Cancers

17 pages, 2722 KiB

Open AccessArticle

Immune Modulation During Treatment with Enzalutamide Alone or with Radium-223 in Patients with Castration Resistant Prostate Cancer

by Peter D. Zang, Diane M. Da Silva, Zhang-Xu Liu, Shivani Kandukuri, Denice Tsao-Wei, Anishka D’Souza, W. Martin Kast, Sumanta K. Pal, Cheryl Kefauver, Maribel Juanqueira, Lixin Yang, David I. Quinn and Tanya B. Dorff

Cancers 2025, 17(10), 1730; https://doi.org/10.3390/cancers17101730 - 21 May 2025

Viewed by 547

Abstract

Introduction: Prostate cancer has been generally resistant to immunotherapy approaches. Radiation can be immunostimulatory, but the extent to which standard prostate cancer treatments induce immune activation has not been well described. The bone-targeted radiopharmaceutical Radium223 (Ra223) has been proposed to enrich immune function, [...] Read more.

Introduction: Prostate cancer has been generally resistant to immunotherapy approaches. Radiation can be immunostimulatory, but the extent to which standard prostate cancer treatments induce immune activation has not been well described. The bone-targeted radiopharmaceutical Radium223 (Ra223) has been proposed to enrich immune function, but clinical studies have not fully delineated whether this is true, or by what mechanisms. Enzalutamide has been shown to increase PD-L1 expression on dendritic cells, which could impact immune activation, though the extent to which this is associated with other evidence of immune activation remains uncertain, and combination strategies remain of interest. We performed a randomized phase II trial to evaluate whether Radium223 (Ra223) added to enzalutamide would induce greater immune activation and clinical responses compared to enzalutamide alone in men with metastatic castration-resistant prostate cancer (mCRPC). Methods: Eligible patients were randomized 2:1 to Arm A (enzalutamide 160 mg PO daily + Ra223 55 kBq/kg IV q4 weeks × 6 doses) or Arm B (enzalutamide 160 mg PO daily). Blood was collected at treatment start and during treatment to measure soluble immune checkpoint biomarkers (BTLA, TIM3, HVEM, GITR, LAG3, PD-1, CTLA-4, PD-L1, PD-L2, ICOS). Immunophenotyping by mass cytometry time of flight (CyTOF) was performed to measure peripheral blood mononuclear cell populations before and after treatment. CyTOF was used to determine changes in circulating immune cell population subsets before and after treatment. Biopsies were performed of an active bone metastatic lesion prior to study treatment and after at least 3 months. IHC was subsequently performed to examine changes in immune cell population subsets before and after treatment, and changes in pSTAT3 levels. Results: In total, 30 patients were enrolled, with median age 68. The median duration of follow up was 36 months. PSA responses, PFS, and OS were not significantly different between the two arms; however, the study was not powered for clinical endpoints. Peripheral blood and bone biopsy specimens were analyzed for immune correlatives. Soluble receptor concentrations showed significantly increased expression of PDL-2 in the combination arm, but this was not seen on CyTOF. Otherwise, there were no significant differences in markers of immune activation/exhaustion or immune cell population subsets in the combination arm and enzalutamide monotherapy arm. IHC also did not show a significant difference in immune cell population subsets in bone biopsy specimens before and after treatment in both arms. However, treatment with the combination arm did show significantly increased levels of pSTAT3 (p = 0.04), which was not seen in the enzalutamide monotherapy arm. Conclusions: Our study showed an overall lack of evidence for immune activation or cytokine induction with the combination, which does not make a strong case for combinatorial immunotherapy approaches. However, the combination did induce higher levels of pSTAT3, which has been implicated in radio-resistance. Therefore, the addition of a STAT3 inhibitor to the combination may be of interest to improve efficacy. Full article

(This article belongs to the Collection Oncology: State-of-the-Art Research in the USA)

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15 pages, 1351 KiB

Open AccessArticle

The Association Between Skeletal Muscle Mass and Surgical Site Infection and Prognosis in Patients Undergoing Free Flap Reconstructive Surgery for Oral Squamous Cell Carcinoma: A Single-Center, Retrospective Study

by Atsuro Noguchi, Kenji Yamagata, Satoshi Fukuzawa, Kaoru Sasaki, Shohei Takaoka, Fumihiko Uchida, Naomi Ishibashi-Kanno, Mitsuru Sekido and Hiroki Bukawa

Cancers 2025, 17(10), 1729; https://doi.org/10.3390/cancers17101729 - 21 May 2025

Viewed by 265

Abstract

Background/Objectives: Local and systemic factors, including nutritional status, influence the prognosis of oral squamous cell carcinoma (OSCC). Skeletal muscle mass (SMM) loss is a poor prognostic factor in older patients and those with cancer. Herein, we examined the SMM index (SMI), rates of [...] Read more.

Background/Objectives: Local and systemic factors, including nutritional status, influence the prognosis of oral squamous cell carcinoma (OSCC). Skeletal muscle mass (SMM) loss is a poor prognostic factor in older patients and those with cancer. Herein, we examined the SMM index (SMI), rates of surgical site infection (SSI), and prognosis of 92 patients (59 males and 33 females) who underwent resection and free flap reconstructive surgery (FFRS) between 2013 and 2021. Methods: Preoperative computed tomography was performed to measure SMM at L3. The median SMI was 45.94 and 38.03 cm²/m² in males and females, respectively. Patients were classified into low and high SMI groups based on median SMI, and overall survival (OS) was analyzed. Results: Overall, 47 (51.1%) and 45 (48.9%) patients had low and high SMIs, respectively. SSI occurred in 11 (12.0%) patients; wound dehiscence and delayed wound healing were observed in 22 (23.9%). SSI rates were not significantly different between the low and high SMI groups. Conversely, OS was significantly associated with age, pathological N (pN), extranodal extension (ENE), and SMI (high, 81.1%; low, 60.2%). Univariate analyses revealed significant associations between OS and age (≥65 vs. <65 years), SMI (low vs. high), pN (present vs. none), ENE (present vs. none), and albumin (<4.0 vs. ≥4.0 mg/dL). Cox multivariate analysis included SMI (low vs. high; hazard ratio [HR]: 2.339, 95% confidence interval [CI]: 1.008–5.429; p = 0.015) and ENE (present vs. none; HR: 7.727, 95% CI: 3.083–19.368; p < 0.001). Conclusions: SMI and ENE were identified as independent predictive factors of OS in patients with OSCC undergoing FFRS. Full article

(This article belongs to the Special Issue Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition))

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16 pages, 818 KiB

Open AccessArticle

Charity-Provided Community-Based PSA Testing for Assessment of Prostate Cancer Risk in the UK: Clinical Implications and Future Opportunities

by Artitaya Lophatananon, Graham Fulford, Jon Young, Susan Hart, Matthew Brine and Kenneth R. Muir

Cancers 2025, 17(10), 1728; https://doi.org/10.3390/cancers17101728 - 21 May 2025

Viewed by 373

Abstract

Background: Prostate cancer is the most common malignancy among UK men, yet the lack of a national screening program creates disparities in early detection. PSA testing during primary care is inconsistent, limiting timely diagnosis. The Graham Fulford Charitable Trust (GFCT) and its associated [...] Read more.

Background: Prostate cancer is the most common malignancy among UK men, yet the lack of a national screening program creates disparities in early detection. PSA testing during primary care is inconsistent, limiting timely diagnosis. The Graham Fulford Charitable Trust (GFCT) and its associated support groups offer community-based PSA testing to help bridge this gap. Objectives: This study evaluates GFCT’s historical testing records and a participant survey (2021–2024) to assess their community-based PSA testing program, which is widely used and offers shared decision support. Additionally, we examine the GFCT’s alignment with emerging initiatives such as the UK TRANSFORM trial and other PSA screening developments across Europe and the USA. Methods: The GFCT systematically collects PSA testing data, conducting over 50,000 tests annually. The study assesses the performance of their traffic light scoring system and a previously defined combination algorithm, “Riskman”, which incorporates PSA, PSAft%, and age to classify individuals into risk categories. Multivariable logistic regression was used to evaluate and compare the predictive performance of each approach. Results: Based on the self-reported data in the survey, the GFCT’s traffic light system—using age-specific PSA thresholds to assign green, amber, or red risk—showed good predictive ability. Men in the red group had over 15-fold increased odds of clinically significant cancer (Grade Group ≥ 3) compared to those in the green group. While the Riskman score achieved a higher AUC (0.84 vs. 0.76), both tools were effective in identifying high-risk individuals. Conclusions: This study highlights the GFCT’s role in improving access to PSA screening and integrating practical risk stratification. Its alignment with evolving screening initiatives demonstrates the value of community-based, data-driven approaches for earlier detection of aggressive prostate cancer. Full article

(This article belongs to the Special Issue Cancer Causes and Control)

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21 pages, 1835 KiB

Open AccessArticle

Radiological, Pathological, and Surgical Outcomes with Neoadjuvant Cemiplimab for Stage II–IV Cutaneous Squamous Cell Carcinoma in the Deep Sequencing in Cutaneous Squamous Cell Carcinomas (DISCERN) Trial

by Annette M. Lim, Benjamin Baker, Peter Lion, Christopher M. Angel, Jennifer Simmons, Bryce Jackson, Matthew Magarey, Angela Webb, Kevin Nguyen, Jo Hudson, Kwang Yang Chin, Anthony Cardin, Rajeev Ravi, Edwin Morrison, Tam Quinn, Ian Hunt and Danny Rischin

Cancers 2025, 17(10), 1727; https://doi.org/10.3390/cancers17101727 - 21 May 2025

Viewed by 441

Abstract

Background: A previous published Phase 2 trial using 2–4 doses of neoadjuvant cemiplimab in stage II–IV resectable cutaneous squamous cell carcinoma (CSCC) demonstrated that a complete pathological (pCR) rate of 51% and major pathological response (mPR) rate of 13% could be achieved with [...] Read more.

Background: A previous published Phase 2 trial using 2–4 doses of neoadjuvant cemiplimab in stage II–IV resectable cutaneous squamous cell carcinoma (CSCC) demonstrated that a complete pathological (pCR) rate of 51% and major pathological response (mPR) rate of 13% could be achieved with durable disease control. Methods: In this open-label, single-institution phase II trial (NCT05878288), patients with stage II–IV resectable CSCC received up to four doses of neoadjuvant cemiplimab prior to surgery. The primary endpoint of the study was to perform comprehensive molecular profiling. The focus of this report are the secondary clinical endpoints of pCR rate, mPR (defined as <10% viable tumour) rate, overall response rate (ORR) using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, immune-modified RECIST (imRECIST) and Immune PET Response Criteria in Solid Tumours (iPERCIST), disease-free survival (DFS), overall survival (OS), safety, and to describe changes in planned surgery. Results: Eleven patients were enrolled, with all proceeding with surgery. An ORR and pCR rate of 73% (8/11; 95% CI 0.39–0.93) was achieved, whilst 3/11 patients progressed on treatment. On pre-operative imaging, all 8/11 pCR patients demonstrated a partial response (RECIST 1.1), whilst 6/8 achieved a complete metabolic response and 2/8 a partial metabolic response (iPERCIST). Median follow-up was 10.2 (IQR 6.7–16.4) months. DFS was 91% (95% CI 0.57–1) and OS was 100% (95% CI 0.68–1), with one non-responder patient who developed recurrent locoregional and distant metastatic disease. There were no unexpected safety signals. Pathological features of response to neoadjuvant immunotherapy most commonly were granulomatous inflammation with keratin, fibrosis and inflammation. No cases with a dense inflammatory infiltrate were observed. Neoadjuvant immunotherapy did not impact the intra-operative planning and execution of surgery, but in the eight pCR cases, it reduced the extent of required surgery, whilst in the three non-responder cases, surgery was more extensive than originally planned. Conclusions: The DISCERN trial confirms that an excellent complete response rate can be achieved with four doses of neoadjuvant immunotherapy in stage II–IV CSCC. Proposed refinements to the pathological assessment of response and metabolic response criteria in CSCC for the neoadjuvant context are provided. Full article

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

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23 pages, 2262 KiB

Open AccessReview

The Role of Nanoparticles in Therapy of Real-World Patients with Pancreatic Cancer: A Scoping Review

by Ioannis Konstantinidis, Sophia Tsokkou, Dimitrios Katsikeros, Paraskevi Chatzikomnitsa, Menelaos Papakonstantinou, Eftychia Liampou, Evdokia Toutziari, Dimitrios Giakoustidis, Petros Bageas, Vasileios Papadopoulos, Alexandros Giakoustidis and Theodora Papamitsou

Cancers 2025, 17(10), 1726; https://doi.org/10.3390/cancers17101726 - 21 May 2025

Viewed by 498

Abstract

Pancreatic cancer (PC) is one of the most aggressive and fatal malignancies worldwide, posing a significant global health challenge due to its high mortality rates, late-stage diagnosis, and limited therapeutic efficacy [...] Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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Graphical abstract

18 pages, 1784 KiB

Open AccessArticle

JC Polyomavirus in Prostate Cancer—Friend or Foe?

by Jacek Kiś, Dominika Sikora, Mirosław J. Jarosz and Małgorzata Polz-Dacewicz

Cancers 2025, 17(10), 1725; https://doi.org/10.3390/cancers17101725 - 21 May 2025

Viewed by 363

Abstract

Background/Objectives: Recently, many researchers have evaluated various viruses, including polyomaviruses (JCV, BKV) and EBV, as potential factors playing a role in the development and/or progression of prostate cancer (PCa), one of the most common cancers in men. Therefore, we aimed to assess [...] Read more.

Background/Objectives: Recently, many researchers have evaluated various viruses, including polyomaviruses (JCV, BKV) and EBV, as potential factors playing a role in the development and/or progression of prostate cancer (PCa), one of the most common cancers in men. Therefore, we aimed to assess the frequency of the JCPyV DNA in tissue collected from PCa patients. Methods: We detected the presence of viral DNA (PCR) in 49.6% of clinical samples, including 71.9% with single EBV infection and 28.1% with EBV/JCV co-infection. We did not detect BKV or a single JCV infection. Therefore, we compared patients with EBV mono-infection with EBV/JCV co-infected patients in the context of risk group, Gleason score, and TNM classification. Results: Our results showed differences in clinicopathological features between single EBV infection and EBV/JCV co-infection. In the group of patients with single EBV infection, most patients were classified as medium/high risk, while in the group with EBV/JCV co-infection, most patients were classified as low risk. Conclusions: Among patients with single EBV infection, a more advanced stage of cancer was observed than in EBV/JCV co-infection. Moreover, the level of anti-EBVCA and anti-EBNA antibodies as well as EBV load was higher in the case of single infection compared to EBV/JCV co-infection. Higher antibody levels were detected in more advanced tumor stages in single EBV infection. Does JCV only “reside” in prostate cells or is it a co-factor in EBV infection? In light of these studies, there is a need to clarify the role of JCV virus in the development and/or progression of prostate cancer. Full article

(This article belongs to the Special Issue Prostate Cancer Epidemiology and Genetics: 2nd Edition)

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19 pages, 1233 KiB

Open AccessArticle

From Intensification to Optimization: Balancing Efficacy, Safety, and Costs in High-Risk Localized Soft Tissue Sarcomas

by Bruno Fuchs, Georg Schelling, Christoph Glanzmann, Gabriela Studer and on behalf of the Swiss Sarcoma Network

Cancers 2025, 17(10), 1724; https://doi.org/10.3390/cancers17101724 - 21 May 2025

Viewed by 385

Abstract

Background/Objectives: The SU2C-SARC032 randomized controlled trial (RCT) tested pembrolizumab combined with preoperative normofractionated radiotherapy as an intensified treatment for high-risk stage III resectable soft tissue sarcoma (STS), demonstrating a moderate improvement in disease-free survival (DFS) compared to preoperative radiotherapy alone, but accompanied by [...] Read more.

Background/Objectives: The SU2C-SARC032 randomized controlled trial (RCT) tested pembrolizumab combined with preoperative normofractionated radiotherapy as an intensified treatment for high-risk stage III resectable soft tissue sarcoma (STS), demonstrating a moderate improvement in disease-free survival (DFS) compared to preoperative radiotherapy alone, but accompanied by significantly increased toxicity, prolonged treatment durations, elevated resource source, and limited real-world applicability. To address the gap between highly controlled trial outcomes and routine clinical practice, this comparative analysis evaluated a streamlined ultra-hypofractionated preoperative radiotherapy (uhpRT) protocol using real-world data (RWD) as a potentially more balanced approach. Methods: Prospectively collected observational RWD from 54 consecutive patients with Stage III (T2 N0 M0) high-risk resectable STS treated at a single institution with uhpRT (25 Gy in 5 fractions in one week, no systemic therapy, median interval of 14 days to surgery) were analyzed. Survival endpoints (overall survival [OS], DFS, local disease-free survival [LDFS], distant disease-free survival [DDFS]), toxicity, and treatment duration were compared qualitatively with published outcomes from the SU2C-SARC032 trial’s intensified pembrolizumab arm and control arm. Results: At 2 years, the optimized uhpRT protocol achieved OS (90%), DFS (66%), and DDFS (70%) comparable to the intensified pembrolizumab arm (OS: 88%, DFS: 67%, DDFS (67%)) and clearly exceeded outcomes of the control arm (OS/DFS/DDFS: 85%/52%/52%). Importantly, the uhpRT protocol markedly reduced treatment-related toxicities (0% Grade 3/4 events vs. 56% in the intensified trial arm) and total treatment duration (<1 month vs. 3–11 months). Conclusions: These findings challenge the necessity of broad treatment intensification for high-risk localized STS, strongly supporting the concept of therapeutic optimization. Given substantial real-world variability in treatment practices and feasibility highlighted by recent research, our findings advocate for treatment strategies that prioritize realistic applicability, patient safety, and value-based care principles over pure intensification. Full article

(This article belongs to the Section Cancer Therapy)

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27 pages, 5360 KiB

Open AccessReview

Positron Emission Tomography Radiotracers for Identification of Site of Recurrence in Prostate Cancer After Primary Treatment Failure

by Ryan Bitar, Pablo Zurita, Lucia Martiniova, Amado J. Zurita and Gregory C. Ravizzini

Cancers 2025, 17(10), 1723; https://doi.org/10.3390/cancers17101723 - 21 May 2025

Viewed by 634

Abstract

Despite substantial improvement in the definitive management of primary prostate cancer, a significant number of patients experience biochemical recurrence—a clinical state in which serum prostate-specific antigen (PSA) levels rise prior to the development of physical signs or symptoms. The early detection and localization [...] Read more.

Despite substantial improvement in the definitive management of primary prostate cancer, a significant number of patients experience biochemical recurrence—a clinical state in which serum prostate-specific antigen (PSA) levels rise prior to the development of physical signs or symptoms. The early detection and localization of biochemical recurrence may confer eligibility for salvage therapy; therefore, imaging techniques that provide accurate disease visualization are imperative. In this review, we discuss various imaging methods for localizing disease in the context of biochemical recurrence in prostate cancer. Particularly, we describe available or investigational positron emission tomography (PET) radiotracers, such as ¹⁸F-FDG, ¹⁸F-NaF, choline (both ¹⁸F and ¹¹C), the ¹⁸F-labeled amino acid derivative fluciclovine, prostate-specific membrane antigen (PSMA) radioligands, and the short peptide compound bombesin. Generally, PET radiotracers such as ¹⁸F-FDG, ¹⁸F-NaF, and ¹⁸F/¹¹C choline have fallen out of favor because of their inferior sensitivity and/or specificity in relation to more recently developed radiotracers. ¹⁸F-fluciclovine has addressed these shortcomings by exploiting the upregulation of amino acid transporters in tumors; however, PSMA-targeting agents have significantly advanced the management of biochemical recurrence of prostate cancer through their high sensitivity and specificity, enabling the identification of candidates for radionuclide therapy. Investigational agents, such as bombesin-based radiotracers, may address the shortcomings of treating prostate cancer with little to no PSMA expression. Full article

(This article belongs to the Special Issue Advancements in the Diagnosis and Surgical Treatment of Prostate Cancer)

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11 pages, 316 KiB

Open AccessPerspective

Optimising Cancer Medicine in Clinical Practices: Are Neoadjuvant and Adjuvant Immunotherapies Affordable for Cancer Patients in Low- and Middle-Income Countries?

by Rashidul Alam Mahumud

Cancers 2025, 17(10), 1722; https://doi.org/10.3390/cancers17101722 - 21 May 2025

Viewed by 386

Abstract

Cancer immunotherapy, encompassing neoadjuvant and adjuvant interventions, has transformed treatment paradigms in multiple malignancies by leveraging the host immune system to combat tumour cells. While immunotherapies have demonstrated remarkable efficacy, particularly immune checkpoint inhibitors, high treatment costs undermine their accessibility and affordability in [...] Read more.

Cancer immunotherapy, encompassing neoadjuvant and adjuvant interventions, has transformed treatment paradigms in multiple malignancies by leveraging the host immune system to combat tumour cells. While immunotherapies have demonstrated remarkable efficacy, particularly immune checkpoint inhibitors, high treatment costs undermine their accessibility and affordability in low- and middle-income countries (LMICs). This paper provides a prospective overview of the clinical benefits of neoadjuvant and adjuvant immunotherapies, examines the barriers to implementing these treatments in LMICs, and suggests potential strategies to improve equitable access. Such interventions necessitate a combined effort from healthcare providers, policymakers, and stakeholders to ensure their sustainable integration into global cancer care. Full article

(This article belongs to the Special Issue Perioperative and Neoadjuvant Immunotherapy in Non-Small Cell Lung Cancer)

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14 pages, 1477 KiB

Open AccessArticle

Global Burden of Rare Cancers: Insights from GLOBOCAN 2022 Estimates

by Mohammed Elmadani, Simon Klara, Mohammed Mustafa, Evans Kasmai Kiptulon and Mate Orsolya

Cancers 2025, 17(10), 1721; https://doi.org/10.3390/cancers17101721 - 21 May 2025

Viewed by 636

Abstract

Background: Rare cancers, defined as those with an incidence rate of fewer than 6 cases per 100,000 individuals, contribute to a substantial portion of the global cancer burden. Despite their impact, they receive less attention than more common malignancies, leading to challenges in [...] Read more.

Background: Rare cancers, defined as those with an incidence rate of fewer than 6 cases per 100,000 individuals, contribute to a substantial portion of the global cancer burden. Despite their impact, they receive less attention than more common malignancies, leading to challenges in early detection, treatment strategies, and research funding. This study aims to assess the global incidence and mortality patterns of rare cancers in 2022 to better understand their contribution to the overall cancer burden and regional disparities. Methods: We conducted a comprehensive analysis using 2022 GLOBOCAN estimates to assess the global incidence and mortality of rare cancers. The study included 24 major rare cancers, such as bladder cancer, leukemia, non-Hodgkin lymphoma, esophageal cancer, and pancreatic cancer. Age-standardized rates (ASRs) were calculated to compare cancer burden across continents, and absolute case and death counts were reported. Results: In 2022, rare cancers accounted for 26.7% of all new cancer cases (5,347,784 cases) and 30% of all cancer-related deaths (2,959,369 deaths) worldwide. Bladder cancer was the most common rare cancer, with an incidence rate of 5.58 per 100,000, followed by non-Hodgkin lymphoma (5.57) and leukemia (5.26). Mortality rates were highest for pancreatic, esophageal, and brain cancers, reflecting their aggressive nature and limited treatment options. Significant regional disparities were observed, with Europe and North America reporting the highest incidence rates for bladder cancer and leukemia, while Asia bore the largest absolute burden of rare cancers. Conclusions: Rare cancers represent a considerable share of the global cancer burden, with notable geographic variations in incidence and mortality. These findings underscore the need for improved early detection, expanded treatment access, and targeted research efforts to address disparities and improve outcomes for patients with rare cancers worldwide. Full article

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

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14 pages, 694 KiB

Open AccessArticle

The Italian Score for Organ Allocation: A Ten-Year Monocentric Retrospective Analysis in Liver Transplantation for Hepatocellular Carcinoma

by Enrico Prosperi, Matteo Cescon, Quirino Lai, Chiara Bonatti, Edoardo Prosperi, Francesca Rizzo, Lorenzo Maroni, Andrea Laurenzi, Matteo Serenari, Maria Cristina Morelli and Matteo Ravaioli

Cancers 2025, 17(10), 1720; https://doi.org/10.3390/cancers17101720 - 21 May 2025

Viewed by 316

Abstract

Background: The Italian Score for Organ Allocation (ISO), a transplant benefit oriented allocation system, was introduced in Italy in 2016. The main objective of this study is to identify risk factors for Drop-Out in hepatocellular (HCC) patients enlisted for LT before (Pre-ISO Era) [...] Read more.

Background: The Italian Score for Organ Allocation (ISO), a transplant benefit oriented allocation system, was introduced in Italy in 2016. The main objective of this study is to identify risk factors for Drop-Out in hepatocellular (HCC) patients enlisted for LT before (Pre-ISO Era) and after ISO (ISO Era) introduction, while the secondary objective is to evaluate the survival results. Methods: CIFs for liver transplantation and Drop-Out were estimated and compared between eras. Factors associated with Drop-Out were identified through multivariable competing risks regression. Survival results were compared using the log-rank test. Results: Between 2011 and 2020, 410 patients with HCC were listed for LT. We observed 103 vs. 217 LT and 49 vs. 41 Drop-Outs (p < 0.001) during the Pre-ISO and ISO Era, respectively. In the multivariable analysis, ISO ([sHR] 0.43; 95%CI 0.28–0.66, p < 0.001) and Alcoholic Cirrhosis ([sHR] 0.27, 95%CI 0.11–0.70; p = 0.007) were revealed to be protective factors for Drop-Out. One year after listing, the CI for Drop-Out decreased from 13.2% to 6.2% (p = 0.02). Despite no differences observed in post-LT survival, a significant difference in the intention-to-treat survival from enlisting was found (p = 0.0019). Conclusions: Among other factors, ISO results were protective for the Drop-Out risk in HCC patients awaiting LT, with a benefit in ITT-OS survival. Full article

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

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16 pages, 803 KiB

Open AccessReview

The Role of Microbiota in Upper Gastrointestinal Cancers

by Giovanni Marasco, Luigi Colecchia, Daniele Salvi, Angelo Bruni, Cecilia Capelli, Elton Dajti, Maria Raffaella Barbaro, Cesare Cremon, Vincenzo Stanghellini and Giovanni Barbara

Cancers 2025, 17(10), 1719; https://doi.org/10.3390/cancers17101719 - 21 May 2025

Viewed by 544

Abstract

The gut microbiota significantly impacts the development and progression of upper gastrointestinal (GI) cancers, including esophageal and gastric cancers. Microbial dysbiosis contributes to carcinogenesis through mechanisms such as inflammation, immune modulation, and direct DNA damage. Techniques for sampling oral, esophageal, and gastric microbiota [...] Read more.

The gut microbiota significantly impacts the development and progression of upper gastrointestinal (GI) cancers, including esophageal and gastric cancers. Microbial dysbiosis contributes to carcinogenesis through mechanisms such as inflammation, immune modulation, and direct DNA damage. Techniques for sampling oral, esophageal, and gastric microbiota vary, with standardization being essential for reliable results. Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) are associated with an enrichment of Gram-negative bacteria, promoting inflammation and cancer progression. Esophageal squamous cell carcinoma (ESCC) also shows distinct microbial patterns, with reduced diversity and increased harmful bacteria like Porphyromonas gingivalis and Fusobacterium nucleatum. In gastric cancer (GC), Helicobacter pylori (HP) and non-HP gastric microbiota play significant roles, with diverse microbial communities contributing to cancer development through nitrate reduction, immune modulation, and inflammation. Emerging evidence highlights the role of non-HP bacteria in promoting carcinogenesis, with specific taxa like Fusobacterium nucleatum and Lactobacillus influencing tumor growth and immune evasion. Further research is needed to elucidate the complex interactions between gut microbiota and upper GI cancers, paving the way for novel diagnostic and therapeutic approaches. Understanding these microbial dynamics offers potential for microbiota-based interventions, improving the early detection, prognosis, and treatment of upper GI cancers. This comprehensive review summarizes the available evidence on the role of microbiota in upper GI oncology and the need for continued exploration in this field. Full article

(This article belongs to the Special Issue Developments in the Management of Gastrointestinal Malignancies)

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10 pages, 1308 KiB

Open AccessArticle

Evaluation of Tumor Budding and Poorly Defined Clusters as Histological Biomarkers in Squamous Cell Carcinomas of the Vulva

by Gilbert Georg Klamminger, Annick Bitterlich, Bashar Haj Hamoud, Erich-Franz Solomayer, Martin Ertz, Laura Schnöder, Bernd Holleczek, Walburgis Brenner, Annette Hasenburg, Mathias Wagner and Meletios P. Nigdelis

Cancers 2025, 17(10), 1718; https://doi.org/10.3390/cancers17101718 - 21 May 2025

Viewed by 398

Abstract

Background/Objectives: Several histopathological risk factors have been examined in vulvar cancer (VC) so far. However, the prognostic relevance of morphological biomarkers such as tumor budding (TB) and poorly defined clusters (PDCs) remains to be determined. Material and Methods: We histologically analyzed the [...] Read more.

Background/Objectives: Several histopathological risk factors have been examined in vulvar cancer (VC) so far. However, the prognostic relevance of morphological biomarkers such as tumor budding (TB) and poorly defined clusters (PDCs) remains to be determined. Material and Methods: We histologically analyzed the formation of peritumoral and intratumoral TB and PDCs in a cohort of 157 patients with VC. We assessed their association with clinico-pathological features and evaluated their prognostic impact in terms of the risk of local recurrence and occurrence of metastasis (Fisher’s exact test) as well as overall survival (Log-rank test). Results: We determined a distinct prognostic relevance of peritumoral TB with regard to occurrence of metastasis (Fisher’s exact test; p = 0.0415) as well as a significant reduced risk of local recurrence in the group with absent intratumoral TB (Fisher’s exact test; p = 0.0004). Furthermore, we showed that patients without peritumoral budding formation had a significant superior prognosis in terms of overall survival (p = 0.0366, x² = 4.370). Conclusions: This study shows that several new histomorphological biomarkers may serve useful in predicting the clinical course of patients with VC, identifying patients at a lower risk of developing metastases/local recurrence as well as improved overall survival. Full article

(This article belongs to the Special Issue Biomarkers for Gynecological Cancers)

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17 pages, 1905 KiB

Open AccessSystematic Review

The Impact of Prophylactic Negative Wound Pressure Treatment (NWPT) on Surgical Site Occurrences After Gynecologic Cancer Surgery: A Meta-Analysis of Randomized Controlled and Observational Cohort Studies

by Maximos Frountzas, Ioannis Karavolias, Christina Nikolaou, Orsalia Toutouza, Vasilios Pergialiotis and Konstantinos G. Toutouzas

Cancers 2025, 17(10), 1717; https://doi.org/10.3390/cancers17101717 - 20 May 2025

Viewed by 351

Abstract

Background: Surgical site infections (SSIs) remain a serious problem following abdominal surgery due to gynecologic malignancies leading to increased hospitalization, high costs, and delays in adjuvant treatments; thus, SSIs affect overall survival. The aim of the present meta-analysis was to investigate the [...] Read more.

Background: Surgical site infections (SSIs) remain a serious problem following abdominal surgery due to gynecologic malignancies leading to increased hospitalization, high costs, and delays in adjuvant treatments; thus, SSIs affect overall survival. The aim of the present meta-analysis was to investigate the impact of closed incision–negative pressure wound treatment (ci-NPWT) systems on postoperative surgical site occurrences (SSOs) after gynecologic oncology surgery. Methods: The present meta-analysis was designed using the PRISMA guidelines. A search in several databases was conducted from inception until March 2025. Results: Overall, five studies were included; these studies enrolled 1174 patients in total, where 412 were treated with ci-NPWT systems and 762 were treated with conventional gauze. Patients treated with ci-NPWT systems presented with lower SSI rates (OR 0.40, 95% CI 0.15–1.10, p = 0.08), lower fascial dehiscence rates (OR 0.72, 95% CI 0.21–2.42, p = 0.59), and lower seroma formation rates (OR 0.70, 95% CI 0.25–1.93, p = 0.49), although statistical significance was not reached in all comparisons. On the other hand, patients treated with ci-NPWT systems also presented with higher postoperative hematoma formation rates (OR 1.38, 95% CI 0.32–5.99, p = 0.66), although statistical significance was not reached. Preoperative patient characteristics, operative parameters, and cancer characteristics were similar among the two study groups. Conclusions: The prophylactic use of ci-NPWT systems showed promising results in reducing postoperative SSOs after gynecologic cancer surgery. Nevertheless, prospectively designed studies are needed in the future to reach robust evidence that would enable the wide implementation of such devices in routine clinical practice. Full article

(This article belongs to the Special Issue Perioperative Care in Gynecologic Oncology: 2nd Edition)

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26 pages, 9951 KiB

Open AccessArticle

Establishment of Two Novel Ovarian Tumor Cell Lines with Characteristics of Mucinous Borderline Tumors or Dedifferentiated Carcinoma—Implications for Tumor Heterogeneity and the Complex Carcinogenesis of Mucinous Tumors

by Hasibul Islam Sohel, Umme Farzana Zahan, Tohru Kiyono, Masako Ishikawa, Sultana Razia, Kosuke Kanno, Hitomi Yamashita, Shahataj Begum Sonia, Kentaro Nakayama and Satoru Kyo

Cancers 2025, 17(10), 1716; https://doi.org/10.3390/cancers17101716 - 20 May 2025

Viewed by 981

Abstract

Background/objective: Mucinous borderline tumors of the ovary (MBOTs) are characterized by their unique histological features and intermediate malignant potential; however, the factors underlying their molecular carcinogenesis and tumor biology remain largely unknown. Developing cell lines from these tumors presents an ongoing challenge. The [...] Read more.

Background/objective: Mucinous borderline tumors of the ovary (MBOTs) are characterized by their unique histological features and intermediate malignant potential; however, the factors underlying their molecular carcinogenesis and tumor biology remain largely unknown. Developing cell lines from these tumors presents an ongoing challenge. The purpose of this study is to establish MBOT cell lines and characterize their biological features. Methods: Epithelial cells were collected and purified from surgically removed MBOT samples and then stably maintained with an extended life span by overexpressing CyclinD1/CDK4 in combination with human telomerase reverse transcriptase. The characterization of resulting cell lines was defined by morphology, growth kinetics, functional analysis, whole-exome sequencing, and tumorigenicity in mice. Results: Two independent cell lines, HMucBOT-1 and HMucBOT-2, were successfully established from the tissues of a patient with an MBOT, with the latter showing more aggressive growth capacity. In the patient-derived xenograft model, HMucBOT-1 cells retained the original morphological characteristics of the MBOT, whereas HMucBOT-2 cells displayed a transition to mucinous carcinoma accompanying undifferentiated carcinoma, suggestive of dedifferentiated carcinoma. Genetic analysis of the original tumor sample and HMucBOT-2 cells revealed shared oncogenic mutations. However, KRAS amplification and certain copy number alterations were uniquely observed in the HMucBOT-2 cells. Conclusions: The above results indicate that HMucBOT-1 can serve as a preclinical model for investigating the biological behavior of and potential targeted therapies for human MBOTs, with HMucBOT-2 serving as a valuable tool for studying the heterogeneity and genetic diversity of this tumor and explaining the potential causes of treatment failure or relapse. Full article

(This article belongs to the Special Issue Gynecologic Cancer: From Diagnosis to Treatment)

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12 pages, 1171 KiB

Open AccessArticle

Survival Outcomes of Luminal Metastatic Breast Cancer Patients According to Changes in Molecular Subtype at Re-Biopsy: Insights from the GIM-13—AMBRA Study

by Marina Elena Cazzaniga, Paolo Pronzato, Domenico Amoroso, Grazia Arpino, Francesco Atzori, Alessandra Beano, Laura Biganzoli, Giancarlo Bisagni, Livio Blasi, Cristina Capello, Rita Chiari, Alessia D’Alonzo, Michelino De Laurentiis, Angela Denaro, Alessandra Fabi, Daniele Farci, Francesco Ferraù, Elena Fiorio, Alessandra Gennari, Francesco Giotta, Filippo Giovanardi, Vanesa Gregorc, Lorenzo Livi, Emanuela Magnolfi, Anna Maria Mosconi, Raffaella Palumbo, Palma Pugliese, Carlo Putzu, Giuseppina Rosaria Rita Ricciardi, Ferdinando Riccardi, Laura Scortichini, Simon Spazzapan, Pierosandro Tagliaferri, Nicola Tinari, Giuseppe Tonini, Anna Maria Vandone and Giorgio Mustacchi Show full author list Hide full author list

Cancers 2025, 17(10), 1715; https://doi.org/10.3390/cancers17101715 - 20 May 2025

Viewed by 370

Abstract

Introduction: The treatment of MBC patients is guided by receptor status, with re-biopsy at relapse recommended to reassess hormone receptor (HR) status. Various treatment options are available for HER2-veMBC, including CDK4/6 inhibitors, PARP inhibitors, and checkpoint inhibitors. The study highlights the importance [...] Read more.

Introduction: The treatment of MBC patients is guided by receptor status, with re-biopsy at relapse recommended to reassess hormone receptor (HR) status. Various treatment options are available for HER2-veMBC, including CDK4/6 inhibitors, PARP inhibitors, and checkpoint inhibitors. The study highlights the importance of determining receptor subtype for guiding treatment choices. Patients and Methods: The GIM 13 AMBRA study is a longitudinal cohort study involving 42 centers in Italy. It includes data from 939 HER2- MBC patients enrolled between May 2015 and September 2020. The study analyzes the impact of HR expression changes on clinical outcomes using Kaplan–Meier survival curves and other statistical methods. Results: Among the 939 patients, 588 were rebiopsied at first relapse. The study found no significant differences in disease-free survival (DFS), progression-free survival (PFS), or overall survival (OS) between patients whose tumors changed molecular subtype and those who did not. However, post-progression survival from first-line treatment (PPS1) was different between the two groups. Discussion: The study confirms the phenomenon of receptor discordance between primary tumors and metastases. It emphasizes the need for re-biopsy in recurrent MBC to guide treatment strategies. The findings align with previous studies and highlight the importance of understanding receptor changes for improving patient outcomes. Conclusions: The GIM 13 AMBRA study provides valuable insights into the impact of molecular subtype changes on survival outcomes in Luminal MBC patients. It underscores the importance of re-biopsy and personalized treatment strategies in managing metastatic breast cancer. Full article

(This article belongs to the Special Issue New Perspectives in the Management of Breast Cancer)

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14 pages, 600 KiB

Open AccessSystematic Review

Active Surveillance in Non-Muscle Invasive Bladder Cancer: A Systematic Review

by Míriam Campistol, Fernando Lozano, Albert Carrion, Carles Xavier Raventós, Juan Morote and Enrique Trilla

Cancers 2025, 17(10), 1714; https://doi.org/10.3390/cancers17101714 - 20 May 2025

Viewed by 441

Abstract

Bladder cancer is the ninth most common cancer globally, with most cases classified as non-muscle-invasive bladder cancer (NMIBC). While transurethral resection of the bladder tumor (TURBT) remains the gold-standard treatment, its complications, high recurrence rates, and economic burden have prompted interest in alternative [...] Read more.

Bladder cancer is the ninth most common cancer globally, with most cases classified as non-muscle-invasive bladder cancer (NMIBC). While transurethral resection of the bladder tumor (TURBT) remains the gold-standard treatment, its complications, high recurrence rates, and economic burden have prompted interest in alternative strategies like active surveillance (AS) for low-grade and low-grade NMBIC recurrences. AS minimizes surgical interventions and patient burden, but lacks standardized protocols for inclusion criteria and follow-up schedules. Most studies suggest intensive monitoring during the first year, with criteria often based on tumor size, number, and grade. Acquisition of evidence: A comprehensive literature search was conducted in December 2024 using Pubmed, Cochrane, and Trip databases to identify studies on AS for low-grade NMBIC recurrences. Only English studies were included, with Boolean operators used to refine the search. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Population, Intervention, Comparison and Outcomes (PICO) selection criteria were followed. The Newcastle–Ottawa quality assessment scale was used to analyze the quality of the included studies. Evidence synthesis: This systematic review included 11 studies evaluating AS for NMIBC. Early studies, such demonstrated AS as a feasible alternative to TURBT, with low progression rates. Subsequent research confirmed its safety in selected patients, with tumor growth and positive cytology being the main reasons for intervention. More recent investigations, further supported AS as a viable strategy, highlighting the low risk of stage and grade progression and its potential to reduce surgical interventions. Conclusions: AS may be considered an alternative approach for low-risk NMIBC recurrences. However, there is need for prospective studies and personalized approaches to optimize AS, addressing follow-up strategies, inclusion criteria and progression thresholds. Full article

(This article belongs to the Special Issue Systematic Reviews and Meta-Analyses of Genitourinary Cancers (2nd Edition))

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21 pages, 10416 KiB

Open AccessArticle

Combinational Radiotherapies Improve Brain Cancer Treatment at High Dose Rates In Vitro

by Michael Valceski, Elette Engels, Sarah Vogel, Jason Paino, Dylan Potter, Carolyn Hollis, Abass Khochaiche, Micah Barnes, Alice O’Keefe, Matthew Cameron, Kiarn Roughley, Anatoly Rosenfeld, Michael Lerch, Stéphanie Corde and Moeava Tehei

Cancers 2025, 17(10), 1713; https://doi.org/10.3390/cancers17101713 - 20 May 2025

Viewed by 839

Abstract

Background/objectives: Brain cancer remains difficult to treat, with survival statistics stagnant for decades. The resistance of glioblastoma brain tumours can greatly challenge the effectiveness of conventional cancer radiotherapy. However, high dose rate radiotherapy has unique effects that allow for normal tissue sparing whilst [...] Read more.

Background/objectives: Brain cancer remains difficult to treat, with survival statistics stagnant for decades. The resistance of glioblastoma brain tumours can greatly challenge the effectiveness of conventional cancer radiotherapy. However, high dose rate radiotherapy has unique effects that allow for normal tissue sparing whilst maintaining tumour control. The addition of targeted radiosensitisers, such as the chemotherapeutic drug methotrexate (MTX) or the high-Z halogenated pyrimidine drug iododeoxyuridine (IUdR), can improve radiotherapy outcomes. Combining these radiosensitiser agents with ultra-high dose rate (UHDR) synchrotron X-rays can bear synergistic effects to enhance the efficacy of these multi-modal UHDR therapies, providing a means to overcome the radioresistance of brain cancer. Methods: Here, we use controlled in vitro assays following treatment, including a clonogenic assay to determine long-term cell survival and γH2AX immunofluorescent confocal microscopy to quantify double-strand DNA breaks (DSBs). Results: We find significant enhancement for highly synergistic combinations of IUdR+MTX with synchrotron X-rays. Cell survival results demonstrate 5.4 times increased 9L gliosarcoma cell killing when these agents are combined with UHDR synchrotron X-rays compared with conventional X-rays alone at the same 5 Gy dose. The underlying mechanisms are unveiled using γH2AX imaging and reveal significant increases in DSBs and dying cells following exposure to UHDR radiation. Conclusions: Our results demonstrate that highly synergistic combination treatments using UHDR synchrotron radiation can yield significantly improved brain cancer killing compared with conventional radiotherapy. We anticipate that these additive, multi-modal combination therapies will provide options for more targeted and effective use of radiotherapies for the future treatment of brain cancer. Full article

(This article belongs to the Section Cancer Therapy)

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Graphical abstract

11 pages, 451 KiB

Open AccessArticle

The Role of Social Support in Buffering the Financial Toxicity of Breast Cancer: A Qualitative Study of Patient Experiences

by Ramona G. Olvera, Sara P. Myers, Alice A. Gaughan, Willi L. Tarver, Sandy Lee, Karen Shiu, Laura J. Rush, Tessa Blevins, Samilia Obeng-Gyasi and Ann Scheck McAlearney

Cancers 2025, 17(10), 1712; https://doi.org/10.3390/cancers17101712 - 20 May 2025

Viewed by 408

Abstract

Background/Objectives: Financial distress from the direct and indirect costs of cancer treatment is a critical issue for many patients with breast cancer, particularly those from underserved populations who may be more vulnerable to financial hardship and its negative impacts on quality of [...] Read more.

Background/Objectives: Financial distress from the direct and indirect costs of cancer treatment is a critical issue for many patients with breast cancer, particularly those from underserved populations who may be more vulnerable to financial hardship and its negative impacts on quality of life and clinical outcomes (i.e., financial toxicity). Few investigations, however, focus on protective factors that safeguard against financial toxicity. This study explores how social support might reduce financial toxicity among patients with breast cancer who are at high risk for financial hardship. Methods: We analyzed interviews with 41 adult women treated for stage I-IV breast cancer that had been conducted between December 2021 and March 2022. Our study specifically sampled women considered to be at elevated risk for financial toxicity: young adults aged 18–40 years old, Black women, women with lower incomes, and those residing in rural communities. We used deductive and inductive coding to identify themes related to social support. Results: Interviewees reported receiving support from family, friends, and their communities during their treatments. They noted how this social support helped with direct and indirect costs, encouraged emotional wellbeing, and safeguarded against economizing behaviors that offset spending (e.g., financial tradeoffs that jeopardize their treatment plan). Conclusions: Patients with breast cancer from groups vulnerable to financial toxicity often rely on the support of family, friends, and their communities to help buffer financial distress from the costs of treatment. These data highlight social support as an area for future studies exploring strategies to mitigate financial toxicity. Full article

(This article belongs to the Special Issue Disparities in Cancer Prevention, Screening, Diagnosis and Management)

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20 pages, 1969 KiB

Open AccessArticle

Early Immune Checkpoint Inhibitor Administration Increases the Risk of Radiation-Induced Pneumonitis in Patients with Stage III Unresectable NSCLC Undergoing Chemoradiotherapy

by Yiwei Qin, You Mo, Pengwei Li, Xinyi Liang, Jinming Yu and Dawei Chen

Cancers 2025, 17(10), 1711; https://doi.org/10.3390/cancers17101711 - 20 May 2025

Viewed by 418

Abstract

Background/Objectives: The PACIFIC trial showed that immune checkpoint inhibitors (ICI) administered after concurrent chemoradiotherapy (cCRT) significantly improve survival in stage III unresectable non-small cell lung cancer (NSCLC). However, the optimal timing of ICI administration with cCRT is still debated, with concerns about increased [...] Read more.

Background/Objectives: The PACIFIC trial showed that immune checkpoint inhibitors (ICI) administered after concurrent chemoradiotherapy (cCRT) significantly improve survival in stage III unresectable non-small cell lung cancer (NSCLC). However, the optimal timing of ICI administration with cCRT is still debated, with concerns about increased risks of adverse effects, particularly radiation-induced pneumonitis (RP), from combining radiotherapy and immunotherapy. Methods: A search of multiple databases identified studies on stage III unresectable NSCLC patients receiving cCRT and ICI. A meta-analysis was performed utilizing the meta package in R software. Furthermore, data from 170 patients treated at Shandong Cancer Hospital and Institute between 2019 and 2023 were analyzed to assess RP following cCRT and ICI treatment. Results: The meta-analysis revealed that the incidences of ≥grade 2 RP were 25.3%, 24.3%, and 45.3% in the ICI following cCRT group, the ICI concurrent with cCRT group, and the ICI prior to cCRT group, respectively. The ICI prior to cCRT group exhibited significantly elevated rates. In the clinical retrospective study, ≥grade 2 RP was more prevalent in the ICI concurrent with cCRT group (HR: 2.258, 95% CI: 1.135–4.492, p = 0.020) and the ICI prior to cCRT group (HR: 2.843, 95% CI: 1.453–5.561, p = 0.002) compared with the ICI following cCRT group. Furthermore, a shorter interval between treatments correlates with an increased incidence of RP. Conclusions: Advancing the timing of ICI administration is associated with an increased incidence of ≥grade 2 RP following cCRT in patients with stage III unresectable NSCLC. Full article

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

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15 pages, 351 KiB

Open AccessReview

Advanced Therapies for Inflammatory Bowel Disease and Risk of Skin Cancer: What’s New?

by Sarah Bencardino, Francesca Bernardi, Mariangela Allocca, Alessandra Zilli, Federica Furfaro, Laurent Peyrin-Biroulet, Silvio Danese and Ferdinando D’Amico

Cancers 2025, 17(10), 1710; https://doi.org/10.3390/cancers17101710 - 20 May 2025

Viewed by 513

Abstract

Introduction: The introduction of biologic therapies and small molecule drugs has revolutionized the management of inflammatory bowel disease (IBD), providing targeted control of inflammation. However, concerns remain regarding their long-term safety profiles, particularly in relation to cancer risk. Chronic inflammation and immunosuppressive therapies [...] Read more.

Introduction: The introduction of biologic therapies and small molecule drugs has revolutionized the management of inflammatory bowel disease (IBD), providing targeted control of inflammation. However, concerns remain regarding their long-term safety profiles, particularly in relation to cancer risk. Chronic inflammation and immunosuppressive therapies contribute to malignancy risk, including skin cancers, such as melanoma and non-melanoma skin cancer (NMSC). This review examines the evidence on skin cancer risks associated with these therapies, focusing on specific drug classes and their mechanisms. Results: Tumor necrosis factor (TNF) inhibitors have shown conflicting evidence regarding melanoma risk, with some studies reporting a modest increase and others finding no significant association. Anti-integrin agents, such as vedolizumab, and interleukin (IL)-12/23 inhibitors, including ustekinumab, have demonstrated favorable safety profiles with minimal skin cancer risks. Selective IL-23 inhibitors and sphingosine-1-phosphate (S1P) receptor modulators have limited long-term data, but early findings indicate a low incidence of skin malignancies. Janus kinase (JAK) inhibitors do not show an increased risk of skin cancers in IBD. Conclusions: Current evidence suggests that skin cancer risk in IBD patients treated with biologics and small molecule drugs varies by drug class. TNF inhibitors and JAK inhibitors are associated with higher risks, while other therapies show lower malignancy risks. Regular skin cancer screening and protective measures remain critical, particularly for patients with additional risk factors. Further long-term studies are essential to refine safety profiles and inform clinical practice in this evolving therapeutic landscape. Full article

(This article belongs to the Section Cancer Therapy)

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21 pages, 621 KiB

Open AccessReview

The Role of the Gut Microbiome in Non-Hodgkin Lymphoma (NHL): A Focus on Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Cutaneous T-Cell Lymphoma, and NK/T-Cell Lymphoma

by Magdalena Łyko, Joanna Maj and Alina Jankowska-Konsur

Cancers 2025, 17(10), 1709; https://doi.org/10.3390/cancers17101709 - 20 May 2025

Viewed by 400

Abstract

Non-Hodgkin lymphomas (NHLs) encompass a diverse group of neoplasms arising from the clonal proliferation of B-cell progenitors, T-cell progenitors, mature B-cells, mature T-cells, and natural killer (NK) cells. These malignancies account for over 90% of lymphoid neoplasms. The link between the gut microbiome [...] Read more.

Non-Hodgkin lymphomas (NHLs) encompass a diverse group of neoplasms arising from the clonal proliferation of B-cell progenitors, T-cell progenitors, mature B-cells, mature T-cells, and natural killer (NK) cells. These malignancies account for over 90% of lymphoid neoplasms. The link between the gut microbiome and neoplasms has been extensively studied in recent years. Growing evidence suggests that the gut microbiome may be involved not only in the development of the disease, but also in modulating the efficacy of implemented therapies. In this review, we summarize the current knowledge on the potential involvement of the gut microbiome in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, and NK/T-cell lymphoma, including cutaneous T-cell lymphoma (CTCL). Moreover, we discuss the relationship between gut microbiome changes before and after treatment and their association with treatment outcomes, focusing on chemotherapy and CAR T-cell therapy. Full article

(This article belongs to the Special Issue Lymphoma Biology, Pathology and Stem Cells)

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17 pages, 278 KiB

Open AccessReview

The Impact of Minimal Residual Disease Measurement in the Management of Chronic Lymphocytic Leukemia

by Megan R. Greenberg, Thomas Lucido, Kritika Singh and Joanna M. Rhodes

Cancers 2025, 17(10), 1708; https://doi.org/10.3390/cancers17101708 - 20 May 2025

Viewed by 411

Abstract

Background: The treatment of chronic lymphocytic leukemia (CLL) has advanced considerably in recent years. Bruton’s tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is) such as venetoclax have largely supplanted chemoimmunotherapy for both frontline and relapsed CLL. With the introduction of additional [...] Read more.

Background: The treatment of chronic lymphocytic leukemia (CLL) has advanced considerably in recent years. Bruton’s tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is) such as venetoclax have largely supplanted chemoimmunotherapy for both frontline and relapsed CLL. With the introduction of additional innovative agents and regimens, the clinical role of measurable residual disease (MRD) has become complicated. Methods: In this article, we will review the existing literature on MRD and its utility in the management of CLL. We will review the definitions of MRD, review MRD detection methods, and discuss the use of MRD in the current CLL treatment landscape. In doing so, we will clarify the present and conceivable future roles of MRD for the treatment of CLL. Conclusions: MRD is a powerful tool to assess response to CLL therapies, and can be prognostic with certain treatment regimens, such as fixed-duration venetoclax-based treatment. While we do not recommend MRD testing in routine clinical practice, we believe it has an important role in assessing treatment response and will be utilized routinely in the future. Further studies to incorporate MRD into treatment strategies for CLL are ongoing and will help to inform how we utilize it in clinical practice. Full article

(This article belongs to the Special Issue Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future)

15 pages, 1085 KiB

Open AccessArticle

Echolaser Focal Treatment for Prostate Cancer Guided by Fiducial Marker Placement

by Timoleon Granitsas, Ioannis Anastassakis, Stamatios Brempos and Kyriakos Brempos

Cancers 2025, 17(10), 1707; https://doi.org/10.3390/cancers17101707 - 20 May 2025

Viewed by 403

Abstract

Background: Focal therapy has emerged as a viable alternative to radical prostate cancer treatment, offering oncologic control while minimizing morbidity. EchoLaser focal laser ablation (FLA) is a minimally invasive technique that utilizes high-precision laser energy for tumor destruction. This study evaluated the [...] Read more.

Background: Focal therapy has emerged as a viable alternative to radical prostate cancer treatment, offering oncologic control while minimizing morbidity. EchoLaser focal laser ablation (FLA) is a minimally invasive technique that utilizes high-precision laser energy for tumor destruction. This study evaluated the oncologic outcomes, procedural efficiency, and safety of EchoLaser focal therapy, comparing fiducial-assisted (FM+) and non-fiducial (FM−) approaches. Methods: A retrospective cohort study was conducted at Athens Medical Center, Greece, including 50 patients with localized prostate cancer treated with EchoLaser therapy. Patients were categorized into FM+ (n = 31) and FM− (n = 19) groups. Oncologic control (MRI and PSA levels at six months), procedural efficiency (operative time), and safety (adverse events) were assessed. Results: At six months, 80% of patients (n = 40) had no residual disease on MRI, while 20% (n = 10) showed persistent or recurrent tumor activity. PSA levels declined from 10.26 ± 14.99 ng/mL to 2.70 ± 2.67 ng/mL, reflecting a 74% median reduction. Procedure time was shorter in FM+ patients (33.48 ± 2.41 min vs. 45.79 ± 2.92 min, p < 0.01). Adverse events occurred only in the FM− group, including one case of urinary retention. Conclusions: FLA with EchoLaser using fiducial marker enhances procedural efficiency and could have a positive impact on oncologic control. These findings suggest that fiducial markers should be integrated into focal therapy protocols. Longer follow-up studies are needed to confirm the long-term outcomes. Full article

(This article belongs to the Special Issue Minimally Invasive Therapies in Urologic Cancers)

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15 pages, 5384 KiB

Open AccessArticle

Clinical Differences Among Histological Categories of Sarcoma: Insights from 97,062 Patients

by Yiqun Han, Ahmed Shah, Yuan Yao, Robert W. Mutter and Meng Xu-Welliver

Cancers 2025, 17(10), 1706; https://doi.org/10.3390/cancers17101706 - 20 May 2025

Viewed by 398

Abstract

Objectives: To evaluate the clinical heterogeneity of sarcomas by examining associations between histological subtypes, metastatic patterns, treatment modalities, and survival outcomes. Methods: We analyzed data from 97,062 adult patients diagnosed with sarcoma between 2000 and 2020, using the Surveillance, Epidemiology, and End Results [...] Read more.

Objectives: To evaluate the clinical heterogeneity of sarcomas by examining associations between histological subtypes, metastatic patterns, treatment modalities, and survival outcomes. Methods: We analyzed data from 97,062 adult patients diagnosed with sarcoma between 2000 and 2020, using the Surveillance, Epidemiology, and End Results (SEER) database. Fourteen histological subtypes were included. Propensity score matching (PSM) was employed to adjust for baseline differences, and Cox proportional hazards models were used to identify prognostic variables. Results: The most prevalent subtypes were sarcoma not otherwise specified (31.9%), leiomyosarcoma (17.1%), and liposarcoma (13.9%). Metastatic patterns differed significantly by subtype; liver metastases were most common in sarcomas with small blue round cell (SBRC) features (8.9%) and stromal sarcoma (6.1%), while lung metastases were frequently observed in Ewing sarcoma (10.0%) and rhabdomyosarcoma (9.7%). Median overall survival (mOS) varied widely, ranging from 234 months in chondrosarcoma to 16–20 months in rhabdomyosarcoma and SBRC sarcoma. Overall, patients with primary sarcoma had significantly better survival than those with treatment-related disease (119.0 vs. 45.0 months, p < 0.0001), with this trend consistent across most subtypes. Treatment responses were subtype- and size-dependent. For instance, surgery plus radiotherapy improved outcomes in giant cell sarcoma regardless of tumor size, whereas chemotherapy provided benefit only in tumors larger than 5 cm. Combined surgery and radiotherapy offered additional survival benefit in select subtypes, including chordoma, leiomyosarcoma (>5 cm), and synovial sarcoma (<5 cm). Conclusions: Sarcomas exhibit substantial clinical and prognostic heterogeneity across histological subtypes. These findings underscore the importance of subtype-specific, individualized treatment strategies in optimizing patient outcomes. Full article

(This article belongs to the Special Issue State of the Art and Novelties in Multidisciplinary Approach to Soft Tissue and Bone Sarcomas)

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12 pages, 724 KiB

Open AccessArticle

Storage Time and DNA Quality Determine BRCA1/2 Sequencing Success in Prostate Cancer: A Multicentre Analysis with Therapeutic Implications

by Mariavittoria Vescovo, Maria Rosaria Raspollini, Lorenzo Nibid, Francesca Castiglione, Eleonora Nardi, Dario de Biase, Francesco Massari, Francesca Giunchi, Francesco Pepe, Giancarlo Troncone, Umberto Malapelle, Mariantonia Carosi, Beatrice Casini, Elisa Melucci, Matteo Fassan, Luisa Toffolatti, Elena Guerini-Rocco, Federica Conversano, Alessandra Rappa, Stefania Tommasi, Claudio Antonio Coppola, Pio Zeppa, Alessandro Caputo, Sara Gaeta, Fabio Pagni, Davide Seminati, Andrea Vecchione, Stefania Scarpino, Daniela Righi, Chiara Taffon, Francesco Prata and Giuseppe Perrone Show full author list Hide full author list

Cancers 2025, 17(10), 1705; https://doi.org/10.3390/cancers17101705 - 20 May 2025

Viewed by 480

Abstract

Background: Approximately 25.0% of metastatic prostate cancer patients harbour DNA damage repair mutations, including BRCA1 and BRCA2, which are actionable targets for poly(ADP-ribose) polymerase (PARP) inhibitors. Accurate detection of BRCA1/2 mutations is critical for guiding targeted therapies, but crucial pre-analytical factors, [...] Read more.

Background: Approximately 25.0% of metastatic prostate cancer patients harbour DNA damage repair mutations, including BRCA1 and BRCA2, which are actionable targets for poly(ADP-ribose) polymerase (PARP) inhibitors. Accurate detection of BRCA1/2 mutations is critical for guiding targeted therapies, but crucial pre-analytical factors, such as tissue storage duration and DNA fragmentation, drastically affect the reliability of next-generation sequencing (NGS) using real-world diagnostic specimens. Methods: This multicentre study analysed 954 formalin-fixed paraffin-embedded tissue samples from 11 centres, including 559 biopsies and 395 surgical specimens. This study examined the impact of storage duration (<1 year, 1–2 years, and >2 years) and DNA parameters (concentration and fragmentation index) on NGS success rates. Logistic regression and Cox regression analyses were used to assess correlations between these factors and sequencing outcomes. Results: NGS success rates decreased significantly with longer storage, from 87.8% (<1 year) to 69.1% (>2 years). Samples with higher DNA concentrations and fragmentation indexes had higher success rates (p < 0.001). Surgical specimens had superior success rates (83.3%) compared with biopsies (72.8%) due to better DNA quality. The DNA degradation rate was more pronounced in older samples, underscoring the negative impact of extended storage. Conclusions: Timely testing of BRCA1/2 mutations is critical for optimizing the identification of prostate cancer patients eligible for PARP inhibitors. Surgical specimens provide more reliable results than biopsies and minimizing the storage duration significantly enhances testing outcomes. Standardizing pre-analytical and laboratory procedures across centres is essential to ensure personalized treatments and improve patient outcomes. Full article

(This article belongs to the Section Cancer Metastasis)

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7 pages, 580 KiB

Open AccessCommunication

Symptom Burden Poorly Responsive to Palliative Care Intervention and Karnofsky Predict Survival in an Acute Palliative Care Unit

by Sebastiano Mercadante, Yasmine Grassi, Alessio Lo Cascio and Alessandra Casuccio

Cancers 2025, 17(10), 1704; https://doi.org/10.3390/cancers17101704 - 19 May 2025

Viewed by 392

Abstract

Background/Objective: Survival prediction in the advanced cancer care setting plays a vital role in treatment planning and patients’ arrangements. The aim of this study was to examine the association of the global Edmonton Symptom Assessment System (GESAS) and Karnofsky scale (KPS) with overall [...] Read more.

Background/Objective: Survival prediction in the advanced cancer care setting plays a vital role in treatment planning and patients’ arrangements. The aim of this study was to examine the association of the global Edmonton Symptom Assessment System (GESAS) and Karnofsky scale (KPS) with overall survival (OS) in patients with advanced cancers admitted to an acute palliative care unit (APCU). The second aim was to assess if GESAS changes after comprehensive palliative treatment could influence OS. Methods: This is a prospective planned sub-analysis of advanced cancer patients. A consecutive sample of 521 patients admitted to an APCU. Patients with available survival in follow-up phone calls, having complete ESAS, and discharged alive were selected. KPS and GESAS were measured at admission and after seven days of individual comprehensive palliative care. Results: Two hundred forty-three of 521 screened patients were assessed according to inclusion criteria. The mean age was 67.1 years (SD 11.5), and 121 patients were male. The mean KPS was 43.5 (SD 9.3). The mean OS was 74.6 (SD 136.2) days. Significant changes in GESAS were observed after one week. Univariate linear regression analysis showed that KPS and GESAS at T0 and at T7 were correlated with OS (p < 0.0005; p = 0.020; p < 0.0005, respectively). At multivariate analysis, OS was correlated with KPS and GESAS at discharge (B = 3.349, 95% CI = 1.560–5.137; B = −2.430, 95% CI = −3.831–−1.029). Discussion: KPS and poor response to intensive treatment, maintaining high GESAS scores, can be considered predictive factors of shorter OS. Further studies should confirm whether a specialized intervention in other settings can improve OS. Full article

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

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24 pages, 1036 KiB

Open AccessReview

ADAM Proteases in Cancer: Biological Roles, Therapeutic Challenges, and Emerging Opportunities

by Sakshi Arora, Andrew M. Scott and Peter W. Janes

Cancers 2025, 17(10), 1703; https://doi.org/10.3390/cancers17101703 - 19 May 2025

Viewed by 934

Abstract

ADAM (A Disintegrin and Metalloproteinase) family members are multifunctional transmembrane proteases that govern tumorigenesis and metastasis by cleaving membrane-bound substrates such as growth factors, cytokines, and cell adhesion molecules. Several ADAMs, including ADAM8, ADAM9, ADAM10, ADAM12, and ADAM17, are overexpressed in malignancies and [...] Read more.

ADAM (A Disintegrin and Metalloproteinase) family members are multifunctional transmembrane proteases that govern tumorigenesis and metastasis by cleaving membrane-bound substrates such as growth factors, cytokines, and cell adhesion molecules. Several ADAMs, including ADAM8, ADAM9, ADAM10, ADAM12, and ADAM17, are overexpressed in malignancies and are linked with a poor prognosis. These proteases contribute to tumour growth by regulating cell proliferation, cell fate, invasion, angiogenesis, and immune evasion. ADAM10 and ADAM17, especially, facilitate the shedding of critical developmental and growth factors and their receptors, as well as immuno-regulatory molecules, hence promoting tumour progression, immune escape, and resistance to therapy. Recent work has unveiled multiple regulatory pathways that modulate ADAM functions, which include trafficking, dimerization, and conformational modifications that affect substrate accessibility. These observations have rekindled efforts to produce selective ADAM inhibitors, avoiding the off-target consequences reported with early small molecule inhibitors targeting the enzyme active site, which is conserved also in matrix metalloproteinases (MMPs). Promising approaches tested in preclinical models and, in some cases, clinical settings include more selective small-molecule inhibitors, monoclonal antibodies, and antibody–drug conjugates designed to specifically target ADAMs. In this review, we will discuss the emerging roles of ADAMs in cancer biology, as well as the molecular processes that control their function. We further discuss the therapeutic potential of targeting ADAMs, with a focus on recent advances and future directions in the development of ADAM-specific cancer therapies. Full article

(This article belongs to the Collection Factors Regulating Cancer Cell Growth, Migration, Invasion, and Apoptosis)

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27 pages, 1016 KiB

Open AccessReview

Current and Emerging Insights into the Causes, Immunopathogenesis, and Treatment of Cutaneous Squamous Cell Carcinoma

by Ronald Anderson, Nomzamo M. Mkhize, Mahlatse M. C. Kgokolo, Helen C. Steel, Theresa M. Rossouw, Lindsay Anderson and Bernardo L. Rapoport

Cancers 2025, 17(10), 1702; https://doi.org/10.3390/cancers17101702 - 19 May 2025

Viewed by 570

Abstract

The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks of metastasis and recurrence, underscores the importance of identifying novel therapies and validated biomarkers to augment patient management, particularly in the context of well-established and advanced disease. Following a [...] Read more.

The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks of metastasis and recurrence, underscores the importance of identifying novel therapies and validated biomarkers to augment patient management, particularly in the context of well-established and advanced disease. Following a brief overview of the well-recognized epidemiology, clinical features, and diagnosis of cSCC, the current review is focused on risk factors, most prominently excessive exposure to ultraviolet radiation (UVR) as a cause of persistent, pro-tumorigenic mutagenesis, and immune suppression. The next phase of the review encompasses an evaluation of the search for key driver mutations in the pathogenesis of cSCC, including the role of these and other mutations in the formation of immunologically reactive neoepitopes. With respect to additional mechanisms of tumorigenesis, immune evasion is prioritized, specifically the involvement of cell-free and infiltrating cellular mediators of immune suppression. Prominent amongst the former are the cytokine, transforming growth factor-β1 (TGF-β1), the prostanoid, prostaglandin E2, and the emerging immune suppressive nucleoside adenosine. In the case of the latter, tumor-infiltrating and circulating regulatory T cells have been implicated as being key players. The final sections of the review are focused on an update of the immunotherapy of established and advanced disease, as well as on the search for novel, reliable lesional and systemic biomarkers with the potential to guide patient management. Full article

(This article belongs to the Special Issue New Concepts and Recent Advances in the Management of Skin Cancer)

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13 pages, 4250 KiB

Open AccessArticle

Investigation of Normal Tissue Toxicity in Pulsed Low Dose Rate Radiotherapy

by Shahabeddin M. Aslmarand, Troy Dos Santos, Dae-Myoung Yang, Dusica Cvetkovic, Lili Chen and C.-M. Charlie Ma

Cancers 2025, 17(10), 1701; https://doi.org/10.3390/cancers17101701 - 19 May 2025

Viewed by 349

Abstract

Purpose: Pulsed low dose rate radiotherapy (PLDR) is a radiotherapy approach expected to reduce normal tissue toxicity while maintaining equivalent tumor control as conventional radiotherapy (CRT). This preliminary study evaluates the effectiveness of PLDR in reducing normal tissue toxicity in vivo. Materials and [...] Read more.

Purpose: Pulsed low dose rate radiotherapy (PLDR) is a radiotherapy approach expected to reduce normal tissue toxicity while maintaining equivalent tumor control as conventional radiotherapy (CRT). This preliminary study evaluates the effectiveness of PLDR in reducing normal tissue toxicity in vivo. Materials and Methods: In the initial phase, C57BL/6 mice underwent histological examination following single-fraction, total-body irradiation. Observations were conducted at 3 and 5 days post-treatment. Mice were divided into control, PLDR, and CRT groups, receiving varying doses ranging from 4 to 12 Gy. Building upon the histological findings, the second phase centered on whole-abdominal irradiation (WAI) and determining the lethal dose for WAI using CRT. Subsequently, this dose was applied in PLDR settings to compare survival rates and changes in body weight. The experiment was replicated to collect histology samples at 1-, 3-, 5-, 7-, and 9-day endpoints, enabling the assessment and comparison of tissue toxicity. Finally, exploration into PLDR’s lethal WAI dose was conducted. Results: Histology results showed the abdominal region as the main site of difference between PLDR and CRT, with both methods causing a dose-dependent increase in atrophy and hyperplasia. However, CRT led to higher tissue toxicity compared to PLDR. In the survival study, the fatal dose for WAI treatment was 18 Gy, with mice in the CRT group experiencing substantial weight loss and dying within 9–12 days post-treatment. In contrast, mice in the PLDR group, despite an initial weight loss, recovered their weight and survived. Histology results also showed that the PLDR group had less tissue toxicity. Furthermore, the fatal dose of WAI for PLDR was revealed to be 29 Gy, which is over 60% higher than the dose required for CRT, indicating a substantial difference in tolerance and potential safety margin provided by PLDR treatment. Conclusions: PLDR demonstrated a reduced normal toxicity compared to CRT, potentially beneficial in re-treatment scenarios or for tumors where CRT-induced toxicity limits tumor control, such as in liver cases. Full article

(This article belongs to the Section Cancer Therapy)

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Cancers, Volume 17, Issue 10 (May-2 2025) – 135 articles

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