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10 pages, 773 KiB

Open AccessArticle

Risk Factors for Surgical Wound Infection and Fascial Dehiscence After Open Gynecologic Oncologic Surgery: A Retrospective Cohort Study

by Carolin Hagedorn, Nadja Dornhöfer, Bahriye Aktas, Laura Weydandt and Massimiliano Lia

Cancers 2024, 16(24), 4157; https://doi.org/10.3390/cancers16244157 - 13 Dec 2024

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Abstract

Background: Numerous studies have identified typical risk factors for surgical site infections (SSI) and fascial dehiscence (FD), but patients with gynecological cancer are often excluded. This study aimed to assess the key risk factors for SSI and FD in gynecological oncological patients undergoing [...] Read more.

Background: Numerous studies have identified typical risk factors for surgical site infections (SSI) and fascial dehiscence (FD), but patients with gynecological cancer are often excluded. This study aimed to assess the key risk factors for SSI and FD in gynecological oncological patients undergoing median laparotomy. Methods: We conducted a retrospective cohort study of patients who underwent median laparotomy for gynecological cancer between January 2017 and December 2020. Machine learning (random forest) was employed to identify interactions among predictors, while multivariable logistic regression was used to develop a model, validated through bootstrapping. Results: A total of 204 women underwent open surgery for malignant gynecological diseases at our institution. A total of 50 patients developed SSI (24.5%) and 18 of these additionally suffered from FD (8.8%). The duration of the surgical procedure was independently associated with both SSI and FD. However, this association was only significant if the bowel was opened during surgery (either accidentally or intentionally). Conversely, if the bowel was left intact, the duration of the operation had no effect on either SSI (p = 0.88) or FD (p = 0.06). Additionally, a lower age of the patients significantly (p = 0.013) independently influenced the effect of body mass index (BMI) on the SSI rate. Conclusions: Our study supports the importance of duration of surgery in predicting SSI and FD in patients with gynecological cancer. This correlation between operation time and wound complications depends on whether bowel surgery was performed. Additionally, the relevance of obesity as a risk factor is higher in younger than in older patients. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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12 pages, 1462 KiB

Open AccessArticle

The Importance of Patient Systemic Health Status in High-Grade Chondrosarcoma Prognosis: A National Multicenter Study

by Veroniek M. van Praag, Dominique Molenaar, Guus A. H. Tendijck, Gerard R. Schaap, Paul C. Jutte, Ingrid C. M. van der Geest, Marta Fiocco and Michiel A. J. van de Sande

Cancers 2024, 16(20), 3484; https://doi.org/10.3390/cancers16203484 - 14 Oct 2024

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Abstract

Background: Due to the relatively advanced age and high mortality rate of patients with high-grade chondrosarcoma (CS), it is important to holistically assess patient- and tumor characteristics in multidisciplinary team and shared decision-making with regard to treatment options. While current prognostic models include [...] Read more.

Background: Due to the relatively advanced age and high mortality rate of patients with high-grade chondrosarcoma (CS), it is important to holistically assess patient- and tumor characteristics in multidisciplinary team and shared decision-making with regard to treatment options. While current prognostic models include multiple tumor and treatment characteristics, the only patient characteristics that are commonly included are age and gender. Based on clinical experience, we believe that factors related to patient preoperative systemic health status such as the American Society of Anesthesiologists (ASA) score may be equally important prognostic factors for overall survival (OS). Methods: A retrospective nationwide cohort study was identified from four specialized bone sarcoma centers in The Netherlands. Patients with a primary CS grade II, III, and dedifferentiated CS were eligible. Prognostic factors including age at presentation, gender, ASA score, CVD, tobacco use, BMI, histological tumor grade, tumor size, pathological fracture, presentation after unplanned excision, type of surgery and surgical margin were evaluated. The outcome measure was OS at the time of surgery. The Kaplan–Meier methodology was employed to estimate OS; a log-rank test was used to assess the difference in survival. To study the impact of prognostic factors on OS, a multivariate Cox proportional hazard regression model was estimated. Results: In total, 249 patients were eligible for this study, and 89 were deceased at the end of follow-up. In multivariate analysis, histological grade (HR 2.247, 95% CI 1.334–3.783), ASA score III (HR 2.615, 95% CI 1.145–5.976, vs. ASA I), and age per year (HR: 1.025, 95% CI 1.004–1.045) were negatively associated with OS. No association was found between tobacco use, BMI, gender or cardiovascular disease and OS in this cohort. Pathological fracture and tumor size were only associated with OS in univariate analysis. Conclusions: This multicenter study is the first on sarcomas to include ASA in a prognostic model. Results show that ASA score as a proxy for patients’ systemic health status should be included when providing a prognosis for patients with a high-grade primary CS, besides the conventional risk factors such as tumor grade and age. Specifically, severe systemic disease (ASA score III) is a strong negative predictor. Conversely, we found no difference in OS between ASA scores I and II. These findings aid multidisciplinary team and shared decision-making with regard to these complex sarcoma patients that often require life-changing surgeries. Level of Evidence: Prognostic level III. See the instructions for authors for the complete description of levels of evidence. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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16 pages, 2365 KiB

Open AccessArticle

Optimizing Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders

by Sheryl Y. T. Lim, Jenny Huo, George S. Laszlo, Frances M. Cole, Allie R. Kehret, Junyang Li, Margaret C. Lunn-Halbert, Jasmyn L. Persicke, Peter B. Rupert, Roland K. Strong and Roland B. Walter

Cancers 2024, 16(20), 3476; https://doi.org/10.3390/cancers16203476 - 14 Oct 2024

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Abstract

Background/Objective: Current treatments for eosinophilic and mast cell disorders are often ineffective. One promising target to improve outcomes is sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8). As limitations, there are few Siglec-8 monoclonal antibodies (mAbs) available to date, and Siglec-8-directed treatments have so far primarily [...] Read more.

Background/Objective: Current treatments for eosinophilic and mast cell disorders are often ineffective. One promising target to improve outcomes is sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8). As limitations, there are few Siglec-8 monoclonal antibodies (mAbs) available to date, and Siglec-8-directed treatments have so far primarily focused on unconjugated mAbs, which may be inadequate, especially against mast cells. Methods: Here, we used transgenic mice to raise a diverse panel of fully human mAbs that either recognize the V-set domain, membrane-distal C2-set domain, or membrane-proximal C2-set domain of full-length Siglec-8 as a basis for novel therapeutics. Results: All mAbs were efficiently internalized into Siglec-8-expressing cells, suggesting their potential to deliver cytotoxic payloads. Tool T cell-engaging bispecific antibodies (BiAbs) and chimeric antigen receptor (CAR)-modified natural killer (NK) cells using single-chain variable fragments from Siglec-8 mAbs showed highly potent cytolytic activity against Siglec-8-positive cells even in cases of very low target antigen abundance, whereas they elicited no cytolytic activity against Siglec-8-negative target cells. Siglec-8^V-set-directed T cell-engaging BiAbs and Siglec-8^V-set-directed CAR-modified NK cells induced substantially greater cytotoxicity against cells expressing an artificial smaller Siglec-8 variant containing only the V-set domain than cells expressing full-length Siglec-8, consistent with the notion that targeting membrane-proximal epitopes enhances effector functions of Siglec-8 antibody-based therapeutics. Indeed, unconjugated Siglec-8^C2-set mAbs, Siglec-8^C2-set-directed T cell-engaging BiAbs, and Siglec-8^C2-set-directed CAR-modified NK cells showed high antigen-specific cytolytic activity against Siglec-8-positive human cell lines and primary patient eosinophils. Conclusions: Together, these data demonstrate Siglec-8-directed immunotherapies can be highly potent, supporting their further development for eosinophilic and mast cell disorders. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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19 pages, 4792 KiB

Open AccessArticle

Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers

by Kunj Bihari Gupta, Truett L. Taylor, Siva S. Panda, Muthusamy Thangaraju and Bal. L. Lokeshwar

Cancers 2024, 16(17), 3108; https://doi.org/10.3390/cancers16173108 - 8 Sep 2024

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Abstract

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid [...] Read more.

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2’s cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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Chemical structure of CMC-2. Full article ">Figure 2
Cur, DCA, and CMC-2 are cytotoxic to BCa cells but were relatively nontoxic to non-transformed bladder epithelial cells, UROtsa: (A). Viability of tumorigenic, chemo-sensitive (HT-1376, 253J, T24, and 5637), chemo-resistant (5637 GemR, 5637 CisR, and 5637 G+C R) and non-tumorigenic (UROtsa) human BCa cell lines, treated with drugs or drug-diluent (control). (B). The viability of chemo-resistant human BCa, 5637 CisR, 5637 GemR, and 5637 G+C R cells as percent of untreated control. The MTT reduction assay was performed after 72 h of respective drug treatment. Results are expressed as mean of percent cell viability ± standard deviation (SD) (n = 4). Except for the non-tumorigenic UROtsa cells, CMC-2 was significantly more cytotoxic than Cur or DCA (p ≤ 0.05). Full article ">Figure 3
Clonal survival of human BCa cells exposed to DCA, Cur, and CMC-2: (A) Colonies formed by surviving cells after treatment with several doses of CMC-2, Cur, and DCA for three days that were then allowed to form colonies of >16 cells in the absence of drugs for next 4–7 days. (B–D). Graphs represent the mean of number of surviving colonies ± standard deviation (n = 3) for each cell type: (B) HT-1376 cells, (C) 5637 naïve, and (D) 5637 G+C R. Paired t-tests were used to determine the significance of difference between control and the exposed cells. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.005. Full article ">Figure 4
Estimating oxidative stress: reactive oxygen species (ROS) produced in (A) HT-1376 and (B) 5637 naïve cells after treatment with DCA, Cur, and CMC-2 for various periods, as estimated using a DCFDA probe. The relative fluorescence unit (RFU) was converted to the percent ROS value. Data represented here are means of ROS produced ± standard deviation (n = 4) after subtracting the ROS values generated in the untreated cells. Cells treated with H2O2 (0.2 µM) served as a positive control. ROS levels were significantly higher (p ≤ 0.05) in CMC-2-treated cells at the dose level of 10 µM of DCA, Cur, and CMC-2 for all treatment periods in both cell lines. Full article ">Figure 5
Estimating mitochondrial ROS (mt-ROS): the mt-ROS produced in the (A) HT-1376 and (B). 5637 naïve cells after the treatment of several doses of DCA, Cur, and CMC-2 exposed for several periods, as estimated using MitoSOX. The relative fluorescence unit (RFU) was converted to percent mt-ROS. Data represented here are means of mt-ROS produced ± standard deviation (n = 4) after subtracting the ROS values generated in the untreated cells. Cells treated with H2O2 (0.2 µM) served as a positive control. mt-ROS levels were significantly higher (p ≤ 0.05) in CMC-2-treated cells at the dose level of 10 µM of DCA, Cur, and CMC-2 for all treatment periods in both cell lines. Full article ">Figure 6
NAC abolishes ROS generation in CMC-2-treated cells: the level of ROS produced in (A) HT-1376, (B) 5637 naïve cells, after treatment with several doses of CMC-2 with and without N-acetyl-L-cysteine (NAC, 1 mM), was estimated using a probe DCFDA for 30 min, and intracellular fluorescence was measured. The relative fluorescence unit (RFU) was converted to the percent ROS value. Data represented here are means of ROS produced ± standard deviation (n = 4) after subtracting the ROS values generated in the untreated cells. Cells treated with H2O2 (0.2 µM) served as a positive control. Full article ">Figure 7
NAC abolishes CMC-2-induced cytotoxicity. MTT assay-based cellular viability was estimated in HT-1376, T24, 5637 naïve, and 5637 G+C R cells after treatment with several concentrations of CMC-2, NAC alone, and in combination. The percent cell viability was calculated relative to the untreated control cells, and results are expressed as the mean of percent cell viability ± standard deviation (n = 4) for each treatment. Paired t-tests were used to determine the significance of the difference in the cellular viability between CMC-2 and the combination treatment group. *** p ≤ 0.005. Full article ">Figure 8
CMC-2 reduces mitochondrial transmembrane potential (ψM). Levels of ψM in human BC HT-1376 and 5637 naïve cells were estimated by JC-1 aggregates using flow cytometry after a 24 h treatment with DCA, Cur, and CMC-2. (A). Distribution of cells based on red and green fluorescence channels. (B). Bar graph demonstrating the red/green ratio of JC-1 fluorescence. The red/green ratio was significantly decreased in cells treated with all three drugs (*** p ≤ 0.001). Full article ">Figure 9
CMC-2-induced cytotoxicity reveals cell cycle arrest in the G1 phase. Cell cycle phase resolution was analyzed by flow cytometry. HT-1376 and 5637 naïve cells were treated with DCA, Cur, and CMC-2 for 24 h, and PI-stained nuclei suspensions were analyzed by flow cytometry to resolve individual cell cycle phase fractions based on the DNA content. (A). Cell cycle phase distribution of each treatment in both cells. (B). Bar graphs represent cell cycle phases upon drug treatment in both cell lines. Flow cytometry data were collected and analyzed using the NovoCyte Quanteon and NovoExpress software. The experiment was performed three times; data shown are mean ± SD, and pairwise t-tests were used to determine significance * p ≤ 0.05, ** p ≤ 0.01. (C). Immunoblots of Cyclin E1 in total cell lysates treated with DCA, Cur, and CMC-2 in both cell types. See <a href="#app1-cancers-16-03108" class="html-app">Figure S2</a>: uncropped blots. β-actin is shown as a loading control in all lanes. All experiments were performed thrice, and a representative immunoblot image is displayed. Full article ">Figure 10
Estimating the markers for apoptotic cell death by measuring the level of Annexin V in the outer leaflet of the plasma membrane. (A) Distribution of bladder cancer cells labeled with Annexin V-FITC (bound to externalized phosphatidyl serine) and PI (DNA) after 24 h of treatment of DCA (10 μM), Cur (10 μM), CMC-2 (1 μM) and Staurosporine (Sta, 0.2 μM; a positive inducer of apoptosis). The single-cell suspensions were analyzed by flow cytometry to determine the intensity of (green) and (red) fluorescence of individual cells. Quadrant analysis shows the percentage of live cells undergoing early- (low green bars) or late-stage (high green bars) apoptosis. (B). Quantification of the relative distribution of cells in each quadrant. (C,D) Immunoblot analysis of protein markers related to apoptotic cell death: cleaved and full-length PARP, Bax, Bcl-2, Bcl-XL, AIF (apoptosis-inducing factor), p-AKT (Ser-473), and AKT. β-actin and GAPDH were used as a loading control. See <a href="#app1-cancers-16-03108" class="html-app">Figure S2</a>: uncropped blots. Three separate preparations of cell lysates from independent experiments were analyzed by immunoblotting, and the best representative image of one set of cell lysates is shown here (*** p ≤ 0.001, when compared to untreated control). Full article ">Figure 11
Antitumor activity of DCA, Cur, and CMC-2 in HT-1376 xenografted mice. (A) Growth curve of tumor volume of each group. (B) Terminal tumor images from formalin-fixed whole tumors of each group. (C) Body weight of each tumor-bearing animal throughout this study. (D) H&E-stained tumor sections of each group to demonstrate the histological details of tumor cells and stroma. Paired t-tests were used to determine significance. Data are represented as mean ± SD, *** p ≤ 0.005. Full article ">

11 pages, 964 KiB

Open AccessArticle

Evaluating Treatment Patterns and the Role of Neoadjuvant Chemotherapy in Plasmacytoid Urothelial Carcinoma: Insights from a Combined National and Institutional Series

by Syed Rahman, Victoria Kong, Michael Jalfon, David Hesse, Joseph Kim, Jonathan L. Wright, Adebowale Adeniran, Peter Humphrey, Darryl T. Martin and Fady Ghali

Cancers 2024, 16(17), 3050; https://doi.org/10.3390/cancers16173050 - 1 Sep 2024

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Abstract

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare histologic subtype of urothelial carcinoma of the bladder (BC). Our objective was to characterize treatment patterns and outcomes of PUC in the NCDB and our recent institutional experience. Methods: The NCDB was queried for localized [...] Read more.

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare histologic subtype of urothelial carcinoma of the bladder (BC). Our objective was to characterize treatment patterns and outcomes of PUC in the NCDB and our recent institutional experience. Methods: The NCDB was queried for localized PUC cases between 2004 and 2020. Patients with PUC from a single institution (Yale School of Medicine) were also incorporated from 2021 onwards to not double-count patients. The primary outcomes were overall survival and treatment trends. Results: A total of 146 patients were included, 123 from NCDB and 23 from Yale. The median overall survival (mOS) was 28 [IQR 7.5, 50.3] months, 23 [IQR 8.4, 46.3] months for the NCDB patients, and 36 [IQR 4.3, 68.1] for the Yale patients. The mOS for patients receiving neoadjuvant chemotherapy (NAC) was 60.0 [28.0, 91.9] vs. 14.8 months [0, 34.3] for patients without NAC, p = 0.038, though the benefit was not preserved in a Cox proportional hazard analysis incorporating the clinical stage, receipt of NAC, and age. The peritoneum was the most common site of metastasis (78.3%), followed by the liver and bones. Conclusion: Our findings underscore the formidable challenge posed by PUC, emphasizing its limited response to current therapies. Despite higher pT0 rates with NAC, the OS benefit remains inconclusive, highlighting the need for more effective treatments. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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13 pages, 962 KiB

Open AccessArticle

Global Trial Representation and Availability of Tyrosine Kinase Inhibitors for Treatment of Chronic Myeloid Leukemia

by Mycal Casey, Lorriane Odhiambo, Nidhi Aggarwal, Mahran Shoukier, K. M. Islam and Jorge Cortes

Cancers 2024, 16(16), 2838; https://doi.org/10.3390/cancers16162838 - 14 Aug 2024

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Abstract

Background: Evaluating clinical trial representation for countries with different socio-demographic index (SDI) and tyrosine kinase inhibitor (TKI) availability for chronic myeloid leukemia (CML). Methods: CML incidence rates (IRs) and disability-adjusted life years (DALYs) (1999–2019) from the Institute of Health Metrics and [...] Read more.

Background: Evaluating clinical trial representation for countries with different socio-demographic index (SDI) and tyrosine kinase inhibitor (TKI) availability for chronic myeloid leukemia (CML). Methods: CML incidence rates (IRs) and disability-adjusted life years (DALYs) (1999–2019) from the Institute of Health Metrics and Evaluation were analyzed. Trials investigating TKI use in CML were obtained from ClinicalTrials.gov. Site data for eligible trials (N = 30) and DALYs were analyzed. TKI approvals, DALYs, and IRs were summarized by SDI. Results: North America (NA) had significant decreases in annual percent change (APC) in DALYs and incidence rates from 1999 to 2004. IRs were highest in Europe and Central Asia (ECA) and NA, while DALYs were highest in South Asia (SAsia) and Sub-Saharan Africa (SSA). Countries in the high-SDI quintile were likely to have lower DALYs than lower-SDI quintiles. Differences in regional DALYs vs. sites in TKI trials were significant for SAsia, SSA, and ECA. High-SDI countries were included in all 30 trials, and TKI approvals were prominent in high-SDI (142) vs. low-SDI (14) countries. Conclusions: The inclusion of disproportionately affected countries during the design of and recruitment into clinical trials should occur, as should TKI availability. The lack of representation demonstrates healthcare disparities. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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13 pages, 749 KiB

Open AccessArticle

Adverse Events in Anti-PD-1-Treated Adjuvant and First-Line Advanced Melanoma Patients

by Daan Jan Willem Rauwerdink, Olivier van Not, Melissa de Meza, Remco van Doorn, Jos van der Hage, A. J. M. van den Eertwegh, John B. Haanen, Maureen J. B. Aarts, Franchette W. P. J. van den Berkmortel, Christiaan U. Blank, Marye J. Boers-Sonderen, Jan Willem B. de Groot, Geke A. P. Hospers, Djura Piersma, Rozemarijn S. van Rijn, A. M. Stevense-den Boer, Astrid A. M. van der Veldt, Gerard Vreugdenhil, Michel W. J. M. Wouters, Karijn P. M. Suijkerbuijk and Ellen Kapiteijn Show full author list Hide full author list

Cancers 2024, 16(15), 2656; https://doi.org/10.3390/cancers16152656 - 26 Jul 2024

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Abstract

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 [...] Read more.

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 in adjuvant or advanced settings between 2015 and 2021. Comorbidities and ECOG performance status were assessed before treatment, and grade III-IV irAEs were monitored during treatment. Univariate and multivariate regression analyses were conducted to identify factors associated with irAE development. Results: A total of 1465 advanced melanoma patients and 908 resected melanoma patients received anti-PD-1 therapy. Adjuvant-treated patients were younger, with a median age of 63 years compared to 69 years in the advanced group (p < 0.01), and had a better ECOG performance status (p < 0.01). Comorbidities were seen more frequently in advanced melanoma patients than in those receiving adjuvant treatment, 76% versus 68% (p < 0.01). Grade III-IV irAEs occurred in 214 (15%) advanced treated patients and in 119 (13%) adjuvant-treated patients. Multivariate analysis showed an increased risk of severe irAE development with the presence of any comorbidity (adjusted OR 1.22, 95% CI 1.02–1.44) and ECOG status greater than 1 (adjusted OR 2.00, 95% CI 1.20–3.32). Adjuvant therapy was not associated with an increased risk of irAE development compared to advanced treatment (adjusted OR 0.95, 95% CI 0.74–1.21) after correcting for comorbidities and ECOG performance score. Anti-PD-1 therapy was halted due to toxicity (any grade irAE) more often in the adjuvant setting than in the advanced setting, 20% versus 15% (p < 0.01). Conclusions: Higher ECOG performance status and presence of any comorbidity were independently associated with an increased risk of Grade III-IV irAE in adjuvant and advanced treated melanoma patients. Patients treated in the adjuvant setting did not have an increased risk of developing severe irAEs compared to advanced melanoma patients. These findings are of clinical significance in consulting patients for adjuvant anti-PD-1 treatment. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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Review

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19 pages, 2093 KiB

Open AccessReview

Histology Agnostic Drug Development: An Updated Review

by Kevin Nguyen, Karina Fama, Guadalupe Mercado, Yin Myat and Kyaw Thein

Cancers 2024, 16(21), 3642; https://doi.org/10.3390/cancers16213642 - 29 Oct 2024

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Abstract

Recent advancements in oncology have led to the development of histology-agnostic therapies, which target genetic alterations irrespective of the tumor’s tissue of origin. This review aimed to provide a comprehensive update on the current state of histology-agnostic drug development, focusing on key therapies, [...] Read more.

Recent advancements in oncology have led to the development of histology-agnostic therapies, which target genetic alterations irrespective of the tumor’s tissue of origin. This review aimed to provide a comprehensive update on the current state of histology-agnostic drug development, focusing on key therapies, including pembrolizumab, larotrectinib, entrectinib, dostarlimab, dabrafenib plus trametinib, selpercatinib, trastuzumab deruxtecan, and reprotrectinib. We performed a detailed analysis of each therapy’s mechanism of action, clinical trial outcomes, and associated biomarkers. The review further explores challenges in drug resistance, such as adaptive signaling pathways and neoantigen variability, as well as diagnostic limitations in identifying optimal patient populations. While these therapies have demonstrated efficacy in various malignancies, significant hurdles remain, including intratumoral heterogeneity and resistance mechanisms that diminish treatment effectiveness. We propose considerations for refining trial designs and emerging biomarkers, such as tumor neoantigen burden, to enhance patient selection. These findings illustrate the transformative potential of histology-agnostic therapies in precision oncology but highlight the need for continued research to optimize their use and overcome existing barriers. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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Overview of the FDA-approved tumor-agnostic treatments. This figure summarizes the tumor-agnostic treatments approved by the U.S. Food and Drug Administration (FDA). Immune checkpoint inhibitors include pembrolizumab, approved for both dMMR/MSI-H and TMB-H solid tumors, and dostarlimab, approved for TMB-H cancers. Targeted therapies include one combinational regimen consisting of dabrafenib plus trametinib, approved for BRAFV600E non-CRC tumors. Larotrectinib, entrectinib, and repotrectinib were both approved for NTRK fusions. Selpercatinib was approved for RET fusion-positive cancers. Trastuzumab deruxtecan represents the first antibody conjugate drug approved for HER2-positive cancers. These targeted therapies represent the emerging era of personalized cancer care driven by mutation type across multiple tumor types. Created in BioRender. Thein, K. (2024) <a href="http://BioRender.com" target="_blank">BioRender.com</a>/d44b340 (accessed on 12 March 2024). Full article ">Figure 2
Timeline of tumor-agnostic FDA approvals. The number of FDA-approved tumor-agnostic therapies continues to grow, reflecting advances in targeted cancer treatments. This figure summarizes the year of FDA approval, the name of the approved regimen, and the targeted biomarker, and lists the patient population (n) and objective response rate (ORR) of the clinical trials that formed the basis of approval. 1. Pembrolizumab was approved in 2017 for dMMR/MSI-H solid tumors, based on 149 patients, with an ORR of 39.6%. 2. Larotrectinib was approved in 2018 for NTRK fusion-positive solid tumors, based on 55 patients, with an ORR of 75%. 3. Entrectinib was approved in 2019 for NTRK fusion-positive solid tumors, based on 55 patients, with an ORR of 75%. 4. Pembrolizumab was approved in 2020 for TMB-H solid tumors. The cutoff value used for TMB-H status was at least 10 mutations per megabase, based on 102 patients, with an ORR of 29%. 5. Dostarlimab was approved in 2021 for dMMR solid tumors, based on 209 patients, with an ORR of 41.6%. 6. Dabrafenib plus trametinib was approved in 2022 for BRAF V600E solid tumors (excluding colorectal cancers), based on 131 adult patients with an ORR of 41% and 36 pediatric patients with an ORR of 25%. 7. Selpercatinib was approved in 2022 for RET fusion-positive solid tumors, based on 41 patients, with an ORR of 44%. 8. Trastuzumab deruxtecan was approved in 2024 for HER2-positive (immunohistochemistry 3+ score) solid tumors, based on a pooled patient population of 192 across three key clinical trials: Destiny-PanTumor02 (ORR = 51.4%), Destiny-Lung01 (ORR = 52.9%), and Destiny-CRC02 (ORR = 46.9%). 9. Repotrectinib was approved in 2024 for NTRK fusion-positive solid tumors. Patients were divided into TRK tyrosine kinase inhibitor (TKI)-pretreated and TKI-naïve cohorts. The TKI-pretreated group, with 48 patients, had an ORR of 50%, while the TKI-nave cohort, with 40 patients, had an ORR of 58%. Full article ">Figure 3
Mechanism of action of FDA-approved tumor-agnostic therapy. This figure summarizes the basic mechanism of action regarding the FDA-approved tumor-agnostic therapies. Immune checkpoint inhibitor—PD-1 inhibitors: PD-1 is a receptor expressed on T cells, and its ligand, PD-L1, is expressed on cancer cells. When PD-1 binds to PD-L1, it suppresses the activity of cytotoxic T cells, allowing tumor cells to evade immune detection and proliferate unchecked. PD-1 inhibitors, such as pembrolizumab and dostarlimab, block this interaction, restoring T-cell activity and enhancing the immune system’s ability to detect and destroy cancer cells. Antibody-drug conjugate (ADC): Trastuzumab deruxtecan consists of a monoclonal antibody, a cytotoxic payload, and a linker. Upon binding to the HER2 receptor on the cancer cell surface, the ADC is internalized through endocytosis. Inside the cell, the endosome fuses with a lysosome, where the complex is degraded, releasing the cytotoxic drug. This payload damages the tumor’s DNA, effectively inhibiting cell proliferation and inducing cancer cell death. BRAF/MEK inhibitor combination: Dabrafenib (a BRAF inhibitor) combined with trametinib (a MEK inhibitor) targets the MAPK signaling pathway, a critical cascade of phosphorylation events involving RAS, BRAF, MEK, and ERK proteins. This pathway regulates cell proliferation, survival, and differentiation. In cancers with BRAF V600E mutations, abnormal activation of this pathway leads to uncontrolled tumor cell growth. By blocking the mutant BRAF protein and inhibiting MEK downstream, this combination therapy effectively disrupts hyperproliferation and prevents paradoxical activation of the MAPK pathway. NTRK fusion inhibitors and RET fusion inhibitors: Gene fusions involving the NTRK and RET genes lead to the production of constitutively active receptor tyrosine kinases, which continuously signal even in the absence of normal regulatory inputs. These aberrantly activated receptors stimulate key proliferative and survival pathways, including the MAPK and PI3K/AKT pathways, driving oncogenic signaling that promotes tumor growth, survival, and metastasis. Targeted therapies, such as NTRK inhibitors (e.g., larotrectinib and entrectinib) and RET inhibitors (e.g., selpercatinib and pralsetinib), block these fusion-driven tyrosine kinases, effectively halting tumor progression by disrupting these essential growth signals. Created by BioRender. Thein, K. (2024) <a href="http://BioRender.com" target="_blank">BioRender.com</a>/i35k906 (accessed on 12 March 2024). Full article ">

38 pages, 6103 KiB

Open AccessReview

Blood–Brain Barrier Conquest in Glioblastoma Nanomedicine: Strategies, Clinical Advances, and Emerging Challenges

by Mengyun Duan, Ruina Cao, Yuan Yang, Xiaoguang Chen, Lian Liu, Boxu Ren, Lingzhi Wang and Boon-Cher Goh

Cancers 2024, 16(19), 3300; https://doi.org/10.3390/cancers16193300 - 27 Sep 2024

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Abstract

Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS) that is associated with a poor prognosis. The standard treatment for GBM includes the surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet, despite these interventions, overall [...] Read more.

Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS) that is associated with a poor prognosis. The standard treatment for GBM includes the surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet, despite these interventions, overall treatment outcomes remain suboptimal. The blood–brain barrier (BBB), which plays a crucial role in maintaining the stability of brain tissue under normal physiological conditions of the CNS, also poses a significant obstacle to the effective delivery of therapeutic agents to GBMs. Recent preclinical studies have demonstrated that nanomedicine delivery systems (NDDSs) offer promising results, demonstrating both effective GBM targeting and safety, thereby presenting a potential solution for targeted drug delivery. In this review, we first explore the various strategies employed in preclinical studies to overcome the BBB for drug delivery. Subsequently, the results of the clinical translation of NDDSs are summarized, highlighting the progress made. Finally, we discuss potential strategies for advancing the development of NDDSs and accelerating their translational research through well-designed clinical trials in GBM therapy. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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Timeline of important events in the history of GBM research and treatment. Full article ">Figure 2
Schematic diagram of the BBB structure and the mechanism of drug entry and exit from the BBB. (a) Schematic cross-section of the BBB. (b) Schematic diagram of different mechanisms for BBB crossing. From left to right is receptor-mediated transport; transporter-mediated transport; adsorptive-mediated transport; cell-mediated transport; the lipophilic pathway (passive diffusion); the paracellular aqueous pathway (passive diffusion); focused ultrasound (FUS) reversibly opens the BBB (passive diffusion); drugs reversibly open the BBB (passive diffusion); active efflux. Full article ">Figure 3
Receptor-mediated transport. RTP-targeting Tf-modified nanoparticles reverse refractory GBM and improve radiosensitivity. (A) Schematic of PEGylated agomir-loaded nanoparticles that can be functionalized to enhance transport across the BBB and target RTP cells. (B) Immunofluorescence staining demonstrating the time-dependent intracellular uptake of Tf-NPs in P2 cells. Scale bar: 10 μm. (C) Tf-NPs entering a GSC spheroid were monitored via 3D confocal laser microscopy. Scale bar: 20 μm. (D) P2 cells were treated with IR in the presence or absence of Tf-NPs, and γ-H2AX focal formation was investigated. Scale bar = 10 μm. (E) In vitro limiting dilution assay. (F,G) In vivo real-time NIR fluorescence imaging of P2 tumor-bearing mice after Tf-NP administration for indicated time periods. (H) Schematic diagram showing experimental time course and details of Tf-NP and IR treatment courses. (I) In vivo bioluminescence images of P2 tumor cells in orthotopic mice intravenously injected with Tf-NPs. (J) Statistical analysis of orthotopic tumor growth from P2 cells. (K) Quantification of tumor sizes. The data were obtained from H&E-stained brain sections of 8 mice per group. (L) Kaplan–Meier survival curves of mice intracranially injected with P2 cells (** p < 0.01, *** p < 0.001, n.s p > 0.05) [<a href="#B12-cancers-16-03300" class="html-bibr">12</a>]. Copyright 2022, Oxford University Press. Full article ">Figure 4
Transporter-mediated transport. (A–C) The 2-DG/aV-siCPT1C NC traverses the BBB via GLUT1 receptors to enter the CNS, thereby achieving starvation therapy for the GBM. (D–F) Biofluorescence imaging of U87-Luci glioma mice with different treatments, the quantification of glioma bioluminescence signals in each group, and the relative tumor fluorescence growth ratio for each treatment (n = 3, ** p < 0.01, *** p < 0.001, ns p > 0.05) [<a href="#B39-cancers-16-03300" class="html-bibr">39</a>]. Copyright 2023, American Chemical Society. Full article ">Figure 5
Adsorptive-mediated transport. (A–B) TAT-AT7 targeted glioma blood vessels in the intracranial glioma tissue of nude mice. Bars represent 200 μm. (C–H) TAT-AT7 inhibited the growth of gliomas in nude mice. Bars represent 100 μm (** p < 0.01, *** p < 0.001 vs. AT7 group; # p < 0.01, ## p < 0.01, ### p < 0.001 vs. TAT group; & p < 0.05, && p < 0.01, &&& p < 0.001 vs. TAT + AT7 group, % p < 0.05 vs. TAT + AT7 group) [<a href="#B65-cancers-16-03300" class="html-bibr">65</a>]. Copyright 2023, MDPI. Full article ">Figure 6
Cell-mediated transport. (A) Preparation of macrophage membrane-based biomimetic vehicles and mechanism of biomimetic MPM@P NGs crossing BBB to penetrate brain parenchyma for MR imaging-guided combination chemotherapy/chemodynamic orthotopic glioma therapy. (B) The targeted MR imaging of orthotopic glioma verified that macrophage membrane decoration facilitated the traversal of MPM@P NGs across the BBB. (C–E) Changes in tumor volume and body weight in C6 glioma-bearing mice after different treatments (* p < 0.05, ** p < 0.01, *** p < 0.001) [<a href="#B75-cancers-16-03300" class="html-bibr">75</a>]. Copyright 2021, American Chemical Society. Full article ">

19 pages, 562 KiB

Open AccessReview

CAR-T Cells in the Treatment of Nervous System Tumors

by Ugo Testa, Germana Castelli and Elvira Pelosi

Cancers 2024, 16(16), 2913; https://doi.org/10.3390/cancers16162913 - 22 Aug 2024

Viewed by 1406

Abstract

Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various [...] Read more.

Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various types of brain tumors due to several factors that have hampered their activity, including tumor antigen heterogeneity, the limited access of CAR-T cells to brain tumor cells, limited CAR-T cell trafficking and in vivo persistence and the presence of a highly immunosuppressive tumor microenvironment. Despite these considerations, some recent studies have shown promising antitumor activity of GD2-CAR-T cells on diffuse midline gliomas and neuroblastomas and of CARv3-TEAM-E cells in glioblastomas. However, strategies are required to improve the effect of CAR-T cells in brain tumors, including advanced CAR-T cell design with multiple antigenic targeting and incorporation of combination therapies. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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22 pages, 2714 KiB

Open AccessReview

Cholangiocarcinoma: The Current Status of Surgical Options including Liver Transplantation

by Abdullah Esmail, Mohamed Badheeb, Batool Alnahar, Bushray Almiqlash, Yara Sakr, Bayan Khasawneh, Ebtesam Al-Najjar, Hadeel Al-Rawi, Ala Abudayyeh, Yaser Rayyan and Maen Abdelrahim

Cancers 2024, 16(11), 1946; https://doi.org/10.3390/cancers16111946 - 21 May 2024

Cited by 5 | Viewed by 2255

Abstract

Cholangiocarcinoma (CCA) poses a substantial threat as it ranks as the second most prevalent primary liver tumor. The documented annual rise in intrahepatic CCA (iCCA) incidence in the United States is concerning, indicating its growing impact. Moreover, the five-year survival rate after tumor [...] Read more.

Cholangiocarcinoma (CCA) poses a substantial threat as it ranks as the second most prevalent primary liver tumor. The documented annual rise in intrahepatic CCA (iCCA) incidence in the United States is concerning, indicating its growing impact. Moreover, the five-year survival rate after tumor resection is only 25%, given that tumor recurrence is the leading cause of death in 53–79% of patients. Pre-operative assessments for iCCA focus on pinpointing tumor location, biliary tract involvement, vascular encasements, and metastasis detection. Numerous studies have revealed that portal vein embolization (PVE) is linked to enhanced survival rates, improved liver synthetic functions, and decreased overall mortality. The challenge in achieving clear resection margins contributes to the notable recurrence rate of iCCA, affecting approximately two-thirds of cases within one year, and results in a median survival of less than 12 months for recurrent cases. Nearly 50% of patients initially considered eligible for surgical resection in iCCA cases are ultimately deemed ineligible during surgical exploration. Therefore, staging laparoscopy has been proposed to reduce unnecessary laparotomy. Eligibility for orthotopic liver transplantation (OLT) requires certain criteria to be granted. OLT offers survival advantages for early-detected unresectable iCCA; it can be combined with other treatments, such as radiofrequency ablation and transarterial chemoembolization, in specific cases. We aim to comprehensively describe the surgical strategies available for treating CCA, including the preoperative measures and interventions, alongside the current options regarding liver resection and OLT. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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