Cancers

11 pages, 497 KiB

Open AccessArticle

Axillary Overtreatment in Patients with Breast Cancer After Neoadjuvant Chemotherapy in the Current Era of Targeted Axillary Dissection

by Ondřej Zapletal, Jan Žatecký, Lucie Gabrielová, Iveta Selingerová, Miloš Holánek, Petr Burkoň and Oldřich Coufal

Cancers 2025, 17(2), 178; https://doi.org/10.3390/cancers17020178 (registering DOI) - 8 Jan 2025

Abstract

Background: In the current era of targeted axillary dissection (TAD), there are still cases where axillary lymph node dissection (ALND) is indicated, but histopathological examination confirms the regression of nodal metastases (ypN0). In this situation, ALND may represent undesirable overtreatment. Methods: A retrospective [...] Read more.

Background: In the current era of targeted axillary dissection (TAD), there are still cases where axillary lymph node dissection (ALND) is indicated, but histopathological examination confirms the regression of nodal metastases (ypN0). In this situation, ALND may represent undesirable overtreatment. Methods: A retrospective study at the Comprehensive Cancer Centre was conducted based on a prospectively maintained database. Patients who underwent surgery after neoadjuvant chemotherapy (NAC) between 2020 and 2023 were selected, specifically those for whom ALND was directly indicated after NAC. Subsequently, clinical–pathological characteristics were compared between cases with ypN0 and those with persistent metastases (ypN+). The reasons for indicating ALND in ypN0 cases were extracted from the medical records. Results: ALND was indicated in 118 cases across 117 patients, of which ypN0 was observed in 44 cases (37%). There were significantly more ypN0 cases for inflammatory carcinomas (68%), the non-luminal HER2-positive phenotype (76%), and carcinomas with histopathological regression of the primary tumor (76%) or the persistence of only the non-invasive component of ypTis (67%). Typical reasons for ALND in ypN0 cases included inflammatory carcinoma (n = 13, 29.5%), locally advanced carcinoma (n = 5, 11.4%), occult carcinoma (n = 2, 4.5%), or persistent lymphadenopathy on ultrasound examination after NAC, especially in the tumor phenotypes HER2-positive and triple-negative breast cancer (TNBC) (n = 8, 18.2%). Conclusions: Through real-world evidence data analysis, subgroups of breast cancer patients treated with NAC were identified who may experience surgical overtreatment in the axilla. These include patients with inflammatory carcinoma, locally advanced carcinoma, occult carcinoma, or patients with persistent lymphadenopathy on US examination after NAC, particularly in the tumor phenotypes HER2-positive and TNBC. Full article

(This article belongs to the Special Issue De-escalation of Axillary and Breast Cancer Surgery in the Setting of Neo-Adjuvant Chemotherapy)

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15 pages, 1760 KiB

Open AccessArticle

Genetic Variations in MDM2 Gene Contribute to Renal Cell Carcinoma Susceptibility: A Genotype–Phenotype Correlation Study

by Shu-Yu Chang, Wen-Shin Chang, Hou-Yu Shih, Chao-Hsiang Chang, Hsi-Chin Wu, Chia-Wen Tsai, Yun-Chi Wang, Jian Gu and Da-Tian Bau

Cancers 2025, 17(2), 177; https://doi.org/10.3390/cancers17020177 (registering DOI) - 8 Jan 2025

Abstract

Background: This study aimed to investigate the polymorphic genotypes of MDM2 rs937282, rs937283, rs2279744, and rs769412, as well as the combined effects of MDM2 genotypes and environmental factors on RCC susceptibility. Methods: A total of 135 RCC patients and 590 controls were recruited [...] Read more.

Background: This study aimed to investigate the polymorphic genotypes of MDM2 rs937282, rs937283, rs2279744, and rs769412, as well as the combined effects of MDM2 genotypes and environmental factors on RCC susceptibility. Methods: A total of 135 RCC patients and 590 controls were recruited for MDM2 genotyping using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Quantitative PCR was performed to assess MDM2 mRNA levels among 30 healthy individuals and 22 RCC patients. Results: MDM2 rs2279744, but not other polymorphisms, was significantly associated with an increased RCC risk (p = 0.0133). The MDM2 rs2279744 G allele was identified as a risk factor for RCC (odds ratio [OR] = 1.49, 95% confidence interval [CI] = 1.14–1.96, p = 0.0047). Among smokers (p = 0.0070), alcohol drinkers (p = 0.0233), individuals with hypertension (p = 0.0041), diabetes (p = 0.0225), and those with a family history of cancer (p = 0.0020), the MDM2 rs2279744 GT and GG genotypes exhibited increased RCC risks. However, this risk effect was not observed in non-smokers, non-drinkers, or individuals without hypertension, diabetes, or a family cancer history (all p > 0.05). Moreover, MDM2 mRNA levels were significantly higher in RCC patients compared to controls and varied among the rs2279744 genotypes, with GG genotype exhibiting the highest expression levels among both RCC patients and controls. Conclusions: This study highlights the association between MDM2 rs2279744 genotypes and RCC risk, suggesting that genotype-associated MDM2 mRNA levels could contribute to early RCC detection. Further studies are warranted to elucidate the detailed mechanisms underlying the role of MDM2 in RCC development. Full article

(This article belongs to the Special Issue The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2 and p53 Research)

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21 pages, 2972 KiB

Open AccessReview

Dermoscopy of Basal Cell Carcinoma Part 2: Dermoscopic Findings by Lesion Subtype, Location, Age of Onset, Size and Patient Phototype

by Irena Wojtowicz and Magdalena Żychowska

Cancers 2025, 17(2), 176; https://doi.org/10.3390/cancers17020176 (registering DOI) - 8 Jan 2025

Abstract

Introduction: Basal cell carcinoma (BCC) is the most prevalent type of skin cancer worldwide. Despite its low metastatic potential, certain subtypes present an aggressive clinical course. Part II focuses on the different dermoscopic patterns observed in BCC, depending on the lesion subtype, its [...] Read more.

Introduction: Basal cell carcinoma (BCC) is the most prevalent type of skin cancer worldwide. Despite its low metastatic potential, certain subtypes present an aggressive clinical course. Part II focuses on the different dermoscopic patterns observed in BCC, depending on the lesion subtype, its location on the body, the patient’s age, the size of the tumor, and skin phototype. Methods: A search of the PubMed database was conducted for studies reporting dermoscopic findings in BCC across all body locations, histopathologic subtypes, tumor sizes, ages of onset and skin phototypes. Results: There are no dermoscopic features indicative of a particular BCC subtype. However, arborizing, truncated or glomerular vessels, shiny white lines, ulceration, white areas, absence of pink zones and large blue-gray ovoid nests suggest high-risk BCCs (morpheaform, micronodular, infiltrative, basosquamous). Pigmented features can occur in all BCC types, though increased pigmentation indicates less aggressive subtypes (nodular, superficial, fibroepithelioma of Pinkus, adenoid). BCCs most commonly develop on the head, typically presenting as nodular and non-pigmented tumors. Those on the nose, eyes and ears may be more aggressive and prone to recurrence. On the trunk, BCCs are usually superficial and pigmented. Lower limb lesions often show polymorphous vessels rather than arborizing ones, which makes the dermoscopic diagnosis challenging. Dermoscopy aids early detection, with larger tumors exhibiting more established features but no size-specific patterns. Aggressive subtypes display similar dermoscopic findings regardless of size. Conclusions: Dermoscopy is a valuable tool for the early detection of BCC, though no specific dermoscopic features can definitively identify subtypes. High-risk BCCs can be suspected when distinct vascular and structural patterns are present, particularly in lesions located on the face, especially around the nose, eyes and ears, while pigmented features may indicate less aggressive subtypes. Full article

(This article belongs to the Special Issue Dermoscopy in Skin Cancer)

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18 pages, 6313 KiB

Open AccessArticle

Differential Response to Local Stimulator of Interferon Genes Agonist Administration in Tumors with Various Stimulator of Interferon Genes Statuses

by Alina Drzyzga, Justyna Czapla, Sybilla Matuszczak, Barbara Łasut-Szyszka, Tomasz Cichoń, Ewelina Pilny, Magdalena Jarosz-Biej and Ryszard Smolarczyk

Cancers 2025, 17(2), 175; https://doi.org/10.3390/cancers17020175 (registering DOI) - 8 Jan 2025

Abstract

Background/Objectives: The stimulator of interferon genes (STING) is currently accepted as a relevant target for anti-cancer therapies. Besides encouraging results showing STING agonist-induced tumor growth inhibition, in some types of tumors the effect is less prominent. We hypothesized that higher STING levels [...] Read more.

Background/Objectives: The stimulator of interferon genes (STING) is currently accepted as a relevant target for anti-cancer therapies. Besides encouraging results showing STING agonist-induced tumor growth inhibition, in some types of tumors the effect is less prominent. We hypothesized that higher STING levels in cancer cells and the possibility of its activation determine a greater anti-cancer response. As the local administration of STING agonists induces a systemic reaction, we emphasized the importance of host tumor-induced hematological disruption in the efficiency of the therapeutic response. Methods: We investigated the response to STING stimulation in murine cancer cell lines—melanoma (B16-F10) and breast carcinoma (4T1)—and murine normal cell lines: fibroblast cells (NIH/3T3), endothelial cells (H5V), and macrophages (J774A.1). We assessed STING agonist-induced tumor growth inhibition and the therapy’s impact on the hematological system parameters and systemic cytokine release. Results: Our results underlined the improved therapeutic effect of STING activation in melanoma (B16-F10) over breast carcinoma (4T1) tumors. The outcomes reflected a high dysregulation of the hematological system in mice with developed 4T1 tumors, which may support persistent inflammation and impede STING-induced therapeutic effects. Moreover, among typical cytokines produced following STING activation, CCL2 fold change was the one that increased the most in the serum of B16-F10-bearing mice and differentiated the observed response to the STING agonist between investigated tumor models. Conclusions: The current study provides new evidence of the different responses to STING activation among two poorly immunogenic tumor models. The high abundance of STING in B16-F10 cells and the possibility of its activation is linked with improved therapeutic response in vivo compared to 4T1. The effect also seems to be connected with a less dysregulated hematological system in mice with B16-F10 tumors over mice with 4T1 tumors. This highlighted the need for general insight into tumor-induced local and systemic responses to the efficiency of the proposed therapy. Full article

(This article belongs to the Special Issue Feature Papers in Section "Tumor Microenvironment")

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16 pages, 2506 KiB

Open AccessArticle

Evaluating Tumor Tissue Modified Viral (TTMV)-HPV DNA for the Early Detection of Anal Squamous Cell Carcinoma Recurrence

by Rafi Kabarriti, Shane Lloyd, James Jabalee, Catherine Del Vecchio Fitz, Randa Tao, Tyler Slater, Corbin Jacobs, Sean Inocencio, Michael Rutenberg, Chance Matthiesen, Kasha Neff, Gene-Fu Liu, Tiffany M. Juarez and Stanley L. Liauw

Cancers 2025, 17(2), 174; https://doi.org/10.3390/cancers17020174 (registering DOI) - 8 Jan 2025

Abstract

Background: The incidence and mortality of anal squamous cell carcinoma (ASCC) are rising, with greater than 80% of cases linked to human papillomavirus (HPV), primarily HPV16. Post-treatment surveillance can be challenging due to the limitations of anoscopy, digital anal rectal exam (DARE), and [...] Read more.

Background: The incidence and mortality of anal squamous cell carcinoma (ASCC) are rising, with greater than 80% of cases linked to human papillomavirus (HPV), primarily HPV16. Post-treatment surveillance can be challenging due to the limitations of anoscopy, digital anal rectal exam (DARE), and imaging. Plasma tumor tissue modified viral (TTMV)-HPV DNA has shown strong sensitivity, specificity, and predictive value in detecting the recurrence of HPV-driven oropharyngeal cancer. Here, we investigate the ability of TTMV-HPV DNA for the early recurrence detection of ASCC. Methods: This retrospective clinical case series included 117 patients with HPV-driven ASCC across 7 U.S. centers, monitored with TTMV-HPV DNA during routine clinical care between March 2020 and June 2024. Physician-reported clinical data and biomarker testing data were combined to create a comprehensive, longitudinal dataset for evaluating test performance metrics. Results: Patients had a median age of 63 years and median post-diagnosis follow-up of 19 months. HPV status was primarily confirmed by TTMV-HPV DNA (52%) or p16 immunohistochemistry (39%). Of those tested for TTMV-HPV DNA pretreatment, 85% had a positive result. TTMV-HPV DNA clearance during or within three months post-treatment was associated with significantly better recurrence-free survival. The per-patient surveillance sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 82.8%, 98.4%, 96.0%, and 92.5%. Of 24 patients with a documented recurrence and a positive TTMV-HPV DNA test, the test was the first evidence of recurrence in 14 patients (58.3%), with a median lead time of 59 days (range: 10–536). TTMV-HPV DNA accurately resolved 94.3% of cases with indeterminate clinical findings. Conclusions: TTMV-HPV DNA testing provides a sensitive and specific approach for detecting patients with recurrent ASCC and resolving the status of patients with indeterminate clinical findings. Full article

(This article belongs to the Section Cancer Biomarkers)

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Distribution of TTMV-HPV DNA tests by treatment stage and timing. (a) Bar graph showing the distribution of patients according to the number of tests received. (b) Bar graph displaying the proportion of post-treatment tests by time interval, with intervals defined as left-inclusive. Full article ">Figure 2
Pretreatment score distribution. Tukey-style boxplot illustrating the distribution of positive pretreatment test scores. Full article ">Figure 3
Post-treatment TTMV-HPV DNA score distribution and effect of positive testing on recurrence-free survival. (a) Tukey-style boxplot illustrating the distribution of positive post-treatment TTMV-HPV DNA scores. (b) Survival curve in which patients with post-treatment positive testing are separated based on whether they have positive testing during post-treatment. Kaplan–Meier method with two-sided log-rank test. CI: Confidence interval. HR: Hazard ratio. Full article ">Figure 4
CONSORT diagram of patient inclusion, testing, and recurrence. * There were a total of 24 recurrences across 19 patients with positive TTMV-HPV DNA testing. ‡ Across 24 total recurrences, 14 were associated with early true positive testing and 10 with confirmatory true positive testing. Full article ">Figure 5
Swimmer plots for patients with clinically confirmed recurrence or positive post-treatment TTMV-HPV DNA testing. (a) Early true positives (n = 14). TTMV-HPV DNA was the first sign of recurrence. (b) Confirmatory true positives (n = 10). Positive TTMV-HPV DNA was coincident with or following clinical recurrence detection. (c) False positives (n = 1). Positive TTMV-HPV DNA in the absence of clinical recurrence detection. (d) False negatives (n = 5). TTMV-HPV DNA was negative and occurred either after, or within three months before, clinical recurrence detection. Only patient “ac” had a biopsy-confirmed HPV-positive recurrence. Full article ">Figure 6
Baseline TTMV-HPV DNA resolution and recurrence-free survival. (a) Tukey-style boxplot comparing pretreatment TTMV-HPV DNA scores for patients whose test resolves vs. those whose tests remain unresolved by three months post-treatment. (b) Survival curve in which patients with pretreatment positive testing are separated based on whether their test score resolves during or within three months after initial treatment. Kaplan–Meier method with two-sided log-rank test. CI: Confidence interval. HR: Hazard ratio. ns: not significant. Full article ">

5 pages, 185 KiB

Open AccessEditorial

Recent Advances in Anticancer Strategies

by Zhiwei Hu and Hassan Bousbaa

Cancers 2025, 17(2), 173; https://doi.org/10.3390/cancers17020173 (registering DOI) - 8 Jan 2025

Abstract

Due to the intricate nature of cancer development and progression, various types of cancer are increasingly prevalent worldwide [...] Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

16 pages, 2086 KiB

Open AccessReview

Advances in Endoscopic Ultrasonography-Based Diagnosis of Pancreatic Lesions: Narrative Review

by Yasunobu Yamashita, Hirofumi Yamazaki, Akiya Nakahata, Tomoya Emori, Yuki Kawaji, Takashi Tamura, Masahiro Itonaga, Reiko Ashida and Masayuki Kitano

Cancers 2025, 17(2), 172; https://doi.org/10.3390/cancers17020172 - 7 Jan 2025

Abstract

Pancreatic cancer is the fourth deadliest cancer in the U [...] Full article

(This article belongs to the Special Issue Ultrasonography for Pancreatobiliary Cancer)

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The time sequence diagram for the development and revolution of EUS equipment. EUS-FNA, EUS-guided fine needle aspiration; EUS-FNB, EUS-guided fine needle biopsy. Full article ">Figure 2
Doppler EUS. Doppler EUS image showing artifacts such as blooming and overpainting, in which vessels appear larger than they really are. Full article ">Figure 3
EUS for detection of pancreatic cancers missed by CT. (a) CT: The main pancreatic duct dilation (arrow) was dilated, but no pancreatic lesion was detected. (b) EUS: A small hypoechoic lesion (9 mm; arrowhead), with dilation of the main pancreatic duct (arrow), was detected. Full article ">Figure 4
Typical contrast-enhanced harmonic EUS (CH-EUS) images of a pancreatic lesion. (a) Representative example of a pancreatic cancer. (Left) B mode EUS detected a pancreatic lesion as an irregular, heterogeneous, and hypoechoic lesion (arrowhead). (Right) CH-EUS shows the pancreatic lesion (arrowhead) as hypovascular compared with the surrounding pancreatic tissue. (b) Representative example of a neuroendocrine neoplasm. (Left) B mode EUS detected a round hypoechoic lesion (arrowhead) pancreatic lesion. (Right) CH-EUS showed the pancreatic lesion to be hypervascular (arrowhead) compared with the surrounding pancreatic tissue. (c) Representative example of an inflammatory mass. (Left) B mode EUS detected a pancreatic lesion as a low echoic mass (arrowhead). (Right) CH-EUS showed that the pancreatic lesion was isovascular (arrowhead) compared with the surrounding pancreatic tissue. Full article ">Figure 5
EUS strain elastography images of pancreatic cancer. Pancreatic lesion was detected as a low echoic lesion (arrowhead) on conventional EUS (left). EUS strain elastography detected a pancreatic lesion with a heterogeneous blue pattern (arrowhead) compared with that of surrounding pancreatic tissue (right). Full article ">Figure 6
Typical contrast-enhanced harmonic EUS (CH-EUS) images of a mural lesion in IPMN. (a) Mural nodule. B mode EUS (left) shows an isoechoic mural lesion (arrowhead) in a cyst. CH-EUS (right) shows a mural lesion with vascularity (arrowhead). (b) Mucous clot. B mode EUS (left) shows an isoechoic mural lesion (arrowhead) in a cyst. CH-EUS (right) shows a mural lesion without vascularity (arrowhead). Full article ">Figure 7
The sensitivity of vascularity for detecting a mural nodule in IPMN using each modality. (a) e-Flow EUS: No vessels are detected in the mural nodule. (b) DFI-EUS: Detected a vessel in the mural nodule. (c) CH-EUS: Detected a mural nodule with vascularity. Full article ">

14 pages, 879 KiB

Open AccessReview

Current Evidence on the Relation Between Microbiota and Oral Cancer—The Role of Fusobacterium nucleatum—A Narrative Review

by Federica Chiscuzzu, Claudia Crescio, Simona Varrucciu, Davide Rizzo, Michela Sali, Giovanni Delogu and Francesco Bussu

Cancers 2025, 17(2), 171; https://doi.org/10.3390/cancers17020171 - 7 Jan 2025

Abstract

Oral squamous cell carcinoma (OSCC) is one the most prevalent head and neck cancers and represents a major cause of morbidity and mortality worldwide. The main established risk factors for OSCC include tobacco and alcohol consumption and betel quid chewing, which may contribute [...] Read more.

Oral squamous cell carcinoma (OSCC) is one the most prevalent head and neck cancers and represents a major cause of morbidity and mortality worldwide. The main established risk factors for OSCC include tobacco and alcohol consumption and betel quid chewing, which may contribute alone or in combination with other environmental factors to carcinogenesis. The oral microbiota is emerging as a key player in the establishment of the molecular and cellular mechanisms that may trigger or promote carcinogenesis, including in the oral cavity. Among the bacterial species found in the oral microbiota, Fusobacterium nucleatum, an anaerobic bacterium commonly found in oral biofilms and a periodontal pathogen, has gained attention due to solid evidence implicating F. nucleatum in colorectal cancer (CRC). F. nucleatum has been shown to induce chronic inflammation, promote cell proliferation and trigger cellular invasion while deploying immune evasion mechanisms. These experimental findings were first obtained in in vitro and in vivo models of CRC and are being confirmed in studies on OSCC. In this review, we summarize the most recent findings on the role of F. nucleatum in OSCC, discuss the clinical implications in terms of prognosis and provide an overview of the key mechanisms involved. Moreover, we identify research questions and aspects that require investigations to clarify the role of F. nucleatum in OSCC. We anticipate that studies in this emerging field may have a significant clinical impact on the diagnosis, prognosis and management of OSCC. Full article

(This article belongs to the Special Issue Communication and Accessibility in the Tumor Microenvironment as a Therapeutic Target)

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13 pages, 1660 KiB

Open AccessArticle

Ongoing Failure to Deliver Guideline-Concordant Care for Patients with Pancreatic Cancer

by Jonathan Ejie, Amir Ashraf Ganjouei, Sophia Hernandez, Jaeyun Jane Wang, Fernanda Romero-Hernandez, Laleh Foroutani, Kenzo Hirose, Eric Nakakura, Carlos Uriel Corvera, Adnan Alseidi and Mohamed Abdelgadir Adam

Cancers 2025, 17(2), 170; https://doi.org/10.3390/cancers17020170 - 7 Jan 2025

Abstract

(1) Background: Comprehensive evaluation of guideline-concordant care (GCC) across all PDAC stages has yet to be thoroughly conducted. This study aimed to characterize treatment patterns and assess factors associated with receiving GCC among patients with pancreatic ductal adenocarcinoma (PDAC) in California. (2) Methods: [...] Read more.

(1) Background: Comprehensive evaluation of guideline-concordant care (GCC) across all PDAC stages has yet to be thoroughly conducted. This study aimed to characterize treatment patterns and assess factors associated with receiving GCC among patients with pancreatic ductal adenocarcinoma (PDAC) in California. (2) Methods: Data on adult patients with PDAC were extracted from the California Cancer Registry (2004–2020). GCC is defined according to the recommendations provided by the National Comprehensive Cancer Network. We used multivariable logistic regression to identify factors associated with receiving GCC. A Cox model was used to examine the association of GCC with overall survival. (3) Results: A total of 50,346 PDAC patients were included (stage 1: 10%; stage 2: 25%; stage 3: 11%; stage 4: 54%). Only 46.7% of all patients received GCC (stage 1: 20%; stage 2: 40%; stage 3: 69%; stage 4: 50%). Only 31% of stage 1 patients underwent surgery. Factors inversely associated with receiving GCC were Hispanic ethnicity (OR 0.78; p < 0.001), Black race (OR 0.74; p < 0.001), having no insurance (OR 0.40; p < 0.001]), and a Charlson–Deyo score of ≥2 (OR 0.68; p < 0.001). Adherence to GCC was associated with improved survival (Hazard Ratio 0.39; p < 0.001). Notably, patients with stage 1 PDAC who received GCC had a median survival of 47 months vs. 8 months for those who did not. (4) Conclusions: Although stage 1 PDAC patients have the greatest potential for survival with GCC, only 20% of patients received such treatment. Thus, it is crucial to identify and address the modifiable factors contributing to these suboptimal care patterns. Full article

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

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Percentage of patients receiving GCC by cancer stage. This bar graph displays the percentage of patients who received care in accordance with pancreatic cancer treatment guidelines in California, stratified by disease stage (I–IV). Stage III patients showed the highest compliance at 69%. In contrast, Stage I patients had the lowest at 19.6%. Full article ">Figure 2
Trends in guide-concordant care over time, stratified by disease stage. This figure illustrates the changes in compliance with the standard of care treatment from 2004 to 2020, categorized by pancreatic cancer stages I–IV. Stage III patients consistently exhibited the highest rates of receiving GCC, with a slope of 1.017 and a significant p-value of <0.001. Conversely, Stage I patients had the lowest compliance rates, with a minimal slope increase of 0.123 and a non-significant p-value of 0.573. Stages II and IV also showed notable improvements, with slopes of 1.422 and 0.715 and p-values of <0.001, respectively. Full article ">Figure 3
Sankey diagram of patient pathways for treatment and compliance in patients with stage 1 PDAC. This Sankey diagram Illustrates the treatment pathways and compliance outcomes for Stage 1 PDAC patients. Colors represent compliance categories (green for GCC and red for non-GCC). This figure highlights the role of lack of a plan for surgery contributing to non-GCC in stage 1 PDAC patients. Full article ">Figure 4
Stage-specific Kaplan–Meier survival curves by receipt of GCC. Full article ">

15 pages, 1163 KiB

Open AccessReview

Squamous Cell Bladder Cancer: A Rare Histological Variant with a Demand for Modern Cancer Therapeutics

by Scott D. Bell, Anthony E. Quinn, Alfred Bajo, Trenton G. Mayberry, Braydon C. Cowan, Austin J. Marrah, Mark R. Wakefield and Yujiang Fang

Cancers 2025, 17(2), 169; https://doi.org/10.3390/cancers17020169 - 7 Jan 2025

Abstract

Bladder cancer is among the most common form of cancer worldwide and is predicted to increase in incidence and mortality over the next decade. Squamous cell carcinoma of the bladder is a rare histological variant typically associated with schistosomiasis, also known as bilharzia, [...] Read more.

Bladder cancer is among the most common form of cancer worldwide and is predicted to increase in incidence and mortality over the next decade. Squamous cell carcinoma of the bladder is a rare histological variant typically associated with schistosomiasis, also known as bilharzia, a parasitic infection caused by flatworms called schistosomes or blood flukes, and is generally seen in underdeveloped nations. However, squamous cell carcinoma of the bladder still represents nearly 5% of bladder cancer diagnoses in the western world. Transitional cell carcinoma is the predominant histological variant of bladder cancer found throughout the western world, and nearly all disease indicators and treatments for bladder cancer are driven by this common variant. Squamous cell carcinoma of the bladder shows characteristic features that differ from transitional cell carcinoma, such as differing levels of protein indicators and different response rates to traditional bladder cancer therapies. Common treatment methods for squamous cell carcinoma of the bladder include radical cystectomy, chemotherapies, and radiation. Reviewing the previous literature on the management of squamous cell carcinoma of the bladder, it becomes apparent that this variant needs to be treated differently than common bladder cancer variants and a proper management course needs to be set in place to maximize positive patient outcomes. Such a study will be very helpful for urologists and oncologists to manage patients with bladder squamous cell carcinoma. Full article

(This article belongs to the Section Cancer Therapy)

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27 pages, 630 KiB

Open AccessReview

A Scoping Review of Primary Breast Cancer Risk Reduction Strategies in East and Southeast Asia

by Filipa Alpeza, Christine Kim Yan Loo, Qingyuan Zhuang, Mikael Hartman, Serene Si Ning Goh and Jingmei Li

Cancers 2025, 17(2), 168; https://doi.org/10.3390/cancers17020168 - 7 Jan 2025

Abstract

Breast cancer (BC) screening enables early detection and timely treatment of cancer. Improving the effectiveness of BC screening can be accomplished by personalizing screening schedules according to each woman’s specific risk level. However, when informing women about their risk classification, especially those at [...] Read more.

Breast cancer (BC) screening enables early detection and timely treatment of cancer. Improving the effectiveness of BC screening can be accomplished by personalizing screening schedules according to each woman’s specific risk level. However, when informing women about their risk classification, especially those at high risk, it is important to give clear recommendations on how to lower their risk. BC risk reduction comprises lifestyle modifications, preventive surgery, and chemoprevention, with the latter two being particularly applicable to high-risk individuals. Public health guidance on risk-reducing interventions is heterogeneous and context-dependent. We conducted a scoping review on BC surgical interventions and chemoprevention in East and Southeast Asia in publications between 2010 and 2024. We searched two databases and identified 23 publications relevant for inclusion. The highest number of publications came from South Korea (n = 9). More publications discussed surgical interventions compared to pharmacological interventions. The studies were largely observational and utilized data from medical records. Most studies defined high-risk individuals as BRCA carriers, many of whom previously had cancer. The field would benefit from randomized studies of BC prevention strategies focusing on Asian populations. Future research could explore women’s sentiments towards chemoprevention compared to prophylactic surgery and could extend the definition of high-risk individuals beyond BRCA carriers. Full article

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

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15 pages, 1899 KiB

Open AccessArticle

Diagnostic Performance of PIVKA-II in Italian Patients with Hepatocellular Carcinoma

by Valeria Guarneri, Elisabetta Loggi, Giuseppe Ramacieri, Carla Serra, Ranka Vukotic, Giovanni Vitale, Alessandra Scuteri, Carmela Cursaro, Marzia Margotti, Silvia Galli, Maria Caracausi, Lucia Brodosi, Filippo Gabrielli and Pietro Andreone

Cancers 2025, 17(2), 167; https://doi.org/10.3390/cancers17020167 - 7 Jan 2025

Abstract

Background and Aims: Hepatocellular carcinoma (HCC) represents the second leading cause of cancer deaths worldwide. Six-month imaging along with alpha-fetoprotein (AFP) serum levels detection are the current gold standard to exclude HCC. Protein induced by vitamin K absence (PIVKA-II) has been proposed as [...] Read more.

Background and Aims: Hepatocellular carcinoma (HCC) represents the second leading cause of cancer deaths worldwide. Six-month imaging along with alpha-fetoprotein (AFP) serum levels detection are the current gold standard to exclude HCC. Protein induced by vitamin K absence (PIVKA-II) has been proposed as a potential screening biomarker for HCC. This study was designed to evaluate the role of PIVKA-II as diagnostic HCC marker, and the correlation between PIVKA-II levels and HCC stage. Methods: PIVKA-II levels were assessed on serum samples of Italian patients. The study population included 80 patients with HCC, 111 with liver cirrhosis (LC), and 111 with chronic hepatitis C (CHC). Results: PIVKA-II serum levels progressively increase from patients with CHC to patients with HCC. In the HCC group, PIVKA-II values are higher in the more advanced stages of the disease, assessed by the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC-B vs. BCLC-A vs. BCLC-0). Youden’s index analysis identified a value >37 mAU/mL as the optimal threshold for the best combination of sensitivity and specificity (80% and 76%, respectively) and, at the best cut-off of 5.2 ng/mL, AFP yielded 53% specificity and 78% sensitivity. The combination of PIVKA-II and AFP reached positive and negative predictive values of 73.9% and 94.2%, respectively. Conclusions: PIVKA-II levels are increased in the HCC patients, compared to control groups. The increase is more evident in patients with advanced HCC. The diagnostic performance of PIVKA-II seems more sensitive than AFP while the combination of PIVKA-II and AFP resulted in the best diagnostic accuracy, reaching 73.9% positive predictive value and 94.2% negative predictive value, thus improving the diagnostic capability of the single marker. Full article

(This article belongs to the Collection Primary Liver Cancer)

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19 pages, 18827 KiB

Open AccessArticle

Expression Pattern of AIFM3, VGLL4, and WNT4 in Patients with Different Stages of Colorectal Cancer

by Danijel Bevanda, Anita Racetin, Nela Kelam, Natalija Filipović, Mateo Bevanda, Marina Rudan Dimlić, Jelena Budimir, Daniela Bevanda Glibo, Ivana Bevanda, Danica Ramljak and Katarina Vukojević

Cancers 2025, 17(2), 166; https://doi.org/10.3390/cancers17020166 (registering DOI) - 7 Jan 2025

Abstract

Background/Objectives: Colorectal cancer (CRC) remains a significant health burden, and its delayed diagnosis at advanced stages leads to poor survival outcome. Detection of known and novel prognostic markers is essential. In this study, the status of likely prognostic markers—the apoptotic inducing factor (AIFM3), [...] Read more.

Background/Objectives: Colorectal cancer (CRC) remains a significant health burden, and its delayed diagnosis at advanced stages leads to poor survival outcome. Detection of known and novel prognostic markers is essential. In this study, the status of likely prognostic markers—the apoptotic inducing factor (AIFM3), vestigial-like family member 4 (VGLL4), and WNT4—was evaluated. Methods: AIFM3, VGLL4, and WNT4 expression in CRC tissues across different stages (Dukes A–D) were analyzed using histological immunofluorescence staining and RNA sequencing analyses. Results: In advanced CRC stages, progressive loss of normal crypt architecture, reduction of goblet cells, and necrotic debris were detected along with differential expression patterns of AIFM3, VGLL4, and WNT4. AIFM3 exhibited high reactivity in the lamina propria of healthy tissue and Dukes A, but this was diminished in advanced CRC stages. VGLL4 expression, initially confined to the lamina propria, increased significantly in the epithelium of Dukes B and C, with a cytoplasmic localization pattern. WNT4 expression was elevated in the CRC epithelium across all stages, contrasting with a significant reduction in lamina propria reactivity. RNA sequencing corroborated these findings, showing significant downregulation of AIFM3 and WNT4 and upregulation of VGLL4 in CRC tissues compared to controls. Expression of AIFM3 and WNT4 showed no correlation with survival outcome, while low VGLL4 expression was correlated with better survival outcome. Conclusions: The results suggest distinct roles for AIFM3, VGLL4, and WNT4 in CRC progression, highlighting only VGLL4 as a potential prognostic marker. Further evaluation of VGLL4 and its specific role in CRC progression remains to be elucidated. Full article

(This article belongs to the Section Molecular Cancer Biology)

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The morphology of intestinal crypts is altered in colorectal cancer tissue compared to healthy tissue. Section of healthy adult colon (a) with circular crypts and basally positioned nuclei within cells with underlying lamina propria; section of Dukes A human colon cancer (b,c) with moderately formed crypts lined by epithelial cells with impaired nuclear position; section of Dukes B human colon cancer (d) with the cellular debris within gland lumen; section of Dukes C and D (e,f) human colon with disrupted glands underlined by atypical epithelial cells. Full article ">Figure 2
Immunofluorescence image of the control adult human colon (a) and CRC stages Dukes A (b), Dukes B (c), Dukes C (d), and Dukes D (e). Arrows indicate positive AIFM3 cells in the epithelium (ep) and lamina propria (lp). DAPI staining (blue nuclei). The percentages of cells positive to AIFM3 staining in control and Dukes A–D CRC stages in the epithelium (f) and lamina propria (g) were calculated from a minimum of ten representative images. For (a–e), scale bar is 100 μm. For statistical analysis, one-way ANOVA followed by Tukey’s multiple comparison tests (f,g) and two-way ANOVA test followed by Šídák’s multiple comparisons test (h) were used. Data are presented as the mean ± SD. Significant differences are indicated by * p < 0.05 and **** p < 0.0001. Full article ">Figure 3
Immunofluorescence image of the control adult human colon (a) and CRC stages Dukes A (b), Dukes B (c), Dukes C (d), and Dukes D (e). Arrows indicate positive VGLL4 cells in the epithelium (ep) and lamina propria (lp). DAPI staining (blue nuclei). The percentages of cells positive to VGLL4 in the control and Dukes A–D CRC stages in the epithelium (f) and lamina propria (g) were calculated from a minimum of ten representative images. For (a–e), scale bar is 100 μm. For statistical analysis, one-way ANOVA followed by Tukey’s multiple comparison tests (f,g) and two-way ANOVA test followed by Šídák’s multiple comparisons test (h) were used. Data are presented as the mean ± SD. Significant differences are indicated by **** p < 0.0001. Full article ">Figure 4
Immunofluorescence image of the control adult colon (a) and CRC stages Dukes A (b), Dukes B (c), Dukes C (d), and Dukes D (e). Arrows indicate positive WNT4 cells in the epithelium (ep) and lamina propria (lp). DAPI staining (blue nuclei). The percentages of cells positive to WNT4 staining in control and Dukes A–D CRC stages in the epithelium (f) and lamina propria (g) were calculated from a minimum of ten representative images. For (a–e), scale bar is 100 μm. For statistical analysis, one-way ANOVA followed by Tukey’s multiple comparison tests (f,g) and two-way ANOVA test and Šídák’s multiple comparisons test (h) were used. Data are shown as the mean ± SD. Significant differences are indicated by: * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Full article ">Figure 5
Cohort TCGA colon and rectal cancer (COADREAD) gene expression analysis of AIFM3 (a), VGLL4 (b), and WNT4 (c) by RNAseq–Illumina HiSeq between control (STN) and CRC patient groups (PT). Data are shown as log2(norm count + 1), with the use of unpaired t-test and Welch’s correction. Significant differences are indicated by: ** p < 0.01 and **** p < 0.0001. Full article ">Figure 6
Graphic presentation of survival analysis (days) with expression of AIFM3 (a), VGLL4 (b), and WNT4 (c). mRNA expression of genes of interest in CRC patients was shown as the average time of survival in days. Red line represents high and blue line low expression. For statistical analysis, we used the Kaplan–Meier method with log-rank test for survival length. Data were obtained from the TCGA colon and rectal cancer (COADREAD) study. Full article ">Figure 7
Expression analysis of AIFM3, WNT4, and VGLL4 genes in relation to microsatellite instability (MSI) status. The boxplots represent normalized log-transformed counts [log2(norm_count+1)] for samples with MSI status categorized as “NO” (microsatellite stable) or “YES” (microsatellite unstable). A significant difference in expression levels of AIFM3 (a) was observed between MSI-stable and MSI-unstable samples. No significant difference in expression levels of WNT4 (b) and VGLL4 (c) was observed. The horizontal line within each box represents the median, the box spans the interquartile range, and whiskers indicate the minimum and maximum values, excluding outliers. The data were analyzed using the Mann–Whitney U test. Significant difference is indicated by * p < 0.05. Full article ">Scheme 1
Workflow for investigating colorectal cancer gene expression and its correlation with patient survival. Samples were collected from colorectal tissue and classified based on tumor pathology. Tumor sections were analyzed for gene expression using immunofluorescence microscopy, highlighting markers such as AIFM3, WNT4, and VGLL4. Data from The Cancer Genome Atlas (TCGA) colon and rectal cancer (COADREAD) study database were used to correlate gene expression levels with patient survival outcomes. Full article ">

18 pages, 3250 KiB

Open AccessArticle

New Promising Steroidal Aromatase Inhibitors with Multi-Target Action on Estrogen and Androgen Receptors for Breast Cancer Treatment

by Cristina Amaral, Cristina F. Almeida, Maria João Valente, Carla L. Varela, Saul C. Costa, Fernanda M. F. Roleira, Elisiário Tavares-da-Silva, Anne Marie Vinggaard, Natércia Teixeira and Georgina Correia-da-Silva

Cancers 2025, 17(2), 165; https://doi.org/10.3390/cancers17020165 - 7 Jan 2025

Abstract

Background/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer—the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch [...] Read more.

Background/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer—the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). Methods: Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells. Results: All the new AIs (10 µM) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 µM) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 µM) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit. Conclusions: Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer. Full article

(This article belongs to the Collection Innovations in Cancer Drug Development Research)

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Chemical structure of the compounds 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). Full article ">Figure 2
Effects of AIs 6, 10a and 13 on the cell viability of the non-tumor cell lines HFF-1 (A) and MCF-10A (B). HFF-1 and MCF-10A cells were incubated with each AI (1–25 μM) over 6 days. Untreated cells representing 100% of cell viability were designated as controls, with the effects of AIs being normalized to these control values. Full article ">Figure 3
Effects of AIs 6, 10a and 13 on the viability of MCF-7aro cells. Cells were treated with T (1 nM) and each AI (1–25 μM) for 3 and 6 days. The actions of each AI were evaluated by MTT (A) and LDH assays (B). Untreated cells representing 100% of cell viability and 1 unit value of LDH release were designated as controls, with data of AIs treatment being normalized to these control values. *** (p < 0.001) denote statistically significant differences between control cells and AI-treated cells. Full article ">Figure 4
Effects of AIs 6, 10a and 13 on MCF-7aro cell death. Cells were incubated with T (1 nM) and with or without each AI at 10 μM for 3 days, in the presence or absence of CDX (1 μM) or ICI (100 nM). Cells without AI treatment were designated as controls, while as a positive control we considered cells incubated with T plus STS (10 µM). The effects on apoptotic cell death were determined by the activation of the effector caspase-7 (A), and data are presented in relative luminescence units (RLUs). The involvement of ERα (B) and AR (C) in the promotion of apoptosis was assessed by caspase-7 activity after incubation of AIs with ICI or CDX, respectively. *** (p < 0.001) denotes statistically significant differences between control cells and AI-treated cells, δδδ (p < 0.001) indicates differences between AI-treated cells in the presence or absence of CDX and ### (p < 0.001) the differences between AI-treated cells in the presence or absence of ICI. Full article ">Figure 5
The impact of aromatase on the effects exerted by AIs 6 (A), 10a (B) and 13 (C) on ER+ breast cancer cells, evaluated by the MTT assay. MCF-7aro cells were incubated with AIs (1, 5 and 10 μM) plus T (1 nM) or E2 (1 nM) over 3 and 6 days. Untreated cells representing 100% of cell viability were designated as control, being data of AIs normalized to these control values. ** (p < 0.01) indicate significant differences between AI-treated cells incubated with E2 or with T. Full article ">Figure 6
The impact of ERα on the effects exerted by AIs 6, 10a and 13. (A) MCF-7aro cell viability effects were determined by MTT assay after treatment over 3 days with T (1 nM) plus AIs (1, 5 and 10 μM) in the presence or absence of ICI (100 nM). (B) ER transactivation assays to explore the effects on ER activation, using VM7Luc4E2 cells incubated with AIs (0.1–10 μM), with (ER antagonism) or without (ER agonism) the hormones T or E2. (C) Effects of AIs 6, 10a and 13 (10 μM) on ERα protein expression. β-actin was used as a loading control, being data of densitometry represented as ERα/β-actin ratio. (D) Effects of AIs 6, 10a and 13 (10 μM) on mRNA transcription of ESR1, TFF1, AREG and EGR3 genes in MCF-7aro cells. The mRNA transcript levels of treated cells were quantified using the housekeeping gene ACTB. Cells without treatment were used as control, to which all results in AI-treated cells were normalized. Cells treated with T plus ICI (100 nM) represented positive control. # (p < 0.05), ## (p < 0.01) and ### (p < 0.001) denote differences in MCF-7aro cells treated with AIs in the absence or presence of ICI, while * (p < 0.05), ** (p < 0.01), and *** (p < 0.001) denote differences of AI-treated cells in relation to control cells (T). On the other hand, the differences of AI-treated cells in contrast to control and in relation to ER agonism are indicated by *** (p < 0.001), while in relation to ER antagonism over T are expressed by &&& (p < 0.001). Full article ">Figure 7
The impact of AR on the effects exerted by AIs 6, 10a and 13. (A) MCF-7aro cell viability effects were determined by MTT assay after treatment, over 3 days, with T (1 nM) plus AIs (1, 5 and 10 μM) in the presence or absence of CDX (1 µM). (B) The AR transactivation assay, AR-EcoScreen™, was used to explore the effects of AIs (0.1–10 μM) with (AR antagonism) or without (AR agonism) R1881 (0.1 nM). (C) Effects of AIs (10 μM) on AR protein expression. β-actin was used as a loading control, being data of densitometry represented as AR/β-actin ratio. Cells without AIs treatment were used as control, to which all results in AI-treated cells were normalized. δ (p < 0.05), δδ (p < 0.01) and δδδ (p < 0.001) denote differences of MCF-7aro cells incubated with AIs in the presence or absence of CDX, while ** (p < 0.01) and *** (p < 0.001) denote differences of AI-treated cells in relation to control cells. On the other hand, the differences of AI-treated cells in contrast to control and in relation to AR agonism, are presented by *** (p < 0.001), whereas in relation to AR antagonism are indicated as & (p < 0.05), && (p < 0.001) and &&& (p < 0.001). Full article ">Figure 8
Effects of 6, 10a and 13 on AI-resistant ER+ breast cancer cells, LTEDaro. The effects of AIs 6 (A), 10a (B) and 13 (C) (1–25 μM) on cell viability were determined by the MTT assay after 3 and 6 days. (D) Effects of AIs (10 μM) on cell death after 3 days, by assessing caspase-7 activity. Cells treated only with STS (10 µM) were denominated as positive control. Data are expressed as relative luminescence units (RLUs). Untreated cells were designated as control, to which all results of AI-treated cells were normalized. * (p < 0.05), ** (p < 0.01) and *** (p < 0.001) indicate differences between the control and AI-treated cells. Full article ">

23 pages, 4520 KiB

Open AccessArticle

An Evaluation of Rare Cancer Policies in Europe: A Survey Among Healthcare Providers

by Kostadin Kostadinov, Georgi Iskrov, Nina Musurlieva and Rumen Stefanov

Cancers 2025, 17(2), 164; https://doi.org/10.3390/cancers17020164 - 7 Jan 2025

Abstract

Rare cancers, defined as those with an annual incidence of fewer than six cases per 100,000 individuals, are associated with significant health inequalities. This study aimed to assess the knowledge, attitudes, and perceptions of healthcare providers with expertise in rare cancers regarding the [...] Read more.

Rare cancers, defined as those with an annual incidence of fewer than six cases per 100,000 individuals, are associated with significant health inequalities. This study aimed to assess the knowledge, attitudes, and perceptions of healthcare providers with expertise in rare cancers regarding the effectiveness of enacted or planned rare cancer policies across Europe. Between 25 March 2023 and 5 March 2024, we conducted an online survey targeting 738 healthcare providers affiliated with the European Reference Networks and the Organization of European Cancer Institutes, yielding 92 complete responses from 28 European countries (response rate: 12.5%). While a significant portion of respondents were unaware of their country’s legal definitions for rare cancers, 67.4% acknowledged that national cancer plans prioritized rare cancers. These plans received the highest ratings for their evidence-based interventions and monitoring efforts. The integration of rare cancer policies into broader oncology frameworks was the preferred policy model. National cancer registries were highly rated for confidentiality and validity but scored the lowest for cost-effectiveness. Government funding was deemed crucial for cancer screening programs. The disease burden and unmet health needs primarily influenced reimbursement decisions in the field of rare cancers. Respondents rated palliative care as more effective in adults with rare cancers compared to in children, particularly regarding symptom management. We confirmed significant variability in rare cancer policy evaluations across Europe, the necessity for a common EU-level definition for rare cancers, and a shift in reimbursement and policy framework models, highlighting the importance of policy integration and enhanced collaboration. However, given the limitations of the study, such as small sample size and possible unstudied confounding factors, we should interpret our findings with caution. A systematic policy review and multistakeholder assessment in the future could complement our results. Full article

(This article belongs to the Special Issue Health Services Research in Cancer Care)

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27 pages, 2776 KiB

Open AccessArticle

A Comprehensive Analysis of Neoadjuvant Chemotherapy in Breast Cancer: Adverse Events, Clinical Response Rates, and Surgical and Pathological Outcomes—Bozyaka Experience

by Cengiz Yılmaz, Baha Zengel, Orhan Üreyen, Zehra Hilal Adıbelli, Funda Taşlı, Hasan Taylan Yılmaz, Özlem Özdemir, Demet Kocatepe Çavdar, Hülya Mollamehmetoğlu, Umut Çakıroğlu, Yaşar İmren, Savaş Yakan and Enver İlhan

Cancers 2025, 17(2), 163; https://doi.org/10.3390/cancers17020163 (registering DOI) - 7 Jan 2025

Abstract

Objectives: To evaluate the neoadjuvant chemotherapy (NACTx) process in breast cancer (BC), its significant treatment-related adverse events (trAEs), tumor clinical response rates, and surgical and pathological outcomes, and to analyze factors influencing cavity shaving and axillary lymph node dissection (ALND) following sentinel lymph [...] Read more.

Objectives: To evaluate the neoadjuvant chemotherapy (NACTx) process in breast cancer (BC), its significant treatment-related adverse events (trAEs), tumor clinical response rates, and surgical and pathological outcomes, and to analyze factors influencing cavity shaving and axillary lymph node dissection (ALND) following sentinel lymph node biopsy (SLNB). Methods: A comprehensive retrospective study was conducted at a single center on patients who received NACTx for BC between 2015 and 2021. Results: Medical records of 242 patients were reviewed. Approximately one-fifth encountered grade ≥ 3 trAEs (21.5%), leading 3.3% to discontinue chemotherapy. Anthracycline cardiotoxicity (2.2%) caused one death (mortality rate = 0.4%). For clinical response and surgical and pathological outcomes, 229 patients were eligible. Clinical progression occurred in 3.9% of the patients (14% in triple-negative BC, p = 0.004). Breast-conserving surgery (BCS) was performed in 55% of the patients. There was no significant difference between the type of breast surgery (BCS vs. mastectomy) and molecular subtype, histology, tumor size, or tumor’s pathological response degree. Cavity shaving was required in one-fifth of the patients who underwent BCS (n = 134) due to an invasive tumor at the surgical margin (SM). Tumor histology (invasive ductal vs. invasive lobular carcinoma; OR: 4.962, 95% CI 1.007–24.441, p = 0.049) and tumor SUVMax value (OR: 0.866, 95% CI 0.755–0.993, p = 0.039) had significant independent efficacy on SM positivity. Initially, 75% underwent SLNB, but nearly half of them needed ALND. ALND rates were significantly higher in the luminal A and LB-HER2(−) groups (87% vs. 69%) than in the HER2(+) and TN groups (43% to 50%) (p = 0.001). All luminal A patients and those with lobular histology required ALND after SLNB, but no patients in the HER2-enriched group required ALND. ER positivity and higher PR expression levels were associated with an increased need for ALND after SLNB, whereas HER2 positivity and higher SUVMax values of LN(s) were associated with a significantly reduced need for ALND. About 27% of the patients achieved overall pCR. No pCR was achieved in the LA group. Conclusions: The BC NACTx process requires close monitoring due to severe AEs and disease progression. NACTx decisions must be made on experienced multidisciplinary tumor boards, considering tumor characteristics and expected targets. Full article

(This article belongs to the Section Cancer Therapy)

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11 pages, 7000 KiB

Open AccessCommunication

SSTR2-Targeted Theranostics in Hepatocellular Carcinoma

by Majid Momeny, Solmaz AghaAmiri, Servando Hernandez Vargas, Belkacem Acidi, Sukhen C. Ghosh, Tyler M. Bateman, Jack T. Adams, Vahid Khalaj, Ahmed O. Kaseb, Hop S. Tran Cao and Ali Azhdarinia

Cancers 2025, 17(2), 162; https://doi.org/10.3390/cancers17020162 - 7 Jan 2025

Viewed by 148

Abstract

Background: While the clinical use of radiolabeled somatostatin analogs is well established in neuroendocrine tumors, there is growing interest in expanding their application to other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the potential utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC). [...] Read more.

Background: While the clinical use of radiolabeled somatostatin analogs is well established in neuroendocrine tumors, there is growing interest in expanding their application to other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the potential utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC). Methods: SSTR2 expression in HCC cell lines and clinical samples was evaluated using qRT-PCR, Western blot analysis, and a public dataset. ⁶⁷Ga-DOTATATE uptake was measured, ¹⁷⁷Lu-DOTATATE cytotoxicity was assessed, and ⁶⁸Ga-DOTATATE tumor targeting was evaluated in HCC animal models and a patient via PET/CT imaging. Results: SSTR2 expression was confirmed in HCC cell lines and clinical samples. Radioligand uptake studies demonstrated SSTR2-mediated ⁶⁷Ga-DOTATATE uptake. ¹⁷⁷Lu-DOTATATE treatment reduced cell proliferation and enhanced the anti-tumor efficacy of the multikinase inhibitor sorafenib. ⁶⁸Ga-DOTATATE PET/CT scans successfully identified tumors in HCC animal models and spinal metastases in a patient with HCC. Conclusion: These findings provide evidence that SSTR2-based theranostics could have significant implications for the detection and treatment of HCC. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors in Cancer Progression)

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SSTR2 amplification and expression in HCC. (A) SSTR2 is amplified and/or overexpressed in a significant proportion of HCC cases, based on data from the TCGA HCC dataset [<a href="#B20-cancers-17-00162" class="html-bibr">20</a>]. (B) Comparative analysis of SSTR2 protein expression in HCC patients versus other solid tumor types, derived from the Human Protein Atlas dataset (<a href="https://www.proteinatlas.org" target="_blank">https://www.proteinatlas.org</a>), accessed on 9 January 2024. (C,D) IHC staining for SSTR2 in an HCC patient (Patient ID #2766) compared with a prostate adenocarcinoma patient (Patient ID #3304), who shows negative SSTR2 staining. Images are from the Human Protein Atlas, with staining conducted using anti-SSTR2 antibody (Sigma, #HPA007264). Full article ">Figure 2
(A) Relative mRNA expression levels of SSTR2 in HCC cell lines measured by qRT-PCR. Data represent the mean ± SD from three independent experiments, each conducted in triplicate. Gene expression was normalized to GAPDH for each cell line and further normalized to HepG2 cells. (B) Western blot analysis of SSTR2 protein expression in HCC cell lines, with comparison to NCI-H69 small cell lung cancer cells. β-actin was used as a loading control. (C) Uptake of 67Ga-DOTATATE in HCC cell lines relative to NCI-H69 and BON-1 cells, with receptor blocking by 100X octreotide. Data were analyzed using two-way ANOVA followed by Šídák’s multiple comparisons test, with statistical significance indicated by * p < 0.05 and **** p < 0.0001. ns indicates not significant. (D) Anti-proliferative effects of 177Lu-DOTATATE in HCC cell lines assessed by WST-1 cell proliferation assay (Sigma), with NCI-H69 cells serving as a benchmark. Data represent the mean ± SD from three independent experiments, each performed in triplicate. Full article ">Figure 3
(A) Anti-proliferative effects of the anti-angiogenic agents lenvatinib, sorafenib, and cabozantinib on HCC cell lines. Cells were treated with increasing concentrations of these drugs (in µM) for 48 h, and cell proliferation was assessed using the WST-1 assay. (B,C) Synergistic interaction between 177Lu-DOTATATE and sorafenib in SNU449 cells. Co-treatment with sorafenib (0.01–5 µM) and 177Lu-DOTATATE (0.1, 0.5, and 1 megabecquerels (MBq)/mL) for 48 h resulted in an IC50 shift and synergistic effects, as determined by Bliss synergy analysis. Cell viability was measured using the WST-1 assay. Full article ">Figure 4
(A) Maximum-intensity projection showing tumor-specific 68Ga-DOTATATE uptake in subcutaneous models of Huh7 and SNU449. Mice were i.v. injected with 7.4 MBq of 68Ga-DOTATATE into the tail vein and PET/CT imaging was performed at 1 h p.i. (B) Quantification of radioactive biodistribution in subcutaneous models of Huh7, SNU449, and HCT116. Data were analyzed using two-way ANOVA followed by Tukey’s multiple comparisons test, with statistical significance indicated by * p < 0.05 and **** p < 0.0001. ns indicates not significant. (C) Corresponding IHC analysis showing SSTR2 expression in FFPE tumor sections from the mice with the HCC tumors. The tumor from the HCT116-bearing mice was used as the negative control. The scale bar is 200 μm. Full article ">Figure 5
A 68Ga-DOTATATE PET/CT scan showing SSTR2 positivity in spinal metastases from a patient with HCC. The blue arrow indicates the location of the spinal metastases originating from the liver. Full article ">

24 pages, 1156 KiB

Open AccessReview

UBR5 in Tumor Biology: Exploring Mechanisms of Immune Regulation and Possible Therapeutic Implications in MPNST

by Diana Akinyi Odhiambo, Selina Fan and Angela C. Hirbe

Cancers 2025, 17(2), 161; https://doi.org/10.3390/cancers17020161 - 7 Jan 2025

Viewed by 127

Abstract

Malignant peripheral nerve sheath tumor (MPNST) is a rare but aggressive soft-tissue sarcoma characterized by poor response to therapy. The primary treatment remains surgical resection with negative margins. Nonetheless, in the setting of neurofibromatosis type 1 (NF1), the five-year survival rate is at [...] Read more.

Malignant peripheral nerve sheath tumor (MPNST) is a rare but aggressive soft-tissue sarcoma characterized by poor response to therapy. The primary treatment remains surgical resection with negative margins. Nonetheless, in the setting of neurofibromatosis type 1 (NF1), the five-year survival rate is at 20–50%, with recurrence occurring in up to 50% of individuals. For patients with metastatic and unresectable disease, current treatment options include cytotoxic chemotherapy, which offers minimal benefit, and most patients die within five years of diagnosis. Despite advances in targeted therapy focusing on inhibiting Ras signaling and its downstream effectors, clinical trials report minimal clinical benefit, highlighting the need to explore alternative pathways in MPNST pathogenesis. Here, we discuss the role of the E3 ubiquitin ligase, UBR5, in cancer progression and immune modulation across various malignancies, including breast, lung, and ovarian cancer. We focus on mechanisms by which UBR5 contributes to tumorigenesis, focusing on its influence on tumor microenvironment and immune modulation. Additionally, we explore UBR5’s roles in normal tissue function, DNA damage response, metastasis, and therapeutic resistance, illustrating its multifaceted contribution to cancer biology. We discuss evidence implicating UBR5 in immune evasion and highlight its potential as a therapeutic target to enhance the efficacy of immune checkpoint blockade (ICB) therapy in MPNST, a tumor typically characterized by an immune cold microenvironment. We outline current immune-based strategies and challenges in MPNST management, ongoing efforts to shift the immune landscape in MPNST, and ultimately, we suggest that targeting UBR5 could be a novel strategy to potentiate ICB therapy-mediated anti-tumor immune response and clinical outcomes, particularly in MPNST patients with inoperable or metastatic disease. Full article

(This article belongs to the Special Issue Sarcoma: Clinical Trials and Management)

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13 pages, 3100 KiB

Open AccessSystematic Review

Symptoms and Side Effects of Bacille Calmette–Guerin Therapy for Non-Muscle Invasive Bladder Cancer as Reported by Patients: A Systematic Review

by John Lahoud, Alfin Okullo, Claudia Rutherford, David P. Smith, Daniel S. J. Costa, Margaret-Ann Tait, Sengupta Shomik and Manish I. Patel

Cancers 2025, 17(2), 160; https://doi.org/10.3390/cancers17020160 - 7 Jan 2025

Viewed by 139

Abstract

Background/Objectives: Knowledge of the symptoms and side effects (SSEs) of Bacille Calmette–Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) is critical when establishing selecting appropriate therapies for patients. The aim of our study was to systematically review the common patient-reported SSEs associated [...] Read more.

Background/Objectives: Knowledge of the symptoms and side effects (SSEs) of Bacille Calmette–Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) is critical when establishing selecting appropriate therapies for patients. The aim of our study was to systematically review the common patient-reported SSEs associated with BCG-based and other intravesical chemotherapy treatment options for NMIBC. Methods: A systematic search of AMED, MEDLINE, EMBASE, PsycINFO, Web of Knowledge, and Scopus was conducted from inception to July 2024. The PRISMA process was followed. Prospective studies with an adult cohort that assessed SSEs through direct patient reports with standardized patient-reported outcome measures were included in this study. A narrative synthesis was performed to compare the frequency of SSEs reported by treatment options. Statistical analysis was performed using chi square and Fisher’s exact tests, with statistical significance at p < 0.05. Results: Thirty-four studies met the eligibility criteria. The main findings indicated that BCG induction is more toxic than BCG induction with maintenance; however, severe SSEs resulting in treatment cessation occurred almost twice as often in patients on BCG induction with maintenance. Patients who received full-dose BCG were more likely to have SSEs compared to those receiving a low dose. BCG monotherapy alone caused more SSEs compared to BCG with chemotherapy. Patients reported more SSEs with BCG compared to chemotherapy alone for induction with maintenance. Limitations of the study include the varied length of maintenance regimes affecting nature of data reported. Conclusions: The findings of this study allow for improved counselling of patients regarding expected side effects in accordance with their recommended treatment options for NMIBC. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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