients underwent TNT with an adherence rate of 87.5%. Statistically significant variables that contributed to adherence include male gender (p = 0.04) and non-use of recreational drugs (p = 0.04). Conclusions: This is the first real-world study assessing TNT adherence. The observed 87.5% adherence rate represents a significant improvement over historical data in which patients were treated with NACRT/TME/AC. Statistically significant variables that contributed to TNT adherence included male gender and non-use of recreational drugs. These factors may provide insight into gender differences and behavioral patterns that put patients in an at-risk category for non-adherence. Full article

(This article belongs to the Special Issue Innovations in Colorectal Cancer)

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19 pages, 714 KB

Open AccessReview

Understanding the Rising Incidence of Early-Onset Colorectal Cancer: Life-Course Determinants and Opportunities for Primary Prevention

by Antoni Alegre-Martinez, Luis Cabañas-Alite, Ines E. Fernández-Benet, Manuel Sánchez-Casalongue and Jose M. Martin-Moreno

Cancers 2026, 18(17), 2852; https://doi.org/10.3390/cancers18172852 - 3 Sep 2026

Abstract

Background/Objectives: Early-onset colorectal cancer (EOCRC), diagnosed before age 50 years, is increasing in many countries, but its causes remain uncertain. Evidence on potentially modifiable determinants is heterogeneous and vulnerable to retrospective assessment and residual confounding. We synthesized metabolic, behavioral, dietary, medication-related, clinical, [...] Read more.

Background/Objectives: Early-onset colorectal cancer (EOCRC), diagnosed before age 50 years, is increasing in many countries, but its causes remain uncertain. Evidence on potentially modifiable determinants is heterogeneous and vulnerable to retrospective assessment and residual confounding. We synthesized metabolic, behavioral, dietary, medication-related, clinical, and socioeconomic factors, emphasizing consistency and life-course relevance. Methods: Two core PubMed searches covering publications from 1 January 2010 through 1 June 2026 were supplemented by targeted PubMed searches and reference-list screening. The present review cited 75 journal publications and synthesized the findings qualitatively; no formal risk-of-bias assessment, certainty-of-evidence grading, or de novo quantitative pooling was performed. Results: Evidence was most consistent for excess adiposity and cardiometabolic dysfunction, with earlier and persistent exposure and cardiometabolic clustering potentially more relevant. Inflammatory bowel disease emerged as a clinically distinct high-risk condition. Sedentary behavior, smoking, and higher alcohol consumption showed recurrent but heterogeneous associations. Dietary findings varied by pattern and component: sugar-sweetened beverages and lower-quality dietary patterns showed positive associations, whereas fiber- and plant-rich diets, calcium, folate, and vitamin D showed possible inverse associations. Dietary evidence was largely retrospective and does not establish causality. Evidence for aspirin and antibiotics was limited and vulnerable to confounding, precluding causal inference. Most patterns resembled later-onset CRC. Conclusions: Current evidence does not support a wholly distinct set of environmental determinants for EOCRC. Earlier exposure, longer duration, and cumulative interaction of CRC risk factors are plausible explanations but remain incompletely tested. Evidence supports life-course primary prevention, but no single factor should determine screening eligibility in isolation. Prospective studies with repeated exposure measurement are needed. Full article

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

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16 pages, 17697 KB

Open AccessArticle

TPPP3 Overexpression Suppresses Nasopharyngeal Carcinoma Progression and Promotes Immune Microenvironment Remodeling Through HSPA8 Association

by Shengwei Li, Jiejun Liao, Jiawei Yang, Yanfeng Han, Zixiao Lei and Zheng Yang

Cancers 2026, 18(17), 2851; https://doi.org/10.3390/cancers18172851 - 3 Sep 2026

Abstract

Objectives: Nasopharyngeal carcinoma (NPC) arises in an immune-suppressive milieu that frequently undermines treatment efficacy. TPPP3 has been implicated as a negative regulator of NPC aggressiveness, yet its relevance to immune modulation or chaperone networks remains poorly defined. We therefore sought to determine [...] Read more.

Objectives: Nasopharyngeal carcinoma (NPC) arises in an immune-suppressive milieu that frequently undermines treatment efficacy. TPPP3 has been implicated as a negative regulator of NPC aggressiveness, yet its relevance to immune modulation or chaperone networks remains poorly defined. We therefore sought to determine how TPPP3 shapes the NPC immune landscape and to identify its interacting protein partners. Methods: Public single-cell RNA-sequencing datasets from head and neck squamous cell carcinoma and nasopharyngeal carcinoma were analyzed using R. HK-1 and C666-1 cells stably overexpressing TPPP3 were established. These cells were used to construct humanized xenograft tumor models, with intratumoral immune cell infiltration evaluated by immunohistochemistry. In vitro, the same cells and their controls were indirectly co-cultured with peripheral blood mononuclear cells. Cellular lysates from TPPP3-overexpressing cells were subjected to immunoprecipitation–mass spectrometry and immunofluorescence staining, which identified HSPA8 as a TPPP3-interacting protein. Three groups—control, TPPP3-overexpressing, and TPPP3-overexpressing plus the HSPA8 inhibitor VER155008—were then compared in wound healing, colony formation, cell-cycle, and xenograft assays, with immunohistochemical staining for Ki67, TPPP3, and CD3 performed on tumor sections. Results: TPPP3 transcripts were barely detectable across most tumor cell subsets but showed preferential enrichment in NPC epithelial clusters. Enforced TPPP3 expression curtailed xenograft outgrowth while increasing intratumoral abundance of CD3⁺ T cells, CD8⁺ T cells, and CD11c⁺ dendritic cells. Pharmacological blockade of HSPA8 with VER155008 further enhanced TPPP3-driven suppression of migration, clonogenicity, and tumor expansion, and also altered cell-cycle progression while boosting CD3⁺ T-cell accumulation within grafts. Conclusions: These findings suggest a functional association between TPPP3 and HSPA8 that may contribute to tumor growth suppression and immune microenvironment remodeling in NPC. Pharmacological disruption of HSPA8-dependent proteostasis enhanced TPPP3-associated antitumor activity in both in vitro and in vivo models, indicating that this chaperone pathway represents a candidate mechanism worthy of further mechanistic investigation and therapeutic exploration. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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2 pages, 323 KB

Open AccessCorrection

Correction: Aggarwal, M. 2,2-Diphenethyl Isothiocyanate Enhances Topoisomerase Inhibitor-Induced Cell Death and Suppresses Multi-Drug Resistance 1 in Breast Cancer Cells. Cancers 2023, 15, 928

by Monika Aggarwal

Cancers 2026, 18(17), 2850; https://doi.org/10.3390/cancers18172850 - 3 Sep 2026

Abstract

In the original publication [...] Full article

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29 pages, 540 KB

Open AccessArticle

Postoperative Complications After Lung Cancer Resection in Patients with a Previous History of Head and Neck Cancer

by Farzin Falahat-Noushzady, Sonia Herrero-Álvarez, Elisa M. Molanes-López, Roy Camacho-Leone, Carlos Alfredo Fraile-Olivero, Joaquín Calatayud-Gastardi, José Ramón Jarabo-Sarceda, Florentino Hernando-Trancho, Elena María Vara and Ana Maria Gómez-Martínez

Cancers 2026, 18(17), 2849; https://doi.org/10.3390/cancers18172849 - 3 Sep 2026

Abstract

Background/Objectives: Surgical pulmonary resection in lung cancer remains the cornerstone of curative treatment; however, it is associated with considerable postoperative pulmonary complications. Patients previously treated for head and neck cancer (HNC) have a significantly increased risk of developing second primary lung cancer [...] Read more.

Background/Objectives: Surgical pulmonary resection in lung cancer remains the cornerstone of curative treatment; however, it is associated with considerable postoperative pulmonary complications. Patients previously treated for head and neck cancer (HNC) have a significantly increased risk of developing second primary lung cancer (LC) and a higher incidence of adverse pulmonary outcomes after LC resective surgery due to increased baseline frailty. Methods: A retrospective observational longitudinal study was conducted on 1679 patients who underwent surgical resection with curative intent for LC at the Thoracic Surgery Department of Hospital Clínico San Carlos, Madrid, Spain, between December 1989 and December 2024. Patients were divided into two groups based on the presence or absence of prior HNC: 87 with HNC vs. 1592 without. Special attention was paid to respiratory complications, particularly bronchopleural fistula (BPF), empyema, atelectasis, and pneumonia. Variables significantly associated with BPF and HNC in univariate analyses (excluding those related to other complications to avoid collinearity), as well as clinically relevant baseline differences between groups, were included in a stepwise multivariable logistic regression modeling procedure to identify independent risk factors associated with BPF. Results: In comparison with the control group, significantly higher rates of postoperative BPF (12.6% vs. 3.6%), empyema (10.3% vs. 2.8%), atelectasis (14.9% vs. 8.3%) and need of reintervention (10.3% vs. 4.2%) were found in the HNC group under unadjusted approach and stratified by surgery period. Sex, history of HNC, chronic obstructive pulmonary disease (COPD) and length of preoperative hospital stay were independently associated with BPF according to several multivariable logistic regression fits, which showed a moderate discriminatory capacity (AUC values ranging from 0.723 to 0.732). In particular, the presence of HNC was significantly associated with BPF, with adjusted odds ratio (aOR) estimates ranging from 3.562 (95% CI: 1.773 to 7.156) to 3.789 (95% CI: 1.863 to 7.709). Conclusions: In our study, COPD, male sex, preoperative hospital stay as well as HNC history were found independently associated with an increased odds of BPF after surgical treatment for LC. In particular, patients previously treated for HNC had more than threefold higher odds of developing BPF than those without a history of HNC, with this association remaining consistent over the 35-year study period. Full article

(This article belongs to the Special Issue Clinical and Translational Research in Head and Neck Cancer—2nd Edition)

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23 pages, 12932 KB

Open AccessArticle

Amplification-Driven S100A11 Overexpression in Hepatocellular Carcinoma Is Associated with Metabolic Reprogramming, ECM Remodelling, and Immune Evasion: A Pan-Cancer Genomic Study

by Stuart Lutimba and Eiman Aleem

Cancers 2026, 18(17), 2848; https://doi.org/10.3390/cancers18172848 - 3 Sep 2026

Abstract

Background: S100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular carcinoma (HCC) carries a dismal prognosis, in part due to a lack of reliable biomarkers for risk stratification of [...] Read more.

Background: S100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular carcinoma (HCC) carries a dismal prognosis, in part due to a lack of reliable biomarkers for risk stratification of established disease. Methods: We conducted a pan-cancer analysis of S100A11 genomic alterations across 31 studies (10,767 samples) obtained from TCGA, encompassing copy number alterations, somatic mutations, and DNA methylation. HCC-specific analyses evaluated S100A11 expression, its potential as a diagnostic/prognostic marker, co-expression networks, and pathway enrichment using TCGA-LIHC data, with univariate and multivariate Cox regression to assess survival associations. Results: S100A11 alterations were predominantly driven by copy number amplification, with the highest frequencies in hepatobiliary cancers, lung and breast cancers. Copy number amplification showed a consistent inverse relationship with promoter methylation, indicating amplification-driven transcriptional activation. In HCC, S100A11 was markedly overexpressed compared with normal liver tissue, with strong diagnostic discriminatory capacity. High S100A11 expression was significantly associated with inferior overall survival (log-rank p = 0.032; HR = 1.46, 95% CI 1.03–2.06) and remained an independent predictor of overall survival after adjustment for age, sex, and AJCC pathologic stage (HR = 1.27, 95% CI 1.01–1.60, p = 0.038). Co-expression and pathway analyses demonstrated an association between S100A11 and metabolic reprogramming, extracellular matrix remodelling, and immune dysregulation. Conclusions: These findings identify S100A11 as a candidate diagnostic and prognostic biomarker in HCC whose overexpression is associated with metabolic reprogramming, ECM remodelling, and immune dysregulation, warranting experimental validation of a mechanistic role. Full article

(This article belongs to the Special Issue Molecular Targets and Therapeutic Pathways in Cancer)

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Graphical abstract

16 pages, 12651 KB

Open AccessArticle

Clinical Applicability of the WHO Reporting System for Axillary Lymph Node Fine-Needle Aspiration in Invasive Breast Carcinoma

by Mariana Canepa, Allison Chang, Stephanie L. Graff and Yihong Wang

Cancers 2026, 18(17), 2847; https://doi.org/10.3390/cancers18172847 - 3 Sep 2026

Abstract

Background: Axillary lymph node (ALN) fine-needle aspirations (FNAs) can guide the next steps in the management of patients with invasive breast carcinoma (BC). The objective is to evaluate the diagnostic performance of ALN FNA in the detection of metastatic breast carcinoma. Methods: We [...] Read more.

Background: Axillary lymph node (ALN) fine-needle aspirations (FNAs) can guide the next steps in the management of patients with invasive breast carcinoma (BC). The objective is to evaluate the diagnostic performance of ALN FNA in the detection of metastatic breast carcinoma. Methods: We evaluated ALN FNAs from 2020 to 2024 to determine the risk of malignancy (ROM) of different cytologic diagnostic categories using a general WHO cytology reporting system framework (insufficient, benign, atypical, suspicious, and malignant). Results: A total of 290 axillary lymph node FNAs from patients with newly diagnosed invasive breast carcinoma were identified, of which 226 (78%) had histologic and/or adequate clinical follow-up. Cytologic diagnoses included six (2.1%) non-diagnostic, 99 (34.1%) benign, two (0.7%) atypical, seven (2.4%) suspicious for malignancy, and 176 (60.7%) malignant cases. The risk of malignancy (ROM) was 50.0% for non-diagnostic, 17.0% for benign, 100% for atypical, 85.7% for suspicious, and 99.2% for malignant diagnoses. Most false-negative benign cases were attributed to sampling limitations rather than interpretive error, with five cases showing only a single sentinel lymph node metastasis measuring <5 mm. Indeterminate diagnoses were most commonly associated with scant cellularity, acellular cell blocks, obscuring blood or fibrin, and equivocal immunohistochemistry. Excluding cases without histologic follow-up, ALN FNA demonstrated a sensitivity of 86.5%, specificity of 97.4%, positive predictive value of 98.5%, negative predictive value of 79.2%, and overall accuracy of 90.3% for the detection of metastatic breast carcinoma (OR = 243.2, Fisher’s exact test, p < 0.0001). Conclusion: ALN FNA is a highly reliable method for confirming axillary lymph node metastasis in invasive breast carcinoma when malignant cells are identified, with a ROM of 99% for the malignant category. The suspicious category was also strongly associated with malignancy (ROM 86%). However, the 17% ROM observed in the benign category indicates that a negative FNA does not reliably exclude metastatic disease, and surgical nodal staging may still be warranted in clinically or radiologically suspicious cases. These findings support the clinical applicability of the WHO System for Reporting Lymph Node Cytopathology and provide breast carcinoma-specific ROM estimates for this clinical setting. Full article

(This article belongs to the Special Issue Advances in Neoadjuvant Chemotherapy and Radiotherapy for Breast Cancer: Surgical Impact and Clinical Outcomes)

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