Cancers

27 pages, 11245 KiB

Open AccessArticle

The Proapoptotic Action of Pyrrolidinedione–Thiazolidinone Hybrids towards Human Breast Carcinoma Cells Does Not Depend on Their Genotype

by Nataliya Finiuk, Yuliia Kozak, Agnieszka Gornowicz, Robert Czarnomysy, Marlena Tynecka, Serhii Holota, Marcin Moniuszko, Rostyslav Stoika, Roman Lesyk, Krzysztof Bielawski and Anna Bielawska

Cancers 2024, 16(16), 2924; https://doi.org/10.3390/cancers16162924 - 22 Aug 2024

Viewed by 1681

Abstract

The development of new, effective agents for the treatment of breast cancer remains a high-priority task in oncology. A strategy of treatment for this pathology depends significantly on the genotype and phenotype of human breast cancer cells. We aimed to investigate the antitumor [...] Read more.

The development of new, effective agents for the treatment of breast cancer remains a high-priority task in oncology. A strategy of treatment for this pathology depends significantly on the genotype and phenotype of human breast cancer cells. We aimed to investigate the antitumor activity of new pyrrolidinedione–thiazolidinone hybrid molecules Les-6287, Les-6294, and Les-6328 towards different types of human breast cancer cells of MDA-MB-231, MCF-7, T-47D, and HCC1954 lines and murine breast cancer 4T1 cells by using the MTT, clonogenic and [³H]-Thymidine incorporation assays, flow cytometry, ELISA, and qPCR. The studied hybrids possessed toxicity towards the mentioned tumor cells, with the IC₅₀ ranging from 1.37 to 21.85 µM. Simultaneously, these derivatives showed low toxicity towards the pseudonormal human breast epithelial cells of the MCF-10A line (IC₅₀ > 93.01 µM). Les-6287 at 1 µM fully inhibited the formation of colonies of the MCF-7, MDA-MB-231, and HCC1954 cells, while Les-6294 and Les-6328 did that at 2.5 and 5 µM, respectively. Les-6287 suppressed DNA biosynthesis in the MCF-7, MDA-MB-231, and HCC1954 cells. At the same time, such an effect on the MCF-10A cells was significantly lower. Les-6287 induces apoptosis using extrinsic and intrinsic pathways via a decrease in the mitochondrial membrane potential, increasing the activity of caspases 3/7, 8, 9, and 10 in all immunohistochemically different human breast cancer cells. Les-6287 decreased the concentration of the metastasis- and invasion-related proteins MMP-2, MMP-9, and ICAM-1. It did not induce autophagy in treated cells. In conclusion, the results of our study suggest that the synthesized hybrid pyrrolidinedione–thiazolidinones might be promising agents for treating breast tumors of different types. Full article

(This article belongs to the Section Cancer Drug Development)

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11 pages, 579 KiB

Open AccessArticle

Disparities in Overall Survival Rates for Cancers across Income Levels in the Republic of Korea

by Su-Min Jeong, Kyu-Won Jung, Juwon Park, Hyeon Ji Lee, Dong Wook Shin and Mina Suh

Cancers 2024, 16(16), 2923; https://doi.org/10.3390/cancers16162923 - 22 Aug 2024

Viewed by 1006

Abstract

Background: The overall survival rates among cancer patients have been improving. However, the increase in survival is not uniform across socioeconomic status. Thus, we investigated income disparities in the 5-year survival rate (5YSR) in cancer patients and the temporal trends. Methods: This study [...] Read more.

Background: The overall survival rates among cancer patients have been improving. However, the increase in survival is not uniform across socioeconomic status. Thus, we investigated income disparities in the 5-year survival rate (5YSR) in cancer patients and the temporal trends. Methods: This study used a national cancer cohort from 2002 to 2018 that was established by linking the Korea Central Cancer Registry and the National Health Insurance Service (NHIS) claim database to calculate the cancer survival rate by income level in the Republic of Korea. Survival data were available from 2002 onward, and the analysis was based on the actuarial method. We compared the survival of the earliest available 5-year period of 2002–2006 and the latest available 5-year period of 2014–2018, observing until 31 December 2021. Income level was classified into six categories: Medical Aid beneficiaries and five NHIS subtypes according to insurance premium. The slope index of inequality (SII) and relative index of inequality were used to measure absolute and relative differences in 5YSR by income, respectively. Results: The 5YSR between the 2002–2006 and 2014–2018 periods for all cancers improved. A significant improvement in 5-year survival rates (5YSR) over the study period was observed in lung, liver, and stomach cancer. The SII of survival rates for lung (17.5, 95% confidence interval (CI) 7.0–28.1), liver (15.1, 95% CI 10.9–19.2), stomach (13.9, 95% CI 3.2–24.7), colorectal (11.4, 95% CI 0.9–22.0), and prostate (10.7, 95% CI 2.5–18.8) cancer was significantly higher, implying higher survival rates as income levels increased. The SII for lung, liver, and stomach cancer increased, while that of thyroid, breast, cervical, prostate, and colorectal cancer decreased over the study period. Conclusions: Although substantial improvement in the 5YSR was observed across cancer types and income levels from 2002 to 2018, this increase was not uniformly distributed across income levels. Our study revealed persistent income disparities in the survival of cancer patients, particularly for lung and liver cancer. Full article

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

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10 pages, 395 KiB

Open AccessArticle

Pathological Features Associated with Lymph Node Disease in Patients with Appendiceal Neuroendocrine Tumors

by Salvador Rodriguez Franco, Sumaya Abdul Ghaffar, Ying Jin, Reed Weiss, Mona Hamermesh, Andrii Khomiak, Toshitaka Sugawara, Oskar Franklin, Alexis D. Leal, Christopher H. Lieu, Richard D. Schulick, Marco Del Chiaro, Steven Ahrendt, Martin D. McCarter and Ana L. Gleisner

Cancers 2024, 16(16), 2922; https://doi.org/10.3390/cancers16162922 - 22 Aug 2024

Viewed by 1155

Abstract

This study aimed to evaluate the role of pathological features beyond tumor size in the risk of lymph node metastasis in appendiceal neuroendocrine tumors. Analyzing data from the national cancer database, we found that among 5353 cases, 18.8% had lymph node metastasis. Focusing [...] Read more.

This study aimed to evaluate the role of pathological features beyond tumor size in the risk of lymph node metastasis in appendiceal neuroendocrine tumors. Analyzing data from the national cancer database, we found that among 5353 cases, 18.8% had lymph node metastasis. Focusing on tumors smaller than 2 cm, a subject of considerable debate in treatment strategies, we identified lymphovascular invasion as one of the strongest predictors of lymph node disease. Interestingly, extension into the subserosa and beyond, a current factor in the staging system, was not a strong predictor. These findings suggest that careful interpretation of pathological features is needed when selecting therapeutic approaches using current staging systems. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition)

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13 pages, 1614 KiB

Open AccessArticle

Clinical Implications of Circulating Tumor Cells in Patients with Esophageal Squamous Cell Carcinoma: Cancer-Draining Blood Versus Peripheral Blood

by Dong Chan Joo, Gwang Ha Kim, Hoseok I, Su Jin Park, Moon Won Lee and Bong Eun Lee

Cancers 2024, 16(16), 2921; https://doi.org/10.3390/cancers16162921 - 22 Aug 2024

Cited by 1 | Viewed by 1314

Abstract

Circulating tumor cells (CTCs) in cancer-draining veins have diagnostic and prognostic value. However, studies on esophageal squamous cell carcinoma (ESCC) are limited. This study aimed to compare CTCs obtained from different sampling sites (peripheral vein vs. cancer-draining azygos vein) and to investigate their [...] Read more.

Circulating tumor cells (CTCs) in cancer-draining veins have diagnostic and prognostic value. However, studies on esophageal squamous cell carcinoma (ESCC) are limited. This study aimed to compare CTCs obtained from different sampling sites (peripheral vein vs. cancer-draining azygos vein) and to investigate their association with the clinicopathological characteristics of ESCC patients. Blood samples were collected preoperatively from both veins in 40 ESCC patients at Pusan National University Hospital from June 2020 to April 2022. CTCs were detected using a centrifugal microfluidic method with fluid-assisted separation. CTCs and TWIST (+) CTCs were detected more frequently in the azygos vein blood than in the peripheral vein blood; however, the difference was not statistically significant (85.0% [34/40] vs. 77.5% [31/40], p = 0.250 and 82.5% [33/40] vs. 75.0% [30/40], p = 0.586, respectively). CTC and TWIST (+) CTC counts were significantly higher in the azygos vein blood than in the peripheral vein blood (7 vs. 3, p < 0.001, and 6 vs. 2, p < 0.001, respectively). CTCs and TWIST (+) CTCs from peripheral and azygos veins showed no association with clinicopathological characteristics. Further large-scale studies are needed to clarify their role as predictive biomarkers for prognosis and chemotherapy responses in ESCC patients. Full article

(This article belongs to the Section Clinical Research of Cancer)

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21 pages, 1110 KiB

Open AccessReview

Long Non-Coding RNAs, Nuclear Receptors and Their Cross-Talks in Cancer—Implications and Perspectives

by Prabha Tiwari and Lokesh P. Tripathi

Cancers 2024, 16(16), 2920; https://doi.org/10.3390/cancers16162920 - 22 Aug 2024

Viewed by 2098

Abstract

Long non-coding RNAs (lncRNAs) play key roles in various epigenetic and post-transcriptional events in the cell, thereby significantly influencing cellular processes including gene expression, development and diseases such as cancer. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that typically regulate [...] Read more.

Long non-coding RNAs (lncRNAs) play key roles in various epigenetic and post-transcriptional events in the cell, thereby significantly influencing cellular processes including gene expression, development and diseases such as cancer. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that typically regulate transcription of genes involved in a broad spectrum of cellular processes, immune responses and in many diseases including cancer. Owing to their many overlapping roles as modulators of gene expression, the paths traversed by lncRNA and NR-mediated signaling often cross each other; these lncRNA-NR cross-talks are being increasingly recognized as important players in many cellular processes and diseases such as cancer. Here, we review the individual roles of lncRNAs and NRs, especially growth factor modulated receptors such as androgen receptors (ARs), in various types of cancers and how the cross-talks between lncRNAs and NRs are involved in cancer progression and metastasis. We discuss the challenges involved in characterizing lncRNA-NR associations and how to overcome them. Furthering our understanding of the mechanisms of lncRNA-NR associations is crucial to realizing their potential as prognostic features, diagnostic biomarkers and therapeutic targets in cancer biology. Full article

(This article belongs to the Special Issue Disruption of Cell Signaling Pathways in Cancer: Prognostic and Treatment Perspectives)

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A representative interplay between growth factors, hormones and lncRNAs in cancer proliferation. The binding of the IGF-1 to IGF-1 receptor (IGF-1R) triggers the PI3K/AKT-mTOR and Jak pathways that contribute to increased expression of Erα-induced genes, thereby leading to accelerated breast cancer growth and proliferation. EGFR signaling can also trigger PI3k-AKT signaling, thereby contributing to the activation of Erα-responsive genes. LncRNA NR2F1-AS1 can also modulate IGF-1R activation by sponging miR-338-3p, a negative regulator of IGF-1. In prostate cancer, IGF-1R signaling activates AR signaling via the IGF-1R-FOXO1 (forkhead box protein O1) signaling axis. AR activation stimulates the expression of HIF1α-induced genes, which contribute to cancer proliferation. HIF1α-responsive genes may also be triggered by EGFR via the PI3K-AKT signaling axis. HOTAIR is an androgen-repressed lncRNA that is upregulated in castration-resistant prostate cancer (CRPC); HOTAIR associates with AR and drives its androgen-independent activation that subsequently leads to induction of AR-target genes in CRPC proliferation. Full article ">Figure 2
Mechanisms underlying cross-talks between lncRNAs and NRs. lncRNAs and NRs can mutually regulate each other through direct physical associations: (A) Transcriptional coactivation—PCGEM1 functions as a coactivator for AR and cMyc and promotes proliferation. (B) Decoy binding—GAS5 binds to the GR DBD as a GRE decoy and limits its binding to GREs in the target genes. LncRNAs and NRs may also mutually regulate or interact indirectly with each other in different ways. (C) Negative feed-forward circuitry—NXSTAR and AR mutually negatively impact transcription. (D) Feedback regulation—positive feedback loop BC200 stabilizes HNF4α mRNA. (E) Activation of signaling—PCAL7 stabilizes HIP1 and activates AR signaling. (F) Regulation of splicing—CRPC-linked lncRNAs associate with splicing factors such U2 to positively regulate AR expression. (G) Transcriptional activation and miRNA sequestration—Erα transcriptionally activates ERLC1; ERLC1 stabilizes ESR1 transcript by sequestrating miR-129. Red × means that because of the preceding event, the downstream process is stopped from proceeding further. Full article ">Figure 3
High-throughput omics technologies can provide heterogeneous lncRNA and biomolecular interaction data; these data can be assembled into an lncRNA-centric interactome that in conjunction with gene expression data may then be used to generate lncRNA-NR gene regulatory networks (GRNs), to hypothesize the mechanisms underlying lncRNA-NR interactions and their phenotypic outcomes. These outcomes can then be leveraged to rank and prioritize biologically and therapeutically relevant candidates for biomedical and drug-target discovery. Full article ">

18 pages, 1653 KiB

Open AccessReview

Overcoming Resistance to Checkpoint Inhibitors with Combination Strategies in the Treatment of Non-Small Cell Lung Cancer

by Amanda Reyes, Ramya Muddasani and Erminia Massarelli

Cancers 2024, 16(16), 2919; https://doi.org/10.3390/cancers16162919 - 22 Aug 2024

Cited by 3 | Viewed by 1581

Abstract

Lung cancer continues to contribute to the highest percentage of cancer-related deaths worldwide. Advancements in the treatment of non-small cell lung cancer like immune checkpoint inhibitors have dramatically improved survival and long-term disease response, even in curative and perioperative settings. Unfortunately, resistance develops [...] Read more.

Lung cancer continues to contribute to the highest percentage of cancer-related deaths worldwide. Advancements in the treatment of non-small cell lung cancer like immune checkpoint inhibitors have dramatically improved survival and long-term disease response, even in curative and perioperative settings. Unfortunately, resistance develops either as an initial response to treatment or more commonly as a progression after the initial response. Several modalities have been utilized to combat this. This review will focus on the various combination treatments with immune checkpoint inhibitors including the addition of chemotherapy, various immunotherapies, radiation, antibody–drug conjugates, bispecific antibodies, neoantigen vaccines, and tumor-infiltrating lymphocytes. We discuss the status of these agents when used in combination with immune checkpoint inhibitors with an emphasis on lung cancer. The early toxicity signals, tolerability, and feasibility of implementation are also reviewed. We conclude with a discussion of the next steps in treatment. Full article

(This article belongs to the Special Issue Combination Immunotherapy for Cancer Treatment)

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16 pages, 3408 KiB Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for Castration-Resistant Prostate Cancer" data-journal="cancers">

Open AccessArticle

TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for Castration-Resistant Prostate Cancer

by Damilola Olatunde and Arrigo De Benedetti

Cancers 2024, 16(16), 2918; https://doi.org/10.3390/cancers16162918 - 22 Aug 2024

Viewed by 1268

Abstract

Despite some advances in controlling the progression of prostate cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. [...] Read more.

Despite some advances in controlling the progression of prostate cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. A common mechanism is the ability to integrate AR signals from vanishing levels of testosterone, with the frequent participation of YAP as a co-activator, and pointing to the deregulation of the Hippo pathway as a major determinant. We have recently shown that YAP is post-transcriptionally activated via the TLK1>NEK1 axis by stabilizing phosphorylation at Y407. We are now solidifying this work by showing the following: (1) The phosphorylation of Y407 is critical for YAP retention/partition in the nuclei, and J54 (TLK1i) reverses this along with YAP-Y407 dephosphorylation. (2) The enhanced degradation of (cytoplasmic) YAP is increased by J54 counteracting its Enzalutamide-induced accumulation. (3) The basis for all these effects, including YAP nuclear retention, can be explained by the stronger association of pYAP-Y407 with its transcriptional co-activators, AR and TEAD1. (4) We demonstrate that ChIP for GFP-YAP-wt, but hardly for the GFP-YAP-Y407F mutant, at the promoters of typical ARE- and TEAD1-driven genes is readily detected but becomes displaced after treatment with J54. (5) While xenografts of LNCaP cells show rapid regression following treatment with ARSI+J54, in the VCaP model, driven by the TMPRSS2-ERG oncogenic translocation, tumors initially respond well to the combination but subsequently recur, despite the continuous suppression of pNek1-T141 and pYAP-Y407. This suggests an alternative parallel pathway for CRPC progression for VCaP tumors in the long term, which may be separate from the observed ENZ-driven YAP deregulation, although clearly some YAP gene targets like PD-L1, that are found to accumulate following prolonged ENZ treatment, are still suppressed by the concomitant addition of J54. Full article

(This article belongs to the Section Cancer Therapy)

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YAP-increased expression in LNCaP treated with ENZ is suppressed with J54. (A) LNCaP cells grown in 6-well plates were treated with ENZ+/−J54 (1 µM each) for indicated times. Cell lysates (20 µg) were processed for WB for YAP and mRNA expression (B). (C) VCaP cells grown in 6-well plates were treated with ENZ+/−J54 (1 µM each) for 4 h, and cell lysates were thereafter processed for WB. The uncropped bolts are shown in <a href="#app1-cancers-16-02918" class="html-app">Supplementary Materials</a>. Full article ">Figure 2
J54 elicits rapid GFP-YAP-Y407 dephosphorylation and nuclear export prior to cytoplasmic degradation—the default of an active Hippo pathway (LATS1-mediated pS396). Microscopic and WB depiction of the process and a graphical illustration. The uncropped bolts are shown in <a href="#app1-cancers-16-02918" class="html-app">Supplementary Materials</a>. Full article ">Figure 3
Cell fractionation reveals nuclear localization of GFP-YAP-wt, and it is predominantly cytoplasmic for the Y407F mutant. (A) shows the subcellular localization of GFP YAP when the cells were probed with anti-GFP while (B) depicts the localization of the pYAP Y407 in the respective cells. (C) Subcellular redistribution YAP and pYAP Y407 upon treatment with J54 (a TLKi). Actin was used as a marker for the cytoplasmic fraction and was absent in the nuclei. Orc2 was used as a marker for the nuclei and was not present in the cytoplasm even when the blot was overexposed to reveal some cross-reacting bands known to be detected with this SL-Bio antiserum (see <a href="#app1-cancers-16-02918" class="html-app">Supplementary Materials</a>). Full article ">Figure 4
Stronger association of GFP-YAP-wt with its transcriptional co-activators. (A) IPs were carried out with GFP antiserum, and WBs were probed for GFP, TEAD1, or AR. Inputs are also shown in the right panel. (B) A luciferase reporter assay showing the stronger association of the YAP-WT and its reversal with J54 treatment. (C) The Matrigel invasion assay reveals the invasive property of the respective cells and the effect of J54 treatment on YAP-WT’s invasive potential. (D) The immunoblot for MMPs ascertains the involvement of MMP9 and MMP10 for basement invasion. The uncropped bolts are shown in <a href="#app1-cancers-16-02918" class="html-app">Supplementary Materials</a>. * Significant as p > 0.01. Full article ">Figure 5
ChIP of GFP-YAP-wt vs. Y407F mutant at promoters of canonical CRE and ARE target genes reveals significantly different occupancy. PIS is pre-immune serum vs. GFP antiserum. GFP-YAP-WT increasingly occupied promoters of (A) FKBP5, (B) PSA, (C) SOX4, (D) SNX25, (E) CTGF, and (F) CYR61 genes compared to Y407F mutant. * Significant as p > 0.01. Full article ">Figure 6
Treatment of mice harboring VCaP subcutaneous flank tumors. (A,B) After inoculation of 106 cells in each flank of NOD-SCID mice, treatment started when the tumors reached 120 mm3, and resulted in a brief growth suppression with ENZ alone and was more sustained in combination with J54, but after ~2 months ((A)–end-point), most tumors relapsed and were processed for multi-panel WBs (C–E). Note that pNek1-T141 and pYAP-Y407 (C) were generally increased in animals treated with ENZ but suppressed when concomitantly treated with J54. Total YAP was slightly decreased with J54. The uncropped bolts are shown in <a href="#app1-cancers-16-02918" class="html-app">Supplementary Materials</a>. Full article ">Figure 6 Cont.
Treatment of mice harboring VCaP subcutaneous flank tumors. (A,B) After inoculation of 106 cells in each flank of NOD-SCID mice, treatment started when the tumors reached 120 mm3, and resulted in a brief growth suppression with ENZ alone and was more sustained in combination with J54, but after ~2 months ((A)–end-point), most tumors relapsed and were processed for multi-panel WBs (C–E). Note that pNek1-T141 and pYAP-Y407 (C) were generally increased in animals treated with ENZ but suppressed when concomitantly treated with J54. Total YAP was slightly decreased with J54. The uncropped bolts are shown in <a href="#app1-cancers-16-02918" class="html-app">Supplementary Materials</a>. Full article ">

20 pages, 10479 KiB

Open AccessArticle

Discrepancies between the Spatial Distribution of Cancer Incidence and Mortality as an Indicator of Unmet Needs in Cancer Prevention and/or Treatment in Hungary

by Róza Ádány, Attila Juhász, Csilla Nagy, Bernadett Burkali, Péter Pikó, Martin McKee and Beatrix Oroszi

Cancers 2024, 16(16), 2917; https://doi.org/10.3390/cancers16162917 - 22 Aug 2024

Cited by 1 | Viewed by 1108 | Correction

Abstract

There is a rich body of literature on the distribution of cancer incidence and mortality in socioeconomically different world regions, but none of the studies has compared the spatial distribution of mortality and incidence to see if they are consistent with each other. [...] Read more.

There is a rich body of literature on the distribution of cancer incidence and mortality in socioeconomically different world regions, but none of the studies has compared the spatial distribution of mortality and incidence to see if they are consistent with each other. All malignant neoplasms combined and cervical, colorectal, breast, pancreatic, lung, and oral cancers separately were studied in the Hungarian population aged 25–64 years for 2007–2018 at the municipality level by sex. In each case, the spatial distribution of incidence and mortality were compared with each other and with the level of deprivation using disease mapping, spatial regression, risk analysis, and spatial scan statistics. A positive association between deprivation and mortality was found for each type of cancer, but there was no significant association for male colorectal cancer (relative risk (RR) 1.00; 95% credible interval (CI) 0.99–1.02), pancreatic cancer (RR: 1.01; 95%CI 0.98–1.04), and female colorectal cancer incidence (RR: 1.01; 95%CI 0.99–1.03), whereas a negative association for breast cancer (RR: 0.98; 95%CI 0.96–0.99) was found. Disease mapping analyses showed only partial overlap between areas of high incidence and mortality, often independent of deprivation. Our results highlight not only the diverse relationship between cancer burden and deprivation, but also the inconsistent relationship between cancer incidence and mortality, pointing to areas with populations that require special public health attention. Full article

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

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11 pages, 235 KiB

Open AccessArticle

Association of Functional Polymorphisms in MSH3 and IL-6 Pathway Genes with Different Types of Microsatellite Instability in Sporadic Colorectal Cancer

by Anamarija Salar, Kristina Vuković Đerfi, Arijana Pačić, Anita Škrtić, Tamara Cacev and Sanja Kapitanović

Cancers 2024, 16(16), 2916; https://doi.org/10.3390/cancers16162916 - 22 Aug 2024

Viewed by 1011

Abstract

Microsatellite instability (MSI) has been recognized as an important factor in colorectal cancer (CRC). It arises due to deficient mismatch repair (MMR), mostly attributed to MLH1 and MSH2 loss of function leading to a global MMR defect affecting mononucleotide and longer microsatellite loci. [...] Read more.

Microsatellite instability (MSI) has been recognized as an important factor in colorectal cancer (CRC). It arises due to deficient mismatch repair (MMR), mostly attributed to MLH1 and MSH2 loss of function leading to a global MMR defect affecting mononucleotide and longer microsatellite loci. Recently, microsatellite instability at tetranucleotide loci, independent of the global MMR defect context, has been suggested to represent a distinct entity with possibly different consequences for tumorigenesis. It arises as a result of an isolated MSH3 loss of function due to its translocation from the nucleus to the cytoplasm under the influence of interleukin-6 (IL-6). In this study the influence of MSH3 and IL-6 signaling pathway polymorphisms (MSH3 exon 1, MSH3+3133A/G, IL-6-174G/C, IL-6R+48892A/C, and gp130+148G/C) on the occurrence of different types of microsatellite instability in sporadic CRC was examined by PCR–RFLP and real-time PCR SNP analyses. A significant difference in distribution of gp130+148G/C genotypes (p = 0.037) and alleles (p = 0.031) was observed in CRC patients with the C allele being less common in tumors with di- and tetranucleotide instability (isolated MSH3 loss of function) compared to tumors without microsatellite instability. A functional polymorphism in gp130 might modulate the IL-6 signaling pathway, directing it toward the occurrence of microsatellite instability corresponding to the IL-6-mediated MSH3 loss of function. Full article

(This article belongs to the Special Issue Advancing Horizons in Colorectal Surgery: Innovative Approaches and Outcomes)

12 pages, 890 KiB

Open AccessReview

Comparative Analysis of AML Classification Systems: Evaluating the WHO, ICC, and ELN Frameworks and Their Distinctions

by Huda Salman

Cancers 2024, 16(16), 2915; https://doi.org/10.3390/cancers16162915 - 22 Aug 2024

Viewed by 1725

Abstract

Comprehensive analyses of the molecular heterogeneity of acute myelogenous leukemia, AML, particularly when malignant cells retain normal karyotype, has significantly evolved. In 2022, significant revisions were introduced in the World Health Organization (WHO) classification and the European LeukemiaNet (ELN) 2022 guidelines of acute [...] Read more.

Comprehensive analyses of the molecular heterogeneity of acute myelogenous leukemia, AML, particularly when malignant cells retain normal karyotype, has significantly evolved. In 2022, significant revisions were introduced in the World Health Organization (WHO) classification and the European LeukemiaNet (ELN) 2022 guidelines of acute myeloid leukemia (AML). These revisions coincided with the inception of the first version of the International Consensus Classification (ICC) for AML. These modifications aim to improve diagnosis and treatment outcomes via a comprehensive incorporation of sophisticated genetic and clinical parameters as well as facilitate accruals to innovative clinical trials. Key updates include modifications to the blast count criteria for AML diagnosis, with WHO 2022 eliminating the ≥20% blast requirement in the presence of AML-defining abnormalities and ICC 2022 setting a 10% cutoff for recurrent genetic abnormalities. Additionally, new categories, such as AML with mutated TP53 and MDS/AML, were introduced. ELN 2022 guidelines retained risk stratification approach and emphasized the critical role of measurable residual disease (MRD) that increased the use of next-generation sequencing (NGS) and flow cytometry testing. These revisions underscore the importance of precise classification for targeted treatment strategies and improved patient outcomes. How much difference versus concordance these classifications present and the impact of those on clinical practice is a continuing discussion. Full article

(This article belongs to the Collection Acute Myeloid Leukemia (AML))

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24 pages, 5267 KiB

Open AccessArticle

Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma

by Andrew Goetz, Frances Shanahan, Logan Brooks, Eva Lin, Rana Mroue, Darlene Dela Cruz, Thomas Hunsaker, Bartosz Czech, Purushottam Dixit, Udi Segal, Scott Martin, Scott A. Foster and Luca Gerosa

Cancers 2024, 16(16), 2914; https://doi.org/10.3390/cancers16162914 - 22 Aug 2024

Viewed by 1644

Abstract

Purpose: This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug [...] Read more.

Purpose: This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. Results: In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose–response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Conclusion: Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations. Full article

(This article belongs to the Special Issue Adaptive Resistance to Targeted Cancer Therapies and Rational Development of Combination Therapies)

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Drug screen revealing the additivity of combined pan-RAF and MEK inhibition in BRAF mutant melanoma but synergy in NRAS mutant melanoma cell lines. (a) Single-agent drug screen on 43 melanoma cell lines including those with BRAF and NRAS mutations. Drug effectiveness quantified via IC50 values. (b) Combination drug screen on the same 43 melanoma cell lines. Drug combination synergies quantified via Bliss scores. (c) Measured in vitro effects of Cobimetinib and Belvarafenib combinations on the relative viability of select cell lines with drug synergies quantified by Bliss excess. Full article ">Figure 2
Computational modeling and molecular experiments implicate a negative feedback loop in the response of NRAS vs. BRAF mutant melanomas to panRAF and MEK inhibitors. (a,b) Schematic of the MAPK pathway in (a) NRAS Q61 and (b) BRAF V600E melanomas. (c,d) Quantification of pMEK, total MEK, pERK, and total ERK protein levels obtained via Western blotting under the indicated combinations of Cobimetinib and Belvarafenib in (c) MEL-JUSO and (d) A-375 cells. %pMEK and %pERK were calculated from pMEK and pERK DMSO-normalized band intensities divided by DMSO-normalized total MEK and ERK, respectively. (e) Model predictions for steady-state percentages of active RAF, pMEK, and pERK under indicated concentrations of Belvarafenib and Cobimetinib. Results are shown for both BRAF V600E and NRAS Q61 models. Full article ">Figure 3
Mechanistic modeling of MAPK signaling quantitatively predicts responses to panRAF and MEK inhibitors in NRAS and BRAF mutant melanoma cell lines. (a,b) Model predictions for pMEK and pERK steady-state levels under indicated concentrations of Belvarafenib and Cobimetinib. Reported values are given relative to drugless conditions. Drug synergy analysis is quantified via Bliss excess. Values are shown for both (a) BRAF V600E and (b) NRAS Q61 model predictions. (c) Model prediction (top) and immunofluorescence data (bottom) for pERK levels in response to Cobimetinib and Belvarafenib combinations. Values provided for BRAF V600E model and cell line, A-375 (left), and NRAS Q61 model and cell line, IPC-298 (right). Full article ">Figure 4
Prediction of in vivo xenograft tumor volume control by panRAF and MEK inhibition achieved using in vitro cell line response and in vivo exposures. (a) Conversion of relative viability to GR metric for IPC-298 in vitro drug responses and projection of mouse PK data onto in vitro responses to obtain predicted tumor growth rates. (b) Comparison between predicted tumor growth rates and experimentally measured tumor growth rates. Part of the tumor volume experiments re-analyzed here were previously published in [<a href="#B25-cancers-16-02914" class="html-bibr">25</a>]. Full article ">Figure 5
Leveraging synergy in NRAS mutant melanoma at equivalent clinical doses requires at least intermediate MEK inhibition, thus allowing lower Belvarafenib doses. (a) Workflow for mapping in vivo free drug concentrations onto in vitro drug responses to predict cell responses and drug synergies at clinically equivalent concentrations. (b) Predicted viability of cell panels and drug synergies at clinically equivalent drug concentrations. Full article ">Figure 6
Pharmacokinetic variability in patients limits the ability to precisely obtain synergistic responses in NRAS mutant melanoma tumors. (a) Individual virtual patient PK trajectories resulting from the indicated drug regimen projected onto in vitro responses. (b) The distribution of GR metric values (left) and Bliss excess values (right) measured from 75 single patient trajectories. Multiple drug regimens are compared; rows and columns indicate the Cobimetinib and Belvarafenib doses used in the specific drug regimen. Full article ">Figure 7
Tumor growth inhibition in patients simulated using a model trained on Phase 1 clinical trials support the additive vs. synergistic dose landscape of BRAF vs. NRAS mutant melanoma patients for panRAF and MEK co-inhibition (a) Simulated tumor growth under indicated Belvarafenib and Cobimetinib regimens for BRAF and NRAS mutant melanoma patients. Belva mono is 400/450 mg BID. (b) Distribution of tumor growth rates for indicated drug regimen within simulated populations of patients with BRAF V600E (top) or NRAS Q61 (bottom) tumors. 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 1483

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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13 pages, 1137 KiB

Open AccessReview

Exploring the Horizon: Anti-Fibroblast Growth Factor Receptor Therapy in Pancreatic Cancer with Aberrant Fibroblast Growth Factor Receptor Expression—A Scoping Review

by Elena Orlandi, Massimo Guasconi, Stefano Vecchia, Serena Trubini, Mario Giuffrida, Manuela Proietto, Elisa Anselmi, Patrizio Capelli and Andrea Romboli

Cancers 2024, 16(16), 2912; https://doi.org/10.3390/cancers16162912 - 22 Aug 2024

Viewed by 1116

Abstract

Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and [...] Read more.

Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and clinical studies on FGFR (Fibroblast Growth Factor Receptor) inhibitors, including tyrosine kinase inhibitors (TKIs) and FGFR-specific inhibitors, in pancreatic cancer with FGFR alterations. We included studies analyzing efficacy, safety, and survival outcomes in various populations. A comprehensive search across major databases identified 73 relevant studies: 32 preclinical, 16 clinical, and 25 from gray literature. The clinical trials focused primarily on efficacy (20 studies) and safety (14 studies), with fewer studies addressing survival outcomes. FGFR1 was the most studied alteration, followed by FGFR2 and FGFR4. Although FGFR alterations are relatively rare in pancreatic cancer, the available data, including promising real-life outcomes, suggest significant potential for FGFR inhibitors. However, more extensive research is needed to identify the correct genetic drivers and gather robust survival data. Ongoing and future trials are expected to provide more comprehensive insights, potentially leading to improved targeted therapies for pancreatic cancer patients with FGFR alterations. Full article

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

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11 pages, 697 KiB

Open AccessArticle

Neutrophil-to-Lymphocyte Ratio and Prognostic Nutritional Index Are Predictors for Overall Survival after Primary Pancreatic Resection of Pancreatic Ductal Adenocarcinoma: A Single Centre Evaluation

by Danilo Hackner, Susanne Merkel, Andreas Weiß, Christian Krautz, Georg F. Weber, Robert Grützmann and Maximilian Brunner

Cancers 2024, 16(16), 2911; https://doi.org/10.3390/cancers16162911 - 22 Aug 2024

Viewed by 867

Abstract

Purpose: Prognostic inflammation-based parameters have been reported as useful tools in various oncologic diseases. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high mortality rate, making reliable prognostic markers highly desirable. However, there is still inconsistency in the literature regarding the efficacy of [...] Read more.

Purpose: Prognostic inflammation-based parameters have been reported as useful tools in various oncologic diseases. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high mortality rate, making reliable prognostic markers highly desirable. However, there is still inconsistency in the literature regarding the efficacy of the different available scores. Methods: A total of 207 patients, who underwent primary resection of PDAC from January 2000 to December 2018 at the University Hospital of Erlangen, were included in this retrospective single-center study. Different biomarkers, including the preoperative neutrophil–lymphocyte ratio (NLR), the platelet–lymphocyte ratio (PLR), the c-reactive protein (CRP)–albumin ratio (CAR), the lymphocyte–CRP ratio (LCR), the prognostic nutritional index (PNI) and the modified Glasgow prognostic score (mGPS) were analyzed for their ability to predict overall survival (OS). Results: In our cohort, the median overall survival was 20.7 months. Among the investigated biomarkers, NLR and PNI were identified as independent prognostic markers (Hazard Ratio (HR) 1.6 (1.0–2.5), p = 0.048 and HR 0.6 (0.4–0.9), p = 0.018), whereas PLR, CAR, LCR and mGPS did not reach significance in the multivariate analysis. Subgroup analysis revealed that the prognostic value of NLR and PNI is particularly evident in locally advanced tumor stages (pT3/4 and pN+). Conclusions: The NLR and PNI could serve as valuable tools for estimating prognosis in patients with PDAC undergoing pancreatic resection in curative intention, especially in locally advanced tumor stages. However, conflicting results in the current literature highlight the need for further prospective studies to validate these findings. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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16 pages, 2819 KiB

Open AccessArticle

Paracrine Activation of STAT3 Drives GM-CSF Expression in Breast Carcinoma Cells, Generating a Symbiotic Signaling Network with Breast Carcinoma-Associated Fibroblasts

by Kingsley O. Osuala, Anita Chalasani, Neha Aggarwal, Kyungmin Ji and Kamiar Moin

Cancers 2024, 16(16), 2910; https://doi.org/10.3390/cancers16162910 - 22 Aug 2024

Cited by 1 | Viewed by 1077

Abstract

This study evaluated the paracrine signaling between breast carcinoma-associated fibroblasts (CAFs) and breast cancer (BCa) cells. Resolving cell–cell communication in the BCa tumor microenvironment (TME) will aid the development of new therapeutics. Here, we utilized our patented TAME (tissue architecture and microenvironment engineering) [...] Read more.

This study evaluated the paracrine signaling between breast carcinoma-associated fibroblasts (CAFs) and breast cancer (BCa) cells. Resolving cell–cell communication in the BCa tumor microenvironment (TME) will aid the development of new therapeutics. Here, we utilized our patented TAME (tissue architecture and microenvironment engineering) 3D culture microphysiological system, which is a suitable pathomimetic avatar for the study of the BCa TME. We cultured in 3D BCa cells and CAFs either alone or together in cocultures and found that when cocultured, CAFs enhanced the invasive characteristics of tumor cells, as shown by increased proliferation and spread of tumor cells into the surrounding matrix. Secretome analysis from 3D cultures revealed a relatively high secretion of IL-6 by CAFs. A marked increase in the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) when carcinoma cells and CAFs were in coculture was also observed. We theorized that the CAF-secreted IL-6 functions in a paracrine manner to induce GM-CSF expression and secretion from carcinoma cells. This was confirmed by evaluating the activation of STAT3 and gene expression of GM-CSF in carcinoma cells exposed to CAF-conditioned media (CAF-CM). In addition, the treatment of CAFs with BCa cell-CM yielded a brief upregulation of GM-CSF followed by a marked decrease, indicating a tightly regulated control of GM-CSF in CAFs. Secretion of IL-6 from CAFs drives the activation of STAT3 in BCa cells, which in turn drives the expression and secretion of GM-CSF. As a result, CAFs exposed to BCa cell-secreted GM-CSF upregulate inflammation-associated genes such as IL-6, IL-6R and IL-8, thereby forming a positive feedback loop. We propose that the tight regulation of GM-CSF in CAFs may be a novel regulatory pathway to target for disrupting the CAF:BCa cell symbiotic relationship. These data provide yet another piece of the cell–cell communication network governing the BCa TME. Full article

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

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Coculture of MCF10.DCIS BCa cells and CAF40TKi CAFs resulted in BCa cell proliferation and increased tumor volume. Cells were grown for a period of 8 days in TAME 3D culture in the absence or presence of CAFs. (A) Image of 16 contiguous DIC fields of MCF10.DCIS cells alone or (C) in coculture with CAFs. Note in the high-magnification panels (B,D) the absence and consequent appearance of protrusions extending from multicellular structures (red arrows). (E) Quantification shows contrast in the volume of MCF10.DCIS BCa structures ± CAFs (p-value = 0.15, n = 3). Graphical data are expressed as mean ± standard deviation using Student’s t-test. Scale bars, (A) 100 microns, (B) 50 microns, (C) 250 microns, and (D) 100 microns. Full article ">Figure 2
Coculture of HCC70 BCa cells and CAF40TKi CAFs resulted in BCa cell proliferation and increased tumor volume. HCC70 cells were grown for a period of 8 days in TAME 3D culture in the absence or presence of CAFs. (A) Image of 16 contiguous DIC fields of HCC70 cells alone or (C) in coculture with CAFs. Note in the high-magnification panels (B,D) the absence and consequent appearance of protrusions extending from multicellular structures (red arrows). (E) Quantitative comparison shows contrast in the volume of HCC70 BCa structures ± CAFs (p-value = 0.13, n = 3). Graphical data are expressed as mean ± standard deviation using Student’s t-test. Scale bars: (A,C) 250 microns; (B,D) 100 microns. Full article ">Figure 3
Coculture of MCF10.DCIS cells with CAFs led to an increase in GM-CSF secretion. Scan of inflammation array membrane shows spot intensities of detected cytokines and growth factors. (A) MCF10.DCIS cells grown alone in 3D. IL-6, GM-CSF, and IL-8 are boxed and labeled. Positive control double-boxed next to negative controls. (B) CAFs grown alone in 3D (IL-6 and GM-CSF boxed). (C) 3D coculture of MCF10.DCIS cells and CAFs (IL-6 and GM-CSF boxed). Note the marked induction of GM-CSF in cocultures (C), as compared to monocultures (A) or (B). Spot densitometry quantification of inflammation arrays for the three culture conditions are shown for IL-8 (D), IL-6 (E) and GM-CSF (F). Graphical data are expressed as mean ± standard deviation (n = 2). Full article ">Figure 4
Incubation of BCa cells with CAF-CM resulted in BCa cell proliferation and increased tumor structure volume. MCF10.DCIS cells were grown for a period of 8 days in TAME 3D culture in the absence or presence of CAF-CM. (A) Image of 16 contiguous DIC fields of MCF10.DCIS cells in control media or (C) in CAF-CM. Note in the high-magnification panels (B,D) the absence and consequent appearance of protrusions extending from multicellular structures (red arrows). (E) Quantification of spheroidal structure area shows a significant increase in BCa treated with CAF-CM. Graphical data are expressed as mean ± standard deviation (n = 10). Scale bars: (A,C) 250 microns; (B,D) 100 microns. Full article ">Figure 5
CAF-CM-driven GM-CSF expression in cancer cells is mediated by STAT3 activation. (A) Immunoblot analysis of lysates from MCF10.DCIS and (B) HCC70 cells grown in 2D culture and treated with CAF-CM ± STAT3 inhibitors (niclosamide or stattic). An 8-day 3D culture of MCF10.DCIS cells (C) or HCC70 cells (D) followed by 24 h exposure to CAF-CM 30 μM static. (E,F) CAF-CM induced the upregulation of GM-CSF in carcinoma cells, which was inhibited by the presence of stattic. The inhibition was statistically significant in the MCF10.DCIS cultures (** p-value = 0.01, n = 3), but not in HCC70 cultures. Data are expressed as mean ± standard deviation of gene expression fold change using Student’s t-test. Full article ">Figure 6
Schematic diagram of pro-tumorigenic paracrine signaling between cancer cells and CAFs. Paracrine cytokines induce STAT3 phosphorylation in cancer cells driving expression of inflammation genes including IL-6, IL-8 and GM-CSF. Cancer cell-secreted GM-CSF in turn supports fibroblast survival and drives the expression of inflammation-associated cytokines by fibroblasts. Expression and secretion of IL-6, IL-6R, IL-8, and CXCL3 from fibroblasts contributes to paracrine signaling between cancer and non-cancer cells. Full article ">

22 pages, 12351 KiB

Open AccessArticle

The Efficacy of Cannabis in Oncology Patient Care and Its Anti-Tumor Effects

by Walid Shalata, Omar Abu Saleh, Lena Tourkey, Sondos Shalata, Ala Eddin Neime, Ali Abu Juma’a, Arina Soklakova, Lama Tourkey, Ashraf Abu Jama and Alexander Yakobson

Cancers 2024, 16(16), 2909; https://doi.org/10.3390/cancers16162909 - 21 Aug 2024

Cited by 1 | Viewed by 2260

Abstract

As the legalization of medical cannabis expands across several countries, interest in its potential advantages among cancer patients and caregivers is burgeoning. However, patients seeking to integrate cannabis into their treatment often encounter frustration when their oncologists lack adequate information to offer guidance. [...] Read more.

As the legalization of medical cannabis expands across several countries, interest in its potential advantages among cancer patients and caregivers is burgeoning. However, patients seeking to integrate cannabis into their treatment often encounter frustration when their oncologists lack adequate information to offer guidance. This knowledge gap is exacerbated by the scarcity of published literature on the benefits of medical cannabis, leaving oncologists reliant on evidence-based data disheartened. This comprehensive narrative article, tailored for both clinicians and patients, endeavors to bridge these informational voids. It synthesizes cannabis history, pharmacology, and physiology and focuses on addressing various symptoms prevalent in cancer care, including insomnia, nausea and vomiting, appetite issues, pain management, and potential anti-cancer effects. Furthermore, by delving into the potential mechanisms of action and exploring their relevance in cancer treatment, this article aims to shed light on the potential benefits and effects of cannabis in oncology. Full article

(This article belongs to the Special Issue Integrating Palliative Care in Oncology)

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21 pages, 1614 KiB

Open AccessReview

WFUMB Review Paper. Incidental Findings in Otherwise Healthy Subjects, How to Manage: Liver

by Roxana Șirli, Alina Popescu, Christian Jenssen, Kathleen Möller, Adrian Lim, Yi Dong, Ioan Sporea, Dieter Nürnberg, Marieke Petry and Christoph F. Dietrich

Cancers 2024, 16(16), 2908; https://doi.org/10.3390/cancers16162908 - 21 Aug 2024

Viewed by 852

Abstract

An incidental focal liver lesion (IFLL) is defined as a hepatic lesion identified in a patient imaged for an unrelated reason. They are frequently encountered in daily practice, sometimes leading to unnecessary, invasive and potentially harmful follow-up investigations. The clinical presentation and the [...] Read more.

An incidental focal liver lesion (IFLL) is defined as a hepatic lesion identified in a patient imaged for an unrelated reason. They are frequently encountered in daily practice, sometimes leading to unnecessary, invasive and potentially harmful follow-up investigations. The clinical presentation and the imaging aspects play an important role in deciding if, and what further evaluation, is needed. In low-risk patients (i.e., without a history of malignant or chronic liver disease or related symptoms), especially in those younger than 40 years old, more than 95% of IFLLs are likely benign. Shear Wave liver Elastography (SWE) of the surrounding liver parenchyma should be considered to exclude liver cirrhosis and for further risk stratification. If an IFLL in a low-risk patient has a typical appearance on B-mode ultrasound of a benign lesion (e.g., simple cyst, calcification, focal fatty change, typical hemangioma), no further imaging is needed. Contrast-Enhanced Ultrasound (CEUS) should be considered as the first-line contrast imaging modality to differentiate benign from malignant IFLLs, since it has a similar accuracy to contrast-enhanced (CE)-MRI. On CEUS, hypoenhancement of a lesion in the late vascular phase is characteristic for malignancy. CE-CT should be avoided for characterizing probable benign FLL and reserved for staging once a lesion is proven malignant. In high-risk patients (i.e., with chronic liver disease or an oncological history), each IFLL should initially be considered as potentially malignant, and every effort should be made to confirm or exclude malignancy. US-guided biopsy should be considered in those with unresectable malignant lesions, particularly if the diagnosis remains unclear, or when a specific tissue diagnosis is needed. Full article

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

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A 35-year-old male presents for consultation for nausea and diarrhea with acute onset. Ultrasound revealed a large, anechoic lesion (between markers x and +) with thin, irregular walls, situated in segment 4–5—typical aspect of simple biliary cyst. Full article ">Figure 2
A 40-year-old female presents for consultation for right renal colic. Ultrasound revealed 2 cystic lesions (between markers x, and <) with thick walls and septa, situated in the right liver lobe. Anti Echinococcus granulosis antibodies positive. Typical aspect of hydatid cyst. Full article ">Figure 3
A 43 year-old obese female (BMI 32 kg/m2) presents for consultation for routine US examination. Ultrasound revealed a large hypoechoic area in segments VII, VIII with clear linear delineation from the rest of the liver. Just anterior to the portal vein (PV) another hypoechoic clearly delineated lesion (between markers +). Liver function tests normal, elevated triglycerides and glycemia, normal values of liver stiffness by 2D-SWE elastography. Typical aspect of focal fatty sparing. Full article ">Figure 4
A 32-year-old male presents for consultation for occasional epigastric pain. Ultrasound revealed a hyperechoic, homogeneous, well delineated lesion (between markers +) 23 mm in diameter, situated in segment V—aspect of typical hemangioma. Full article ">Figure 5
Several echogenic FLL with a hypoechoic peripheral rim “halo sign” (between arrows)—typical for metastases, in a 68-year-old patient with a history of colonic cancer. Full article ">

16 pages, 4605 KiB

Open AccessArticle

Molecular Profiling of KIT/PDGFRA-Mutant and Wild-Type Gastrointestinal Stromal Tumors (GISTs) with Clinicopathological Correlation: An 18-Year Experience at a Tertiary Center in Kuwait

by Rola H. Ali, Ahmad R. Alsaber, Asit K. Mohanty, Abdulsalam Alnajjar, Eiman M. A. Mohammed, Mona Alateeqi, Hiba Jama, Ammar Almarzooq, Noelle Benobaid, Zainab Alqallaf, Amir A. Ahmed, Shakir Bahzad and Mohammad Alkandari

Cancers 2024, 16(16), 2907; https://doi.org/10.3390/cancers16162907 - 21 Aug 2024

Viewed by 1040

Abstract

In gastrointestinal stromal tumors (GISTs), identifying prototypical mutations in the KIT/PDGFRA oncogenes, or in rare alternate genes, is essential for prognostication and predicting response to tyrosine kinase inhibitors. Conversely, wild-type GISTs (WT-GIST), which lack known mutations, have limited treatment options. Data on the [...] Read more.

In gastrointestinal stromal tumors (GISTs), identifying prototypical mutations in the KIT/PDGFRA oncogenes, or in rare alternate genes, is essential for prognostication and predicting response to tyrosine kinase inhibitors. Conversely, wild-type GISTs (WT-GIST), which lack known mutations, have limited treatment options. Data on the mutational landscape of GISTs and their impact on disease progression are very limited in Kuwait. Using a targeted next-generation sequencing panel, we investigated the spectrum and frequency of KIT, PDGFRA, and RAS-pathway-related mutations in 95 out of 200 GISTs diagnosed at Kuwait Cancer Center from 2005 to 2023 and assessed their correlation with clinicopathological parameters. Among the 200 tumors (median age 55 years; 15–91), 54% originated in the stomach, 33% in the small bowel, 7% in the colorectum, 1.5% in the peritoneum, and 4.5% had an unknown primary site. Of the 95 molecularly profiled cases, 88% had a mutation: KIT (61%), PDGFRA (25%), NF1 (2%), and one NTRK1 rearrangement. Ten WT-GISTs were identified (stomach = 6, small bowel = 2, and colorectum = 2). WT-GISTs tended to be smaller (median 4.0 cm; 0.5–8.0) (p = 0.018), with mitosis ≤5/5 mm², and were of lower risk (p = 0.019). KIT mutations were an adverse indicator of disease progression (p = 0.049), while wild-type status did not significantly impact progression (p = 0.934). The genetic landscape in this cohort mirrors that of global studies, but regional collaborations are needed to correlate outcomes with genetic variants. Full article

(This article belongs to the Section Cancer Pathophysiology)

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Frequencies of KIT and PDGFRA mutations (n = 95). KIT exon 11 mutations are heterogeneous, with W557_K558del being the most common. PDGFRA exon 18 and KIT exon 9 show a predominance of one variant each: D842V and A502_Y503dup, respectively. TK1 = Tyrosine kinase domain 1; TK2 = Tyrosine kinase domain 2. Full article ">Figure 2
Genomic and amino-acid sequences of KIT exon 11 mutations. (A) Codon positions. (B) Frequency of codons involved in mutation. * KIT 4q12 locus. Full article ">Figure 3
Distribution of molecular alterations based on gastrointestinal locations (n = 95). * NTRK-fused spindle cell neoplasms are currently classified as a separate entity. Full article ">Figure 4
Graphical summary of molecular and clinicopathological findings (n = 95), with each row representing an individual patient. * Metastatic at diagnosis; ** Tyrosine kinase inhibitors, in adjuvant and/or metastatic setting; *** PDGFRA-specific TKIs not available; PFS = progression-free survival; IHC = immunohistochemistry; NA = not available. Full article ">Figure 5
Histopathology of KIT/PDGFRA wild-type GISTs with corresponding KIT immunostaining. (A,D) NF1-mutant in the duodenum with spindle cell morphology and diffuse KIT expression in a known neurofibromatosis type 1 patient. (B,E) KIT/PDGFRA/RAS wild-type in the colon with spindle cell morphology and diffuse KIT expression. (C,F) KIT/PDGFRA/RAS wild-type in the stomach with epithelioid morphology and faint KIT expression. All are at 20× magnification. Full article ">

28 pages, 7926 KiB

Open AccessArticle

Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells

by Christy Zheng, Kaelyn O. Allen, Tianrui Liu, Natalia M. Solodin, Mark B. Meyer, Kelley Salem, Phillipos K. Tsourkas, Sean J. McIlwain, Jessica M. Vera, Erika R. Cromwell, Mary Szatkowski Ozers, Amy M. Fowler and Elaine T. Alarid

Cancers 2024, 16(16), 2906; https://doi.org/10.3390/cancers16162906 - 21 Aug 2024

Viewed by 1392

Abstract

Estrogen receptor (ER)-positive breast cancer is characterized by late recurrences following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is overexpressed in ER-positive breast cancers and is linked to poorer prognosis as compared to ER-negative breast cancers. To understand [...] Read more.

Estrogen receptor (ER)-positive breast cancer is characterized by late recurrences following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is overexpressed in ER-positive breast cancers and is linked to poorer prognosis as compared to ER-negative breast cancers. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER-positive cells. We demonstrated that elevated GRHL2 imparts plasticity with stem cell- and dormancy-associated traits. RNA sequencing and immunocytochemistry revealed that high GRHL2 not only strengthens the epithelial identity but supports a hybrid epithelial to mesenchymal transition (EMT). Proliferation and tumor studies exhibited a decrease in growth and an upregulation of dormancy markers, such as NR2F1 and CDKN1B. Mammosphere assays and flow cytometry revealed enrichment of stem cell markers CD44 and ALDH1, and increased self-renewal capacity. Cistrome analyses revealed a change in transcription factor motifs near GRHL2 sites from developmental factors to those associated with disease progression. Together, these data support the idea that the plasticity and properties induced by elevated GRHL2 may provide a selective advantage to explain the association between GRHL2 and breast cancer progression. Full article

(This article belongs to the Section Molecular Cancer Biology)

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16 pages, 558 KiB

Open AccessSystematic Review

Clinical, Dermoscopic, and Molecular Features of Acantholytic Squamous Cell Carcinoma: A Systematic Review

by Catherine Keying Zhu, Lorena Alexandra Mija, Santina Conte, Sarah Ghezelbash, Bonika Nallanathan, Geneviève Fortier-Riberdy, Margaret Redpath and Philippe Lefrançois

Cancers 2024, 16(16), 2905; https://doi.org/10.3390/cancers16162905 - 21 Aug 2024

Viewed by 1336

Abstract

Introduction: Acantholytic squamous cell carcinoma (aSCC) is a rare clinicopathological subtype of cutaneous squamous cell carcinoma, accounting for approximately 4.9% of all SCC cases. However, there are currently no standardized criteria for the diagnosis of aSCC. This systematic review is the first to [...] Read more.

Introduction: Acantholytic squamous cell carcinoma (aSCC) is a rare clinicopathological subtype of cutaneous squamous cell carcinoma, accounting for approximately 4.9% of all SCC cases. However, there are currently no standardized criteria for the diagnosis of aSCC. This systematic review is the first to summarize the clinical and molecular features of aSCC. Methods: A systematic search of Medline, Embase, Scopus, and PubMed was performed. All articles in English or French were included, with no restriction of publication date. All articles with original data pertaining to clinical or molecular characteristics of aSCC were included. Two reviewers screened articles and resolved conflicts. Results: Our systematic review included 52 studies on the clinical and molecular features of aSCC, including a total of 482 patients (76% male, mean age at diagnosis 68.9 years): 430 cases assessed clinical features, while 149 cases assessed molecular features. The most common location of aSCC was the head and neck (n = 329/430; 76.5%). In terms of morphology, most lesions were described as nodules (n = 93/430, 21.6%), with common surface changes being hyperkeratosis (n = 6), erosion (n = 6), ulceration (n = 5), and crusting (n = 3). With regard to dermoscopy, only six cases were noted in the literature, including findings such as ulceration (n = 3), keratin clots (n = 2), and erosions (n = 2). Thirty-four studies discussed the molecular markers of aSCC, with the most prevalent markers being cytokeratins. CD15 negativity was noted in 23 cases, while common endothelial vascular markers such as CD34 (n = 16), CD31 (n = 15), factor VIII-related antigen (n = 10), and ERG (n = 1) were often not expressed. Finally, expression of intracellular adhesion molecules (i.e., E-cadherin, CD138) was markedly decreased compared to non-acantholytic invasive SCC. Conclusions: This systematic review summarizes the clinical characteristics and molecular features of aSCC. As clinical differentiation can be difficult, clinicopathological correlation with molecular markers may help ensure proper diagnosis. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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22 pages, 825 KiB

Open AccessReview

The Mutational and Microenvironmental Landscape of Cutaneous Squamous Cell Carcinoma: A Review

by Tara M. Hosseini, Soo J. Park and Theresa Guo

Cancers 2024, 16(16), 2904; https://doi.org/10.3390/cancers16162904 - 21 Aug 2024

Viewed by 1402

Abstract

Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult [...] Read more.

Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. Despite this, several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR. In addition to mutations, the tumor microenvironment and the manipulation and evasion of the immune system play a critical role in cSCC progression. Novel therapeutic approaches, such as immunotherapy and EGFR inhibitors, have been used to target these dysregulations, and have shown promise in treating advanced cSCC cases, emphasizing the need for targeted interventions considering both genetic and microenvironmental factors for improved patient outcomes. Full article

(This article belongs to the Section Tumor Microenvironment)

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12 pages, 1632 KiB

Open AccessArticle

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratio: Side by Side with Molecular Mutations in Patients with Non-Small Cell Lung Cancer—The INOLUNG Study

by Corina Eugenia Budin, Iuliu Gabriel Cocuz, Liviu Sorin Enache, Ionuț Alexandru Rența, Cristian Cazacu, Dariana Elena Pătrîntașu, Mihai Olteanu, Ruxandra-Mioara Râjnoveanu, Edith Simona Ianoși, Armand Râjnoveanu and Ovidiu Simion Cotoi

Cancers 2024, 16(16), 2903; https://doi.org/10.3390/cancers16162903 - 21 Aug 2024

Viewed by 931

Abstract

Background and objective: Analysis of inflammatory biomarkers, along with the neutrophil/lymphocyte ratio (NLR) or platelet/lymphocyte ratio (PLR), supports the connection between inflammation and carcinogenesis. Methods: We conducted a retrospective observational study at the Clinical County Hospital Mureș involving patients with lung cancer. The [...] Read more.

Background and objective: Analysis of inflammatory biomarkers, along with the neutrophil/lymphocyte ratio (NLR) or platelet/lymphocyte ratio (PLR), supports the connection between inflammation and carcinogenesis. Methods: We conducted a retrospective observational study at the Clinical County Hospital Mureș involving patients with lung cancer. The parameters analyzed included histopathological type (NSCLC: squamous cell carcinoma or adenocarcinoma; SCLC), molecular mutations (EGFR, ALK, PD-L1), parameters from the complete blood count, inflammatory parameters, and associated comorbidities. Results: A total of 380 patients were included: 115 patients in the cancer group and 265 patients in the control group. Among patients in the lung cancer group, 88 were diagnosed with NSCLC (44 adenocarcinomas, 44 squamous cell carcinomas) and 27 with SCLC. Both NLR and PLR were significantly higher in cancer patients than in the control group (5.30 versus 2.60, p < 0.001; 217 versus 136, p < 0.001, respectively). NLR and PLR differ between men and women (p = 0.005 and p = 0.056, respectively). C-reactive protein was not correlated with either NLR (p-value: 0.0669) or PLR (p-value: 0.6733) in lung cancer patients. Conclusions: The NLR and PLR values may serve as new predictive biomarkers for the diagnosis of disease in patients with lung cancer, especially those with NSCLC. Full article

(This article belongs to the Special Issue Predictive Biomarkers for Lung Cancer)

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21 pages, 2769 KiB

Open AccessArticle

IOS-1002, a Stabilized HLA-B57 Open Format, Exerts Potent Anti-Tumor Activity

by Anahita Rafiei, Marco Gualandi, Chia-Lung Yang, Richard Woods, Anil Kumar, Kathrin Brunner, John Sigrist, Hilmar Ebersbach, Steve Coats, Christoph Renner and Osiris Marroquin Belaunzaran

Cancers 2024, 16(16), 2902; https://doi.org/10.3390/cancers16162902 - 21 Aug 2024

Cited by 1 | Viewed by 1648

Abstract

HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present [...] Read more.

HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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Figure 1
Structure, expression and receptor binding characteristics of IOS-1002. (A) Schematic representation of the IOS-1002 molecule constructed through the ligation of HLA-B57(A46E/V97R) on N-terminus of human IgG4 Fc domain. (B) The topological structure of HLA-B57:01:01 including the B2m molecule. Mutation site residues A46 and V97 highlighted as spheres (PDB: 5VUF). (C) SEC-HPLC profile of purified IOS-1002. (D) Thermal unfolding profile of IOS-1002, determined by DSF. (E) Quantification of the binding affinities of IOS-1002 to LILRB1 (n = 4), LILRB2 (n = 5) and KIR3DL1 (n = 1) surface receptors determined by SPR. Red line represents raw data and black line represents the fit of 1:1 binding. RU: response units; KD: binding constant represented as mean ± standard deviation. (F) The topological structure of the HLA-B57:01:01 interaction site generated by superimposing the HLA-B57 structure (PDB: 2HJK) onto LILRB1/HLA-G and LILRB2/HLA-G. The residues lining the binding interfaces between HLA-B57-B2m:LILRB1 and HLA-B57-B2m:LILRB2 are highlighted under the dashed circles and displayed as sticks. The crystal structure of HLA-B57:01 and KIR3DL1 allotype 015 (PDB: 5B39), which describes a separate epitope on the HLA-B57 α1-helix, incorporating residues 77–83, known as the Bw4 motif. Structural images generated using PyMOL. (G) Quantification of the binding affinity of IOS-1002 to FcγRI determined by SPR (n = 1). The specified n indicates the number of independent experiments. Full article ">Figure 2
IOS-1002 binds to target receptors on human primary cells and inhibits the associated downstream signaling. (A) CHO cells were transduced with LILRB1, LILRB2 and CD64 FcγRI and interaction of AF488 labeled molecules was measured by flow cytometry (n = 2). Mean ± standard deviation is presented. MFI: median of fluorescence intensity. (B) Dose-dependent binding of IOS-1002 on human primary monocytes and the monocyte-derived macrophages isolated from PBMCs (n = 4). Mean ± standard deviation is presented. MFI: mean of fluorescence intensity. The non-linear regression curve and EC50 (95% Confidential Interval) were calculated using the model agonist vs. response variable slope (four parameters) in A and B. (C) Competition between IOS-1002, anti-LILRB1, anti-LILRB2, dual anti-LILRB1/2 and anti-CD64 antibody for cell surface epitopes on monocytes. Fold change of background-subtracted MFI relative to the cells pre-treated with IgG1 null antibody is presented, (n = 4). Mean ± standard deviation is presented. Statistical analysis of various conditions against IgG1 null control was performed using one-sample t-test (hypothetical mean = 1) and pre-treatment of combined dual anti-LILRB1/2 and anti-CD64 antibodies against anti-LILRB1/2 or anti-CD64 antibodies was analyzed by one-way ANOVA with Bonferroni multiple comparisons test. (D) Simple Western analysis showing expression and phosphorylation of ITIM-associated phosphatases, SHP-1 and SHP-2 in human primary monocytes-derived macrophages (n = 5). Quantification of phosphorylation over total protein relative to isotype control is presented in the graph on the right. Mean ± standard deviation is presented. Stars indicate the statistical significance against IgG4 control (one-sample t-test, hypothetical mean = 1). * p < 0.05; ** p < 0.01; **** p < 0.0001. ns, non-significant. In (A) n indicates the number of independent experiments, in (B–D) n indicates the number of independent donors. Full article ">Figure 3
IOS-1002 affects the differentiation of monocytes toward MDSCs and enhances phagocytosis of monocyte-derived macrophages. (A) Scheme of different monocyte-derived immune cell-based assays performed. (B,C) The effect of IOS-1002 on the differentiation potential of monocytes toward MDSCs (n = 3) (B) and M2 macrophages (n = 4) (C) is presented and compared with anti-LILRB2 antibody. Mean ± standard deviation is presented. In C, stars indicate the statistical significance toward IgG4 control. (D) Macrophage phagocytosis in the presence of different concentrations of IOS-1002 toward H460 (NSCLC cell line) (n = 4). Mean ± standard deviation of 3 technical replicates is presented. A 4P-L curve was interpolated for quantification of the EC50. (E) Macrophage phagocytosis in the presence of IOS-1002 on different Fc backbones toward H460 cell line (n = 2). Mean ± standard deviation is presented. Statistical analysis was performed using one-way ANOVA and Dunnett’s multiple comparisons test. Unless mentioned otherwise, all indicated compounds were used at a concentration of 20ug/mL. * p < 0.05, ** p < 0.01, *** p < 0.001. The specified n indicates the number of independent donors. Full article ">Figure 4
IOS-1002 activates T and NK cells and demonstrates efficacy in ex vivo patient samples. (A) Isolated human primary NK cells were incubated with HCT116 colon cancer cell line in a cell-cell contact manner and the percentage of cancer cell killing was measured for 60 h. Area under the curve (AUC) of the percent cytotoxicity over time was calculated and is represented in the graph (n = 4). Different colors represent independent donors. Statistical analysis was performed using RM one-way ANOVA with Dunnett’s multiple comparisons test. (B) Non-activated T cells were incubated with MIA PaCa-2 (pancreatic carcinoma, n = 2) and H1703 (NSCLC, n = 2) cancer cell lines in a cell-cell contact manner and co-cultures were monitored for 72 h; left, the T cells number at endpoint (72 h) is presented in fold changes over timepoint 0; right, the number of dead cancer cells at 72 h, expressed in percentage, is represented. Mean ± standard deviation is shown. Statistical analysis was performed using two-way ANOVA with Dunnet’s multiple comparisons. (C) TNFa levels in cell supernatant of PBMCs incubated with H1703 in a cell-cell contact manner for 48 h. TNFa concentration (pg/mL) for each individual donor is represented (n = 6). Every donor is color-coded throughout the treatments. Statistical analysis was performed using RM one-way ANOVA with Dunnett’s multiple comparisons test. Paired t-test analysis was used to compare activated PBMCs monoculture and PBS control co-culture. Act.: Activated, N. Act.: Non-activated. (D,E) Relative total tumoroid area normalized against the untreated sample and shown for individual patient samples (D) and in total cohort (E) upon different treatments. Each reported measurement is a median of up to 8 technical replicates. Imun15 sample has no SEA control recorded due to the technical error in the experiment. * p < 0.05, ** p < 0.01, *** p < 0.001. ns, non-significant. The specified n indicates the number of independent donors. Full article ">

11 pages, 866 KiB

Open AccessReview

Small Bowel Cancer in Crohn’s Disease

by Ilaria Faggiani, Ferdinando D’Amico, Federica Furfaro, Alessandra Zilli, Tommaso Lorenzo Parigi, Clelia Cicerone, Gionata Fiorino, Laurent Peyrin-Biroulet, Silvio Danese and Mariangela Allocca

Cancers 2024, 16(16), 2901; https://doi.org/10.3390/cancers16162901 - 21 Aug 2024

Viewed by 1296

Abstract

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) that frequently affects the small bowel. Individuals diagnosed with CD are at increased risk of developing bowel cancer compared to the general population. Small bowel cancer is a rare but significant CD complication. [...] Read more.

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) that frequently affects the small bowel. Individuals diagnosed with CD are at increased risk of developing bowel cancer compared to the general population. Small bowel cancer is a rare but significant CD complication. Adenocarcinoma represents the most prevalent of these neoplasms, followed by neuroendocrine tumors and sarcomas. The primary risk factors identified are being of the male sex, disease duration, previous surgical intervention, perianal disease, and chronic inflammation. The precise etiology remains unclear. Another crucial issue concerns the role of immunomodulators and advanced therapies. By inhibiting inflammation, these therapies can reduce the risk of cancer, which is often initiated by the inflammation–dysplasia–adenocarcinoma sequence. In accordance with the most recent guidelines, it is not necessary to conduct surveillance in patients with small bowel cancer among CD patients, as it is considered a rare disease. Nevertheless, it is of significant importance for gastroenterologists to be aware of this potential CD complication, as well as the patients who are most at risk of developing it. The purpose of this review is to provide a comprehensive overview of CD-SBC, focusing on epidemiology, etiopathogenesis, risk factors, diagnosis, and the role of advanced therapies in CD-SBC. Full article

(This article belongs to the Special Issue Cancer and Immunomediated Inflammatory Diseases (IMIDs))

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18 pages, 14297 KiB

Open AccessReview

Radiographic Response Assessments and Standardized Imaging Interpretation Criteria in Head and Neck Cancer on FDG PET/CT: A Narrative Review

by Jennifer A. Schroeder, Jorge D. Oldan, Valerie L. Jewells and Paul M. Bunch

Cancers 2024, 16(16), 2900; https://doi.org/10.3390/cancers16162900 - 21 Aug 2024

Viewed by 1008

Abstract

Introduction: There is growing interest in the development and application of standardized imaging criteria (SIC), to minimize variability and improve the reproducibility of image interpretation in head and neck squamous cell carcinoma (HNSCC). Methods: “Squamous cell carcinoma” AND “standardized interpretation criteria” OR “radiographic [...] Read more.

Introduction: There is growing interest in the development and application of standardized imaging criteria (SIC), to minimize variability and improve the reproducibility of image interpretation in head and neck squamous cell carcinoma (HNSCC). Methods: “Squamous cell carcinoma” AND “standardized interpretation criteria” OR “radiographic response assessment” were searched using PubMed and Google Scholar for articles published between 2009 and 2024, returning 56 publications. After abstract review, 18 were selected for further evaluation, and 6 different SICs (i.e., PERCIST, Porceddu, Hopkins, NI-RADS, modified Deauville, and Cuneo) were included in this review. Each SIC is evaluated in the context of 8 desired traits of a standardized reporting system. Results: Two SICs have societal endorsements (i.e., PERCIST, NI-RADS); four can be used in the evaluation of locoregional and systemic disease (i.e., PERCIST, Hopkins, NI-RADS, Cuneo), and four have specific categories for equivocal imaging results (i.e., Porceddu, NI-RADS, modified Deauville, and Cuneo). All demonstrated areas for future improvement in the context of the 8 desired traits. Conclusion: Multiple SICs have been developed for and demonstrated value in HNSCC post-treatment imaging; however, these systems remain underutilized. Selecting an SIC with features that best match the needs of one’s practice is expected to maximize the likelihood of successful implementation. Full article

(This article belongs to the Special Issue Head and Neck Cancer: Advanced PET/CT and MRI Imaging with a Focus on Current and Emerging Molecular Theranostics)

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Figure 1
Axial fused image of a post-therapy FDG PET/CT in a 74-year-old woman status post-radiation of right tonsil cancer which demonstrates no residual FDG uptake in the right tonsil (dark blue arrow) nor in the previously avid nodes (all sites below mediastinal blood pool, marked by light blue arrow). This case represents a complete metabolic response by all criteria. More specifically, this exam would be assigned CR by PERCIST as the tumor has disappeared; H1 (negative) by Hopkins as the uptake is less than the IJV; N1 (no evidence of recurrence) by NIRADS as there is no uptake of visible mass on CT; M1 (negative) by MDS as the uptake is less than the mediastinal blood pool; C1 (negative) by Cuneo for the same reason; and P1 (negative) by Porceddu as there is no residual uptake above the mediastinal blood pool in the nodes. Full article ">Figure 2
Axial fused image of a post-therapy FDG PET/CT in a 63-year-old woman with left tonsillar squamous cell carcinoma which demonstrates potentially ambiguous tongue uptake at the site of the primary tumor (uptake between that of the blood pool and the liver marked with arrow) that may result in a variable interpretation if written in free-form text. For this patient, this was the only residual site of uptake, thus determining her post-therapy disease status. Indeed, even by SICs there is variability in the resulting clinical assessment with both negative and equivocal disease assessments possible in this case. More specifically, this finding is assigned as PR by PERCIST given the large and incomplete decline in uptake; H2 (equivocal) by Hopkins, being between the IJV and the liver; NIRADS 2 (equivocal), having low-grade focal uptake; M2 (equivocal), being between the mediastinal blood pool and the liver; C 2 (negative) by Cuneo since the uptake is between the mediastinal blood pool and the liver but the background is less than the reference lesion. Porceddu does not evaluate the primary site and thus is not applicable for this exam. Full article ">Figure 3
Axial fused image from a post-therapy FDG PET/CT in a 71-year-old woman with tongue cancer demonstrating a newly avid level 1B node (arrow) with uptake that is greater than in the liver and background tissues. By all criteria, this represents progressive disease. More specifically, this case is assigned PR by PERCIST given the incomplete decline; P3 (positive) by Porceddu given the uptake being greater than in the liver; H4 (positive) by Hopkins for the same reason; N3 (high suspicion) by NIRADS given the intense focal uptake; M4 (positive) by MDS for a new site of disease; and Cuneo 6 (positive) due to being greater than in the liver. Full article ">

17 pages, 1242 KiB

Open AccessReview

Open-Face Masks in Radiotherapy: Enhancing Therapeutic Strategies for Head and Neck and Brain Cancer Patients—A Comprehensive Scoping Review

by Andrea Lastrucci, Ilaria Morelli, Claudio Votta, Irene Maran, Nicola Iosca, Ilaria Pia Monaco, Viola Salvestrini, Isacco Desideri, Livia Marrazzo, Yannick Wandael, Patrizia Cornacchione, Stefania Pallotta, Daniele Giansanti, Renzo Ricci, Lorenzo Livi and Pierluigi Bonomo

Cancers 2024, 16(16), 2899; https://doi.org/10.3390/cancers16162899 - 21 Aug 2024

Viewed by 1621

Abstract

Introduction: The main goal of radiotherapy (RT) is to deliver a precise dose to the target while sparing the surrounding normal tissue and minimizing side effects. Appropriate patient immobilization is crucial, especially for head and neck cancer (HNC) and Brain Cancer (BC). [...] Read more.

Introduction: The main goal of radiotherapy (RT) is to deliver a precise dose to the target while sparing the surrounding normal tissue and minimizing side effects. Appropriate patient immobilization is crucial, especially for head and neck cancer (HNC) and Brain Cancer (BC). Conventional closed-face masks (CFMs), while effective in minimizing head motion, can cause significant discomfort, anxiety, and claustrophobia. Open-face masks (OFMs) have been developed to increase patient comfort while providing precise immobilization. Methods: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) extension for scoping reviews and the Arskey and O’Malley framework, an electronic search of EMBASE, PubMed, SCOPUS, and Web of Science was conducted to identify original studies reporting the use and description of OFMs in clinical practice up to April 2024. The inclusion criteria were English-language articles focusing on OFMs for HNC and BC patients undergoing RT. Results: Of 618 titles, 19 articles fulfilled the selection criteria. Most studies were comparative (n = 13) or observational (n = 6). The articles were categorized by treatment site, resulting in three groups: BC (n = 14, 68.4%), HNC (n = 4, 21.4%), and mixed (n = 2, 10.5%), which includes both BC and HNC. Of note, 82.4% (n = 16) of the included studies were published from 2020 onwards, emphasizing the recent adoption of OFM in clinical practice. Conclusions: The reviewed studies show that OFMs, in combination with SGRT, offer significant advantages in terms of patient comfort and positioning accuracy in HNC and BC treatments. Reproducibility in the sub-millimeter and sub-degree range can be achieved, which supports the use of OFMs in clinical practice. Future research should explore innovative combinations of immobilization and monitoring to further improve RT outcomes and ensure precise treatment while increasing patient comfort. Full article

(This article belongs to the Special Issue Emerging Technologies in Head and Neck Cancer Surgery)

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13 pages, 945 KiB

Open AccessArticle

Long-Term Outcomes of Childhood Acute Lymphocytic Leukemia Treated with Adapted Berlin–Frankfurt–Münster (BFM) Protocols: A Multicentric Analysis from a Developing Country

by Patricia Regina Cavalcanti Barbosa Horn, Marilza de Moura Ribeiro-Carvalho, Alice Maria Boulhosa de Azevedo, Adriana Martins de Sousa, Simone Faria, Cristina Wiggers, Soraia Rouxinol, Marcia Trindade Schramm, Bárbara Sarni Sanches, Nathalia Lopez Duarte, Teresa de Souza Fernandez Seixas, Bernadete Evangelho Gomes, Elen de Oliveira, Leonardo Javier Arcuri, Elaine Sobral da Costa, Marcelo Gerardin Poirot Land and Maria Helena Faria Ornellas de Souza

Cancers 2024, 16(16), 2898; https://doi.org/10.3390/cancers16162898 - 21 Aug 2024

Viewed by 1084

Abstract

Introduction: The objective of the current study was to determine the survival probabilities of children and adolescents with acute lymphocytic leukemia treated with adapted Berlin–Frankfurt–Münster (BFM) protocols and compare our results with the original BFM reports. Methods: This retrospective study included 695 patients [...] Read more.

Introduction: The objective of the current study was to determine the survival probabilities of children and adolescents with acute lymphocytic leukemia treated with adapted Berlin–Frankfurt–Münster (BFM) protocols and compare our results with the original BFM reports. Methods: This retrospective study included 695 patients up to 19 years old treated with adapted BFM protocols between 1997 and 2018 in four hospitals in Rio de Janeiro. The 1997–2007 and 2008–2018 cohorts were analyzed separately. Results: More than half of the patients were stratified into the high-risk BFM classification. Overall and event-free survivals were, in the 1997–2007 period, respectively, 88% and 80% (BFM standard risk group—SRG), 75% and 67% (intermediate risk group—IRG), and 48% and 33% (high-risk group—HRG). The corresponding numbers for the 2008–2018 period were 93% and 84% (SRG), 75% and 63% (IRG), and 64% and 57% (HRG). In the second period, both the OS (HR = 0.71, p = 0.011) and EFS (HR = 0.62, p < 0.001) were higher. Except for the intermediate-risk group, the latter results are comparable to the BFM. Conclusion: The BFM protocol adaptations can be safely implemented in developing countries, accounting for local specificities. Full article

(This article belongs to the Section Pediatric Oncology)

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2 pages, 1062 KiB

Open AccessCorrection

Correction: Gravina et al. ATX-101, a Peptide Targeting PCNA, Has Antitumor Efficacy Alone or in Combination with Radiotherapy in Murine Models of Human Glioblastoma. Cancers 2022, 14, 289

by Giovanni Luca Gravina, Alessandro Colapietro, Andrea Mancini, Alessandra Rossetti, Stefano Martellucci, Luca Ventura, Martina Di Franco, Francesco Marampon, Vincenzo Mattei, Leda Assunta Biordi, Marit Otterlei and Claudio Festuccia

Cancers 2024, 16(16), 2897; https://doi.org/10.3390/cancers16162897 - 21 Aug 2024

Viewed by 637

Abstract

In the original publication [...] Full article

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20 pages, 2118 KiB

Open AccessReview

Radioimmunotheragnosis in Cancer Research

by Guillermo Garaulet, Bárbara Beatriz Báez, Guillermo Medrano, María Rivas-Sánchez, David Sánchez-Alonso, Jorge L. Martinez-Torrecuadrada and Francisca Mulero

Cancers 2024, 16(16), 2896; https://doi.org/10.3390/cancers16162896 - 20 Aug 2024

Cited by 1 | Viewed by 1039

Abstract

The combination of immunoPET—where an antibody (Ab) is labeled with an isotope for PET imaging—and radioimmunotherapy (RIT), using the same antibody with a therapeutic isotope, offers significant advantages in cancer management. ImmunoPET allows non-invasive imaging of antigen expression, which aids in patient selection [...] Read more.

The combination of immunoPET—where an antibody (Ab) is labeled with an isotope for PET imaging—and radioimmunotherapy (RIT), using the same antibody with a therapeutic isotope, offers significant advantages in cancer management. ImmunoPET allows non-invasive imaging of antigen expression, which aids in patient selection for subsequent radioimmunotherapy. It also facilitates the assessment of tumor response to therapy, allowing for treatment adjustments if necessary. In addition, immunoPET provides critical pharmacokinetic data, including antibody biodistribution and clearance rates, which are essential for dosimetry calculations and treatment protocol optimization. There are still challenges to overcome. Identifying appropriate target antigens that are selectively expressed on cancer cells while minimally expressed on normal tissues remains a major hurdle to reduce off-target toxicity. In addition, it is critical to optimize the pharmacokinetics of radiolabeled antibodies to maximize tumor uptake and minimize normal tissue uptake, particularly in vital organs such as the liver and kidney. This approach offers the potential for targeted and personalized cancer therapy with reduced systemic toxicity by exploiting the specificity of monoclonal antibodies and the cytotoxic effects of radiation. However, further research is needed to address remaining challenges and to optimize these technologies for clinical use. Full article

(This article belongs to the Special Issue Theranostic Imaging and Dosimetry for Cancer)

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Graphical abstract

14 pages, 3739 KiB

Open AccessArticle

Tumor-Infiltrating Lymphocyte Scoring in Neoadjuvant-Treated Breast Cancer

by Noémie Thomas, Soizic Garaud, Mireille Langouo, Doïna Sofronii, Anaïs Boisson, Alexandre De Wind, Valérie Duwel, Ligia Craciun, Dennis Larsimont, Ahmad Awada and Karen Willard-Gallo

Cancers 2024, 16(16), 2895; https://doi.org/10.3390/cancers16162895 - 20 Aug 2024

Viewed by 1100

Abstract

Neoadjuvant chemotherapy (NAC) is now the standard of care for patients with locally advanced breast cancer (BC). TIL scoring is prognostic and adds predictive value to the residual cancer burden evaluation after NAC. However, NAC induces changes in the tumor, and the reliability [...] Read more.

Neoadjuvant chemotherapy (NAC) is now the standard of care for patients with locally advanced breast cancer (BC). TIL scoring is prognostic and adds predictive value to the residual cancer burden evaluation after NAC. However, NAC induces changes in the tumor, and the reliability of TIL scoring in post-NAC samples has not yet been studied. H&E- and dual CD3/CD20 chromogenic IHC-stained tissues were scored for stromal and intra-tumoral TIL by two experienced pathologists on pre- and post-treatment BC tissues. Digital TIL scoring was performed using the HALO^® image analysis software (version 2.2). In patients with residual disease, we show a good inter-pathologist correlation for stromal TIL on H&E-stained tissues (CCC value 0.73). A good correlation for scoring with both staining methods (CCC 0.81) and the digital TIL scoring (CCC 0.77) was also observed. Overall concordance for TIL scoring in patients with a complete response was however poor. This study reveals there is good reliability for TIL scoring in patients with detectable residual tumors after NAC treatment, which is comparable to the scoring of untreated breast cancer patients. Based on the good consistency observed with digital TIL scoring, the development of a validated algorithm in the future might be advantageous. Full article

(This article belongs to the Section Cancer Pathophysiology)

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Representative images of the scoring areas defined by the pathologists are shown. Full article ">Figure 2
Scores from pathologists 1 and 2 were compared for the H&E-stained tissues. (A,D) The forest plot shows the concordance correlation coefficient (CCC) with the 95% confidence interval (CI). (B,E) Bland–Altman plots for stromal and intra-tumoral TIL scores are shown as a ratio of pathologist 1 to pathologist 2 (y-axis) plotted versus the mean score for each sample (x-axis). The mean ratio (central line) of these scores with the 95% limits of agreement are shown as horizontal lines. (C,F) Passing–Bablock regression analysis for stromal and intra-tumoral TIL scores from pathologist 1 (y-axis) compared to pathologist 2 (x-axis). The regression lines with the 95% CI (colored band) are drawn. Constant and proportional bias are indicated by the intercept and slope of the regression line, respectively. Full article ">Figure 3
Pathologist TIL scores on H&E- versus CD3/CD20-stained tissue were compared (A,D). The forest plot shows the concordance correlation coefficient (CCC) for H&E- versus CD3/CD20-stained tissue (B,E). Bland–Altman plots demonstrate the ratio of TIL scores on H&E- to CD3/CD20-stained tissue (y-axis) plotted against the geometric mean scores for each sample (x-axis). (C,F) Passing–Bablock regression analysis for TIL scores on H&E- (y-axis) compared to CD3/CD20-stained tissue (x-axis). Full article ">Figure 4
TIL scores on H&E- and CD3/CD20-stained tissue for all blocks are shown per patient. If multiple blocks had the same TIL score, the number of blocks with that score is indicated in the dot for the corresponding score. The score of the selected block used for the comparative analysis is indicated by a black star. The mean score is indicated by a black line. Full article ">Figure 5
TIL scores obtained by digital analysis were compared to the mean pathologist TIL score from CD3/C20-stained tissue. (A) A forest plot shows the CCC values. (B) Bland Altmann plots demonstrate the ratio of mean pathologist scores to digital scores (y-axis) plotted versus the mean score for each sample (x-axis). (C) Passing–Bablock regression analysis shows mean pathologist scores (y-axis) compared to digital scores (x-axis). Full article ">

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