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13 pages, 619 KiB

Open AccessArticle

Germline Genetic Mutations in Adult Patients with Sarcoma: Insight into the Middle East Genetic Landscape

by Ramiz Abu-Hijlih, Baha Sharaf, Samer Salah, Hira Bani Hani, Mohammad Alqaisieh, Abdulla Alzibdeh, Layan Ababneh, Suleiman Mahafdah and Hikmat Abdel-Razeq

Cancers 2024, 16(9), 1668; https://doi.org/10.3390/cancers16091668 - 25 Apr 2024

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Abstract

Data on germline mutations in soft tissue and bone sarcomas are scarce. We sought to identify the prevalence of germline mutations in adult sarcoma patients treated at a tertiary cancer center. Newly diagnosed patients were offered germline genetic testing via an 84-gene panel. [...] Read more.

Data on germline mutations in soft tissue and bone sarcomas are scarce. We sought to identify the prevalence of germline mutations in adult sarcoma patients treated at a tertiary cancer center. Newly diagnosed patients were offered germline genetic testing via an 84-gene panel. The prevalence of pathogenic germline variants (PGVs) and their association with disease-, and patient- related factors are reported. A total of 87 patients were enrolled, the median age was 48 (19–78) years, and 47 (54%) were females. Gastrointestinal stromal tumors (n = 12, 13.8%), liposarcoma (n = 10, 11.5%), and Ewing sarcoma (n = 10, 11.5%) were the main subtypes. A total of 20 PGVs were detected in 18 (20.7%) patients. Variants of uncertain significance, in the absence of PGVs, were detected in 40 (45.9%) patients. Young age (p = 0.031), presence of a second primary cancer (p = 0.019), and female gender (p = 0.042) were correlated with the presence of PGVs. All identified PGVs have potential clinical actionability and cascade testing, and eight (44.44%) suggested eligibility for a targeted therapy. Almost one in five adult patients with soft tissue and bone sarcomas harbor pathogenic or likely pathogenic variants. Many of these variants are potentially actionable, and almost all have implications on cancer screening and family counselling. In this cohort from the Middle East, younger age, presence of a second primary tumor, and female gender were significantly associated with higher PGVs rates. Larger studies able to correlate treatment outcomes with genetic variants are highly needed. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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12 pages, 1511 KiB

Open AccessArticle

Prognostic Value of the Lung Immune Prognostic Index on Recurrence after Radical Surgery for High-Risk Renal Cell Carcinoma

by Yudai Ishiyama, Tsunenori Kondo, Kazuhiko Yoshida, Junpei Iizuka and Toshio Takagi

Cancers 2024, 16(4), 776; https://doi.org/10.3390/cancers16040776 - 14 Feb 2024

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Abstract

With emerging options in immediate postoperative settings for high-risk renal cell carcinoma (hrRCC), further risk stratification may be relevant for informed decision making. Balancing the benefits and drawbacks of adjuvant immunotherapy is recommended. We aimed to evaluate the effects of the lung immune [...] Read more.

With emerging options in immediate postoperative settings for high-risk renal cell carcinoma (hrRCC), further risk stratification may be relevant for informed decision making. Balancing the benefits and drawbacks of adjuvant immunotherapy is recommended. We aimed to evaluate the effects of the lung immune prognostic index (LIPI) in this setting. This bi-institutional retrospective study recruited 235 patients who underwent radical surgery for hrRCC between 2004 and 2021. LIPI scores were calculated based on the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels. The association between LIPI scores and local or distant recurrence was analyzed, along with other possible clinical factors. The median recurrence-free survival (RFS) period was 36.4 months. Based on the LIPI scores, 119, 91, and 25 patients were allocated to the good, intermediate, and poor groups, respectively. The RFS was significantly correlated with the LIPI scores, and the 36 month survival rates were 67.3, 36.2, and 11.0% in the good, intermediate, and poor groups, respectively. In the multivariate model, the LIPI independently predicted the RFS, along with symptoms at diagnosis, Eastern Cooperative Oncology Group performance status, pT status, pN status, and tumor grade. The C-index of the LIPI in predicting RFS was 0.63, and prediction accuracy improved with the addition of the LIPI to both GRade, Age, Nodes, Tumor, and the UCLA Integrated Staging System. Conclusively, the LIPI can be a significant prognostic biomarker for predicting hrRCC recurrence, particularly for identifying the highest-risk cohort. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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13 pages, 421 KiB

Open AccessArticle

The Burden of Thin Melanomas in Tuscany, Italy, 1985–2017: Age- and Sex-Specific Temporal Trends in Incidence and Mortality

by Gianfranco Manneschi, Adele Caldarella, Saverio Caini, Saverio Checchi, Teresa Intrieri, Alessandra Chiarugi, Paolo Nardini and Giovanna Masala

Cancers 2024, 16(3), 536; https://doi.org/10.3390/cancers16030536 - 26 Jan 2024

Cited by 1 | Viewed by 947

Abstract

A steady increase in the incidence and mortality burden correlated to thin melanomas (≤1 mm) has been reported in recent years in some international studies, but there is currently a paucity of data from the Mediterranean area. We aimed to describe the epidemiological [...] Read more.

A steady increase in the incidence and mortality burden correlated to thin melanomas (≤1 mm) has been reported in recent years in some international studies, but there is currently a paucity of data from the Mediterranean area. We aimed to describe the epidemiological characteristics of thin melanoma in Tuscany, Central Italy. A total of 6002 first cutaneous invasive melanomas occurring from 1985 to 2017 were selected for analysis; data were retrieved from the local population-based cancer registry. The standardized incidence rate was 15.0 per 100,000 in the population, higher among men than women (16.5 vs. 14.1). Incidence rates tended to increase over time across all age group-specific population strata, with annual percent changes moderately higher among men (+8.0%) than women (+6.9%), especially among the elderly. Among both sexes and in each age group, the trend toward increasing incidence rates was particularly strong for thin melanomas. Survival was better among women than men across all categories of thickness. Approximately 15% of deaths occurred among patients with thin lesions, with no major temporal changes in recent years. This study contributes to an improved understanding of melanoma epidemiology in Tuscany and underscores the need for primary prevention strategies tackling the growing burden of thin melanomas. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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9 pages, 429 KiB

Open AccessArticle

Does Genotype-Specific Phenotype in Patients with Multiple Endocrine Neoplasia Type 2 Occur as Current Guidelines Predict?

by Teresa Binter, Sabina Baumgartner-Parzer, Marie Helene Schernthaner-Reiter, Melisa Arikan, Lindsay Hargitai, Martin Bruno Niederle, Bruno Niederle, Christian Scheuba and Philipp Riss

Cancers 2024, 16(3), 494; https://doi.org/10.3390/cancers16030494 - 24 Jan 2024

Cited by 1 | Viewed by 1320

Abstract

The clinical manifestation of multiple endocrine neoplasia type 2 (MEN2) in terms of developing medullary thyroid cancer (MTC), pheochromocytoma (PCC), and/or primary hyperparathyroidism (PHPT) is related to the respective pathogenic variant of the RET proto-oncogene. The aim of this study is to retrospectively [...] Read more.

The clinical manifestation of multiple endocrine neoplasia type 2 (MEN2) in terms of developing medullary thyroid cancer (MTC), pheochromocytoma (PCC), and/or primary hyperparathyroidism (PHPT) is related to the respective pathogenic variant of the RET proto-oncogene. The aim of this study is to retrospectively analyze the individual, genotype-dependent clinical manifestations of a large cohort of MEN2 patients. By comparing their clinical profile with currently existing evidence-based knowledge, an optimal therapy and prevention strategy in terms of prophylactic thyroidectomy and clinical follow-up could be ensured. This is a retrospective single-center study of 158 MEN2 patients who were diagnosed and/or surgically treated at a tertiary referral care center between 1990 and 2022. All participants were categorized according to their pathogenic variant of the RET proto-oncogene. Subsequently, the clinical manifestation of the disease and its time of occurrence was documented. Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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21 pages, 4035 KiB

Open AccessArticle

Targeting Translation and the Cell Cycle Inversely Affects CTC Metabolism but Not Metastasis

by Tetiana Y. Bowley, Seth D. Merkley, Irina V. Lagutina, Mireya C. Ortiz, Margaret Lee, Bernard Tawfik and Dario Marchetti

Cancers 2023, 15(21), 5263; https://doi.org/10.3390/cancers15215263 - 2 Nov 2023

Cited by 2 | Viewed by 2003

Abstract

Melanoma brain metastasis (MBM) is significantly associated with poor prognosis and is diagnosed in 80% of patients at autopsy. Circulating tumor cells (CTCs) are “seeds” of metastasis and the smallest functional units of cancer. Our multilevel approach has previously identified a CTC RPL/RPS [...] Read more.

Melanoma brain metastasis (MBM) is significantly associated with poor prognosis and is diagnosed in 80% of patients at autopsy. Circulating tumor cells (CTCs) are “seeds” of metastasis and the smallest functional units of cancer. Our multilevel approach has previously identified a CTC RPL/RPS gene signature directly linked to MBM onset. We hypothesized that targeting ribogenesis prevents MBM/metastasis in CTC-derived xenografts. We treated parallel cohorts of MBM mice with FDA-approved protein translation inhibitor omacetaxine with or without CDK4/CDK6 inhibitor palbociclib, and monitored metastatic development and cell proliferation. Necropsies and IVIS imaging showed decreased MBM/extracranial metastasis in drug-treated mice, and RNA-Seq on mouse-blood-derived CTCs revealed downregulation of four RPL/RPS genes. However, mitochondrial stress tests and RT-qPCR showed that omacetaxine and palbociclib inversely affected glycolytic metabolism, demonstrating that dual targeting of cell translation/proliferation is critical to suppress plasticity in metastasis-competent CTCs. Equally relevant, we provide the first-ever functional metabolic characterization of patient-derived circulating neoplastic cells/CTCs. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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16 pages, 14594 KiB

Open AccessArticle

Elafin as a Prognostic Marker in Esophageal Squamous Cell Carcinoma: A Pilot Study Using Three-Dimensional Imaging and Genomic Profiling

by Wei-Chung Chen, Chun-Chieh Wu, Yu-Peng Liu, Guan-Yu Zhuo, Yao-Kuang Wang, Yi-Hsun Chen, Chu-Chih Chen, Yin-Han Wang, Ming-Tsang Wu and I-Chen Wu

Cancers 2023, 15(15), 3825; https://doi.org/10.3390/cancers15153825 - 27 Jul 2023

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Abstract

Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. [...] Read more.

Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. To explore this question, we first used three-dimensional confocal imaging to create a model of the spatial distribution of elafin inside locoregional ESCC tissues. Then, after analyzing data obtained from whole-genome microarrays for ESCC cell lines and their more invasive sublines, we performed in vitro experiments using RNA sequencing to identify possible elafin-related pathways. Three-dimensional tissue imaging showed elafin distributed as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poorer prognoses. By contrast, the signal was confined inside or around the tumor nest in patients who had lower serum levels and better survival. The analysis of a TCGA dataset revealed that higher levels of elafin mRNA in stage I–IIIA ESCC patients were associated with shorter survival. The in vitro studies revealed that elafin promoted ESCC cell proliferation, migration, and invasion via the epithelial–mesenchymal transition pathway. Thus, elafin inhibition could potentially be used therapeutically to improve survival in patients with locoregional ESCC. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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Review

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20 pages, 1242 KiB

Open AccessReview

Glioma Stem Cells—Features for New Therapy Design

by Nives Pećina-Šlaus and Reno Hrašćan

Cancers 2024, 16(8), 1557; https://doi.org/10.3390/cancers16081557 - 19 Apr 2024

Cited by 2 | Viewed by 1532

Abstract

On a molecular level, glioma is very diverse and presents a whole spectrum of specific genetic and epigenetic alterations. The tumors are unfortunately resistant to available therapies and the survival rate is low. The explanation of significant intra- and inter-tumor heterogeneity and the [...] Read more.

On a molecular level, glioma is very diverse and presents a whole spectrum of specific genetic and epigenetic alterations. The tumors are unfortunately resistant to available therapies and the survival rate is low. The explanation of significant intra- and inter-tumor heterogeneity and the infiltrative capability of gliomas, as well as its resistance to therapy, recurrence and aggressive behavior, lies in a small subset of tumor-initiating cells that behave like stem cells and are known as glioma cancer stem cells (GCSCs). They are responsible for tumor plasticity and are influenced by genetic drivers. Additionally, GCSCs also display greater migratory abilities. A great effort is under way in order to find ways to eliminate or neutralize GCSCs. Many different treatment strategies are currently being explored, including modulation of the tumor microenvironment, posttranscriptional regulation, epigenetic modulation and immunotherapy. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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26 pages, 3123 KiB

Open AccessReview

Nasopharynx Battlefield: Cellular Immune Responses Mediated by Midkine in Nasopharyngeal Carcinoma and COVID-19

by Ngar-Woon Kam, Cho-Yiu Lau, Chi-Ming Che and Victor Ho-Fun Lee

Cancers 2023, 15(19), 4850; https://doi.org/10.3390/cancers15194850 - 4 Oct 2023

Cited by 1 | Viewed by 1819

Abstract

Clinical evidence suggests that the severe respiratory illness coronavirus disease 2019 (COVID-19) is often associated with a cytokine storm that results in dysregulated immune responses. Prolonged COVID-19 positivity is thought to disproportionately affect cancer patients. With COVID-19 disrupting the delivery of cancer care, [...] Read more.

Clinical evidence suggests that the severe respiratory illness coronavirus disease 2019 (COVID-19) is often associated with a cytokine storm that results in dysregulated immune responses. Prolonged COVID-19 positivity is thought to disproportionately affect cancer patients. With COVID-19 disrupting the delivery of cancer care, it is crucial to gain momentum and awareness of the mechanistic intersection between these two diseases. This review discusses the role of the cytokine midkine (MK) as an immunomodulator in patients with COVID-19 and nasopharyngeal carcinoma (NPC), both of which affect the nasal cavity. We conducted a review and analysis of immunocellular similarities and differences based on clinical studies, research articles, and published transcriptomic datasets. We specifically focused on ligand–receptor pairs that could be used to infer intercellular communication, as well as the current medications used for each disease, including NPC patients who have contracted COVID-19. Based on our findings, we recommend close monitoring of the MK axis to maintain the desirable effects of therapeutic regimens in fighting both NPC and COVID-19 infections. Full article

(This article belongs to the Special Issue Recent Advances in Rare Cancers: From Bench to Bedside and Back)

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