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Cancers
Volume 15
Issue 3
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Cancers, Volume 15, Issue 3 (February-1 2023) – 439 articles

Cover Story (view full-size image): Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitor receptor (VEGFR) inhibitors are currently both acceptable options for patients with treatment-naïve advanced papillary renal cell carcinoma (pRCC). ICI combinations—either with VEGFR or with MET inhibitors—are also promising therapeutic strategies. Several ongoing trials in this setting will help to clarify the optimal approach for the treatment of advanced pRCC. View this paper
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10 pages, 473 KiB  
Review
PARP Inhibitors and Proteins Interacting with SLX4
by Lars Petter Jordheim
Cancers 2023, 15(3), 997; https://doi.org/10.3390/cancers15030997 - 03 Feb 2023
Cited by 1 | Viewed by 2071
Abstract
PARP inhibitors are small molecules currently used with success in the treatment of certain cancer patients. Their action was first shown to be specific to cells with DNA repair deficiencies, such as BRCA-mutant cancers. However, recent work has suggested clinical interest of these [...] Read more.
PARP inhibitors are small molecules currently used with success in the treatment of certain cancer patients. Their action was first shown to be specific to cells with DNA repair deficiencies, such as BRCA-mutant cancers. However, recent work has suggested clinical interest of these drugs beyond this group of patients. Preclinical data on relationships between the activity of PARP inhibitors and other proteins involved in DNA repair exist, and this review will only highlight findings on the SLX4 protein and its interacting protein partners. As suggested from these available data and depending on further validations, new treatment strategies could be developed in order to broaden the use for PARP inhibitors in cancer patients. Full article
(This article belongs to the Special Issue Cancer Chemotherapy: Combination with Inhibitors)
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13 pages, 752 KiB  
Article
Re-Irradiation by Stereotactic Radiotherapy of Brain Metastases in the Case of Local Recurrence
by Ruben Touati, Vincent Bourbonne, Gurvan Dissaux, Gaëlle Goasduff, Olivier Pradier, Charles Peltier, Romuald Seizeur, Ulrike Schick and François Lucia
Cancers 2023, 15(3), 996; https://doi.org/10.3390/cancers15030996 - 03 Feb 2023
Cited by 1 | Viewed by 2196
Abstract
Purpose: To evaluate the efficacy and safety of a second course of stereotactic radiotherapy (SRT2) treatment for a local recurrence of brain metastases previously treated with SRT (SRT1), using the Hypofractionated Treatment Effects in the Clinic (HyTEC) reporting standards and the European Society [...] Read more.
Purpose: To evaluate the efficacy and safety of a second course of stereotactic radiotherapy (SRT2) treatment for a local recurrence of brain metastases previously treated with SRT (SRT1), using the Hypofractionated Treatment Effects in the Clinic (HyTEC) reporting standards and the European Society for Radiotherapy and Oncology guidelines. Methods: From December 2014 to May 2021, 32 patients with 34 brain metastases received salvage SRT2 after failed SRT1. A total dose of 21 to 27 Gy in 3 fractions or 30 Gy in 5 fractions was prescribed to the periphery of the PTV (99% of the prescribed dose covering 99% of the PTV). After SRT2, multiparametric MRI, sometimes combined with 18F-DOPA PET-CT, was performed every 3 months to determine local control (LC) and radionecrosis (RN). Results: After a median follow-up of 12 months (range: 1–37 months), the crude LC and RN rates were 68% and 12%, respectively, and the median overall survival was 25 months. In a multivariate analysis, the performance of surgery was predictive of a significantly better LC (p = 0.002) and survival benefit (p = 0.04). The volume of a normal brain receiving 5 Gy during SRT2 (p = 0.04), a dose delivered to the PTV in SRT1 (p = 0.003), and concomitant systemic therapy (p = 0.04) were associated with an increased risk of RN. Conclusion: SRT2 is an effective approach for the local recurrence of BM after initial SRT treatment and is a potential salvage therapy option for well-selected people with a good performance status. Surgery was associated with a higher LC. Full article
(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)
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21 pages, 6877 KiB  
Article
Repurposing the Bis-Biguanide Alexidine in Combination with Tyrosine Kinase Inhibitors to Eliminate Leukemic Stem/Progenitor Cells in Chronic Myeloid Leukemia
by Fabien Muselli, Lucas Mourgues, Nathalie Rochet, Marielle Nebout, Agnès Guerci, Els Verhoeyen, Adrien Krug, Laurence Legros, Jean-François Peyron and Didier Mary
Cancers 2023, 15(3), 995; https://doi.org/10.3390/cancers15030995 - 03 Feb 2023
Cited by 1 | Viewed by 1761
Abstract
Background & aims: In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells [...] Read more.
Background & aims: In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells self-renewal induced a CCNG2/dependent proliferation arrest leading to elimination of Chronic Myeloid Leukemia (CML) cells. Unfortunately, as of today, pharmacological inhibition of BMI1 has not made its way to the clinic. Methods: We used the Connectivity Map bioinformatic database to identify pharmacological molecules that could mimick BMI1 silencing, to induce CML cell death. We selected the bis-biguanide Alexidin (ALX) that produced a transcriptomic profile positively correlating with the one obtained after BMI silencing in K562 CML cells. We then evaluated the efficiency of ALX in combination with TKI on CML cells. Results: Here we report that cell growth and clonogenic activity of K562 and LAMA-84 CML cell lines were strongly inhibited by ALX. ALX didn’t modify BCR::ABL1 phosphorylation and didn’t affect BMI1 expression but was able to increase CCNG2 expression leading to autophagic processes that preceed cell death. Besides, ALX could enhance the apoptotic response induced by any Tyrosine Kinase Inhibitors (TKI) of the three generations. We also noted a strong synergism between ALX and TKIs to increase expression of caspase-9 and caspase-3 and induce PARP cleavage, Bad expression and significantly decreased Bcl-xL family member expression. We also observed that the blockage of the mitochondrial respiratory chain by ALX can be associated with inhibition of glycolysis by 2-DG to achieve an enhanced inhibition of K562 proliferation and clonogenicity. ALX specifically affected the differentiation of BCR::ABL1-transduced healthy CD34+ cells but not of mock-infected healthy CD34+ control cells. Importantly, ALX strongly synergized with TKIs to inhibit clonogenicity of primary CML CD34+ cells from diagnosed patients. Long Term Culture of Initiating Cell (LTC-IC) and dilution of the fluorescent marker CFSE allowed us to observe that ALX and Imatinib (IM) partially reduced the number of LSCs by themselves but that the ALX/IM combination drastically reduced this cell compartment. Using an in vivo model of NSG mice intravenously injected with K562-Luciferase transduced CML cells, we showed that ALX combined with IM improved mice survival. Conclusions: Collectively, our results validate the use of ALX bis-biguanide to potentiate the action of conventional TKI treatment as a potential new therapeutic solution to eradicate CML LSCs Full article
(This article belongs to the Special Issue New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies)
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20 pages, 7065 KiB  
Article
Alterations in Natural Killer Cells in Colorectal Cancer Patients with Stroma AReactive Invasion Front Areas (SARIFA)
by Nic G. Reitsam, Bruno Märkl, Sebastian Dintner, Eva Sipos, Przemyslaw Grochowski, Bianca Grosser, Florian Sommer, Stefan Eser, Pia Nerlinger, Frank Jordan, Andreas Rank, Phillip Löhr and Johanna Waidhauser
Cancers 2023, 15(3), 994; https://doi.org/10.3390/cancers15030994 - 03 Feb 2023
Cited by 8 | Viewed by 2073
Abstract
Background: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct [...] Read more.
Background: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct tumor biology. Considering it is already known that peripheral immune cells are altered in colorectal cancer (CRC) patients, this study aims to investigate the changes in lymphocyte subsets in SARIFA-positive cases and correlate these changes with the local immune response. Methods: Flow cytometry was performed to analyze B, T, and natural killer (NK) cells in the peripheral blood (PB) of 45 CRC patients. Consecutively, lymphocytes in PB, tumor-infiltrating lymphocytes (TILs), and CD56+ and CD57+ lymphocytes at the invasion front and the tumor center were compared between patients with SARIFA-positive and SARIFA-negative CRCs. Results: Whereas no differences could be observed regarding most PB lymphocyte populations as well as TILs, NK cells were dramatically reduced in the PB of SARIFA-positive cases. Moreover, CD56 and CD57 immunohistochemistry suggested SARIFA-status-dependent changes regarding NK cells and NK-like lymphocytes in the tumor microenvironment. Conclusion: This study proves that our newly introduced biomarker, SARIFA, comes along with distinct immunologic alterations, especially regarding NK cells. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)
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66 pages, 3055 KiB  
Review
Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies
by Samhita De, Sourav Paul, Anirban Manna, Chirantan Majumder, Koustav Pal, Nicolette Casarcia, Arijit Mondal, Sabyasachi Banerjee, Vinod Kumar Nelson, Suvranil Ghosh, Joyita Hazra, Ashish Bhattacharjee, Subhash Chandra Mandal, Mahadeb Pal and Anupam Bishayee
Cancers 2023, 15(3), 993; https://doi.org/10.3390/cancers15030993 - 03 Feb 2023
Cited by 11 | Viewed by 3811
Abstract
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of [...] Read more.
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as “colorectal cancer” AND “phenolic compounds”, “colorectal cancer” AND “polyphenol”, “colorectal cancer” AND “phenolic acids”, “colorectal cancer” AND “flavonoids”, “colorectal cancer” AND “stilbene”, and “colorectal cancer” AND “lignan” from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Cancer Prevention and Intervention with Bioactive Food Components)
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10 pages, 893 KiB  
Article
Three Months’ PSA and Toxicity from a Prospective Trial Investigating STereotactic sAlvage Radiotherapy for Macroscopic Prostate Bed Recurrence after Prostatectomy—STARR (NCT05455736)
by Giulio Francolini, Pietro Garlatti, Vanessa Di Cataldo, Beatrice Detti, Mauro Loi, Daniela Greto, Gabriele Simontacchi, Ilaria Morelli, Luca Burchini, Andrea Gaetano Allegra, Giulio Frosini, Michele Ganovelli, Viola Salvestrini, Emanuela Olmetto, Luca Visani, Carlotta Becherini, Marianna Valzano, Maria Grazia Carnevale, Manuele Roghi, Sergio Serni, Chiara Mattioli, Isacco Desideri and Lorenzo Liviadd Show full author list remove Hide full author list
Cancers 2023, 15(3), 992; https://doi.org/10.3390/cancers15030992 - 03 Feb 2023
Cited by 4 | Viewed by 1407
Abstract
Biochemical recurrences after radical prostatectomy (RP) can be managed with curative purpose through salvage radiation therapy (SRT). RT dose escalation, such as stereotactic RT (SSRT), may improve relapse-free survival in this setting. STARR trial (NCT05455736) is a prospective multicenter study including patients affected [...] Read more.
Biochemical recurrences after radical prostatectomy (RP) can be managed with curative purpose through salvage radiation therapy (SRT). RT dose escalation, such as stereotactic RT (SSRT), may improve relapse-free survival in this setting. STARR trial (NCT05455736) is a prospective multicenter study including patients affected by macroscopic recurrence within the prostate bed after RP treated with SSRT. Recurrence was detected with a Choline or PSMA CT-PET. In the current analysis, the early biochemical response (BR) rate and toxicity profile after three months of follow-up were assessed. Twenty-five patients were enrolled, and data about BR and toxicity at three months after treatment were available for 19 cases. Overall, BR was detected after three months in 58% of cases. Four G1–G2 adverse events were recorded; no G ≥ 3 adverse events were detected. SSRT appears feasible and safe, with more than half of patients experiencing BR and an encouraging toxicity profile. The STARR trial is one of the few prospective studies aimed at implementing this promising treatment strategy in this scenario. Full article
(This article belongs to the Special Issue High-Risk Localized and Locally Advanced Prostate Cancer)
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13 pages, 1232 KiB  
Article
Survival in Colon, Rectal and Small Intestinal Cancers in the Nordic Countries through a Half Century
by Filip Tichanek, Asta Försti, Vaclav Liska, Akseli Hemminki and Kari Hemminki
Cancers 2023, 15(3), 991; https://doi.org/10.3390/cancers15030991 - 03 Feb 2023
Cited by 11 | Viewed by 1613
Abstract
Background: Survival studies in intestinal cancers have generally shown favorable development, but few studies have been able to pinpoint the timing of the changes in survival over an extended period. Here, we compared the relative survival rates for colon, rectal and small intestinal [...] Read more.
Background: Survival studies in intestinal cancers have generally shown favorable development, but few studies have been able to pinpoint the timing of the changes in survival over an extended period. Here, we compared the relative survival rates for colon, rectal and small intestinal cancers from Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE). Design: Relative 1-, 5- and 5/1-year conditional survival data were obtained from the NORDCAN database for the years 1971–2020. Results: The 50-year survival patterns were country-specific. For colon and rectal cancers, the slopes of survival curves bended upwards for DK, were almost linear for NO and bended downwards for FI and SE; 5-year survival was the highest in DK. Survival in small intestinal cancer was initially below colon and rectal cancers but in FI and NO it caught up toward the end of the follow-up. Conclusions: Relative survival in intestinal cancers has developed well in the Nordic countries, and DK is an example of a country which in 20 years was able to achieve excellent survival rates in colon and rectal cancers. In the other countries, the increase in survival curves for colon and rectal cancer has slowed down, which may be a challenge posed by metastatic cancers. Full article
(This article belongs to the Special Issue Cancer Survival)
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18 pages, 8566 KiB  
Article
Antigene MYCN Silencing by BGA002 Inhibits SCLC Progression Blocking mTOR Pathway and Overcomes Multidrug Resistance
by Sonia Bortolotti, Silvia Angelucci, Luca Montemurro, Damiano Bartolucci, Salvatore Raieli, Silvia Lampis, Camilla Amadesi, Annalisa Scardovi, Giammario Nieddu, Lucia Cerisoli, Francesca Paganelli, Francesca Chiarini, Gabriella Teti, Mirella Falconi, Andrea Pession, Patrizia Hrelia and Roberto Tonelli
Cancers 2023, 15(3), 990; https://doi.org/10.3390/cancers15030990 - 03 Feb 2023
Cited by 2 | Viewed by 2283
Abstract
Small-cell lung cancer (SCLC) is the most aggressive lung cancer type, and is associated with smoking, low survival rate due to high vascularization, metastasis and drug resistance. Alterations in MYC family members are biomarkers of poor prognosis for a large number of SCLC. [...] Read more.
Small-cell lung cancer (SCLC) is the most aggressive lung cancer type, and is associated with smoking, low survival rate due to high vascularization, metastasis and drug resistance. Alterations in MYC family members are biomarkers of poor prognosis for a large number of SCLC. In particular, MYCN alterations define SCLC cases with immunotherapy failure. MYCN has a highly restricted pattern of expression in normal cells and is an ideal target for cancer therapy but is undruggable by traditional approaches. We propose an innovative approach to MYCN inhibition by an MYCN-specific antigene—PNA oligonucleotide (BGA002)—as a new precision medicine for MYCN-related SCLC. We found that BGA002 profoundly and specifically inhibited MYCN expression in SCLC cells, leading to cell-growth inhibition and apoptosis, while also overcoming multidrug resistance. These effects are driven by mTOR pathway block in concomitance with autophagy reactivation, thus avoiding the side effects of targeting mTOR in healthy cells. Moreover, we identified an MYCN-related SCLC gene signature comprehending CNTFR, DLX5 and TNFAIP3, that was reverted by BGA002. Finally, systemic treatment with BGA002 significantly increased survival in MYCN-amplified SCLC mouse models, including in a multidrug-resistant model in which tumor vascularization was also eliminated. These findings warrant the clinical testing of BGA002 in MYCN-related SCLC. Full article
(This article belongs to the Special Issue Lung Cancer - Molecular Insights and Targeted Therapies)
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15 pages, 1028 KiB  
Article
Lower Expression of CFTR Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer
by Patricia Scott, Shuo Wang, Guillaume Onyeaghala, Nathan Pankratz, Timothy Starr and Anna E. Prizment
Cancers 2023, 15(3), 989; https://doi.org/10.3390/cancers15030989 - 03 Feb 2023
Cited by 1 | Viewed by 1706
Abstract
Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of [...] Read more.
Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral CFTR mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced CFTR expression in this population, we investigated association of tumoral CFTR expression with overall and disease-specific mortality in CRC patients. CFTR mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] CFTR expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased CFTR expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, CFTR expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57–0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47–0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and CFTR expression, (p-interaction: 0.06). The findings from these three datasets support the hypothesis that low CFTR expression is associated with increased CRC mortality. Full article
(This article belongs to the Special Issue Colorectal Cancer: Recent Advances and Challenges)
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15 pages, 292 KiB  
Review
Management of Locally Advanced or Metastatic Combined Hepatocellular Cholangiocarcinoma
by Jemmy Zhao, Susann Stephan-Falkenau, Markus Schuler and Börge Arndt
Cancers 2023, 15(3), 988; https://doi.org/10.3390/cancers15030988 - 03 Feb 2023
Cited by 1 | Viewed by 2075
Abstract
Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the [...] Read more.
Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the mainstay treatment. However, most patients relapse or display advanced disease and were not surgical candidates. Although the majority of patients are either primarily or secondarily treated in palliative intent, no guideline recommendations or prospective trial reports exist to allow reliable evaluation of debated treatment options. We review different locoregional or medical treatment options for advanced combined hepatocellular cholangiocarcinoma (cHCC-CC) in the neoadjuvant, adjuvant, or palliative setting and discuss the possibility of predictive biomarker-guided therapeutic options. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
19 pages, 2596 KiB  
Article
Characterization of Inorganic Scintillator Detectors for Dosimetry in Image-Guided Small Animal Radiotherapy Platforms
by Ileana Silvestre Patallo, Anna Subiel, Rebecca Carter, Samuel Flynn, Giuseppe Schettino and Andrew Nisbet
Cancers 2023, 15(3), 987; https://doi.org/10.3390/cancers15030987 - 03 Feb 2023
Viewed by 1781
Abstract
The purpose of the study was to characterize a detection system based on inorganic scintillators and determine its suitability for dosimetry in preclinical radiation research. Dose rate, linearity, and repeatability of the response (among others) were assessed for medium-energy X-ray beam qualities. The [...] Read more.
The purpose of the study was to characterize a detection system based on inorganic scintillators and determine its suitability for dosimetry in preclinical radiation research. Dose rate, linearity, and repeatability of the response (among others) were assessed for medium-energy X-ray beam qualities. The response’s variation with temperature and beam angle incidence was also evaluated. Absorbed dose quality-dependent calibration coefficients, based on a cross-calibration against air kerma secondary standard ionization chambers, were determined. Relative output factors (ROF) for small, collimated fields (≤10 mm × 10 mm) were measured and compared with Gafchromic film and to a CMOS imaging sensor. Independently of the beam quality, the scintillator signal repeatability was adequate and linear with dose. Compared with EBT3 films and CMOS, ROF was within 5% (except for smaller circular fields). We demonstrated that when the detector is cross-calibrated in the user’s beam, it is a useful tool for dosimetry in medium-energy X-rays with small fields delivered by Image-Guided Small Animal Radiotherapy Platforms. It supports the development of procedures for independent “live” dose verification of complex preclinical radiotherapy plans with the possibility to insert the detectors in phantoms. Full article
(This article belongs to the Special Issue Radiation Dose in Cancer Radiotherapy)
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12 pages, 673 KiB  
Review
Global Longitudinal Strain in Cardio-Oncology: A Review
by Grzegorz Sławiński, Maja Hawryszko, Aleksandra Liżewska-Springer, Izabela Nabiałek-Trojanowska and Ewa Lewicka
Cancers 2023, 15(3), 986; https://doi.org/10.3390/cancers15030986 - 03 Feb 2023
Cited by 8 | Viewed by 3238
Abstract
Several therapies used in cancer treatment are potentially cardiotoxic and may cause left ventricular (LV) dysfunction and heart failure. For decades, echocardiography has been the main modality for cardiac assessment in cancer patients, and the parameter examined in the context of cardiotoxicity was [...] Read more.
Several therapies used in cancer treatment are potentially cardiotoxic and may cause left ventricular (LV) dysfunction and heart failure. For decades, echocardiography has been the main modality for cardiac assessment in cancer patients, and the parameter examined in the context of cardiotoxicity was the left ventricular ejection fraction (LVEF). The assessment of the global longitudinal strain (GLS) using speckle tracking echocardiography (STE) is an emerging method for detecting and quantifying subtle disturbances in the global long-axis LV systolic function. In the latest ESC guidelines on cardio-oncology, GLS is an important element in diagnosing the cardiotoxicity of oncological therapy. A relative decrease in GLS of >15% during cancer treatment is the recommended cut-off point for suspecting subclinical cardiac dysfunction. An early diagnosis of asymptomatic cardiotoxicity allows the initiation of a cardioprotective treatment and reduces the risk of interruptions or changes in the oncological treatment in the event of LVEF deterioration, which may affect survival. Full article
(This article belongs to the Section Cancer Therapy)
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28 pages, 705 KiB  
Systematic Review
Immersive and Non-Immersive Virtual Reality for Pain and Anxiety Management in Pediatric Patients with Hematological or Solid Cancer: A Systematic Review
by Dania Comparcini, Valentina Simonetti, Francesco Galli, Ilaria Saltarella, Concetta Altamura, Marco Tomietto, Jean-François Desaphy and Giancarlo Cicolini
Cancers 2023, 15(3), 985; https://doi.org/10.3390/cancers15030985 - 03 Feb 2023
Cited by 5 | Viewed by 3267
Abstract
Invasive and painful procedures, which often induce feelings of anxiety, are necessary components of pediatric cancer treatment, and adequate pain and anxiety management during these treatments is of pivotal importance. In this context, it is widely recognized that a holistic approach, including pharmacological [...] Read more.
Invasive and painful procedures, which often induce feelings of anxiety, are necessary components of pediatric cancer treatment, and adequate pain and anxiety management during these treatments is of pivotal importance. In this context, it is widely recognized that a holistic approach, including pharmacological and non-pharmacological modalities, such as distraction techniques, should be the standard of care. Recent evidence suggested the use of virtual reality (VR) as an effective non-pharmacological intervention in pediatrics. Therefore, this systematic review aims to analyze previously published studies on the effectiveness of VR for the management of pain and/or anxiety in children and adolescents with hematological or solid cancer. Medline, SCOPUS, Web of Science, ProQuest, CINAHL, and The Cochrane Central Register of Controlled Trials were used to search for relevant studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Randomized controlled trial, crossover trial, cluster randomized trial, and quasi-experimental studies were included. Thirteen studies, published between 1999 and 2022, that fulfilled the inclusion criteria were included. Regarding the primary outcomes measured, pain was considered in five studies, anxiety in three studies, and the remaining five studies analyzed the effectiveness of VR for both pain and anxiety reduction. Our findings suggested a beneficial effect of VR during painful vascular access procedures. Limited data are available on the reduction of anxiety in children with cancer. Full article
(This article belongs to the Section Cancer Survivorship and Quality of Life)
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22 pages, 1528 KiB  
Review
Heat-Shock Proteins in Leukemia and Lymphoma: Multitargets for Innovative Therapeutic Approaches
by Vincent Cabaud-Gibouin, Manon Durand, Ronan Quéré, François Girodon, Carmen Garrido and Gaëtan Jego
Cancers 2023, 15(3), 984; https://doi.org/10.3390/cancers15030984 - 03 Feb 2023
Cited by 9 | Viewed by 2330
Abstract
Heat-shock proteins (HSPs) are powerful chaperones that provide support for cellular functions under stress conditions but also for the homeostasis of basic cellular machinery. All cancer cells strongly rely on HSPs, as they must continuously adapt to internal but also microenvironmental stresses to [...] Read more.
Heat-shock proteins (HSPs) are powerful chaperones that provide support for cellular functions under stress conditions but also for the homeostasis of basic cellular machinery. All cancer cells strongly rely on HSPs, as they must continuously adapt to internal but also microenvironmental stresses to survive. In solid tumors, HSPs have been described as helping to correct the folding of misfolded proteins, sustain oncogenic pathways, and prevent apoptosis. Leukemias and lymphomas also overexpress HSPs, which are frequently associated with resistance to therapy. HSPs have therefore been proposed as new therapeutic targets. Given the specific biology of hematological malignancies, it is essential to revise their role in this field, providing a more adaptable and comprehensive picture that would help design future clinical trials. To that end, this review will describe the different pathways and functions regulated by HSP27, HSP70, HSP90, and, not least, HSP110 in leukemias and lymphomas. Full article
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10 pages, 410 KiB  
Article
Long-Term Survival of Patients with Mantle Cell Lymphoma after Total Body Irradiation, High-Dose Chemotherapy and Stem Cell Transplantation: A Monocenter Study
by Kai Kröger, Jan Siats, Andrea Kerkhoff, Georg Lenz, Matthias Stelljes, Hans Theodor Eich and Gabriele Reinartz
Cancers 2023, 15(3), 983; https://doi.org/10.3390/cancers15030983 - 03 Feb 2023
Cited by 1 | Viewed by 1552
Abstract
Introduction: In patients with mantle cell lymphoma (MCL), long-term remissions can be achieved by stem cell transplantation (SCT). Different conditioning treatment protocols exist with or without total body irradiation (TBI). There are few data published on the role of TBI before autologous stem [...] Read more.
Introduction: In patients with mantle cell lymphoma (MCL), long-term remissions can be achieved by stem cell transplantation (SCT). Different conditioning treatment protocols exist with or without total body irradiation (TBI). There are few data published on the role of TBI before autologous stem cell transplantation (autoSCT) or allogenic stem cell transplantation (alloSCT). We report on the long-term survival data of patients treated by TBI prior to autologous or allogenic SCT at our center. Patients: In a retrospective analysis, the data of patients treated at the University Hospital of Muenster from May 2004 to February 2015 were collected and evaluated. For the analysis, all data of patients who were histopathologically diagnosed with MCL and underwent TBI prior to stem cell transplantation (SCT) were evaluated. Results: A total of 22 patients (19 men and 3 women) were treated with a TBI-based conditioning prior to SCT. The median age at initial diagnosis was 57.5 years (38–65 years). Seventeen patients had Ann Arbor stage IV, two patients had Ann Arbor stage III, and three patients Ann Arbor stage II disease. AutoSCT was performed in 19 patients and alloSCT was performed in 3 patients. In 18 patients, autoSCT was applied as part of first-line therapy, and in one patient after relapse. Two patients received alloSCT after relapse of MCL, and one patient received alloSCT during first-line therapy after an inadequate treatment response. TBI was performed in 12 patients with 10 Gy and in 6 patients with 12 Gy, these patients subsequently received autoSCT. In the group of four patients who received TBI with four Gy, four patients subsequently received alloSCT and one patient received autoSCT. Median overall survival after autoSCT and previous TBI was 11.4 years (142 months). In total, 11 out of 19 patients treated with autoSCT lived longer than 6.8 years (82–202 months). After alloSCT and previous TBI, the median overall survival was 3.25 years (14–59 months). Conclusions: A large proportion of patients with advanced MCL survived remarkably longer than 11.4 years after high-dose chemotherapy, TBI, and SCT. The present results of multimodal treatment support the published reports that TBI-based high-dose therapy followed by autoSCT is highly effective in this prognostically unfavorable disease situation. Full article
(This article belongs to the Special Issue Hot Topics and New Treatment Approaches in Lymphoma)
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33 pages, 6100 KiB  
Article
Glucose Metabolism Reprogramming in Bladder Cancer: Hexokinase 2 (HK2) as Prognostic Biomarker and Target for Bladder Cancer Therapy
by Julieta Afonso, Céline Gonçalves, Marta Costa, Débora Ferreira, Lúcio Santos, Adhemar Longatto-Filho and Fátima Baltazar
Cancers 2023, 15(3), 982; https://doi.org/10.3390/cancers15030982 - 03 Feb 2023
Cited by 7 | Viewed by 3030
Abstract
Proliferating cancer cells are able to reprogram their energy metabolism, favouring glycolysis even in the presence of oxygen and fully functioning mitochondria. Research is needed to validate the glycolysis-related proteins as prognostic/predictive biomarkers in urothelial bladder carcinoma (UBC), a malignancy tagged by high [...] Read more.
Proliferating cancer cells are able to reprogram their energy metabolism, favouring glycolysis even in the presence of oxygen and fully functioning mitochondria. Research is needed to validate the glycolysis-related proteins as prognostic/predictive biomarkers in urothelial bladder carcinoma (UBC), a malignancy tagged by high recurrence rates and poor response to chemotherapy. Here, we assessed GLUT1, HK2, PFKL, PKM2, phospho-PDH, and LDHA immunoexpression in 76 UBC samples, differentiating among urothelial, fibroblast, and endothelial cells and among normoxic versus hypoxic areas. We additionally studied the functional effects of the HK2 inhibitor 2-deoxy-D-glucose (2DG) in “in vitro” and “in vivo” preclinical UBC models. We showed that the expression of the glycolysis-related proteins is associated with UBC aggressiveness and poor prognosis. HK2 remained as an independent prognostic factor for disease-free and overall survival. 2DG decreased the UBC cell’s viability, proliferation, migration, and invasion; the inhibition of cell cycle progression and apoptosis occurrence was also verified. A significant reduction in tumour growth and blood vessel formation upon 2DG treatment was observed in the chick chorioallantoic membrane assay. 2DG potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. This study highlights HK2 as a prognostic biomarker for UBC patients and demonstrates the potential benefits of using 2DG as a glycolysis inhibitor. Future studies should focus on integrating 2DG into chemotherapy design, as an attempt to overcome cisplatin resistance. Full article
(This article belongs to the Special Issue Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer)
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20 pages, 3049 KiB  
Article
Mechanism of cis-Nerolidol-Induced Bladder Carcinoma Cell Death
by Mateo Glumac, Vedrana Čikeš Čulić, Ivana Marinović-Terzić and Mila Radan
Cancers 2023, 15(3), 981; https://doi.org/10.3390/cancers15030981 - 03 Feb 2023
Cited by 3 | Viewed by 1805
Abstract
Nerolidol is a naturally occurring sesquiterpene alcohol with multiple properties, including antioxidant, antibacterial, and antiparasitic activities. A few studies investigating the antitumor properties of nerolidol have shown positive results in both cell culture and mouse models. In this study, we investigated the antitumor [...] Read more.
Nerolidol is a naturally occurring sesquiterpene alcohol with multiple properties, including antioxidant, antibacterial, and antiparasitic activities. A few studies investigating the antitumor properties of nerolidol have shown positive results in both cell culture and mouse models. In this study, we investigated the antitumor mechanism of cis-nerolidol in bladder carcinoma cell lines. The results of our experiments on two bladder carcinoma cell lines revealed that nerolidol inhibited cell proliferation and induced two distinct cell death pathways. We confirmed that cis-nerolidol induces DNA damage and ER stress. A mechanistic study identified a common cAMP, Ca2+, and MAPK axis involved in signal propagation and amplification, leading to ER stress. Inhibition of any part of this signaling cascade prevented both cell death pathways. The two cell death mechanisms can be distinguished by the involvement of caspases. The early occurring cell death pathway is characterized by membrane blebbing and cell swelling followed by membrane rupture, which can be prevented by the inhibition of caspase activation. In the late cell death pathway, which was found to be caspase-independent, cytoplasmic vacuolization and changes in cell shape were observed. cis-Nerolidol shows promising antitumor activity through an unorthodox mechanism of action that could help target resistant forms of malignancies, such as bladder cancer. Full article
(This article belongs to the Special Issue Identification of the Targets to Overcome Clinical Problems in Bladder Cancer)
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17 pages, 5332 KiB  
Systematic Review
Hormone Receptor Expression in Meningiomas: A Systematic Review
by Mikaël Agopiantz, Mélanie Carnot, Constance Denis, Elena Martin and Guillaume Gauchotte
Cancers 2023, 15(3), 980; https://doi.org/10.3390/cancers15030980 - 03 Feb 2023
Cited by 9 | Viewed by 2363
Abstract
Meningiomas are, in most cases, low grade intracranial tumors. However, relapses are frequent. To date, only a few prognostic markers are described in the literature. Several studies have discussed the expression of progesterone, estrogen, androgen, and somatostatin receptors. The utility of analyzing these [...] Read more.
Meningiomas are, in most cases, low grade intracranial tumors. However, relapses are frequent. To date, only a few prognostic markers are described in the literature. Several studies have discussed the expression of progesterone, estrogen, androgen, and somatostatin receptors. The utility of analyzing these expressions for prognostic, theragnostic, and therapeutic purposes remains unclear. The aim of this study was to report the expression of these receptors, based on immunohistochemistry. Cochrane Collaboration guidelines and PRISMA statements were followed. We did an online search in PubMed using the MeSH database. References were selected if the investigations occurred from 1990 to 2022. 61 references were included (34 descriptive observational studies, 26 analytical observational studies, and one case report). In this review, we describe the expression of these receptors in function of age, sex, hormonal context, localization, histological subtype, grade, and recurrence. Full article
(This article belongs to the Special Issue Predictive and Prognostic Markers in Brain Tumors: From Physiopathology to Clinical Applications)
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12 pages, 1290 KiB  
Article
Effect of Selenium and Lycopene on Radiation Sensitivity in Prostate Cancer Patients Relative to Controls
by Varinderpal S. Dhillon, Permal Deo and Michael Fenech
Cancers 2023, 15(3), 979; https://doi.org/10.3390/cancers15030979 - 03 Feb 2023
Cited by 3 | Viewed by 4331
Abstract
Almost half of prostate cancer (PC) patients receive radiation therapy as primary curative treatment. In spite of advances in our understanding of both nutrition and the genomics of prostate cancer, studies on the effects of nutrients on the radiation sensitivity of PC patients [...] Read more.
Almost half of prostate cancer (PC) patients receive radiation therapy as primary curative treatment. In spite of advances in our understanding of both nutrition and the genomics of prostate cancer, studies on the effects of nutrients on the radiation sensitivity of PC patients are lacking. We tested the hypothesis that low plasma levels of selenium and lycopene have detrimental effects on ionising radiation-induced DNA damage in prostate cancer patients relative to healthy individuals. The present study was performed in 106 PC patients and 132 age-matched controls. We found that the radiation-induced micronucleus (MN) and nuclear buds (NBuds) frequencies were significantly higher in PC patients with low selenium (p = 0.008 and p = 0.0006 respectively) or low lycopene (p = 0.007 and p = 0.0006 respectively) levels compared to the controls. The frequency of NBuds was significantly higher (p < 0.0001) in PC patients who had low levels of both selenium and lycopene compared to (i) controls with low levels of both selenium and lycopene and (ii) PC patients with high levels of both selenium and lycopene (p = 0.0001). Our results support the hypothesis that low selenium and lycopene levels increase the sensitivity to radiation-induced DNA damage and suggest that nutrition-based treatment strategies are important to minimise the DNA-damaging effects in PC patients receiving radiotherapy. Full article
(This article belongs to the Section Cancer Biomarkers)
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11 pages, 1621 KiB  
Article
Comparable Overall Survival in Patients with Hepatocellular Carcinoma Diagnosed within and outside a Surveillance Programme: The Potential Impact of Liver Cirrhosis
by Rosemary E. Faulkes, Zaira Rehman, Swetha Palanichamy, Nekisa Zakeri, Chris Coldham, Bobby V. M. Dasari, M. Thamara P. R. Perera, Neil Rajoriya, Shishir Shetty and Tahir Shah
Cancers 2023, 15(3), 978; https://doi.org/10.3390/cancers15030978 - 03 Feb 2023
Cited by 1 | Viewed by 1682
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is rising. Mortality from HCC is predicted to increase by 140% by 2035. Surveillance of high-risk patients with cirrhosis or chronic liver disease may be one means of reducing [...] Read more.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is rising. Mortality from HCC is predicted to increase by 140% by 2035. Surveillance of high-risk patients with cirrhosis or chronic liver disease may be one means of reducing HCC mortality, but the level of supporting evidence for international guidelines is low/moderate. This study explores the real-world experience of HCC surveillance at a tertiary referral centre. Electronic patient records for all new HCCs diagnosed between August 2012 and December 2021 were retrospectively reviewed. Patient and tumour characteristics were evaluated, including the co-existence of chronic liver disease, cancer treatment and survival, and categorised according to HCC diagnosis within or outside a surveillance programme. Patients with HCC who presented through surveillance had smaller tumours diagnosed at an earlier stage, but this did not translate into improved overall survival. All patients in surveillance had chronic liver disease, including 91% (n = 101) with cirrhosis, compared to 45% (n = 29) in the non-surveillance cohort. We propose that the immune dysfunction associated with cirrhosis predisposes patients to a more aggressive tumour biology than the largely non-cirrhotic population in the non-surveillance group. Full article
(This article belongs to the Collection Primary Liver Cancer)
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11 pages, 2444 KiB  
Communication
Epiploic Adipose Tissue (EPAT) in Obese Individuals Promotes Colonic Tumorigenesis: A Novel Model for EPAT-Dependent Colorectal Cancer Progression
by Rida Iftikhar, Patricia Snarski, Angelle N. King, Jenisha Ghimire, Emmanuelle Ruiz, Frank Lau and Suzana D. Savkovic
Cancers 2023, 15(3), 977; https://doi.org/10.3390/cancers15030977 - 03 Feb 2023
Cited by 2 | Viewed by 1893
Abstract
The obesity epidemic is associated with increased colorectal cancer (CRC) risk and progression, the mechanisms of which remain unclear. In obese individuals, hypertrophic epiploic adipose tissue (EPAT), attached to the colon, has unique characteristics compared to other fats. We hypothesized that this understudied [...] Read more.
The obesity epidemic is associated with increased colorectal cancer (CRC) risk and progression, the mechanisms of which remain unclear. In obese individuals, hypertrophic epiploic adipose tissue (EPAT), attached to the colon, has unique characteristics compared to other fats. We hypothesized that this understudied fat could serve as a tumor-promoting tissue and developed a novel microphysiological system (MPS) for human EPAT-dependent colorectal cancer (CRC-MPS). In CRC-MPS, obese EPAT, unlike lean EPAT, considerably attracted colon cancer HT29-GFP cells and enhanced their growth. Conditioned media (CM) from the obese CRC-MPS significantly increased the growth and migration of HT29 and HCT116 cells (p < 0.001). In HT29 cells, CM stimulated differential gene expression (hOEC867) linked to cancer, tumor morphology, and metabolism similar to those in the colon of high-fat-diet obese mice. The hOEC867 signature represented pathways found in human colon cancer. In unsupervised clustering, hOEC867 separated transcriptomes of colon cancer samples from normal with high significance (PCA, p = 9.6 × 10−11). These genes, validated in CM-treated HT29 cells (p < 0.05), regulate the cell cycle, cancer stem cells, methylation, and metastasis, and are similarly altered in human colon cancer (TCGA). These findings highlight a tumor-promoting role of EPAT in CRC facilitated with obesity and establishes a platform to explore critical mechanisms and develop effective treatments. Full article
(This article belongs to the Special Issue Metabolic Alterations in Cancer)
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11 pages, 2909 KiB  
Article
Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients
by Yan Liu, Billy C. Wang, Craig W. Zuppan, Peter Chau, James Fitts, Richard Chinnock and Jun Wang
Cancers 2023, 15(3), 976; https://doi.org/10.3390/cancers15030976 - 03 Feb 2023
Cited by 5 | Viewed by 1558
Abstract
Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. [...] Read more.
Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. A total of 558 children and infants underwent cardiac transplantation at our institution between 1985 and 2019 and were followed until March 2021. Forty-nine of 558 patients developed PTLD (8.8%). As compared to older children (>one year of age), infant recipients (<three months of age) were less likely to develop PTLD. Monomorphic PTLDs (M-PTLD, 61%) was the most common subtype at initial diagnosis, followed by non-destructive (21%), polymorphic (14%), and classic Hodgkin lymphoma (cHL, 4%). Patients who underwent transplantation at a young age (<three months) had significantly lower rates of M-PTLD or cHL and a longer time from transplant to PTLD diagnosis as compared to children older than one year at transplant (p = 0.04). Although not reaching statistical significance, patients with a shorter time to PTLD diagnosis showed a trend toward higher rates of M-PTLD or cHL. As expected, the overall survival (OS) of patients with M-PTLD or cHL was significantly lower than patients with non-destructive or polymorphic PTLD. Full article
(This article belongs to the Special Issue Advances in Virus-Associated Lymphomas)
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14 pages, 1077 KiB  
Article
Development and Internal Validation of a Risk Prediction Model to Identify Myeloma Based on Routine Blood Tests: A Case-Control Study
by Lesley Smith, Jonathan Carmichael, Gordon Cook, Bethany Shinkins and Richard D. Neal
Cancers 2023, 15(3), 975; https://doi.org/10.3390/cancers15030975 - 03 Feb 2023
Cited by 1 | Viewed by 1773
Abstract
Myeloma is one of the hardest cancers to diagnose in primary care due to its rarity and non-specific symptoms. A rate-limiting step in diagnosing myeloma is the clinician considering myeloma and initiating appropriate investigations. We developed and internally validated a risk prediction model [...] Read more.
Myeloma is one of the hardest cancers to diagnose in primary care due to its rarity and non-specific symptoms. A rate-limiting step in diagnosing myeloma is the clinician considering myeloma and initiating appropriate investigations. We developed and internally validated a risk prediction model to identify those with a high risk of having undiagnosed myeloma based on results from routine blood tests taken for other reasons. A case-control study, based on 367 myeloma cases and 1488 age- and sex-matched controls, was used to develop a risk prediction model including results from 15 blood tests. The model had excellent discrimination (C-statistic 0.85 (95%CI 0.83, 0.89)) and good calibration (calibration slope 0.87 (95%CI 0.75, 0.90)). At a prevalence of 15 per 100,000 population and a probability threshold of 0.4, approximately 600 patients would need additional reflex testing to detect one case. We showed that it is possible to combine signals and abnormalities from several routine blood test parameters to identify individuals at high-risk of having undiagnosed myeloma who may benefit from additional reflex testing. Further work is needed to explore the full potential of such a strategy, including whether it is clinically useful and cost-effective and how to make it ethically acceptable. Full article
(This article belongs to the Special Issue Cancer Detection in Primary Care)
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13 pages, 2369 KiB  
Communication
A Comparison of Different Sample Processing Protocols for MALDI Imaging Mass Spectrometry Analysis of Formalin-Fixed Multiple Myeloma Cells
by Rita Casadonte, Jörg Kriegsmann, Mark Kriegsmann, Katharina Kriegsmann, Roberta Torcasio, Maria Eugenia Gallo Cantafio, Giuseppe Viglietto and Nicola Amodio
Cancers 2023, 15(3), 974; https://doi.org/10.3390/cancers15030974 - 03 Feb 2023
Cited by 1 | Viewed by 1896
Abstract
Sample processing of formalin-fixed specimens constitutes a major challenge in molecular profiling efforts. Pre-analytical factors such as fixative temperature, dehydration, and embedding media affect downstream analysis, generating data dependent on technical processing rather than disease state. In this study, we investigated two different [...] Read more.
Sample processing of formalin-fixed specimens constitutes a major challenge in molecular profiling efforts. Pre-analytical factors such as fixative temperature, dehydration, and embedding media affect downstream analysis, generating data dependent on technical processing rather than disease state. In this study, we investigated two different sample processing methods, including the use of the cytospin sample preparation and automated sample processing apparatuses for proteomic analysis of multiple myeloma (MM) cell lines using imaging mass spectrometry (IMS). In addition, two sample-embedding instruments using different reagents and processing times were considered. Three MM cell lines fixed in 4% paraformaldehyde were either directly centrifuged onto glass slides using cytospin preparation techniques or processed to create paraffin-embedded specimens with an automatic tissue processor, and further cut onto glass slides for IMS analysis. The number of peaks obtained from paraffin-embedded samples was comparable between the two different sample processing instruments. Interestingly, spectra profiles showed enhanced ion yield in cytospin compared to paraffin-embedded samples along with high reproducibility compared to the sample replicate. Full article
(This article belongs to the Special Issue Advances in Mass Spectrometry Imaging-Based Cancer Research)
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17 pages, 6854 KiB  
Article
Intestinal Epithelial Cells Adapt to Chronic Inflammation through Partial Genetic Reprogramming
by Guillaume Collin, Jean-Philippe Foy, Nicolas Aznar, Nicolas Rama, Anne Wierinckx, Pierre Saintigny, Alain Puisieux and Stéphane Ansieau
Cancers 2023, 15(3), 973; https://doi.org/10.3390/cancers15030973 - 03 Feb 2023
Cited by 1 | Viewed by 1821
Abstract
Reactive oxygen species (ROS) are considered to be the main drivers of inflammatory bowel disease. We investigated whether this permanent insult compels intestinal stem cells to develop strategies to dampen the deleterious effects of ROS. As an adverse effect, this adaptation process may [...] Read more.
Reactive oxygen species (ROS) are considered to be the main drivers of inflammatory bowel disease. We investigated whether this permanent insult compels intestinal stem cells to develop strategies to dampen the deleterious effects of ROS. As an adverse effect, this adaptation process may increase their tolerance to oncogenic insults and facilitate their neoplastic transformation. We submitted immortalized human colonic epithelial cells to either a mimic of chronic inflammation or to a chemical peroxide, analyzed how they adapted to stress, and addressed the biological relevance of these observations in databases. We demonstrated that cells adapt to chronic-inflammation-associated oxidative stress in vitro through a partial genetic reprogramming. Through a gene set enrichment analysis, we showed that this program is recurrently active in the intestinal mucosae of Crohn’s and ulcerative colitis disease patients and evolves alongside disease progression. Based on a previously reported characterization of intestinal stem and precursor cells using tracing experiments, we lastly confirmed the activation of the program in intestinal precursor cells during murine colorectal cancer development. This adaptive process is thus likely to play a role in the progression of Crohn’s and ulcerative disease, and potentially in the initiation of colorectal cancer. Full article
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15 pages, 2049 KiB  
Article
Prognostic Relevance of Multi-Antigenic Myeloma-Specific T-Cell Assay in Patients with Monoclonal Gammopathies
by Ivana Lagreca, Vincenzo Nasillo, Patrizia Barozzi, Ilaria Castelli, Sabrina Basso, Sara Castellano, Ambra Paolini, Monica Maccaferri, Elisabetta Colaci, Daniela Vallerini, Patrizia Natali, Daria Debbia, Tommaso Pirotti, Anna Maria Ottomano, Rossana Maffei, Francesca Bettelli, Davide Giusti, Andrea Messerotti, Andrea Gilioli, Valeria Pioli, Giovanna Leonardi, Fabio Forghieri, Paola Bresciani, Angela Cuoghi, Monica Morselli, Rossella Manfredini, Giuseppe Longo, Anna Candoni, Roberto Marasca, Leonardo Potenza, Enrico Tagliafico, Tommaso Trenti, Patrizia Comoli, Mario Luppi and Giovanni Rivaadd Show full author list remove Hide full author list
Cancers 2023, 15(3), 972; https://doi.org/10.3390/cancers15030972 - 03 Feb 2023
Cited by 1 | Viewed by 1735
Abstract
Multiple Myeloma (MM) typically originates from underlying precursor conditions, known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Validated risk factors, related to the main features of the clonal plasma cells, are employed in the current prognostic models to [...] Read more.
Multiple Myeloma (MM) typically originates from underlying precursor conditions, known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Validated risk factors, related to the main features of the clonal plasma cells, are employed in the current prognostic models to assess long-term probabilities of progression to MM. In addition, new prognostic immunologic parameters, measuring protective MM-specific T-cell responses, could help to identify patients with shorter time-to-progression. In this report, we described a novel Multi-antigenic Myeloma-specific (MaMs) T-cell assay, based on ELISpot technology, providing simultaneous evaluation of T-cell responses towards ten different MM-associated antigens. When performed during long-term follow-up (mean 28 months) of 33 patients with either MGUS or SMM, such deca-antigenic myeloma-specific immunoassay allowed to significantly distinguish between stable vs. progressive disease (p < 0.001), independently from the Mayo Clinic risk category. Here, we report the first clinical experience showing that a wide (multi-antigen), standardized (irrespective to patients’ HLA), MM-specific T-cell assay may routinely be applied, as a promising prognostic tool, during the follow-up of MGUS/SMM patients. Larger studies are needed to improve the antigenic panel and further explore the prognostic value of MaMs test in the risk assessment of patients with monoclonal gammopathies. Full article
(This article belongs to the Special Issue Gammopathies of Certain Significance: Managing MGUS and Smoldering Myeloma)
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12 pages, 593 KiB  
Review
Targeted Therapy of Interleukin-34 as a Promising Approach to Overcome Cancer Therapy Resistance
by Giovanni Monteleone, Eleonora Franzè, Claudia Maresca, Marco Colella, Teresa Pacifico and Carmine Stolfi
Cancers 2023, 15(3), 971; https://doi.org/10.3390/cancers15030971 - 03 Feb 2023
Cited by 4 | Viewed by 2030
Abstract
Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel [...] Read more.
Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel effective therapeutic compounds. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are major components of the suppressive tumor microenvironment and are critical drivers of immunosuppression, creating a tumor-promoting and drug-resistant niche. In this regard, therapeutic strategies to tackle immunosuppressive cells are an interesting option to increase anti-tumor immune responses and overcome the occurrence of drug resistance. Accumulating evidence indicates that interleukin-34 (IL-34), a cytokine produced by cancer cells, and/or TAMs act as a linker between induction of a tumor-associated immunosuppressive microenvironment and drug resistance. In this article, we review the current data supporting the role of IL-34 in the differentiation/function of immune suppressive cells and, hence, in the mechanisms leading to therapeutic resistance in various cancers. Full article
(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)
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12 pages, 925 KiB  
Article
Utility of Comprehensive Genomic Profiling Tests for Patients with Incurable Pancreatic Cancer in Clinical Practice
by Takuo Yamai, Kenji Ikezawa, Naotoshi Sugimoto, Makiko Urabe, Yugo Kai, Ryoji Takada, Tasuku Nakabori, Hiroyuki Uehara, Takahisa Kawamura, Kei Kunimasa, Sachiko Yamamoto, Toru Wakamatsu, Takuji Hayashi, Yoji Kukita, Fumie Fujisawa, Tazuko Inoue, Yuko Yamaguchi, Tomoyuki Yamasaki, Keiichiro Honma and Kazuyoshi Ohkawa
Cancers 2023, 15(3), 970; https://doi.org/10.3390/cancers15030970 - 03 Feb 2023
Cited by 3 | Viewed by 1942
Abstract
Although comprehensive genomic profiling (CGP) tests have been covered under the Japanese national health insurance program since 2018, the utility and issues of CGP tests have not been clarified. We retrospectively reviewed 115 patients with incurable pancreatic cancer (IPC) who underwent CGP tests [...] Read more.
Although comprehensive genomic profiling (CGP) tests have been covered under the Japanese national health insurance program since 2018, the utility and issues of CGP tests have not been clarified. We retrospectively reviewed 115 patients with incurable pancreatic cancer (IPC) who underwent CGP tests in a Japanese cancer referral center from November 2019 to August 2021. We evaluated the results of CGP tests, treatments based on CGP tests, and survival time. Eight cases (6.9%) were diagnosed as tumor mutation burden-high (TMB-H) and/or microsatellite instability-high (MSI-H). The gene mutation rates of KRAS/TP53/CDKN2A/SMAD4 were 93.0/83.0/53.0/25.2%, respectively. Twenty-five patients (21.7%) had homologous recombination deficiency (HRD)-related genetic mutations. Four patients (3.5%) having TMB-H and/or MSI-H were treated with pembrolizumab, and only two patients (1.7%) participated in the clinical trials. Patient characteristics were not significantly different between patients with and without HRD-related gene mutations. The median OS was significantly longer in the HRD (+) group than in the HRD (−) group (749 days vs. 519 days, p = 0.047). In multivariate analysis, HRD-related gene mutation was an independent prognostic factor associated with favorable OS. CGP tests for patients with IPC have the potential utility of detecting HRD-related gene mutations as prognostic factors as well as a therapeutic search. Full article
(This article belongs to the Special Issue Modern Evaluation and Treatment of Malignant Pancreatic, Liver and Biliary Tract Tumours)
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14 pages, 1088 KiB  
Article
Surgery-Related Muscle Loss after Pancreatic Resection and Its Association with Postoperative Nutritional Intake
by Rianne N. M. Hogenbirk, Judith E. K. R. Hentzen, Willemijn Y. van der Plas, Marjo J. E. Campmans-Kuijpers, Schelto Kruijff and Joost M. Klaase
Cancers 2023, 15(3), 969; https://doi.org/10.3390/cancers15030969 - 03 Feb 2023
Viewed by 1573
Abstract
To study the occurrence of surgery-related muscle loss (SRML) and its association with in-hospital nutritional intake, we conducted a prospective observational cohort study including patients who underwent pancreatic surgery because of (suspected) malignant diseases. Muscle diameter was measured by using bedside ultrasound 1 [...] Read more.
To study the occurrence of surgery-related muscle loss (SRML) and its association with in-hospital nutritional intake, we conducted a prospective observational cohort study including patients who underwent pancreatic surgery because of (suspected) malignant diseases. Muscle diameter was measured by using bedside ultrasound 1 day prior to surgery and 7 days postoperatively. Clinically relevant SRML was defined as ≥10% muscle diameter loss in minimally one arm and leg muscle within 1 week after surgery. Protein and caloric intake was measured by nutritional diaries. The primary endpoint included the number of patients with SRML. Secondary endpoints included the association between SRML and postoperative nutritional intake. Of the 63 included patients (60.3% men; age 67.1 ± 10.2 years), a total of 24 patients (38.1%) showed SRML. No differences were observed in severe complication rate or length of hospital stay between patients with and without SRML. During the first postoperative week, patients with clinically relevant SRML experienced more days without any nutritional intake compared with the non-SRML group (1 [0–4] versus 0 [0–1] days, p = 0.007). Significantly lower nutritional intake was found in the SRML group at postoperative days 2, 3 and 5 (p < 0.05). Since this study shows that SRML occurred in 38.1% of the patients and most of the patients failed to reach internationally set nutritional goals, it is suggested that more awareness concerning direct postoperative nutritional intake is needed in our surgical community. Full article
(This article belongs to the Special Issue The Progressive Skeletal Muscle and Body Weight Loss in Cancer Patients)
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21 pages, 1829 KiB  
Review
CDK4/6 Inhibitors in Pancreatobiliary Cancers: Opportunities and Challenges
by Tatjana Arsenijevic, Katia Coulonval, Eric Raspé, Anne Demols, Pierre P. Roger and Jean-Luc Van Laethem
Cancers 2023, 15(3), 968; https://doi.org/10.3390/cancers15030968 - 03 Feb 2023
Cited by 3 | Viewed by 2610
Abstract
Existing treatment strategies for pancreatobiliary malignancies are limited. Nowadays, surgery is the only path to cure these types of cancer, but only a small number of patients present with resectable tumors at the time of diagnosis. The notoriously poor prognosis, lack of diverse [...] Read more.
Existing treatment strategies for pancreatobiliary malignancies are limited. Nowadays, surgery is the only path to cure these types of cancer, but only a small number of patients present with resectable tumors at the time of diagnosis. The notoriously poor prognosis, lack of diverse treatment options associated with pancreaticobiliary cancers, and their resistance to current therapies reflect the urge for the development of novel therapeutic targets. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as an attractive therapeutic strategy in a number of cancers since their approval for treatment in patients with ER+/HER- breast cancer in combination with antiestrogens. In this article, we discuss the therapeutic potential of CDK4/6 inhibitors in pancreatobiliary cancers, notably cholangiocarcinoma and pancreatic ductal adenocarcinoma. Full article
(This article belongs to the Special Issue Combination Therapies for Pancreatic Cancer: How to Make Comprehensive Progress?)
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